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Metabolic Bone Disease in The Tropics

ABSTRACT

 

Metabolic bone disease (MBD) encompasses a heterogeneous group of disorders having a diverse spectrum of manifestations varying from asymptomatic to florid. MBD is prevalent globally, but certain unique features characterize those occurring in the tropics. Dietary deviations, including malnutrition, environmental influences, genetic factors, and limited access to healthcare, modify the tropical presentation of MBD. Osteoporosis remains the most prevalent MBD in the tropics. Anti-osteoporotic agents are widely available, but the compliance and follow-up are poor. Fracture liaison services are gaining importance to address the low rates of patient work-up and treatment following a fracture. Though the tropics have long been plagued with communicable diseases, there is a recent increase in noncommunicable lifestyle diseases and obesity, which are major risk factors for sarcopenia. A significant subset of adults over the age of 65 years have sarcopenia complicated by obesity and are at risk of synergistic complications from both obesity and sarcopenia. "Thin-fat obesity" or "sarcopenic obesity," also known as normal weight obesity, is a recognized phenotype in South Asia, with a comparable risk for cardiometabolic disease as obesity. In addition to osteosarcopenia, other MBDs, such as rickets and osteomalacia, still prevail in tropical countries. Symptomatic hyperparathyroidism is still seen in tropical countries, unlike the West, where asymptomatic hyperparathyroidism is more common. Skeletal fluorosis, an MBD caused by chronically ingesting excess fluoride, can be asymptomatic, but a broad range of manifestations can occur, such as diffuse skeletal pain, limited mobility, osteopenia, and ossification of ligaments and interosseous membranes. The oral cavity can be a window to other MBDs like dental fluorosis in the tropics. Several infective disorders that can affect bones and joints, such as tuberculosis, leprosy, treponemal and fungal infections are prevalent in the tropics and should be considered in the differential diagnosis of tropical MBD.

 

INTRODUCTION

 

Metabolic bone disease (MBD) encompasses a diverse variety of bone and mineral metabolism disorders that often pose diagnostic and therapeutic challenges. The manifestations might differ in the tropics because of nutritional, environmental, and genetic factors. The presentation is often late and severe because of limited access to healthcare facilities and a lack of routine screening practices. Osteoporosis, the most prevalent MBD globally, is also widespread in the tropics. Despite ample sunlight exposure, vitamin D deficiency continues to be common. Certain conditions, such as fluorosis, lead, and cadmium toxicity, and infective skeletal disorders e.g., tuberculosis, syphilis, and leprosy, are unique to these regions. The altered presentation of the globally prevalent MBDs and conditions specific to the tropics have been highlighted here.

 

OSTEOPOROSIS IN THE TROPICS

 

Osteoporosis is the most common MBD globally and in tropical countries. Different studies in the South Asian region have suggested the prevalence of osteoporosis to be 30 to 50% among postmenopausal women and up to 20% in men above 50 years (1, 2). With increasing life expectancy in tropical countries, this prevalence will likely increase in the coming years. Several factors contribute to the high frequency and unique features of osteoporosis in tropical countries. These are summarized in table 1.

 

Table 1. Unique Features of Osteoporosis in the Tropical Region (3)

1.

Lower peak bone mass

2.

Poor dietary intake of calcium

3.

A large proportion of individuals with vitamin D deficiency

4.

Paucity of dual-energy X-ray absorptiometry scanners leading to delayed diagnosis

5.

Relatively earlier age of menopause

6.

Limited food fortification for calcium and vitamin D

7.

Lower bone mineral density threshold for developing a fragility fracture

8.

Less awareness and knowledge about osteoporosis

 

Despite the high mortality from hip fractures and the immense costs associated with its management, awareness about osteoporosis and its screening is poor among patients and physicians. In a study from southern India, 60% of postmenopausal women (n =302, mean age of 58 years) lacked knowledge of osteoporosis. In another study among general practitioners (n = 220), the total mean score on awareness was only 22% (1, 4).

 

Given the limitation of the diagnostic facilities, simple, cost-effective screening tools have been validated for use in the tropics. These may range from simple clinical findings like dental health assessment to more comprehensive evaluation through the FRAX tool. Easy-to-follow clinical practice guidelines have been developed that help manage patients with osteoporosis despite the above-mentioned constraints (5, 6).

 

Given poor dietary calcium intake and low levels of 25-hydroxyvitamin D [25(OH)D] despite abundant sunlight, adequate calcium and vitamin D is an essential component of osteoporosis management in these patients. Anti-osteoporotic agents are widely available, but compliance and follow-up are poor. The usage of bone turnover markers is still emerging and may evolve as a cost-effective tool. Moreover, strategies such as the fracture liaison service (FLS) will be helpful to enhance care for secondary prevention of fragility fractures (7).

 

DISORDERS OF BONE MINERAL METABOLISM IN THE TROPICS

 

Rickets And Osteomalacia

 

Rickets and osteomalacia are also prevalent in tropical countries. In children, the prevalence of nutritional calcipenic rickets has decreased significantly but remains the usual cause of a rachitic presentation. It’s a bit paradoxical for tropical countries with abundant sunlight to have a high occurrence of vitamin D deficiency. Though rare, the genetic causes of calcipenic and phosphopenic rickets may be more frequent in specific pockets where consanguinity is practiced.

 

Like children, dietary deficiency is the usual etiology of osteomalacia in adults. However, certain acquired causes are common and must be ruled out. These include renal tubular dysfunction caused by heavy metal exposure, often from native medications. Moreover, Fanconi syndrome can result from certain drugs used to treat infectious disorders. For example, tenofovir used to treat hepatitis B can lead to proximal renal tubular acidosis. The rampant use of glucocorticoids in different over-the-counter products enhances the risk of glucocorticoid-induced osteomalacia. Furthermore, a gradual increase in chronic kidney disease (CKD) in tropical countries, is leading to a higher incidence of renal osteodystrophy (8).

 

Vitamin D deficiency in the tropics is widespread and ranges from 40 to 80%. Several postulates have been proposed to explain the lower vitamin D levels despite adequate sunlight. These include increased melanin in the skin, predominant indoor habits, and lack of vitamin D fortification. The relatively higher amount of fat for a given body mass index affects the redistribution of vitamin D. Lastly, air pollution in certain metropolitan cities reduces exposure to sunlight. Other causes of osteomalacia in tropical countries include renal tubular dysfunction and acquired hypophosphatemic disorders, covered in the “Diseases of Bone and Mineral Metabolism” section in Endotext.

 

Hyperparathyroidism

 

Parathyroid disorders could be classified as primary – wherein the parathyroid gland is diseased and secretes excessive parathyroid hormone (PTH), or secondary – where excess PTH secretion occurs as a compensatory response to systemic conditions such as vitamin D deficiency, chronic kidney disease, etc. The third variety, tertiary hyperparathyroidism, is characterized by the autonomous transformation of the parathyroid gland during prolonged secondary PTH hypersecretion (9).

 

Hyperparathyroidism differs in clinical presentation in tropical countries and often manifests as florid disease. Parathyroid disorders are usually slowly evolving, and overt skeletal defects are declining as more facilities start to screen for calcium in the tropics routinely. Thus, the prevalence of asymptomatic disease is gradually increasing (10). The salient differences in tropical countries are summarized in table 2.

 

Table 2. Difference in Parathyroid Disorders in Tropical Countries

1.

Symptomatic hyperparathyroidism is still seen in tropical countries, unlike the West, where asymptomatic hyperparathyroidism is more common

2.

Higher calcium and parathyroid hormone levels are found in tropics

3.

Higher prevalence of vitamin D deficiency in the tropics

4.

Intraoperatively a larger tumor/gland size in the tropics is usually observed

5.

Brown tumors and severe bone diseases seen in the tropics are rare in the West

 

Scurvy

 

Nutritional deficiencies are rare in the developed world but are observed in tropical countries. Vitamin C deficiency is a rare cause of MBD but should be considered while evaluating patients with suggestive symptoms and radiological features. It may affect the bone and joints, but initial diagnosis is often missed due to nonspecific symptoms and signs. Initial manifestations include irritability, decreased appetite, and delayed development followed by a pseudo-paralysis-like state wherein the patient lies still with little movement because of generalized pain, most apparent in bones due to subperiosteal hemorrhages. Swelling may be noted along the shaft of long bones.

 

Radiological changes in the long bones, particularly around the knee, are peculiar to scurvy. The bones are often fragile, with bone mineral density (BMD) in the osteopenic range. Fracture healing is often associated with large callus formation. Moreover, the epiphyses and periosteum are easily detachable due to the sub-periosteal bleeding. A classical feature on radiography known as the Wimberger ring is a circular, opaque radiologic shadow surrounded by a white line, seen in the growth centers around the epiphysis, as shown in Figure 1. The cortical bone in vitamin C deficiency is characterized by thinning, often described as a “pencil-point” cortex.

 

Figure 1. Illustration of the radiological features of scurvy.

 

The physis exhibits the Frankel line, characterized by thickening and sclerosis accompanied by a subjacent zone of lucency. The physeal thickening is known as a Frankel line, and the adjacent lucent zone on its diaphyseal side is the Trümmerfeld zone or the scurvy line. Metaphyseal “beaks” and transverse lines of increased or decreased opacity may be seen in scurvy. The “beaks,” known as Pelkan spurs, are associated with healing fractures of the Trümmerfeld zone at the periphery of the site of calcification. Costochondral junctions of the first six or eight thoracic ribs may be expanded; this change may be related to fracturing of the zone of provisional calcification during normal respiration. The costochondral junctions are rounded and appear smooth, knobby, and steplike. The enlargement of the costochondral junctions simulates findings seen in rickets but is often painful.

 

The diagnosis of scurvy is based on a combination of clinical and radiographic findings. A dietary history suggestive of poor vitamin C intake for at least one to three months is required for the appearance of clinical symptoms. Unlike other MBDs, accurate laboratory measurement of vitamin C levels is unreliable as it does not reflect the tissue levels. Healing occurs rapidly with the oral administration of 100 to 200 mg/d of vitamin C (11).

 

Paget’s Disease Of The Bone

 

Paget’s disease of the bone is a rare disorder in the tropics compared to the temperate regions but has been reported in certain pockets, especially in southern India. The overall global prevalence seems to be declining. Several viruses, such as paramyxoviridae, respiratory syncytial virus, canine distemper virus, and measles virus, have been linked to its etiopathogenesis. Given the high prevalence of many of these viruses in the tropics, the tropical connection of Paget’s disease has received renewed attention.

 

An underlying genetic etiology also predisposes to a higher occurrence in consanguineous populations. Due to the nonspecific symptoms, poor awareness among treating physicians, and limited availability of bone scans, the diagnosis is often missed. Thus, its true prevalence is unlikely to be determined. In a study from southern India, the mean age was 60 years in a cohort of 48 patients. It was reported predominantly in men (65%), and about one-fifth of them were asymptomatic. Among the symptomatic patients, 87% have polyostotic involvement. Sixty-nine percent of them were treated with zoledronic acid, and all achieved remission immediately after therapy (12).

 

Renal Tubular Disorders (Acquired & Genetic)

 

Different varieties of genetic and acquired renal tubular acidosis (RTA) are known to occur in the tropics. Specifically, the SLC4A1 (solute carrier family 4 A1) gene mutation-induced dysfunction of the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) causes distal RTA in some areas of the tropics. The mutation is prevalent in Thailand, Malaysia, the Philippines, and Papua New Guinea. The inheritance is autosomal recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations (13). Wilson’s disease, sickle cell anemia, and medullary sponge kidney are the other genetic causes of RTA more frequently encountered in regions where consanguinity is common.

 

Among the acquired causes, several drugs have been implicated in the pathogenesis of RTA. Some of these are used in managing common infective disorders in tropical countries, for example, tenofovir, for treating hepatitis B. One study reported lower bone mass (12.3%) in patients with hepatitis B on tenofovir compared to those not on the drug or those without hepatitis B (8). Among other acquired causes of RTA, amphotericin B, analgesic abuse, recurrent urinary tract infection, and hyperparathyroidism have been commonly reported in some tropical countries.

 

INFECTIVE DISORDERS ASSOCIATED WITH METABOLIC BONE DISEASE

 

Several infective disorders affect bones and joints, causing debilitating disease. Given the high incidence of infectious conditions in the tropical countries, the concurrence of bone lesions is expected. 

 

Tuberculosis

 

Tuberculosis is an unusual cause of bony lesions, but immunocompromised states such as human immunodeficiency virus (HIV) infection and diabetes increase the risk. Spine involvement can present insidiously, with progressive back pain in endemic areas, especially when consecutive thoracic vertebrae are affected with relative disc preservation. Paravertebral and epidural soft tissue lesions may present as a cold abscess. Atypical tubercular osteoarticular manifestations involving the extraspinal skeleton, a prosthetic joint, or the trochanteric area, and nontuberculous mycobacterial infections should raise suspicion for immunocompromised states. Surgery combined with prolonged antitubercular therapy is indicated for neurological manifestations or deformities and provides satisfactory results in most cases. Because of the increasing resistance to antitubercular treatment, appropriate culture and sensitivity testing should be ordered whenever indicated (14).

 

Leprosy

 

Mycobacterium leprae primarily affects the skin and nerves. Effective antimicrobial therapy has improved outcome in the acute stage of infection. However, long-term sequelae such as foot drop are not unusual if the diagnosis is delayed. Ineffective penetration of antimycobacterial therapy into neural tissue can predispose to continued nerve damage and result in Charcot’s neuroarthropathy. Other chronic effects include male osteoporosis and hypogonadism. Testicular atrophy following invasion by Mycobacterium leprae have caused osteoporosis in a few cases (15).

 

Treponemal Diseases

 

The spirochete Treponema pallidum causes syphilis. Earlier published series have described three broad types of skeletal malformations. They include - group I: metaphyseal dystrophy, group II: osteitis-like dystrophy, and group III: periosteal dystrophy. Advances in case detection, treatment, and prevention have significantly lowered the incidence of the disease and its associated complications (16). Contrary to the earlier view that the malformations are inflammatory, newer evidence suggests that dystrophic changes are responsible. In a series of 55 cases, the most frequent osseous findings were metaphysitis, zone of rarefaction, periostitis, disorganized metaphysis, bone erosion, and Wimberger sign. The bones commonly affected were the long bones such as radius, ulna, tibia, femur, humerus, and fibula (17).

 

Fungal Infection

 

Osteoarticular mycoses are uncommon in clinical practice and Aspergillus and Candida are the organisms involved usually. Dimorphic fungi such as Histoplasma, Blastomyces, Coccidiosis, and Paracoccidiodes can affect the bones in endemic areas. They occur predominantly in immunocompetent hosts and are characterized by hematogenous dissemination. The natural history is typically indolent but occasionally the organisms behave virulently.

 

While mucormycosis is highly aggressive and destructive in the lung, sinuses, and brain, it is relatively indolent in the bone. Mucormycosis can affect any bones and joints without specific predilection for any particular site. Most cases occur from direct inoculation of the bone rather than through systemic seeding. Osteoarticular mucormycosis can sometimes necessitate bony amputation to prevent the nidus from spreading through the systemic circulation. A high index of suspicion, early diagnosis, and intensive treatment are the key to successful management (18).

 

 

Skeletal Fluorosis

 

Skeletal fluorosis is caused by chronically ingesting excess fluoride, usually from natural sources. Skeletal fluorosis can be asymptomatic, but a broad range of manifestations, including diffuse skeletal pain, limited mobility, osteopenia, and ossification of ligaments and interosseous membranes, are known to occur. The severity of the disease depends on the amount and duration of fluoride exposure. The portal of entry is oral, and after absorption from the gastrointestinal tract, it is deposited in the skeleton, where it has a half-life of more than seven years. Incorporation of the fluoride in the hydroxyapatite crystal affects bone strength, and influences bone remodeling through the Runt-related transcription factor 2 (Runx2) and receptor activator of nuclear factor kappa-В ligand (RANKL). This alters the expression of osteocalcin and osteoprotegerin with resultant increased osteoblastic activity (19).

 

The usual clinical features are dental mottling, bony pains, chronic fatigue, joint stiffness with restricted range of motion, flexion contractures, radiculo-myelopathy, and increased fracture risk. The diagnosis is based on a high index of clinical suspicion and confirmed by a 24-hour estimation of the urinary fluoride level. There is no effective treatment for established skeletal fluorosis. Management consists of symptomatic therapy with analgesics and provision of adequate calcium and vitamin D. Decompressive laminectomy may be performed to relieve neurological deficits due to spine involvement. Identifying the source of high fluoride intake, defluoridation, or changing the water source helps prevent worsening.

 

Lead Toxicity And Its Effect On Bone

 

Lead toxicity remains a substantial public health problem globally and in tropical countries. Bone is a major reservoir of lead in both adults and children, accounting for 75-90% of the total body lead. The accumulated lead can gradually be released to other soft tissues and pathological sites. Bone lead accrual occurs after both environmental and occupational exposure. It is a marker of past lead exposure with a half-life of 20 years and thus increases gradually with age. (20)

 

Lead exerts a detrimental effect by reducing osteocalcin production and inhibiting alkaline phosphatase activity in osteoblasts. Lead suppresses type II and type X collagen expression in chondrocytes and alters growth factors and second messenger signaling responses during chondrocyte maturation. Lead stimulates the osteoclasts to enhance bone resorption. Strict vigilance and robust policy decisions to decrease lead exposure will improve skeletal health in the tropics.

 

Cadmium Toxicity And Metabolic Bone Disease

 

Exposure to cadmium is associated with kidney, bone, and cardiovascular disorders. Like lead, cadmium is stored in the renal tissue for many years (half-life 10–30 years), which could result in renal tubular dysfunction, glomerular damage, and renal failure. A population-based study among postmenopausal women showed a clear link between a high burden of cadmium and low BMD (21). There are two proposed mechanisms for bone loss; a direct action on bone cells and an indirect action on the kidney resulting in phosphate and calcium excretion. In vitro studies have demonstrated that cadmium can increase the RANKL expression, tartarate-resistant acid phosphatase (TRAP) activity, and formation of TRAP-positive cells in the presence of RANKL, resulting in increased osteoclastic activity.

 

In tropical countries, silversmiths have exposure to cadmium in the absence of personal protective equipment. Case reports of exposure to cadmium and consequent renal osteodystrophy have been reported (22).

 

Alcohol And Metabolic Bone Disease

 

Alcohol consumption can, directly and indirectly, affect bone health. The mechanisms are summarized in Figure 2. In a study by Peris et al., vertebral fractures were observed in 36% of those consuming alcohol chronically, but only 6.5% had BMD below the fracture threshold. Thus chronic alcohol consumption may lead to a higher propensity for vertebral fractures without impacting the BMD (23). The evaluation and treatment would depend upon the clinical profile.

 

Figure 2. Impact of chronic alcohol consumption on metabolic bone disease.

 

NEPHROLITHIASIS IN TROPICS

 

Renal stone disease is a common problem worldwide. The prevalence and composition of renal stones differ according to country, climate, and culture (24). Conforming to that trend, renal stone diseases in tropical countries exhibit some unique features. The usual constituents of stones include calcium oxalate, calcium phosphate, uric acid, cysteine, struvite, or a mixture of these. In many tropical countries, local factors influence the composition of the stone. Nephrolithiasis, in general, has been reviewed elsewhere in endotext.org (25).

 

The prevalence of renal stone disease in older reports ranged from 7 to 13% in North America, 5–9% in Europe, and 1–5% in Asia (26). The lower frequency in Asia could be partially from underreporting. Recent findings demonstrate that the incidence of renal stones has increased by 48.5% in the last three decades across the globe (26, 27). The age-standardized incidence rate (ASIR) was greater in countries with high, middle, and low-middle sociodemographic index (SDI) than in low SDI regions. Some African countries, such as Madagascar, South Sudan, and Burundi, had a lower incidence of renal stones (27). An increased oxalate-degrading bacteria count in the gut of black South Africans could be a possible explanation (28).

 

The tropical region of Asia, spanning West Asia, South Asia, and Southeast Asia, constitutes a stone-forming belt with high prevalence (5% to 19.1%) (29). Higher temperatures and sunlight exposure increase the risk in these regions (30). Similar trends are also described in Latin America (31). Globally, the peak incidence of nephrolithiasis occurs between 50 to 70 years, though in Asians, the maximum incidence is around 30 years. Males are affected more often globally and in Asia (27, 29).

 

Unique Aspects In Tropics

 

TROPICAL CLIMATE AND STONE FORMATION

 

Higher ambient temperature and low humidity in the tropics increase fluid loss through sweating. Urinary concentration increases as compensation, and relatively insoluble salts such as calcium oxalate and urates tend to precipitate and serve as foci of stone formation. Sweating-induced reduction in urinary pH favors the crystallization of uric acid and further enhances the risk of urate stone (32). Renal colic is thus more common during warmer months (33). Additionally, studies suggest that males are more susceptible to developing kidney stones due to increased temperature. However, whether this is related to the total cumulative heat exposure or differential pathophysiological response is unclear (34, 35).

 

METABOLIC SYNDROME AND NEPHROLITHIASIS

 

The prevalence of metabolic syndrome in topical countries is on the rise (36-38). The upsurge in the frequency of nephrolithiasis could be attributed somewhat to the increasing burden of metabolic disorders. A consistent association between the prevalence of metabolic syndrome and renal stones has been demonstrated (39). Obesity, diabetes, hypertension, and insulin resistance, all components of metabolic syndrome, are risk factors for stone formation (40). Hyperuricemia, another manifestation of insulin resistance, is a recognized pathophysiologic link. Insulin resistance decreases urinary ammonium production leading to the formation of acidic urine, augmenting the potential for lithogenesis (41, 42). However, the predominant stone type in metabolic syndrome is oxalate. Hyperoxaluria in metabolic syndrome is multifactorial in etiology and could be related to changes in gut flora, increased renal oxidative stress, and alteration in the balance between promoters and inhibitors of lithogenesis (43, 44).

 

CHILDHOOD ENDEMIC BLADDER STONES

 

The incidence of vesical calculus has declined significantly over the last few decades in developed nations but is still prevalent in the tropics. Reliance on carbohydrate-rich food and lack of protein early in life results in a relative deficiency of phosphates and leads to the formation of insoluble urinary salts. The boys are predisposed as their long tortuous urethra is a hindrance to clearing the debris (45, 46).

 

OTHER VARIETIES OF RENAL STONE SPECIFIC TO TROPICS       

 

In a study from Taiwan, environmental melamine exposure was found to be associated with nephrolithiasis (47). Betel nut chewing is also linked to stone formation. The pathogenesis could be mediated by arecoline, an alkaloid in betel nut (48).

 

DENTAL DISORDERS IN THE TROPICS

 

Tropical oral disorders include a wide range of conditions that may be manifestations of systemic diseases. Osteoporosis continues to be one of the most underdiagnosed and under-reported conditions in the tropics. Though the diagnosis of osteoporosis is based on DXA, it has been suggested that signs in the oral cavity and dental X-rays can be used for primary screening in resource-limited settings. Several radiographic indices, such as mandibular cortical index, mandibular cortical width, antegonial Index, gonial index, panoramic mandibular index, and alveolar crest resorption degree (M/M ratio), have been explored as screening tools for osteoporosis (49).

 

The oral cavity can be a window to many other MBDs in the tropics. Vitamin D is crucial for the mineralization of bones and teeth. Low vitamin D levels lead to malformed, hypomineralized teeth that are brittle and vulnerable to decay, also known as “rachitic teeth (50). Dental abscesses are characteristic of vitamin D-resistant rickets (VDRR). Other characteristic manifestations of VDRR include dentin defects, unusually large pulp chambers, enlarged pulp horns, and enamel hypoplasia (51). Brown tumor, loss of bone density, soft tissue calcification, and dental abnormalities, such as developmental defects and changes in tooth eruption, are common oral symptoms in hyperparathyroidism. Malocclusion due to the drifting of teeth and spacing of the teeth may be the first signs of hyperparathyroidism (52).

 

Tropical infective diseases such as tuberculosis can atypically present with oral manifestations. Lesions in the jaw in the form of osteomyelitis or simple bone radiolucency, as well as superficial ulcers, patches, and indurated soft tissue lesions, are described (53). Dental fluorosis is caused by excessive fluoride ingestion during tooth development. Dental fluorosis is common in the tropics and is described in the previous section (54, 55). Clinically, mild cases of dental fluorosis manifest as an opaque white appearance of the enamel from increased subsurface porosity. Moderate dental fluorosis manifests as yellow to light brown staining in the areas of enamel damage. Severe dental fluorosis results in a porous enamel that is poorly mineralized and stains brown (56). Preventive strategies involve control of fluoride levels in drinking water (57).

 

SARCOPENIA AND BONE – A TROPICAL PERSPECTIVE

 

Sarcopenia, defined as the loss of muscle mass and strength, is an emerging global health problem. In a recent meta-analysis on the worldwide prevalence of sarcopenia, using different classifications and cut-off points, the prevalence of sarcopenia varied between 10 to 27% (58). Multi-center research from nine nations (Finland, Poland, Spain, China, Ghana, India, Mexico, Russia, and South Africa) across three continents revealed an overall frequency of 15.2% (59).

 

Types Of Sarcopenia

 

When no other etiology other than aging is apparent, the condition is called "primary" (or age-related) sarcopenia.  The term "secondary" sarcopenia refers to sarcopenia from one more additional cause (60). Many tropical countries are seeing a rapid increase in the aging population owing to improved healthcare facilities (61, 62). Hence, primary sarcopenia can potentially become a serious health concern globally, particularly in the developing world. Secondary sarcopenia could be activity related (resulting from bed rest, a sedentary lifestyle), disease-related (associated with endocrine diseases, advanced organ failure, malignancy, inflammatory disease), or nutrition-related (inadequate dietary intake of energy/protein, malabsorption, use of medications that cause anorexia, etc.) (60).

 

Risk Factors For Sarcopenia In The Tropics

 

Though the tropics have been plagued with communicable diseases for a long time, there is a recent increase in noncommunicable lifestyle diseases and obesity, major risk factors for sarcopenia (63, 64). A significant subset of adults over 65 years have sarcopenia complicated by obesity and are at risk of synergistic complications from obesity and sarcopenia (65). "Thin-fat obesity" or "sarcopenic obesity," also known as normal-weight obesity, is a recognized phenotype in South Asia with a comparable risk for cardiometabolic disease to conventional obesity. It is described as a condition in which a person has a normal body mass index (BMI) but a higher body fat percentage (based on ethnicity and gender-specific cut-offs) (66).

 

Muscle mass and strength are lower in South Asians than in Caucasians (67). The South Asian Working Action Group on Sarcopenia (SWAG-SARCO) consensus has been developed for diagnosing sarcopenia in South Asian nations while considering these ethnic characteristics (64). Malnutrition is still a significant public health issue in underdeveloped nations, notwithstanding the rise in obesity (68-70). In addition to the traditional risk factors, HIV-associated sarcopenia is prevalent in Africa. In a study from Brazil, HIV-infected patients had a 4.95 higher risk for sarcopenia than the controls, which persisted even following adjustments for age and BMI (71).

 

Osteosarcopenia

 

Numerous studies support the concept of a bone-muscle unit, in which molecules released by the skeletal muscle secretome influence bone, and the osteokines secreted by osteoblasts and osteocytes modulate the muscle cells (72). Duque et al. originally used the term "osteosarcopenia" to refer to an older population subgroup having both sarcopenia and osteoporosis. Clinically, unfavorable outcomes such as falls, fractures, loss of function, and frailty arise when both illnesses coexist. Resistance training, adequate protein and calcium consumption, and maintenance of optimum levels of vitamin D are simple therapies that have a dual favorable effect on bone and muscle and decrease falls, fractures, and disability (73).

 

CHALLENGES IN THE DIAGNOSIS AND MANAGEMENT OF MBD IN THE TROPICS

 

Prevalence Of Vitamin D Deficiency

 

Since skin exposure to ultraviolet radiation is the major source of vitamin D, it has long been believed that residing in tropical countries ensures adequate vitamin D levels. However, there is overwhelming evidence for widespread vitamin D deficiency in the tropics. Several other factors which could affect vitamin D levels, such as adiposity, skin pigmentation, genetic factors, clothing habits, sun avoidance, regular use of sunscreen, cloud cover and pollution, have been implicated (74).

 

Most studies have defined vitamin D insufficiency as serum 25(OH)D less than 50 nmol/L (20 ng/mL). Using this diagnostic cut-off, South Asia has a prevalence of vitamin D insufficiency of 70% or more, and the prevalence in Southeast Asia ranges from 6-70% (75).

 

Diagnosis Of Osteoporosis: Pitfalls And Challenges

 

The diagnosis and management of MBD in the tropics is fraught with challenges. The gold standard tool for measuring BMD is the dual-energy X-ray absorptiometry (DXA) scan (76). However, the limited availability of DXA and the associated costs continue to be  a major hurdle (77). The World Health Organization (WHO) defined T-score of ≤-2.5 SD, originally designed as an epidemiological tool, has been widely adopted as both a diagnostic and intervention threshold for osteoporosis (78). The (National Health and Nutrition Examination (NHANES III) Survey was employed to create the Caucasian reference database. NHANES III is a nationally representative sample of 14,646 women and men in the United States. The data from this survey is used as the reference database in most DXA machines (79, 80). There is a need to have country-specific reference ranges appropriate for the representative population (81, 82).

 

Utility Of Cost-Effective Screening Tools

 

To circumvent the challenges associated with the cost and availability of DXA machines, a number of cost-effective screening tools for osteoporosis have been explored. FRAX®, developed by the former WHO Collaborating Centre at the University of Sheffield, is the most widely validated and used fracture risk assessment tool (83). The risk of hip fracture and other osteoporotic fractures varies greatly globally. The FRAX models are calibrated to countries where fracture and death epidemiology is known to adjust for these fluctuations (84). Currently, FRAX is available in 65 countries, including two Asian, 35 European, nine Middle East and African, two North American, seven Latin American, and two Oceanian. However, country-specific FRAX thresholds are unavailable in many tropical countries (85, 86). Another screening tool of note, the Osteoporosis Self-Assessment Tool for Asians (OSTA),  has been validated in multiethnic population in Asian countries (87,88).These screening tools identify patients at high risk for osteoporosis and optimize use of DXA in resource-limited settings (89).

 

Osteoporosis Awareness

 

Studies in multiethnic populations across Asia have consistently demonstrated poor knowledge of osteoporosis among women (90-92). Similarly, poor awareness among at-risk populations is a major concern across regions of Africa and South America (93-95). Low awareness among physicians and healthcare authorities contributes to the enormous treatment gap in osteoporosis (93,96-98). Though osteoporosis and osteoporosis-related fractures have consumed significant health resources, it is not recognized as a health priority in tropical countries due to the ‘more’ essential diseases such as tuberculosis, malaria, and human immunodeficiency virus (94). Supporting research, raising awareness and establishing public health services will go a long way in preventing the enormous morbidity and mortality associated with fractures in these regions.

 

Fracture Liaison Services

 

FLS are gaining importance to address the low rates of patient work-up and treatment following a fracture. The FLS model attempts to avoid future fractures because there is at least a two-fold risk of refracture (99). The International Osteoporosis Foundation recommends the establishment of FLS to identify and treat patients with fractures properly. Universal FLS implementation in Brazil, Mexico, Colombia, and Argentina was predicted to prevent 31,400 fractures, avoid 292,281 bed days, and save 58.4 million USD in 2019 (100). However, FLS programs are yet to be universally established (100-102). Educating and engaging both private and public sectors in the efficient delivery of FLS could be a pragmatic solution to prevent osteoporotic fractures.

 

CONCLUSION

 

MBD is widely prevalent but often ignored in the tropics. Understanding the spectrum of MBD in the tropics will not only address the gap but may also throw light on unique pathophysiological aspects of bone metabolism. Nutrition, environment, infections, and genetic traits are responsible for the development of a diverse array of MBD in the tropics. Optimum utilization of resources is a key to tackle this challenge.

 

REFERENCES

 

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Adrenal Cortex: Embryonic Development, Anatomy, Histology and Physiology

ABSTRACT

 

The adrenal glands consist of the adrenal cortex and medulla, which have distinct, albeit interdependent functional properties. The adrenal cortex contains the zona glomerulosa that produces mineralocorticoids, the zona fasciculatathat is the site of glucocorticoid biosynthesis, and the zona reticularis, which is responsible for the production of adrenal androgens. In this chapter, we discuss the embryonic development, anatomy, histology and physiology of the adrenal cortex.

 

INTRODUCTION

 

The adrenal gland was first described by Eustachius in 1563 and its importance was later recognized by the work of Thomas Addison in 1855 and Brown-Sequard in 1856 (1-3). The latter performed a series of bilateral adrenalectomies in dogs, demonstrating that these endocrine glands were necessary for life (2, 3). In the midst of the 19th century, newly emerged histochemical techniques showed that the adrenal consists of a cortex and medulla and have divergent albeit interdependent cellular and functional properties. Indeed, the adrenal cortex consists of the zona glomerulosa, the zona fasciculata, and the zona reticularis, which respectively produce mineralocorticoids (aldosterone), glucocorticoids (cortisol in man and corticosterone in rodents), and adrenal androgens (4, 5). On the other hand, the adrenal medulla contains chromaffin cells, which are responsible for the biosynthesis and secretion of the catecholamines epinephrine and norepinephrine. Adrenal cortex hormones are steroid molecules, which are derived from cholesterol through serial conversions catalyzed by specific enzymes, the “steroid hydroxylases” that belong to the cytochrome P450 (CYP) superfamily. This biochemical process is known as “adrenal steroidogenesis” (4, 5). At the molecular and cellular level, adrenal cortex hormones mediate their pleiotropic actions through binding to their cognate receptors, which are nuclear receptors that function as ligand-activated transcription factors, influencing gene expression in a positive or negative fashion (4, 5).  

 

EMBRYONIC DEVELOPMENT OF ADRENAL CORTEX

 

The adrenal gland is composed of two embryologically distinct tissues, the cortex and medulla, arising from the mesoderm of the urogenital ridge and ectodermal neural chromaffin cells, respectively (6, 7). An isolated clump of cells appears within the urogenital ridge, known as the adrenal-gonadal primordium, at 28-30 days post conception. These cells express the transcription factor steroidogenic factor-1 (SF1 or Ad4BP or NR5A1), which contributes substantially to adrenal development and steroidogenesis. Adrenal-gonadal primordium gives rise to the fetal adrenal cortex and to Leydig cells. At 7-8 weeks of gestation, the adrenal cortex consists of a large inner zone, the fetal zone (FZ), and a small outer zone, the definitive zone (DZ) (8, 9). At the end of the 9th week of gestation, adrenals become fully encapsulated (10). The main steroid of the FZ is dehydroepiandrosterone (DHEA), as cells within this zone express the enzyme cytochrome P450 17α (CYP17A1) (7). Corticotropin-releasing hormone (CRH) secreted by the human placenta and the chromaffin cells of the adrenal medulla stimulates DHEA secretion by the FZ (11). DHEA is converted into 16-hydroxy-DHEA by the fetal liver and is converted into estriol by the placenta (12).

 

After birth, shrinkage of the fetal zone due to increased apoptotic activity occurs, leading to a decrease of the weight of adrenal glands by 50% (13). In the next three years, cells of the DZ and, to a lesser extent, cellular remnants of the FZ differentiate into the three functionally and histologically distinct zones: the outer zona glomerulosa, the intermediate zona fasciculata, and the inner zona reticularis (4, 5).

 

ANATOMY OF THE ADRENAL CORTEX

 

The adrenal glands are located in the retroperitoneum on the top of the kidneys. They are surrounded by a stroma of connective tissue that maintains adrenal structure, termed the “capsule” (4, 5).

 

Blood Supply

 

With an estimated flow rate of about 5 ml per minute, though small in size, the adrenal glands are among the most extensively vascularized organs (Fig. 1). Blood supply is maintained by up to fifty arterial branches for each adrenal gland, which arise directly from the aorta, the renal arteries, and the inferior phrenic arteries. Blood is channeled into the subcapsular arteriolar plexus, and subsequently distributed to the sinusoids, that then supply the adrenal cortex and medulla.

 

Endothelial cells were demonstrated to interfere with adrenocortical cells through specific factors and the vasculature seems to play a crucial role for the zonation and function of the adrenal cortex.

 

A direct blood supply of the medulla is maintained by shunt arterioles (14, 15). After supplying the cortex and medulla, blood collects at the cortico-medullary junction and drains through the central adrenal vein to the renal vein or directly into the inferior vena cava.

 

Figure 1. Extensively vascularized adrenal cortex.

 

Innervation

 

The adrenal cortex receives afferent and efferent innervation (Fig 2). A direct contact of nerve terminals with adrenocortical cells has been suggested (16) and chemoreceptors and baroreceptors present in the adrenal cortex infer efferent innervation (17, 18). Diurnal variation in cortisol secretion and compensatory adrenal hypertrophy are influenced by adrenal innervation (19, 20). Splanchnic nerve innervation has an effect in the regulation of adrenal steroid release (20).

 

Figure 2. Silver-stained nerve cells (dark spots) and fibers (dark lines).

 

HISTOLOGY OF THE ADRENAL CORTEX

 

In contrast to the fetal cortex, which is constructed from primarily the zona fetalis, the adult adrenal cortex consists of three anatomically distinct zones (Fig. 3):

  1. The outer zona glomerulosa, site of mineralocorticoid production (e.g., aldosterone), mainly regulated by angiotensin II, potassium, and ACTH. In addition, dopamine, atrial natriuretic peptide (ANP) and other neuropeptides modulate adrenal zona glomerulosa function.
  2. The central zona fasciculata, responsible mainly for glucocorticoid synthesis, is regulated by ACTH. In addition, several cytokines (IL-1, IL-6, TNF), neuropeptides, and catecholamines influence the biosynthesis of glucocorticoids.
  3. The inner zona reticularis, site of adrenal androgen (predominantly dehydroepiandrostenedione [DHEA], DHEA sulfate [DHEA-S] and Δ4-androstenedione) secretion, as well as some glucocorticoid production (cortisol and corticosterone).

Figure 3. Double immunostained cross-section of a human adrenal gland for 17-α-Hydroxylase and chromogranin A. zM = adrenal medulla, zR = zona reticularis, zF = zona fasciculata, zG = zona glomerulosa, Caps = adrenal capsule.

 

Adrenocortical cells are arranged in a cord-like manner, extending from the adrenal capsule to the medulla, and are embedded within a widespread capillary network. These cells are rich in mitochondria and smooth endoplasmic reticulum, which form an extended network of anastomosing tubules. Zona glomerulosa cells are scattered and produce and secrete aldosterone (5). The zona fasciculata contains large cells replete with lipids, the “clear cells”, which synthesize and release cortisol (5). The zona reticularis consists of cells containing lipofuscin granules, termed “compact” cells that are responsible for adrenal androgen biosynthesis and secretion. This cellular zone develops at the age of 5 years in females and 6 years in males, a physiologic process termed as “adrenarche” (5). 

 

In some rat species, a fourth zone can further be distinguished, the zona intermedia, between the glomerulosa and the fasciculata currently postulated to be a site of initiation of adrenocyte proliferation and differentiation and a zone containing the adrenal cortical stem cells.

 

However, evidence suggests that adrenocortical cells arise within or underneath the capsule under the influence of sonic hedghog signaling and move centripetally along gradients towards the border to the adrenal medulla where they form cortical islets and / or undergo apoptosis (14, 21, 22). It may even be possible that cortical cells adopt different functional states as they “wander” from their origin somewhere in the outer cortex and pass along blood vessels into the direction of the innermost cortex through the different zones.

 

In addition to adrenocortical cells, macrophages are distributed throughout the adrenal cortex (23). In addition to their phagocytic activity, they produce and secrete cytokines (TNFb, IL-1, IL-6) and peptides (VIP), which interact with adrenocortical cells and influence their functions (24-26). Lymphocytes are scattered in the adrenal cortex (Fig. 4), and have been shown to produce ACTH-like substances (27). It has also been shown, that immuno-endocrine interactions between lymphocytes and adrenal zona reticularis cells can stimulate dehydroepiandrosterone production (28, 29).

 

Figure 4. Lymphocytes (dark spots), immunostained for CD 45.

 

PHYSIOLOGY OF THE ADRENAL CORTEX

 

The most important function of the adrenal cortex is adrenal steroidogenesis that occurs in all three cellular zones (5). This physiologic process is regulated by distinct systems, depending on steroid type produced. Aldosterone production by the zona glomerulosa depends on the activity of the renin-angiotensin system and serum potassium concentrations, and, to a lesser extent on plasma ACTH concentrations. Cortisol biosynthesis by the zona fasciculata is triggered by ACTH. Adrenal androgens are produced by the zona reticularis, which is also regulated by ACTH and other as yet unknown factors (5).

 

All adrenal steroids are biosynthesized from cholesterol molecules, which are derived primarily from low-density lipoprotein (LDL) or from cholesterol esters hydrolyzed in adrenocortical cells (Fig. 5). To initiate steroidogenesis, adrenocortical cells are stimulated by several signals to increase their uptake of lipoproteins from the systemic circulation to provide the appropriate concentrations of cholesterol (30, 31). The latter is then converted into steroid molecules in serial biochemical reactions that are mediated by the “steroid hydroxylases” (5). The first and rate-limiting step in steroidogenesis begins when ACTH and/or other signals increase the expression of the “steroidogenic acute regulatory protein” (StAR), which facilitates the import of cholesterol to the inner mitochondrial membrane (30, 32, 33). Within the mitochondria, the C27 cholesterol loses six carbons and is converted into the C21 pregnenolone through the enzyme CYP11A or cholesterol desmolase (P450scc) (34). Pregnenolone moves to the cytoplasm to undergo further enzymatic conversions.

 

In the zona glomerulosa, pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD) (35). Progesterone is converted to deoxycorticosterone (DOC) through 21-hydroxylation by CYP21 or 21-hydroxylase (P450c21). DOC is then11β-hydroxylated to form corticosterone, which is converted to aldosterone through 18-hydroxylation and 18-oxidation. The last three reactions are catalyzed by the P450 enzyme CYP11B2 or aldosterone synthase (P450aldo) (Fig. 5) (36).

 

In the zona fasciculata, pregnenolone is converted to 17α-hydroxypregnenolone in the endoplasmic reticulum by the enzyme CYP17 or 17α-hydroxylase/17,20-lyase (P450c17) (37). 17α-Hydroxypregnenolone is then converted to 17α-hydroxyprogesterone by 3β-HSD, and the latter steroid molecule is 21-hydroxylated to form 11-deoxycortisol by CYP21. Finally, 11-deoxycortisol is enzymatically converted to cortisol by CYP11B1 or 11β-hydroxylase (P450c11), a reaction that occurs within the mitochondria (5) (Fig. 5).

 

In the zona reticularis, both pregnenolone and progesterone are 17α-hydroxylated (5). 17α-Hydroxypregnenolone forms dehydroepiandrosterone (DHEA) by the enzyme CYP17. DHEA is converted to Delta4-androstenedione by 3β-HSD. Importantly, DHEA may become sulfonated to form DHEAS by the enzyme sulfotransferase SULT2A1. In the gonads, Delta4-androstenedione is converted to testosterone by 17β-hydroxysteroid dehydrogenase (38). In the ovaries of pubertal girls, CYP19 or aromatase (P450c19) catalyzes the conversion of both Delta4-androstenedione to estrone, and testosterone to 17β-estradiol (39). In androgen-target tissues, testosterone is converted to dihydrotestosterone by 5α-reductase (40) (Fig. 5).

 

The adrenal glands also biosynthesize 11-oxyandrogens, which are androgens that share an oxygen atom on carbon position 11 (41-44). Among them, 11- hydroxyandrostenedione is the most abundant. The C11-oxy biochemical pathway begins when Delta4-androstenedione and testosterone are converted to 11β-hydroxyandrostenedione and 11β-hydroxytestosterone, respectively, by CYP11B1 (Fig. 5). 11β-Hydroxy-testosterone is converted to 11β-hydroxy-dihydrotestosterone by the enzyme SRD5A1. 11β-Hydroxy-androstenedione forms 11-ketoandrostenedione by HSD11B. 11-Ketoandrostenedione forms 11-ketotestosterone by ACR1C3, and, then, 11-ketodihydrotestosterone by SRD5A (Fig. 5). Moreover, 11OH-dihydrotestosterone can be converted to 11-ketodihydrotestosterone by HSD11B (Fig.5) (41-44).

 

Figure 5. Schematic presentation of adrenal steroidogenesis.

 

Adrenal cortex hormones bind onto specific steroid receptors that belong to the nuclear receptor superfamily of transcription factors, and play fundamental roles in all physiologic functions. Indeed, glucocorticoids bind onto the glucocorticoid receptor (GR) (45), mineralocorticoids signal through the mineralocorticoid receptor (MR) (46), and adrenal androgens may bind onto the androgen receptor (AR), or, following aromatization, onto the estrogen receptor (ER) (47).

 

ADRENAL CORTEX-MEDULLA INTERACTIONS

 

With regard to function, there is no strict separation between the steroid-producing adrenal cortex and the catecholamine-producing medulla. Several studies have provided evidence that chromaffin cells once thought to be located exclusively in the medulla, are found in all zones of the adult adrenal cortex, and that cortical cells are found in the medulla (48-50). This close anatomical co-localization is a prerequisite for paracrine interactions (Fig. 6). The interaction between adrenal cortex and medulla is also supported by clinical data (reviewed in 51). Patients with congenital adrenal hyperplasia or Addison’s disease display dysfunction of the adrenal medulla (52-54).

 

Figure 6. Electromicrograph of rat adrenal gland. Chromafine cell with characteristic granules (G) in direct contact with adrenal cortical cell with characteristic mitochondria (M).

 

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Disorders of Adrenal Glands and Sex Development in Children: Insights From the Tropics

ABSTRACT

 

The adrenal gland is essential for survival and its function is compartmentalized into specific zones. Disorders of the adrenal gland can be classified as those affecting the adrenal cortex or medulla. Pediatric adrenal disorders can have distinct presentations and etiologies in comparison to adults, such as adrenal insufficiency associated with genetic syndromes or Cushing’s syndrome associated with adrenocortical tumors and primary pigmented nodular adrenocortical disease. Congenital adrenal hyperplasia (CAH) has been commonly reported from the tropics, and rare variants of CAH have also been recognized in populations where consanguinity is prevalent. Pheochromocytomas and paragangliomas (PPGL) have been reported from tropical countries, some with rare presentations. The frequent rate of heritability and mutations in PPGL highlights the importance of genetic studies among children. The role of functional imaging is evolving for PPGLs as data is emerging from cohort studies. Disorders of Sex Development (DSD) comprise a heterogeneous group of disorders that can present in any age group. DSDs in childhood usually present with ambiguous genitalia and a multidisciplinary approach is required for its management. The diagnosis of adrenal disorders can sometimes pose a challenge in tropical countries due to resource constraints, lack of awareness, and access to medical care. However, available data from cohort studies and case reports have highlighted differences in etiology and presentation as compared to other parts of the world and the need for further studies.

 

INTRODUCTION

 

Adrenal disorders commonly seen in the tropics include adrenal insufficiency, congenital adrenal hyperplasia, adrenal Cushing’s syndrome, and pheochromocytoma/paragangliomas

 

Adrenal Insufficiency

 

It is characterized by decreased production of cortisol by the adrenals. The identification of adrenal insufficiency in children requires a high index of suspicion. This is important not only to prevent an adrenal crisis but to identify the associated comorbidities.  Acute adrenal crisis can present in infancy as a salt-wasting crisis or precipitated in children due to stressors such as illness, trauma, or surgery. They often present as an emergency with abdominal pain, vomiting, hypotension, hypoglycemia with seizures, and hyponatremia which eventually leads to shock and cardiovascular collapse if undiagnosed. Chronic adrenal insufficiency presents as prolonged neonatal jaundice, failure to thrive, hyperpigmentation, anorexia, fatigue, nausea and vomiting, salt craving, diarrhea, abdominal pain, postural hypotension, and tachycardia. A study from Pakistan characterized the presentation of children with adrenal insufficiency of which 19% presented with an adrenal crisis following an acute illness (1). The chronic symptoms reported were not different from that seen in another cohort form South Africa (2). Rare primary presentations of adrenal insufficiency as infantile cholestasis (3) and gigantism with motor delay have been reported (4).

 

The causes of adrenal insufficiency in children are different as compared to adults.  Etiologically it can be divided into primary and secondary adrenal insufficiency. It can also be seen as an isolated condition or in association with specific syndromes.

 

Primary adrenal insufficiency may be related to an underlying genetic or metabolic cause. Congenital Adrenal Hyperplasia (CAH) is the most common cause of primary adrenal insufficiency. Autoimmunity, infections, and hemorrhage are also important causes of primary adrenal insufficiency. The largest cohort study from Sudan diagnosed 80 children with adrenal insufficiency. The etiology ranged from Allgrove syndrome (36%), auto-immune polyendocrinopathy syndrome (11%), adrenoleukodystrophy (9 %), bilateral hemorrhage (1%), to unspecified (42%) (5). Case reports and series also reported similar causes such as Allgrove syndrome (6-8), adrenoleukodystrophy (9), to rare causes such as familial primary glucocorticoid deficiency (3), Steroidogenic acute regulatory protein (StAR) deficiency (10), Nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene or DAX1 gene mutation (11) as well as primary multidrug-resistant adrenal tuberculosis (12).

 

The diagnosis of adrenal insufficiency is made by a peak cortisol value less than 18 mcg/dl on ACTH (Synacthen) stimulation test. A raised plasma ACTH level confirms primary adrenal insufficiency. The dose of Synacthen recommended for children less than 2 years is 15 µg/kg body weight and for children more than 2 years 250 µg im. However, Synacthen is not easily available in many countries. Acton Prolongatum, a long-acting synthetic ACTH preparation of the 39-amino acid native porcine sequence in a carboxymethylcellulose base has been studied and validated in India for the diagnosis of adrenal insufficiency in children > 5 years (13).

 

Table 1. Acton Prolongatum (ACTH Stimulation) Test

Indication

To diagnose adrenal insufficiency *

Preparation

Injection Acton Prolongatum® Ferring pharmaceuticals (Saint Prex, Switzerland) is available as a 5-mL vial with a concentration of 60 IU/mL.

To prepare 25 IU** of Acton Prolongatum, 0.4 ml of Acton Prolongatum is taken in 1 ml syringe and diluted with 0.5 ml NS

Performing the test

After overnight fast, basal sample for cortisol is taken at 8 AM and 25 IU of Acton Prolongatum is injected intramuscularly over the deltoid.

One hour (9 AM) post stimulation, a second cortisol sample is taken

Interpretation

Peak cortisol (at 60 minutes) <18 mcg/dl: suggestive of adrenal insufficiency (94% specific and 57% sensitive)

Peak cortisol (at 60 minutes) >22 mcg/dl : rules out adrenal insufficiency

 NB: * Test is validated for children above 5 years (13). ** Studies in adults have also been done with 30 IU of Acton Prolongatum (0.5 ml) (95) (96).

 

Congenital Adrenal Hyperplasia

 

CAH is a group of autosomal recessive disorders characterized by enzymatic defects in adrenal steroidogenesis and diminished cortisol synthesis. The accumulation of precursors proximal to the blocked pathway and hypocortisolemia are responsible for the clinical features of these disorders. The presentation is varied and includes early classic presentation of salt-wasting (SW) and simple virilizing (SV) disorder to the non-classical presentation. Rare presentations of CAH as adrenal insufficiency (14), genital ambiguity (15) (16), hypoglycemia (17, 18), and precocious puberty (19) due to enzyme defects other than 21 hydroxylase deficiency have also been reported.

 

Newborn screen (NBS) for CAH from India revealed a prevalence of 1 in 576 (20). However retrospective data in the absence of NBS revealed the presentation of adrenal crisis in >80% of subjects with 70% presenting as SW-CAH and a delayed diagnosis in boys as compared to girls highlighting the importance of NBS (21).

 

CAH due to 21 hydroxylase deficiency (21OHD) accounts for 90-95% of the cases followed by 11β-hydroxylase deficiency (11βOHD), and 3β-hydroxysteroid dehydrogenase 2 (3βHSD2). Regional differences in the prevalence of enzyme deficiencies confirmed by genetic tests have been described from Cameroon (n=24) which found that 11βOHD was more common (66.6%) followed by 21OHD and as well from Algeria (n=273) which showed that 3βHSD2 (5%) was the second most common form after 21OHD. These differences may be attributed to the founder mutations (22, 23).

 

Diagnosis is made by screening for 17 OH Progesterone (OHP) which is elevated, followed by 17 OHP and other steroid responses to synacthen test. However, confirmation of specific enzyme deficiency requires genetic testing. The spectrum of genetic mutations has been described in various cohorts for CYP21A2, which was able to diagnose mutations in 80-96% of the subjects, and genotype-phenotype correlations have been established for various forms of CAH (24-27). Additionally, allele-specific PCR for screening common CYP21A2 mutations has been suggested as a cost-effective tool, especially in resource-constraint settings (28). The diagnosis of other enzyme deficiencies is often challenging due to a lack of genetic tests and steroid precursor assays. However, studies are emerging for other CAH variants such as 11βOHD from India (29) and 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency from Algeria (23) with the discovery of novel mutations indicating genetic heterogeneity. Combined genetic mutations have also been reported (30).

 

A child diagnosed with CAH requires lifelong treatment and monitoring. A longitudinal data from Egypt indicated that CAH subjects with older age, poor hormonal control, and frequent hospitalizations have relatively poorer health-related quality of life. The challenges faced in the management of CAH include late diagnosis, poor follow-up (31), and the development of adrenal rest tumors (23, 29).

 

Cushing Syndrome

 

Cushing syndrome is suspected in a child who presents with weight gain and growth failure. The characteristic cushingoid features described in adults are usually not seen and they often present with generalized obesity. Endogenous Cushing syndrome varies with the age of diagnosis with adrenal tumors predominating in children < 7 years and Cushing disease after 7 years. However, it is important to note that the most common cause of Cushing’s syndrome is exogenous and even topical routes of administration have been implicated in children (32-34).

 

Of the ACTH-independent Cushing syndrome, primary pigmented nodular adrenocortical disease (PPNAD) has been the most frequently described from the tropics in case series and reports some of which have been found in association with Carney’s complex (35-39). The other important cause reported is in association with Adrenocortical tumors as described below.

 

Adrenocortical Tumors

 

These tumors account for 0.2% of all pediatric tumors. The largest case series from India with 17 cases reported that 82% presented with endocrine dysfunction, of which the most common was Cushing syndrome with or without virilization seen in 53% of the subjects (40). Another cohort of 7 children from Sri Lanka also reported peripheral precocious puberty in all the subjects and one boy had the phenotypic features of Beckwith–Wiedemann syndrome (41). Case reports have also reported similar presentations some of which are the rare variants of adrenocortical oncocytoma (42-49). Large non-functioning adrenal cortical carcinoma can present with mass effects without any features (40, 50). The prognosis depends on the diagnosis with adenomas having complete remission. However, the prognosis of subjects with carcinoma was poor (40) (41).

 

Pheochromocytomas and Paragangliomas

 

Pheochromocytoma (PCC) refers to the catecholamine-producing tumor of the adrenal medulla whereas paragangliomas (PGL) are extra-adrenal tumors of sympathetic and parasympathetic ganglia. Of the PPGLs, 10-20% occur in the pediatric age group. There is a high rate of germline mutations and heritability in pediatric PPGLs. A cohort of 30 children from India with PPGL showed that 26.7% of the subjects had syndromic or familial association, of which Von Hippel-Lindau was the most common. Fourteen (46.7%) children had germline mutations (VHL 10 (33.3%), SDHB 2 (6.6%), and SDHD 2 (6.6%). Bilateral pheochromocytomas and symptomatic presentation was more frequent in children as compared to adult PPGL. Children with VHL mutation had more frequent bilateral PCC, coexisting PGL and recurrence (51).

  

PPGLs often mimic other diseases and rare presentations such as myocarditis (52), diabetes insipidus (53), hypertensive encephalopathy (54) (55), Cushing syndrome (56), pseudo renal artery stenosis (57), and papilledema (58) have been described.  

After biochemical confirmation, imaging studies are advised for anatomical localization. Functional imaging is recommended for larger tumors, suspected multifocal or extra adrenal tumors, succinate dehydrogenase subunit B (SDHB) or alpha-thalassemia/mental retardation syndrome X-linked mutations (ATRX) and dopamine secreting PPGLs. A cohort study from India revealed that 68Ga-DOTATATE PET/CT (95%) had a higher sensitivity than 18F-FDG-PET/CT (80%) and 131I-MIBG (65%) for overall lesions. 68Ga-DOTATATE PET/CT was more sensitive than 131I-MIBG (93 vs. 42%) for detecting metastases (59).  The definitive management of PPGL is surgical resection. Pre-operative preparation with experienced anesthetic (60) and surgical team (61) is important for successful outcomes following surgery. The management of metastatic PPGL is challenging especially in countries with limited resources. Fractionated low dose 131 I-metaiodobenzylguanidine (MIBG) therapy has been used in the treatment of metastatic paraganglioma (62). Lifelong surveillance is recommended in children to detect early recurrence (63).

 

DISORDERS OF SEX DEVELOPMENT (DSD)

 

DSD is a condition in which chromosomal, gonadal, or anatomical sex is atypical (64). Observational studies from Egypt and Cameroon reported that these constitute 2-9.4% of the subjects presenting to endocrine clinics (65, 66).

 

Epidemiology

 

DSDs can be broadly classified into sex chromosomes, 46 XX and 46 XY DSDs. Cohort studies have revealed a prevalence of 5-15 % for sex chromosomal DSDs, 33.7-71% for 46 XY DSD, and 24-51% for 46 XX DSD (65-67). Regional differences were observed in the prevalence of these disorders attributed to consanguinity and endogamous marriages (66).

 

Table 2. Classification of DSDs

SEX CHROMOSOME DSD

46 XY DSD

46 XX DSD

Turner’s syndrome (and 45X variants)

Disorders of testis development

 

Complete testicular dysgenesis (Swyer syndrome)

Partial gonadal dysgenesis

Testicular regression

Disorders of ovarian development

Gonadal dysgenesis

Ovotesticular DSD

·         RSPO gene mutation

·         NR5A1 gene mutation

Testicular DSD

·         SRY+

·         SOX9/SOX3 duplication

·         WNT 4 mutation

Klinefelter’s syndrome (and 47XXY variants)

Disorders of androgen synthesis

STAR mutation    

CAH

·         3β-hydroxysteroid dehydrogenase 2

·         17α-hydroxylase/17,20-lyase

·         P450 oxidoreductase

Isolated testosterone deficiency

·         17β-hydroxysteroid dehydrogenase

·         5α-reductase 2

Androgen excess

CAH

·         21-hydroxylase

·         3β-hydroxysteroid dehydrogenase 2

·         P450 oxidoreductase

·         11β-hydroxylase

·         Glucocorticoid receptor mutations

 

Maternal

·         Virilising tumors

·         Exogenous androgens

 

Mixed gonadal dysgenesis Ovotesticular DSD

Disorders of androgen action

Androgen insensitivity syndrome

Luteinizing hormone receptor defects

Others

Mullerian agenesis (MRKH syndrome)

Uterine abnormalities

Syndromic associations (cloacal exostrophy)

 

Others

Persistent mullerian duct syndrome

Complex syndromic disorders

Isolated hypospadias

 

 

Clinical Features

 

DSDs have a varied presentation which includes ambiguous genitalia of varying severity, primary amenorrhea, and virilization at puberty to infertility in adulthood. The recognition of DSDs has critical implications due to their syndromic associations such as Wilm’s tumor and renal failure with Denys-Drash syndrome, adrenal insufficiency with CAH, and future risk of gonadoblastoma. In addition, there are long-term social and psychological impacts such as gender of rearing and fertility prospects. 

 

46 XY DSD

 

46 XY DSD can be classified as disorders of testis development, androgen synthesis, or androgen action.

 

The most common DSD reported among these are disorders of androgen synthesis of which 5 alpha reductase deficiency is the most commonly reported with a prevalence of 10%- 33% with a presentation as ambiguous genitalia (65-68). The higher rates reported in recent literature are attributed to the genetic confirmation some of which are novel and founder mutations, as opposed to the earlier diagnosis based on biochemical ratios of Testosterone: Dihydrotestosterone (69-71). Rare variants of CAH with presentation as infertility, hypertension, or virilization been reported (15, 72-74).

 

Androgen insensitivity syndrome (AIS); partial (PAIS) or complete (CAIS) is the next most commonly reported 46 XY DSD from various countries with a prevalence of 5-28% (65-67, 75, 76). However, cohort studies with genetic confirmation reported a prevalence of 10-38% (77, 78). A point to be noted was that only 31% of patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene (78). Patients with CAIS are reared as females and have a later presentation with primary amenorrhea. The presentation of PAIS may be earlier with atypical genitalia or gynecomastia.

 

The third most commonly reported cause is gonadal dysgenesis which can be partial or complete with a prevalence of 4-10% (65-67, 79), Case reports of gonadal development disorders with dysgenesis are also emerging which include WT-1 mutation (80-82), Desert hedgehog (DHH) gene (83), and Mitogen‐activated protein 3 kinase 1 (MAP3K1) gene (84). 

 

Other rare causes such as persistent Mullerian duct syndrome (85, 86) and Leydig cell hypoplasia (87) have been reported from the Middle-eastern countries.

 

Syndromic causes of 46 XY DSD accounts for 1-1.8% of the cohort studies cited earlier.

 

46 XX DSD

 

In contrast to the 46 XY DSDs which can have variable presentation and etiology, the most common cause of 46 XX DSD is CAH of which 21 hydroxylase deficiency is the most common cause. However, Sap et al from Cameroon reported 11 hydroxylase was the most common cause of CAH in their population (66). The prevalence of 46 XX DSD ranges from 20%-55% (65-67). 

 

The other important causes of 46 XX DSD are ovotesticular DSD (16.2%) and vaginal atresia (2%). Rare case reports of aromatase deficiency (88) and isodicentric Y chromosome in 45 X individuals have been reported (89). 

 

Management

 

The diagnosis and management of DSDs are challenging, especially in countries with low resources. The most important step in the initial evaluation of ambiguous genitalia is the presence of gonads which gives us a clue in narrowing the cause and guiding further workup. Karyotyping, imaging by pelvic USG or MRI, followed by biochemical evaluation helps in establishing a diagnosis. The emergence of genetic tests has further simplified the evaluation of such patients and will prove to be a valuable tool in the future.

 

Diagnosis of DSD and gender assignment has lifelong implications for the patients. There have been reports of gender change and gender identity confusion especially in 46 XY DSDs (90-92). However, patients with AIS have less prevalence of gender dysphoria (77, 92).

 

For 46 XX DSDs with virilization, feminizing genitoplasty is an important concern especially the timing of surgery. An observational study from Malaysia of 59 females with CAH who had undergone feminizing genitoplasty (FG) reported that infancy and early childhood as the best timing for first FG, most preferring single-stage over 2-stage surgery (93).

 

Data regarding the risk of gonadoblastoma and prophylactic gonadectomy is scarce. A case series of 5 subjects of 46 XY DSD reared as females revealed malignancy in only one patient with CAIS (94).

 

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Combined Dyslipidemia in Children and Adolescents

ABSTRACT

 

Combined dyslipidemia (CD) is now the predominant hyperlipidemic pattern in childhood, characterized by moderate to severe elevation in triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) with reduced high-density lipoprotein cholesterol (HDL-C).  In youth, CD occurs almost exclusively with obesity and is highly prevalent, seen in 30-60% of obese adolescents. With nuclear magnetic resonance spectroscopy, the CD pattern is represented as increased small, dense LDL and overall LDL particle number and decreased total HDL-C and large HDL particles, a highly atherogenic pattern. CD in childhood is associated with pathologic evidence of atherosclerosis and ultrasound findings of vascular dysfunction in children, adolescents, and young adults; it is also predictive of early clinical cardiovascular events in adult life. CD is strongly associated with visceral adiposity, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and the metabolic syndrome, suggesting an underlying, integrated pathophysiologic response to excessive weight gain. In almost all cases, CD responds well to lifestyle intervention including weight loss, changes in dietary composition, and increased physical activity. Evidence-based recommendations for management of CD are provided. Rarely, drug therapy is needed and the evidence for drug treatment of CD in childhood is reviewed.

 

DEFINITION, ATHEROGENICITY, AND PREVALENCE

 

The pediatric obesity epidemic has resulted in a large population of children and adolescents with secondary combined dyslipidemia (CD). This is now the predominant hyperlipidemic pattern in childhood, characterized by moderate to severe elevation in triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) with reduced high-density lipoprotein cholesterol (HDL-C) (1).

 

Analysis by nuclear magnetic resonance spectroscopy (NMR) shows that the combined dyslipidemia pattern on standard lipid profile is represented at the lipid subpopulation level as increased small, dense LDL and LDL particle number with decreased total HDL-C and large HDL particles (2,3,4). High LDL particle number and elevated small, dense LDL particles have each been shown to predict clinical cardiovascular disease (5-11). The atherogenicity of this lipid sub-population pattern is complex and includes the high concentration of circulating LDL particles, decreased binding of small, dense LDL particles to the LDL receptor, prolonged residence time in plasma and therefore prolonged arterial wall exposure, greater binding of small, dense LDL particles to arterial wall proteoglycans, and increased susceptibility to oxidation (12-18). Consistent with these findings, genetic evidence from mutational analyses, genome-wide association studies, and Mendelian randomization studies indicates that triglycerides and triglyceride-rich lipoproteins are an important source of increased small, dense LDL particle populations. The combined dyslipidemia pattern on traditional lipid profile analysis identifies the atherogenic pattern on lipid sub-population analysis.

 

Obesity is highly prevalent, affecting 18.5% of all-American youth and 20.6% in adolescents based on NHANES data from 2015-2016; up to 85% of overweight adolescents become obese adults (19,20). In the short term, 50% of obese adolescents have at least one, and 10% have 3 or more cardiovascular risk factors, including combined dyslipidemia, hypertension, and insulin resistance (21,22). In the long term, childhood obesity predicts type 2 diabetes mellitus, premature cardiovascular disease (CVD), and early mortality (23).  NHANES data from 1999-2006 indicated CD was highly prevalent in obese youth, present in more than 40% of adolescents with body mass index (BMI) >95th%ile (24). A 2019 analysis of trends in fasting serum lipids using NHANES data from 1999-2000 to 2015-2016 in US adolescents aged 12 to 19 years showed significant favorable changes in mean levels of all lipid parameters for the sample population as a whole. By contrast, when analyzed by BMI category, obese adolescents showed no significant trend towards improvement in mean HDL-C or LDL-C levels. Although there was a trend towards improvement among obese subjects in total cholesterol, TGs, and non-HDL-C, the prevalence of adverse levels in the last survey in 2015-2016 remained high: 22.3% for TGs, 29% for HDL-C and 10% for LDL-C (25). In cross-sectional data from multiple populations, 30 to 60% of obese youth have elevated TGs, usually associated with reduced HDL-C (26-28). The prevalence of CD increases as obesity severity increases (29-31).  

 

In addition, selected second generation antipsychotic medications, increasingly prescribed in pediatric patients, are associated with severe weight gain and significant increases in triglycerides and reductions in HDL-C (32,33). Thus, CD is a prevalent and important problem.

 

LIPID PROFILE MEASURES

 

Normal lipid values in childhood are shown in Table 1 (1). In children younger than 10 years, the 95th%ile for TG is 100 mg/dL and at 10-18 years, the 95th%ile is 130 mg/dL. Normal non-HDL-C levels are <145 mg/dL. HDL-C averages 55 mg/dL in males and females before puberty, after which mean HDL-C drops to a mean of 45 mg/dL in males. The diagnosis of CD requires that the average of a least 2 measurements of TG and/or non-HDL-C fall above the 95th%ile, plus HDL-C at or below the 5th%ile. TC and LDL-C levels may also be mildly elevated. In the typical lipid profile of a child or adolescent with CD, TG levels are between 150 and 400 mg/dL, HDL-C is < 40mg/dL, non-HDL-C is >145 mg/dL and TG/HDL-C ratio exceeds 3 in whites and 2.5 in blacks.

 

Table 1.  Acceptable, Borderline, and High Plasma Lipid and Lipoprotein Concentrations (mg/dL) for Children and Adolescents* (1)

Category

Acceptable

Borderline

High

TC

< 170

170-199

> 200

LDL-C

< 110

110-129

> 130

Non-HDL-C

< 120

120-144

> 145

Triglycerides

0-9 years

< 75

75-99

> 100

10-19 years

< 90

90-129

> 130

Category    

Acceptable    

Borderline

Low

HDL-C

>45

40-45

<40

NOTE: Values given are in mg/dL; to convert to SI units, divide the results for TC, LDL-C, HDL-C and non-HDL-C by 38.6; for TG, divide by 88.6.

* Values for plasma lipid and lipoprotein levels are from the 2011 NHLBI Expert Panel Guidelines (1). The cut points for high and borderline high represent the 95th and 75th percentiles, respectively. The low-cut point for HDL-C represents the 10th percentile.

www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm.

 

In addition to the standard lipid profile measures, non-HDL-C and the TG/HDL-C ratio are useful measures in patients being evaluated for CD. Non-HDL-C is a measure of the cholesterol content of all the plasma atherogenic lipoproteins. TC and HDL-C can be measured accurately in the non-fasting state with non-HDL-C calculated by subtracting HDL-C from TC (1). Epidemiologic studies show that childhood non-HDL-C correlates well with adult levels, independent of baseline BMI and BMI change (34). In autopsy studies in children, adolescents and young adults, non-HDL-C and HDL-C levels were the best lipid predictors of pathologic atherosclerotic lesions, better than any other lipid measure (35). Non-HDL-C measured in childhood was a significant predictor of subclinical atherosclerosis in adulthood, assessed by higher carotid intima media thickness (cIMT) measurements (36). In adults, non-HDL-C has been shown to be the best independent lipid predictor of cardiovascular disease events (37,38).  Normative values for non-HDL-C are included in the 2011 NHLBI pediatric guidelines which recommend this measure for population screening (1) (Table 1).

                                                                                                                          

The TG/HDL-C ratio is a strong predictor of coronary disease extent in adults and is considered to be a surrogate index of the atherogenicity of the plasma lipid profile (39,40). In children, an elevated TG/HDL-C ratio correlates with insulin resistance and with non-alcoholic fatty liver disease (41-43). In a study of normal weight, overweight, and obese white children and adolescents, top tertile TG/HDL-C correlated significantly with increased cIMT in multivariate analysis (43). There are ethnic differences in lipid measures which manifest during adolescence: African-Americans have significantly lower triglycerides and higher HDL-C levels and this impacts non-HDL-C and the TG/HDL-C ratio (44-47). In a study of obese black and white adolescents, TG/HDL-C and non-HDL-C were surrogate markers for elevated small dense lipoprotein particles on NMR spectroscopic analysis (48). A TG/HDL-C ratio above 3 and non-HDL-C above 120 mg/dL in white subjects, and TG/HDL-C ratio above 2.5 and non-HDL-C levels above 145 mg/dL in black subjects were the best lipid predictors of LDL-C particle concentration (48). The HEALTHY study characterized lipids in a large, diverse population of sixth grade children and found that 33% of overweight/obese children had an elevated TG/HDL-C ratio and 11.2% had an elevated non-HDL-C (49). NMR spectroscopy confirmed that the CD findings on standard lipid profile identified the lipid subpopulation pattern of increased total and small, dense LDL particles (50).

 

GENETIC ASPECTS OF COMBINED DYSLIPIDEMIA

 

In the literature, the terminology describing combined dyslipidemia also includes “mixed dyslipidemia” and “atherogenic dyslipidemia” (51,52). Combined dyslipidemia is the term used most commonly in pediatrics (53). There is overlap in the lipid phenotype between CD and familial combined hyperlipidemia (FCHL), which was originally considered to be a genetically discrete entity (54,55). However, current evidence suggests that FCHL is a multigenic dyslipidemia with variable expression in different pedigrees (56,57). There is well-established familial aggregation of the combined dyslipidemia phenotype in pediatric and adult studies, beyond the historic studies of FCHL (58,59).  Emerging evidence from gene sequencing studies suggests that variants in the genes controlling TG metabolism, particularly those encoding lipoprotein lipase, may be important factors in the expression of hypertriglyceridemia and combined dyslipidemia (59,60). As with CD, the mechanism of increased CVD risk in FCHL is the presence of increased numbers of apolipoprotein B-containing particles, particularly small, dense LDL particles, so genetic analysis is not critical for patient management at this time (61,62).  

 

EVIDENCE FOR ACCELERATED ATHEROSCLEROSIS WITH COMBINED DYSLIPIDEMIA

 

An important initiating step in atherosclerosis is subendothelial retention of LDL-containing lipoproteins (63). Combined dyslipidemia is highly atherogenic because its sub-population composition with increased LDL particles and small dense LDL is associated with facilitated sub-endothelial retention by multiple mechanisms (12-18). Consistent with these findings, recent genetic evidence from mutational analyses, genome-wide association studies, and Mendelian randomization studies indicates that triglycerides and triglyceride-rich lipoproteins are an important source of increased small, dense LDL particle populations. In childhood, the atherogenicity of combined dyslipidemia is seen in anatomic and histologic changes at autopsy and with structural and functional vascular changes in vivo. CD in childhood is also predictive of accelerated atherosclerosis and of early cardiovascular events in adult life. In both the Pathobiological Determinants of Atherosclerosis in Youth Study and the Bogalusa Heart Study, high non-HDL-C and low HDL-C were strongly associated with autopsy evidence of premature atherosclerosis (64-66). Obese youth with elevations in TG and low HDL-C had thicker CIMT, higher pulse wave velocity (PWV), and increased carotid artery stiffness (67-69). A strong association between higher TG/HDL-C ratio, higher non-HDL-C, and higher PWV in both lean and obese children has been demonstrated after adjustment for other CVD risk factors (70). CD identified in childhood is associated with atherosclerotic vascular change measured in adulthood by CIMT and PWV (71-73). Most importantly, in the long-term Princeton Follow-up Study, elevated TG and TG/HDL-C ratio at a mean age of 12 years predicted clinical cardiovascular events at late follow-up 3 to 4 decades later (74,75). This is the first childhood lipid parameter shown to be associated with premature clinical cardiovascular disease. Thus, the combined dyslipidemia pattern seen with obesity in childhood and adolescence identifies pathologic evidence of atherosclerosis and vascular dysfunction in adolescence and young adulthood, and predicts early clinical events in adult life.

 

While evidence like this in pediatrics strongly supported the importance of high triglycerides/ combined dyslipidemia in the development of atherosclerotic vascular change and subsequent premature cardiovascular clinical cardiovascular disease, LDL-C has been the principal, long-time focus for investigation and management in adult atherosclerosis. Since the time this chapter was first developed in 2016, a flurry of studies in adults have addressed the importance of hypertriglyceridemia – the “neglected major cardiovascular risk factor” – in atherogenesis (76). These include epidemiologic studies which identify high serum TGs as a marker for TG-rich lipoproteins, now recognized as strong, independent predictors of ASCVD and all-cause mortality; Mendelian randomization studies which identify TG-rich lipoproteins as causally associated with ASCVD and all-cause mortality; and intervention trials identifying high TGs and non-HDL-C as the mediators of residual atherosclerotic risk when LDL-C levels are below prescribed targets (77-80). Unfortunately, as discussed in other Endotext chapters, recent randomized trials using triglyceride lowering drugs have failed to demonstrate a decrease in atherosclerotic cardiovascular events in adults.

 

PATHOPHYSIOLOGIC ASSOCIATIONS

 

There is a tight connection between CD and obesity, visceral adiposity, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and the metabolic syndrome.

 

Obesity

 

The association between CD and obesity is strong and consistent with CD seen in 20 to 60% of obese youth (25-27). The prevalence of CD increases as obesity severity increases (28-30). In multiple studies, excessive intake of sugars, particularly fructose, has been associated with obesity and with combined dyslipidemia in children and adults (81-87). By contrast, low sugar intake is associated with higher HDL in females during adolescence (88).

 

Visceral Adiposity   

 

There is a close correlation between CD and abdominal obesity. In susceptible individuals with an underlying racial/ethnic/familial/genetic predisposition, excessive weight gain occurs disproportionately as visceral fat (VAT). This is thought to reflect the inability of the subcutaneous adipose tissue depot to expand, resulting in ectopic fat deposition, primarily in the viscera but also in the liver, heart, and skeletal muscle (89,90). Based on correlation with dual-energy x-ray absorptiometry, waist circumference (WC) is an effective measure of abdominal obesity in youth, with WC above the 90th %ile for age and sex strongly predicting high TGs, reduced HDL-C, and hyperinsulinemia (91,92). Using NHANES norms for WC, the prevalence of abdominal obesity increased more than 65% in boys and girls aged 2 to 19 years between 1988-1994 and 1999-2004 (93,94). From NHANES survey results in 5- to 18-year-olds from 1999 to 2008, waist/height ratio (WHtR), another measure of central adiposity, was integrated with BMI percentiles and measures of cardiometabolic risk: obese subjects with normal WHtR < 0.5 had cardiometabolic risk similar to subjects with normal BMI percentiles, while increasing WHtR was significantly associated with dyslipidemia, insulin resistance and the metabolic syndrome (95).

 

There are known racial/ethnic differences in the tendency to develop visceral adiposity with Hispanic, Native-American, and Asian populations at elevated risk (96). Especially in Asians, increased VAT can develop in the absence of any other measure of adiposity and this is associated with hypertriglyceridemia, CD, insulin resistance, and type 2 diabetes (T2DM) (97), VAT contributes directly to high TGs because delivery of FFAs to the liver via the portal vein is proportionate to visceral fat mass. Progression of VAT correlates significantly with development of CD (98)

 

Insulin Resistance and Type 2 Diabetes  

 

Insulin resistance is considered a primary abnormality in development of CD and associated cardiovascular disease. Obesity correlates with hyperinsulinemia in children, adolescents, and adults (99,100). In the Bogalusa Heart Study, serial cross-sectional surveys showed that higher BMI was associated with higher fasting insulin levels in childhood and adolescence and with higher fasting glucose levels in young adulthood (101). Insulin resistance (IR) correlates strongly with abdominal obesity, high TGs, and reduced HDL-C in children, adolescents, and adults. During puberty, insulin resistance is physiologic with an average 50% decrease in insulin sensitivity, associated with compensatory doubling of insulin secretion to maintain glucose homeostasis. The pattern of insulin resistance is exaggerated in obese adolescents and persists after puberty is complete (102).

 

Hyperinsulinemia enhances hepatic VLDL synthesis, manifest as high TGs (103). At the tissue level, IR promotes lipoprotein lipase dysfunction, further elevating TGs (104). In normoglycemic adolescents, IR and CD were seen only in obese subjects and the dyslipidemia correlated with the degree of IR (105). In a hyperinsulinemic–euglycemic clamp study, elevated TGs with reduced HDL-C identified in vivo IR (41).

 

Progression from IR to impaired fasting glucose to type 2 diabetes (T2DM) has been documented in youth, especially with a family history of diabetes (101). T2DM is increasingly common in adolescents with a prevalence of 0.46 per 1000 individuals in 2009, a 31% increase from 2001 (106). In children and adults, the interplay between insulin resistance and dyslipidemia in normoglycemic and hyperglycemic individuals is complex and at this time, incompletely elucidated (107).

 

Non-Alcoholic Fatty Liver Disease  

 

CD is also strongly linked with non-alcoholic fatty liver disease (NAFLD), defined as hepatic fat infiltration in >5% of hepatocytes with no evidence of hepatocellular injury on liver biopsy and no history of alcohol intake (109).  NAFLD is highly correlated with obesity, affecting at least 38% of obese adolescents in autopsy series and ~50% in epidemiologic surveys (109,110). On evaluation, the most common findings are hepatomegaly and mild-to-moderate elevation in serum alanine aminotransferase (ALT) (108). Hepatic fat deposition usually occurs in the context of generalized obesity but reflects much more strongly, the presence of increased visceral adiposity. In obese children and adolescents, sequential increase in waist circumference, a proxy measure of visceral fat, is associated with progressive increase in odds ratio for prediction of ultrasound-detected hepatic steatosis (112). NAFLD is strongly associated with insulin resistance and all of the components of the metabolic syndrome (112-114). In a study of adolescents with biopsy-proven NAFLD, 80% had biochemical evidence of insulin resistance (114). In more than half of subjects with NAFLD, the atherogenic CD pattern is seen on a standard lipid profile and with NMR analysis (115). As with CD, dietary sugar is considered to play a significant role in the development and progression of NAFLD – in a recent randomized controlled trial, provision of a diet low in free sugar content for 8 weeks led to significant improvements in hepatic steatosis (116). In children and adolescents, NAFLD is associated with atherosclerosis at autopsy and with ultrasound vascular markers associated with atherosclerosis (117). In adults, NAFLD has been shown to be a strong, independent predictor of CVD (118).

    

Metabolic Syndrome

 

CD, insulin resistance, and visceral adiposity are each components of the metabolic syndrome (MS), first described by Reaven in 1988 and identified as a high-risk constellation for atherosclerotic disease (119). Non-alcoholic fatty liver disease (NAFLD) has been added as a sixth component of the metabolic syndrome (120). In the U.S., the metabolic syndrome is reported in 23% of adults, including 7% of men and 6% of women in the 20- to 30-year-old age group (121,122). There is as yet no agreed-upon definition for the metabolic syndrome in childhood, but analysis of cross-sectional data from NHANES (1988-1994) revealed the MS cluster in 28.7% of obese adolescents compared with 0.1% of those with a BMI below the 85th percentile. As age and the degree of obesity increased, the prevalence of the MS cluster increased, reported in 38.7% of moderately obese (mean body mass index [BMI] 33.4 kg/m2) and 49.7% of severely obese (mean BMI 40.6 kg/m2) adolescents (123,124). Presence of the metabolic syndrome cluster at a mean of 12 years of age was an independent predictor of adult cardiovascular disease 25 years later (125).

 

Summary

 

CD is strongly associated with a complex of related cardiometabolic factors. From existing studies, it appears that visceral adiposity develops in children and adolescents with underlying racial/ethnic/familial/genetic susceptibility in response to excessive weight gain. This initiates a cascade of pathophysiologic reactions which result in CD, insulin resistance/ T2DM, and NAFLD and combined, the metabolic syndrome. These prevalent combinations are powerful predictors of cardiometabolic risk (1,115,116).

 

MAKING THE DIAGNOSIS OF COMBINED DYSLIPIDEMIA

 

The 2011 NHLBI pediatric guidelines were the first to recognize the importance of high TGs and CD in childhood (1). The guidelines recommend selective lipid screening when overweight or obesity is first identified (BMI > 85th%ile for age/sex); when any other major cardiovascular risk is present; and when there is a family history of early cardiovascular disease or of treated dyslipidemia (1). While non-fasting measures of total cholesterol and HDL–C are accurate and non-HDL-C can be used for general screening, hypertriglyceridemia can only be identified on a fasting lipid profile (FLP) so a FLP is recommended for selective screening in these settings.

 

  • Normative values for the lipid components are shown in table 1 with values above the 95th%ile considered elevated for TC, TG, non-HDL-C, and LDL-C; and below the 5th%ile considered as reduced for HDL-C.
  • If the first FLP results are abnormal, testing should be repeated after 2 weeks but before 3 months and results averaged to determine baseline lipid values.
  • Measurement of TGs is subject to considerable biologic variability with median variation between measurements of 23.5% compared with ~ 5-6% for cholesterol and HDL-C so if the first 2 test results are highly disparate, a third fasting measurement is recommended (127,128).
  • For the rare child with CD in whom TGs consistently exceed 500 mg/dL and who is at risk for pancreatitis, treatment is described in detail in the NHLBI guidelines and in other Endotext chapters (1).
  • When high TGs or CD are confirmed, specific evaluation for co-morbidities is recommended:
  • Waist circumference and WHtR as measures of visceral adiposity (91-93)
  • Assessment of fasting glucose to evaluate glucose intolerance per the recommendations of the American Diabetic Association (129)
  • ALT measurement to check for NAFLD (108)
  • Evaluation for the MS cluster

 

As noted, there are racial, ethnic and gender differences in TG levels in childhood and adolescence. African-Americans have significantly lower triglycerides and higher HDL-C levels compared with Hispanics and non-Hispanic whites (45-47). With puberty, HDL-C levels drop a mean of 10 mg/dL in males with no change in females, regardless of race/ethnicity (1). These differences suggest that race-, gender- and developmental stage-specific cut points may be needed to optimally identify high TGs and CD but normative tables for American youth based on these factors are not currently available.

 

LIFESTYLE MANAGEMENT OF COMBINED DYSLIPIDEMIA

 

Evidence for Response to Lifestyle Changes

 

Multiple studies have shown significant improvements in CD in response to weight loss, change in diet composition, and increased activity (130). In all age groups, even small amounts of weight loss are associated with significant decreases in TGs, often with increases in HDL–C (1,131-137). In adults, weight loss of as little as 5% results in a 20% decrease in TGs and an 8 to 10 % increase in HDL-C (133). In youth, a decrease in BMI z-score of at least 0.15 kg/m2is associated with significant improvement in triglycerides and HDL-C (134). The magnitude of TG decreases correlates directly with the amount of weight loss. Acute weight loss in children and adolescents has been shown to significantly decrease TGs and LDL particles and small dense LDL on NMR analysis (137).

 

Changes in diet composition have also been shown to be an effective treatment for high TGs and CD. In light of the strong evidence in children and adults associating excessive sugar intake with obesity and with combined dyslipidemia, decreasing simple carbohydrate intake especially in the form of added sugars is a common and important focus (73-80). In adults, a low-carbohydrate diet with monounsaturated fat enrichment significantly decreased TGs by a mean of 63%, with associated increases in HDL–C (138). One-year follow-up of young children (mean age 21 months) with elevated TGs treated with a diet restricted in sugar and carbohydrates was associated with a significant TG decrease from a mean of 274.1 +/- 13.1 mg/dL before treatment to 88.8 +/- 13.3 mg/dL (139). In adolescents and young adults, low glycemic-load diets are as effective as low-fat diets in achieving weight loss and are associated with decreased TGs and increased HDL-C (140-143). In obese children and adolescents, a low-carbohydrate diet with or without weight loss significantly reduces TGs (144,145). These diet composition changes have also been shown to significantly improve the LDL subpopulation pattern (138,148). Combined, diet composition changes lower TGs by at least 20% (135). 

 

Exercise has also been effective in treating CD in youth, alone and in the context of a weight loss plan. Aerobic activity facilitates the hydrolysis and utilization of triglycerides in skeletal muscle, reducing deposition as adipose tissue. In adults, moderately intense activity vs no activity was associated with 20% lower TGs, with lowest levels in the highest activity subjects (147). In cross-sectional studies in youth, low cardiorespiratory fitness is a strong predictor of high triglycerides as part of the MS cluster, and high fitness is associated with a low metabolic risk score (149-151). In randomized controlled trials, aerobic exercise interventions are associated with significant decreases in TG levels and increases in HDL-C, proportionate to training intensity (152-155). 

 

Several studies have attempted to define the optimal type, volume, and intensity of activity required for cardiovascular risk reduction.  A systematic review of activity-related benefits concluded that youth aged 5 to 17 years required at least 60 minutes of at least moderate intensity activity every day (156). Aerobic activities should make up the majority, at vigorous intensity whenever possible. These recommendations are very similar to the Physical Activity Guidelines from the U.S. Department of Health and Human Services (157). A randomized, controlled trial in obese children showed that 20 or 40 minutes of supervised aerobic exercise 5 days per week demonstrated dose-response benefits for insulin resistance and visceral adiposity, both strongly associated with CD (158). Pooled data from the International Children’s Accelerometry Database shows that replacement of 10 mins of sedentary time/day with 10 minutes of moderate-to-vigorous activity was associated with significantly lower fasting insulin and TG levels (159).

 

No studies of youth with high TGs or CD have evaluated clinical cardiovascular events in response to lifestyle changes initiated in childhood.  However, in longitudinal cohort studies, low cardiovascular risk in childhood is significantly predictive of better vascular health in adulthood and lifestyle interventions have been shown to improve vascular measures (160-162). In obese youth with high TGs and CD, diet and exercise intervention studies show that subjects who were successful in weight loss showed improvements in vascular measures (163-165).

 

Lifestyle Intervention: Diet and Exercise Recommendations         

 

With this evidence, primary recommended treatment for CD and for related visceral adiposity, IR, and NAFLD is weight loss with optimized diet composition. A comprehensive, straightforward weight management approach can be initiated in any practice setting, beginning with calculation of appropriate energy intake for age, gender, and activity using table 2 from the 2011 NHLBI pediatric guidelines (1). Estimation of current caloric intake allows development of a plan to gradually decrease calories towards the appropriate level over several weeks with the guidance of a registered dietitian.

 

Table 2.  Estimated Calorie Requirements (in Kilocalories [kcals]) for Gender and Age Group at Three Levels of Physical Activitya

 

Calorie Requirements (kcals) by Activity Level b,c,d

Gender

Age (Years)

Sedentaryb

Moderately Activec

Actived

Child

2–3

1,000

1,000–1,400e

1,000–1,400e

Female

4–8
9–13
14–18
19–30

1,200
1,600
1,800
2,000

1,400–1,600
1,600–2,000
2,000
2,000–2,200

1,400–1,800
1,800–2,200
2,400
2,400

Male

4–8
9–13
14–18
19–30

1,400
1,800
2,200
2,400

1,400–1,600
1,800–2,200
2,400–2,800
2,600–2,800

1,600–2,000
2,000–2,600
2,800–3,200
3,000

(Estimates determined using the Institute of Medicine equation & rounded to nearest 200 kcals.)

a These levels are based on Estimated Energy Requirements from the IOM Dietary Reference Intakes macronutrients report (2002), calculated by gender, age, and activity level for reference-size individuals.  “Reference size,” as determined by the IOM, is based on median height and weight for ages up to age 18 years and median height and weight for that height to give a body mass index of 21.5 for adult females and 22.5 for adult males.

b A sedentary activity level in childhood, as in adults, means a lifestyle that includes only the light physical activity associated with typical day-to-day life.

c Moderately active in childhood means a lifestyle that includes some physical activity, equivalent to an adult walking about 1.5 to 3 miles per day at 3 to 4 miles per hour, in addition to the light physical activity associated with typical day-to-day life.

d Active means a lifestyle that includes more physical activity, equivalent to an adult walking more than 3 miles per day at 3 to 4 miles per hour, in addition to the light physical activity associated with typical day-to-day life.

 

Diet composition is focused on limitation of simple carbohydrates especially sweets and added sugars with complete elimination of all sugar-sweetened beverages. The diet recommendations from the NHLBI guidelines are shown in table 3.  

Table 3. DIET COMPOSITION: Healthy Lifestyle/ Combined Dyslipidemia/ High TGs               

·1) Teach portions based on estimated energy requirements for age/gender/activity level. (Table 2)

·2) Primary beverage:  Fat-free unflavored milk.

·3) No sugar-sweetened beverages; encourage water intake.

· 4) Limit refined carbohydrates (sugars, baked goods, white rice, white bread, plain pasta), replacing with
complex carbohydrates (brown rice, whole grain bread, whole grain pasta).

5) Encourage dietary fish content*

 * The Food and Drug Administration (FDA) and the Environmental Protection Agency are advising women of childbearing age who may become pregnant, pregnant women, nursing mothers, and young children to avoid some types of fish and shellfish and eat fish and shellfish that are lower in mercury.  For more information, call the FDA’s food information line toll free at 1–888–SAFEFOOD or visit: http://www.cfsan.fda.gov/~dms/admehg3.html

·        

6) Fat content:                                                                                        

o   Total fat 25–30% of daily kcal/EER

Saturated fat </= 8% of daily kcal/EER 

Cholesterol <300 mg/d

Avoidtrans fats as much as possible

Mono- and polyunsaturated fat up to 20% of daily kcal/ EER 

·7) Encourage high dietary fiber intake from naturally fiber-rich foods (fruits, vegetables, whole grains) with a goal of “age plus 5 g/d.

 

These diet recommendations are those recommended for all healthy children over age 2 from the NHLBI Guidelines with intensification of limitation of simple carbohydrates.

 

Simple carbohydrates like white rice, white bread, and plain pasta are replaced with complex carbohydrates like brown rice and whole grain bread and pasta. Foods high in natural fiber are encouraged with a goal of age plus 5 grams per day. For all dietary change in youth, initial family-based training with a registered dietitian is the most effective way to begin and sustain change (1). The DASH eating plan adapted for children and adolescents as part of the 2011 NHLBI guidelines reflects the recommended TG/CD diet composition and is easy to use, organized for selected energy(kcal) intake from table 2 and by servings per day per food group (Table 4) (1).

 

Table 4.  DASH-Style Eating Plan: Servings per Day by Food Group & Total Energy Intake.

 

Food Group

 

1,200 Calories

 

1,400 Calories

 

 

1,600 Calories

 

1,800 Calories

 

2,000 Calories

 

2,600 Calories

 

Serving Sizes

 

Examples and Notes

Significance of Food Group to DASH Eating Plan

Grains*

4-5

5-6

6

6

6–8

10-11

1 slice bread

1 oz dry cereal

½ cup cooked rice, pasta, or cereal†

Whole- wheat bread and rolls, whole-wheat pasta, English muffin, pita bread, bagel, cereals, grits, oatmeal, brown rice, unsalted pretzels and popcorn

Major sources of energy and fiber

Vegetables

3-4

3-4

3-4

4-5

4–5

5-6

1 cup raw leafy vegetable

½ cup cut-up raw or cooked vegetable

½ cup vegetable juice

Broccoli, carrots, collards, green beans, green peas, kale, lima beans, potatoes, spinach, squash, sweet potatoes, tomatoes

Rich sources of potassium, magnesium, and fiber

Fruits

3-4

4

4

4-5

4–5

5-6

1 medium fruit

¼ cup dried fruit

½ cup fresh, frozen, or canned fruit

½ cup fruit juice

Apples, apricots, bananas, dates, grapes, oranges, grapefruit, grapefruit juice, mangoes, melons, peaches, pineapples, raisins, strawberries, tangerines

Important sources of potassium, magnesium, and fiber

Fat-free or low-fat milk and milk products

2-3

2-3

2-3

2-3

2–3

3

1 cup milk or yogurt

1½ oz cheese

Fat-free milk or buttermilk; fat-free, low-fat, or reduced-fat cheese; fat-free/low-fat regular or frozen yogurt

Major sources of calcium and protein

Lean meats, poultry, and fish

3 or less

3-4 or less

3-4 or less

6 or less

6 or less

6 or less

1 oz cooked meats, poultry, or fish

1 egg‡

Select only lean; trim away visible fats; broil, roast, or poach; remove skin from poultry

Rich sources of protein and magnesium

Nuts, seeds, and legumes

3 per week

3 per week

3-4 per week

4 per week

4–5 per week

1

1/3 cup or 1½ oz nuts

2 Tbsp peanut butter

2 Tbsp or ½ oz seeds

½ cup cooked legumes (dried beans, peas)

Almonds, filberts, mixed nuts, peanuts, walnuts, sunflower seeds, peanut butter, kidney beans, lentils, split peas

Rich sources of energy, magnesium, protein, and fiber

Fats and oils^

1

1

2

2-3

2-3

3

1 tsp soft margarine

1 tsp vegetable oil

1 Tbsp mayonnaise

2 Tbsp salad dressing

Soft margarine, vegetable oil (canola, corn, olive, safflower), low-fat mayonnaise light salad dressing

DASH study had 27% of calories as fat, including fat in or added to foods.

Sweets and added sugars

3 or less per week

3 or less per week

3 or less per week

5 or less per week

5 or less per week

 

< 2

1 Tbsp sugar

1 Tbsp jelly or jam

½ cup sorbet, gelatin dessert

1 cup lemonade

Fruit-flavored gelatin, fruit punch, hard candy, jelly, maple syrup, sorbet and ices, sugar

Sweets should be low in fat.

* Whole grains are recommended for most grain servings as a good source of fiber and nutrients.

† Serving sizes vary between ½ cup and 1 1/4 cups, depending on cereal type.  Check product’s Nutrition Facts label.

‡ Two egg whites have the same protein content as 1 oz meat.

^ Fat content changes serving amount for fats and oils.  For example, 1 Tbsp regular salad dressing = one serving; 1 Tbsp low-fat dressing = one-half serving; 1 Tbsp fat-free dressing = zero servings.

Abbreviations: oz = ounce; Tbsp = tablespoon; tsp = teaspoon. 

 

Successful weight loss programs in children and adolescents include frequent contact for support and monitoring by the physician and/or dietitian, as often as weekly for the first 6 months and this should be considered when initiating diet changes for children with CD (166). While not necessary for lipid management, a repeat fasting lipid panel after 1 to 3 months of diet change can be an effective motivator for children and families since TG levels decrease rapidly in response to changes in diet composition and even minimal weight loss (167).

 

A regular exercise schedule derived from the evidence is prescribed, simultaneous with the diet recommendations. All children and adolescents should be involved in 60 minutes or more of moderate to vigorous aerobic activity daily, with vigorous intensity activity at least 3 days/week (1,168,169). Any kind of aerobic activity is useful but weight bearing activity is most effective.  To promote compliance, a discussion about the kind of exercise that will be easiest for each child and family to sustain should be undertaken and specific follow-up of activity at subsequent evaluations is recommended. A combined diet and activity approach to weight loss like this has been shown to be effective in management of high TGs and CD (167-174).

 

For obese children and their families, weight loss can be an emotional issue so an alternative approach aimed at changing diet composition and activity without a direct approach to weight can be used. The same diet change and activity recommendations described above are prescribed but there is no calculation of caloric needs and no specific focus on weight loss. This approach has been shown to be successful in addressing high TGs and CD, particularly when combined with cognitive behavioral therapy (167,174-180).

 

Follow-Up    

 

After 6 months of the selected diet and activity plan, the fasting lipid profile (FLP) should be repeated:

 

  • If TGs are normal (<100 mg/dL, <10 years; <130 mg/dL, 10–19 years), continue the diet and activity recommendations and reassess the FLP every 12 months
  • If TGs are > 100 mg/dL but < 200 mg/d in children < 10 years of age, > 130 mg/dL but < 200 mg/dL in 10-19 years old:
  • Intensify counselling for the high TG/CD diet and increased activity.
  • Recommend increased dietary fish content.
  • Increase frequency of contact with MD and/or RD.
  • Repeat FLP in 6 months
  • If TG are > 200 mg/dL but less than 500 mg/dL and lifestyle recommendations have been attempted with no weight loss, consider referral to an intensive weight loss program (1).
  • If TG are > 200 mg/dL but less than 500 mg/dL despite weight loss in an adolescent who has at least 2 additional high-level cardiovascular risk factors (table 5), medication can be considered (1).

 

Table 5. High Level Cardiovascular Risk Factors for Management of Combined Dyslipidemia in Childhood

(+) Family history: Myocardial infarction, angina, coronary artery bypass graft/ stent/   angioplasty, sudden cardiac death in parent, grandparent, aunt, or uncle;                               Male < 55 y, female < 65 y.

Diabetes mellitus, type 1 or type 2

Hypertension requiring drug treatment

Current cigarette smoking

BMI>97th%ile

 

Application of these recommendations is usually associated with significant improvements in hypertriglyceridemia and CD on intermediate-term follow-up, with increasing evidence of lipid subpopulation and vascular response to lifestyle change. There are no published long-term studies of lifestyle change.

 

MEDICATION THERAPY FOR HYPERTRIGLYCERIDEMIA AND COMBINED DYSLIPIDEMIA

 

Information on drug therapy for treatment of hypertriglyceridemia and CD in childhood is limited. Drugs which could potentially be used are described below.

 

HMG-CoA Reductase Inhibitors (Statins)

 

In adults with high cholesterol and CD, statin therapy beneficially alters the standard lipid and LDL particle profiles and improves vascular function and clinical cardiovascular outcomes (181-183). In childhood, statin treatment has focused on children with monogenic hyper-cholesterolemia (FH) in whom statins effectively lower LDL-C levels and improve LDL-C subpopulation characteristics (184,185). Two pediatric trials of children with FH showed improved vascular measures in response to statin therapy (185,186). There are as yet no published studies examining statin effects on clinical outcomes in youth with CD.  A systematic review of statin therapy in children with FH analyzed studies that included more than 1000 children (188). Treatment with statins significantly decreased LDL-C but change in TGs was much less consistent. No statistically significant differences were found between statin-treated and placebo-treated children for the occurrence of any adverse events, including problems with sexual development, muscle toxicity, or liver toxicity.  An important study reported late follow-up of 184 patients with genetically confirmed familial hypercholesterolemia (FH) who were started on pravastatin therapy at a mean age of 12 years as part of a placebo-controlled trial. After 20 years, FH participants had mean LDL cholesterol levels 32% below baseline levels in the original trial. Mean progression of carotid intima–media thickness in FH subjects was similar to that of unaffected siblings. The cumulative incidence of cardiovascular events and death from cardiovascular causes was lower among the FH participants than among their affected parents for whom statins were available much later in life. This landmark report emphasizes the safety, effectiveness and benefit of long-term statin therapy initiated in childhood for treatment of FH (189).  DoIt!, an ongoing Pediatric Heart Network trial is evaluating the clinical and vascular responses to statin therapy in adolescents with obesity and CD. Enrollment is ongoing with a planned sample size of more than 300 subjects. Results are anticipated soon (190).

 

Omega-3 Fish Oil

 

Omega-3 fish oil therapy has been shown to be safe in adults, with some reports that TG levels decreased by as much as 30–45%, with associated increases in HDL–C (191). However, more recent reports including a Cochrane systematic review of 25 randomized, controlled trials have shown no conclusive benefits of standard fish oil treatment (usually 1 gram per day) on serum lipids or cardiovascular disease outcomes (192-194). Two randomized, controlled trials of omega-3 fish oil in adolescents showed statistically insignificant decreases in TGs and no change in LDL particle number or size (195,196). Evidence from multiple trials in adults with established CV risk shows conflicting results for benefit from omega-3 fatty acids and/or EPA. A detailed discussion of the potential benefits of omega-3-fattys on cardiovascular outcomes are discussed in detail in other Endotext chapters. There is as yet no information on use of EPA in children or adolescents.

 

 

PPAR-Alpha Agonists (Fibrates) 

 

In adults, fibrates have been used effectively and safely to lower TG levels, alone and in combination with statins (fenofibrate should be used in combination as gemfibrozil increases the risk of muscle disorders) (197). Fibrates reduce cholesterol synthesis and lower plasma TGs by 30-50% with an increase in HDL-C of 2-20%. Fibrate therapy beneficially alters LDL subclass distribution with an increase in LDL size and a decrease in LDL particles (198).

 

In children, treatment with fibrates in a single small randomized trial (n=14) and 3 case series (n=7, n=17, n=47) was associated with significant TG lowering by as much as 54% with an associated 17% increase in HDL-C (199-202). One child was thought to have myositis on clinical grounds with no lab changes and there were mild, transient elevations in liver enzymes in 2 subjects but no other potentially adverse effects were reported. There are no long-term trials of fibrates in children and no studies of the vascular or clinical response to treatment. 

 

Summary

 

Evidence for drug therapy of moderate hypertriglyceridemia or CD in childhood is limited.  Statins improve LDL-C subpopulation characteristics on NMR analysis in children with FH (184,185). There is substantial evidence that statins as a group are safe and effective for long-term treatment of hypercholesterolemia beginning in childhood (189).  Despite concern about hepatic side-effects, current evidence indicates that statins are safe in patients with NAFLD and may improve liver function tests (203).  Statin therapy therefore appears to be the logical theoretical choice for treatment of CD if drug therapy is needed. The possibility of eicosapentaenoic acid (EPA) as secondary treatment for adults with established CVD and residual risk due to high TGs represents a theoretical treatment option but results are controversial and there is no reported experience for use in youth (204). There are no current trials of any other medication in children with combined dyslipidemia.  A large body of evidence indicates that lifestyle therapy is highly effective for management of CD in youth and that a decision to initiate drug treatment should only be made in an adolescent with multiple additional high-level risk factors after intensive long-term efforts at lifestyle modification.

 

CONCLUSION

 

In youth, CD is a prevalent, highly atherogenic lipid disorder, almost always associated with obesity. High TGs and CD are strongly associated with a complex of related risk factors including visceral adiposity, insulin resistance/T2DM, NAFLD, and the metabolic syndrome complex which significantly exponentiate risk for CVD.  Primary therapy is lifestyle change focused on weight loss, change in diet composition, and increased activity.  These interventions are usually very effective. Drug therapy is only rarely needed in the multiple risk adolescent with CD with statin medications as the theoretical drug of choice.

 

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Pediatric Endocrinology- A Tropical Perspective

ABSTRACT

 

Pediatric endocrine disorders are frequently seen in tropical countries. While broadly the spectrum of pediatric endocrine disorders in the tropics is not entirely different from that seen in other parts of the world, some aspects of these disorders are unique to the tropics. Many pediatric endocrine disorders are underreported from the tropics, presumably because of limited access to medical care in terms of both diagnostic and therapeutic facilities. Lack of formal training of pediatricians and physicians in pediatric endocrinology may be a contributor. Some conditions such as exogenous Cushing syndrome are seen very frequently in tropics because of easy access and unrestrained use of glucocorticoids by quacks/ faith healers. Malnutrition is an important contributor to short stature in many tropical countries where a large section of the population is living in abject poverty. Iodine deficiency disorders are seen in many countries despite iodine fortification of salt or other edible items. Lack of universal screening for congenital hypothyroidism often leads to late detection of this disorders contributing to significant morbidity and mortality. Vitamin D deficiency and nutritional rickets is rampant even in areas where sunlight is abundant year around. Since most of the pediatric endocrine disorders are easily treatable and can have severe consequences when diagnosis or treatment is delayed, increasing the awareness of these disorders in the healthcare workers in the tropics is necessary.

 

PITUITARY DISEASE

 

The common pituitary disorders reported from the tropics include craniopharyngiomas, growth hormone deficiency, pituitary adenomas (including prolactinomas), and Cushing’s disease.

Craniopharyngiomas

Craniopharyngiomas are common suprasellar tumors in childhood.  A retrospective analysis of 62 pediatric (onset <18 years) craniopharyngiomas was reported from a tertiary care hospital from India. The presenting features included central diabetes insipidus (6.5%), central hypothyroidism (43.5%), secondary adrenal insufficiency (32%), and delayed puberty (24%). On follow up 90% had some form of anterior pituitary deficiency and 22.6% developed obesity. GH therapy was given to 14% of cases.  Incomplete  surgical removal was frequent and radiotherapy was used in many cases (1). Another study from Egypt reported 137 patients with pediatric craniopharyngiomas. They were treated with surgery alone (65), radiotherapy after surgery (71), or surgery for Ommaya insertion with intracystic interferon injection (1). Subtotal resection was seen in 58 patients (42.33%) while 48 cases (35.04%) had gross total resection/near total resection. The  5-year progression-free survival (PFS) was 52.3%, ( surgery alone 34.49% and  radiotherapy after surgery  72.25% ) (2). Both craniopharyngiomas and gliomas were most common supratentorial pediatric brain tumors in Nigeria (3). In a study of 37 pediatric craniopharyngiomas who underwent surgery, gross total resection was possible in 43.2%, near total resection in six patients 16.2%.  and subtotal resection (STR) in 40.5%. The recurrence-free survival rate was 81.1% and 70.3% at 5- and 10-year follow-up, respectively. Diabetes insipidus, anterior pituitary hormone deficits, and obesity were common in follow up (4). In a study from Pakistan, craniopharyngiomas were 14.3% of the reported pediatric intracranial tumors (5). Another study from Pakistan has reported the use of gamma knife radiosurgery in craniopharyngiomas. The patients included 17 children. Nearly 80% of the patients achieved tumor control with gamma knife (6). An uncommon variant called papillary craniopharyngiomas  has been reported in 13 cases from Pakistan (7).

Isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD) are the two presentations of growth hormone (GH) deficiency. The mutations involved in IGHD are GH1 and GHRHR while CPHD is associated with mutations in transcription factor genes PROP1, POU1F1, and HESX1. Genetic analysis performed in 51 patients with CPHD at a tertiary care center in India reported that 10 (20%) patients had POU1F1 and PROP1 mutations and of these 5 were novel and 2 previously reported. No mutations were identified in HESX1 (8).

A study of growth hormone deficient patients from South India reported that smaller pituitary size was associated with worse height deficits and bone age delays. However, they had a  better response to GH therapy (9).

Children with IGHD had several biochemical and cardiac parameters that may be associated with an increased CVD risk in later life. This included higher waist-hip-ratio, total cholesterol, non-high-density lipoprotein-cholesterol, serum homocysteine, C-reactive protein (CRP), and pro-brain natriuretic peptide (pro-BNP). Left ventricular mass (LVM) and interventricular septal thickness were significantly lower (10).

A novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) was identified by Sanger sequencing carried out in 160 trios and 100 controls. In vitro studies showed that the this mutation codes for a truncated protein with reduced transactivation capacity on downstream targets like  growth hormone (GH) and prolactin (PRL) (11).

Laron dwarfism first reported among Israeli Jewish children is a rare disorder characterized by low IGF-1 and high GH levels. A case series of nine such cases (6 male, 3 female) was reported from South India. The short stature was extreme with a mean height Z score of 7.7 (SD 0.8).  Clinical features included characteristic facial features, microcephaly, micropenis and developmental delay. All children had typical hormonal profile of low IGF-1 and elevated GH (12). Laron syndrome has been reported from Africa and South America (13)(14)(15).

 

Pituitary Adenomas

While adult pituitary tumors are relatively common, pediatric pituitary adenomas (PPA) are less common. A retrospective study of 74 cases of PPA was published from a center in North India. The median age was 15 years and 42 % were females. Headache and menstrual abnormalities were common presentations. Corticotroph adenomas (32.4%) and somatotropinomas (25.7%) were among the common types. TSHoma and pituitary blastomas were very few. In 81% cases, transsphenoidal surgery was performed while adjuvant medical management and radiotherapy was required in 25% and 18% respectively. Remission rates in Cushing's and acromegaly were 62.5% and 57.8%, respectively, and post operative hormone deficits were seen in 33% (16).

Giant prolactinoma (GP) are rare pituitary tumors in childhood and adolescence. A series of 18 cases of GP has been reported from India. GP constituted 20% of pediatric prolactinomas at this center. The authors conducted a systematic review including these 18 and 77 other cases from the literature. They found a male predominance with pubertal arrest/delay. Dopamine agonist (DA)  monotherapy showed good results as monotherapy (17).

 

Cushing’s Disease

Cushing’s disease is an important cause of hypercortisolism in children. It is caused by an ACTH secreting pituitary adenoma. A retrospective study of 48 pediatric cases of Cushing’s disease who underwent transsphenoidal adenectomy between 1998 and 2008 was published from India. Weight gain, round facies, and short stature were the most common clinical manifestations. Low dose dexamethasone suppression test and midnight cortisol showed 100% sensitivity for establishing hypercortisolism, while midnight ACTH had 100% sensitivity for confirming ACTH dependence. Magnetic resonance imaging and unstimulated BIPSS were used to confirm Cushing’s disease. Post surgical remission was 56% after first transsphenoidal adenectomy with higher remission rate of 75% in those with microadenoma. Eight patients were given radiotherapy and four of these achieved remission (18).

GROWTH AND PUBERTAL DISORDERS

Short stature and delayed puberty are commonly seen in children visiting pediatric endocrine clinics in the tropics.

Short Stature

Malnutrition, systemic illnesses, endocrine disorders, and syndromic disorders are among the major causes of short stature in the tropics.

 

MALNUTRITION

Malnutrition in early childhood is an important cause of short stature in tropical counties. The role of early childhood undernutrition on physical growth and cognitive achievement was assessed in a nationwide population-based cohort study in India. Data on undernutrition was taken from Human Development Survey (IHDS) in 2004 to 2005 while the outcomes on physical and cognitive outcomes during preadolescent (8 to 11 years) years was assessed in 2011 to 2012. The study assessed 7868 children and 4334 were undernourished. Undernourished children had 1.73 times increased odds of short stature. It was associated with decreased odds of achieving a higher reading and arithmetic outcomes. The findings were worse in female children.(19)

SYNDROMIC SHORT STATURE AND OTHER CAUSES

Noonan syndrome (NS), an autosomal dominant disorder, is caused by mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. A large series of 363 patients with Noonan’ syndrome was published from India. The exons of PTPN11 gene were sequenced in all patients. Congenital cardiac anomalies (mostly right sided defects) were present in 84% of patients. The downward-slanting palpebral fissures, hypertelorism, low-set posteriorly rotated ears, short stature, pectus excavatum, and unilateral or bilateral cryptorchidism were common clinical findings. The most common variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients (20). Similar findings were reported from a study in Morocco (21). Noonan syndrome has been described in Latin America, Africa and other countries in Asia. The facial characteristics of Noonan syndrome cases worldwide  were similar to those of European descent (22).

Achondroplasia is a skeletal dysplasia that is a common cause of disproportionate short stature. In a study of forty cases with disproportionate short stature from India , achondroplasia was the most common skeletal dysplasia with  c. 1138 G>A, p. Gly380Arg mutation seen in all cases (23). Achondroplasia has been reported from Pakistan and Africa also (24,25).

Idiopathic short stature (ISS)refers to the short stature where all the conventional clinical and biochemical work up is normal. Genetic studies in 61 patients with ISS in India showed that four patients had a heterozygous variant in SHOX gene while two had novel, likely pathogenic variants, in the IGFALS gene (26).

Thalassemia is a frequent cause of short stature and pubertal delay. Inadequate chelation therapy and lack of awareness among treating physicians on endocrine complications lead to higher prevalence of undiagnosed endocrine issues in these children. In a study from central India, short stature (88%), delayed puberty (71.7%), hypothyroidism (16%), and diabetes mellitus (10%), were reported in children with thalassemia (88).

Puberty

 

Pubertal disorders can be broadly classified as delayed puberty and early (precocious puberty). Secular trends of gradual reduction in the age of puberty have started becoming apparent in tropics.

 

The age of normal puberty has shown a decline in many tropical countries- a trend which mimics that witnessed in the developed world decades earlier. Data regarding normal puberty from Egypt suggests that in girls with BMI ≥85th percentile all pubertal stages started earlier as compare to girls with BMI less than 85th centile. No such association between BMI and pubertal stage was noticed in males (27). A decline in the age of pubertal maturation of girls in Nigeria was also reported. The median age at beginning of breast maturation (B2) and menarche were 9 and 12 years respectively. The age at menarche was significantly associated with overweight/obesity and high social class (28). Similar findings have been reported from India where a study of 2010 school girls reported that median age of thelarche and menarche was 10.8 and 12.4 years with obese girls showing a six month earlier onset of thelarche and menarche when compared to those with normal BMI (29). Similar findings were reported from Western India (30). School girls in Riyadh, Saudi Arabia also had earlier onset of puberty similar to that seen developed countries (31).

DELAYED PUBERTY

Delayed puberty is a common pubertal disorder. It may be a normal variant such as constitutional delay in growth and puberty or represent a pathology. Pathological causes are classified as hypogonadotropic or hypergonadotropic hypogonadism. In a retrospective study of 136 patients with delayed puberty from Sudan, permanent or functional hypogonadotropic hypogonadism was seen in 37.5 and 36% while hypergonadotropic hypogonadism was seen in 11.7%. Constitutional delay in growth and puberty was present in 14.7%. Type 1 diabetes and celiac disease were common systemic illnesses (32). A study of 42 cases of delayed puberty from India (19 boys, 23 girls) underlying systemic illnesses were the dominant cause of pubertal delay in girls (11/23) while the major cause in boys were endocrinopathies (6/19). Malnutrition, chronic infections, and anemia were common systemic illnesses (33).

An unusual association of hypopituitarism along with Turner syndrome was reported in six Tunisian patients (34).  A study of 11 Turner syndrome patients was reported from Cameroon, seven had monosomy while four had mosaic Turner syndrome. Most of these had presented with delayed puberty or short stature. Other clinical features were short neck, forearm carrying-angle deformity, a low hairline, and a webbed neck. Horse shoe kidney was found in two cases but none had cardiac abnormalities. The average age at diagnosis was 18.4 years indicating a delay in the diagnosis (35).

Differentiation between CDGP and hypogonadotropic hypogonadism is challenging in tropical countries. Most patients do not have regular height measurements and estimation of growth velocity in the years preceding to the presentation is often not possible. GnRH stimulation test has been employed but has limited utility because of significant overlap in the hormonal levels between the two groups. GnRHa-stimulated inhibin B (GnRH-iB) has been developed as a convenient test to differentiate between CDGP and hypogonadotropic hypogonadism. A cut-off value of 113.5 pg/ml in boys and 72.6 pg/ml in girls could  predict  spontaneous pubertal onset with  100% sensitivity and specificity (36).

PRECOCIOUS PUBERTY

Precocious puberty is a common pubertal disorder. It is classified as central precocious puberty (caused by premature activation of the hypothalamic-pituitary-gonadal axis) or peripheral precocious puberty (due to secretion of gonadal steroids from other causes without activation of the hypothalamic-pituitary-gonadal axis).

A retrospective analysis of 55 children (36 girls) with precocious puberty was reported from India. Central precocious puberty occurred in 62% (34 cases, out of which 19 were idiopathic) while peripheral precocious puberty was found in 14 children. The  commonest cause of peripheral precocious puberty  was congenital adrenal hyperplasia (46%) (37). A rare case of precocious pseudopuberty due to a virilizing adrenocortical carcinoma progressing to central precocious puberty after surgery has also been reported (38). Idiopathic precocious puberty responds well to GnRH analogue therapy as reported from a series for India (39).

There appears to be an increase in the incidence of central precocious puberty especially in girls in the COVID-19 lockdown in India as compared to the pre-lockdown period (40).

DISORDERS OF BONE AND MINERAL METABOLISM

Vitamin D deficiency and nutritional rickets are very common in tropics.  Primary hyperparathyroidism and less common forms of rickets like vitamin D resistant and hypophosphatemic rickets also occur.

 

Vitamin D Deficiency And Nutritional Rickets

Tropical countries have high prevalence of nutritional rickets. The human body can generate vitamin D in the skin from sunlight. Although tropical countries get abundant sunlight, vitamin D deficiency (VDD) is common. Harsh summers limit sunlight exposure in many tropical countries. Adequate sunlight exposure was found in only 27 % neonates in Ethiopia (41). In some countries, atmospheric pollutions limits sunlight penetration in winters (42). Darker skin color with high melanin content, different socio-cultural factors, and genetic variation also contribute to vitamin D deficiency. Infants are at a high risk of vitamin D deficiency which could be due to low vitamin D content in breastmilk, and inadequate vitamin D content of complementary foods and maternal vitamin D deficiency. Routine vitamin D supplementation  at a dose of 400 IU per day till 12 months of age in breastfed infants has been recommended in India (43). Oral vitamin D  supplementation of mothers during lactation has been shown to reduce risk of vitamin D deficiency in infants at 6 months of age by almost 95% (44). Nationwide data from India suggests that prevalence of vitamin D deficiency defined as serum 25OHD <12 ng/ml was 14% (1-4 years), 18% (5- 9 years), and 24%  (10-19 years) (43). However, VDD  prevalence ranging from 60-87 % has been reported in low birth weight infants and 71-88% in normal birth weight infants in Delhi, India (45) (46). In Uganda, a study found that prevalence of VDD in LBW infants was 12.1 % but most of these had received supplemental vitamin D (47). A larger study including five countries from sub-Saharan Africa, showed that prevalence of vitamin D deficiency in children aged 0-8 years was 7.8% (48). Countries closed to the Equator had less VDD. In India, a study from the state of Kerala reported a VDD prevalence of 11.1%. The reasons implicated for this relatively lower prevalence were latitude and fish intake in the diet (49). Data suggests that in several African countries nutritional rickets is common although VDD prevalence is not high. Children requiring surgical correction of deformities resulting from rickets in Malawi, Africa had lower dietary calcium intake but VDD was uncommon (50). Low dietary calcium intake has been implicated as a causative factor for rickets in Studies from Nigeria and Bangladesh (51,52). Serum alkaline phosphatase has been explored as a low-cost biochemical test to screen for nutritional rickets in children in Nigeria. A cut off of ALP > 350 U/L has been proposed in one study (53).Severe vitamin D deficiency can present as osteomalacic myopathy in children and adolescents (54).

For the treatment of  rickets and vitamin D deficiency, oral cholecalciferol in a daily dosing schedule (2000 IU below 1 year of age and 3000 IU in older children) for 12 weeks has been recommended by some Indian guidelines (43). However, compliance issues are common in underprivileged populations. When compliance to daily dosing cannot be ensured, this guideline has suggested intermittent regimen provided the child is above 6 months of age. Sunlight exposure was shown to be inferior to oral vitamin supplementation (400IU/day) in preventing rickets or vitamin D deficiency in infants in India (55). A single intramuscular dose of 600,000 IU of vitamin D has shown to be safe and effective for treatment of nutritional rickets in India (56).

Primary Hyperparathyroidism

Pediatric primary hyperparathyroidism (PHPT)has been reported in two studies from India. George et al performed a retrospective analysis of 15 children and adolescents with PHPT (age <20 yr.) between 1993 and 2006. The mean age was 17.7 (range 13-20 years) with 80% of patients being female. Clinical features included bone pain, proximal myopathy, bony deformities, fractures, palpable osteitis fibrosa cystica, nephrolithiasis, and acute pancreatitis. No cases had evidence of multiple endocrine neoplasia. Nearly a third of the cases developed post-operative hungry bone syndrome occurred in 33.3%. Histology was suggestive of parathyroid adenoma in all cases (57). Sharanappa et al reported retrospective data (September 1989-August 2019) of 35 pediatric PHPT patients (< 18 years) who underwent parathyroidectomy. The mean age was 15.2±2.9 years and with male to female ratio of 1:1.9. Skeletal manifestations were seen in 83% while renal manifestations occurred in 29%. Parathyroid adenoma was present in 91.4% patients, whereas the remaining had hyperplasia. Except one patients all others had  hungry bone syndrome in postoperative period (58). Adolescent PHPT can present as posterior reversible encephalopathy syndrome (59). Neonatal severe hyperparathyroidism is a rare disorder. One such case has been reported from India (60).

 

Other Forms Of Rickets

A case series of 36 patients with refractory rickets published from India reports that renal tubular acidosis (63%), vitamin D dependent rickets (14 %) (VDDR I in 2 and VDDR II in 3 patients), chronic renal failure (11%), hypophosphatemic rickets  (6 %), and chronic liver disease (6%) were common causes (61). Pseudohypoparathyroidism may also present with bony deformities resembling rickets (62). Hereditary vitamin-D resistant rickets was reported in eight patients in Tunisia. Two mutations in vitamin D receptor gene were found: p.K45E (5 patients with alopecia) and a novel p.T415R mutation located in the ligand-binding domain.

X linked hypophosphatemic rickets is the most common cause of phosphopenic rickets. It can be caused by loss of function mutations in the PHEX gene which leads to an increase in the phosphaturic hormone fibroblast growth factor-23 (FGF-23). Two novel mutations in the PHEX gene has been reported from two families from India (63). A family suffering from XLH has been reported from Pakistan (64). Idiopathic tumoral calcinosis (ITC) refers to the deposition of calcium hydroxyapatite crystals or amorphous calcium usually in juxta-articular tissue in a tumor-like fashion. ITC has been reported in  an 8-year-old child who had the symptoms  at 4 years of age (65).

THYROID

Common thyroid disorders in pediatric age group include hypothyroidism, iodine deficiency disorders, thyroiditis, and thyroid cancer

Congenital Hypothyroidism

Congenital hypothyroidism can be a devastating disease if not diagnosed and treated on time. Congenital hypothyroidism is much more common in tropical countries as compared to developed world. The prevalence in India is estimated to be one in 1000-1500 births (66). The Indian Society for Pediatric and Adolescent Endocrinology (ISPAE) has published guidelines on  screening, diagnosis, and management of congenital hypothyroidism (66,67). High prevalence of CH has been reported from Sri Lanka as well as Iran (68,69).  A cut off of ≥20 mIU/L for capillary TSH screening for CH  beyond 24 hours of life has been proposed in the India for deciding on recalling the patient for further workup while a repeat capillary sample was advised for TSH values between 10 and 20  mIU/L (70).

Despite the above research, most tropical countries do not have universal screening for CH. This contributes to significant morbidity due to this potentially treatable condition.

Iodine Deficiency Disorder

Iodine deficiency disorders are among the top causes of thyroid disease worldwide. Several tropical countries are affected by IDD. India and Pakistan have both initiated fortification of common salt with iodine. This measure has been successful in reducing total goiter rate in children, indicating an improvement in iodine status. However, several underprivileged populations in both countries have evidence of iodine deficiency (71,72). Africa also had a high prevalence of mild to moderate iodine deficiency but several iodine fortification programs have been started which resulted in improvement in the overall iodine status. Some high risk populations such as pregnant females may still face iodine deficiency (73).

Thyroiditis

A case series of 97 children with Hashimoto’s thyroiditis aged 5-12 years has been reported from India. The children were followed up for a six-month period.  Goiter was seen in 89 while eight had an atrophic form. The mean age was 9.9 years and the male to female ratio was 1:5.4. Overt hypothyroidism was present in 73.4% while hyperthyroidism was seen in 3.1%.  13.2 % were subclinical hypothyroidism and 10.3% were euthyroid. A large percentage of subclinical hypothyroid and euthyroid children developed overt hypothyroidism in the 6 month follow up. (79)

It is possible that the prevalence of autoimmune thyroiditis has increased after iodine fortification of the diet. In a case control study, 43 children with goiter and autoimmune thyroiditis were compared with 43 children with euthyroid goiter without autoimmune thyroiditis. Urinary iodine concentration (UIC) was significantly higher in children with autoimmune thyroiditis. A positive correlation between UIC and antimicrosomal antibody titers was found. A UIC  ≥300 μg/L  was strongly associated with autoimmune thyroiditis (80).

Hypothyroidism

 

Acquired hypothyroidism in most tropical countries is now predominantly autoimmune, barring those where severe iodine deficiency is still prevalent.

The control of hypothyroidism with levothyroxine therapy in children in tropical countries is often poor because of poverty, lack of proper advice, and reduced access to laboratory testing. Research work on treatment of hypothyroidism is being done.  Both bedtime and early morning intake of thyroxine had equal efficacy in maintaining a normal TSH in children with hypothyroidism in a randomized controlled trial from North India (78).

Van Wyk Grumbach syndrome is a syndrome characterized by prolonged untreated hypothyroidism, short stature, and isosexual precocious puberty. This syndrome is considered to be rare with very few cases reported so far in recent times. However, many cases of Van Wyk Grumbach have been reported from tropical countries like India and Sri Lanka (74,75,76). A case series of this rare syndrome has been reported from Pakistan (77). This illustrates that availability of trained physicians as well as laboratory facilities is still a challenge in tropical countries.

Hyperthyroidism

Pediatric hyperthyroidism has been reported in the tropics. Graves’ disease is the most common cause of pediatric hyperthyroidism. The factors differentiating pediatric Graves from adult disease are predominance of neuropsychiatricsymptoms, gradual and often insidious onset, and absence of infiltrative ophthalmopathy.

In a seven-year period, 24 children with hyperthyroidism were reported in a study from India.  Twenty of these had Graves’ disease while one had toxic nodular goiter and one had neonatal Graves’ disease while the remaining two were factitious. Behavioral problems, excitability, hyperkinesis, and irritability were most common symptoms. Ocular involvement was present in 85% while 30 % had cardiac involvement. Goiter was noted in 18 out of 24 cases. Carbimazole was used for treatment and remission occurred in seventeen cases (81). Neonatal thyrotoxicosis has been reported from India (82).

A case of a three and a half-year-old boy who had an  autonomous functioning thyroid nodule which was cured by radioiodine ablation has been reported from India (83). Radioiodine therapy has been used for pediatric and adolescent Graves’ disease. Carbimazole therapy does not appear to influence the outcome of radioiodine therapy (84). Thyroid storm precipitated by empyema thoracis has been reported in a 16 year old girl (85).

Thyroid Cancer

Thyroid cancer is not common in pediatric populations and usually occurs as papillary carcinoma (PTC). A publication from a oncology center in India reports that pediatric differentiated thyroid cancer has high rates of extrathyroidal involvement as well as lymph node and distant metastasis (86). These findings however are not unique to tropical countries as similar profile has been reported from other parts of the world. Pediatric PTC often do not have TERT  promoter mutations and have a lower prevalence of BRAFV600E mutation as reported in a study from India (87). Globally, the mortality rates of pediatric PTC are similar to that of adult PTC. The data on survival in pediatric PTC from tropical countries is limited.

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Calcium and Phosphate Homeostasis

ABSTRACT

 

Calcium and phosphate are critical to human physiology (e.g., neuromuscular function) and are also needed for skeletal mineralization.  An understanding of calcium and phosphate metabolism is required for the clinician to evaluate disorders of the levels of calcium and phosphorus as well as metabolic skeletal disorders.  In this chapter, we review calcium and phosphate homeostasis including the critical organs involved (skeleton, parathyroids, GI tract, kidneys etc.) as well as the hormones (PTH, vitamin D, FGF23, calcitonin) that regulate calcium and phosphate.

 

INTRODUCTION

 

Understanding the physiology of calcium and phosphate homeostasis is needed to manage patients with abnormalities of this homeostatic system. Disorders of calcium, phosphate, and skeletal metabolism are among the most common group of diseases in endocrinology (1). They can involve abnormalities in the serum concentrations of the two minerals, especially calcium; abnormalities of bone; and abnormalities of the major regulating organ systems, especially the parathyroid gland, kidneys and gastrointestinal (GI) tract (Table 1). The serum calcium concentration can be abnormally high, as in malignancy and primary hyperparathyroidism, or abnormally low as it is in renal failure and hypoparathyroidism. The skeleton can have low bone density, as occurs in osteoporosis and osteomalacia, or high bone density as Paget’s disease of bone, osteopetrosis, and other osteosclerotic disorders. The GI tract can exhibit low calcium absorption, as in malabsorptive states, or high calcium absorption, as in vitamin D intoxication and the milk-alkali syndrome. The kidneys can under-excrete calcium, as occurs in some hypercalcemic disorders; over-excrete calcium, as in some patients with nephrolithiasis; under-excrete phosphorus, as in renal failure and defects in fibroblast growth factor 23 (FGF23) action; and over-excrete phosphorus, as in some renal tubular disorders and renal phosphate wasting due to excess FGF23 and other phosphatonins. Corresponding events occur for magnesium, but they will not be discussed in this chapter. The goal of this chapter is to discuss the normal regulation of bone and mineral metabolism in order to provide the clinician a basis for diagnosis and management of patients with the common disorders that involve this homeostatic system.

 

Table 1. Regulation of Calcium and Skeletal Metabolism

Minerals

   Calcium (Ca)

   Phosphorus (P)

   Magnesium (Mg)

Organ Systems

   Skeleton

   Kidney

   GI tract

   Skin

   Other

Hormones

   Calciotropic hormones

   Parathyroid Hormone (PTH)

   Calcitriol (1,25(OH2)D)

   PTH-related Protein (PTHrP)

   FGF23 and other phosphatonins

   Calcitonin (CT

Other hormones

   Gonadal and adrenal steroids

   Thyroid hormones

   Growth factor and cytokines

 

As detailed in other chapters, disorders of mineral and skeletal metabolism can be due to a primary disease of one of the involved organ systems, as in primary hyperparathyroidism due to a tumor of one or more parathyroid glands; secondary hyperparathyroidism, due to a compensatory response of the parathyroid glands to a low serum calcium, low vitamin D, calcium malabsorption, kidney disease, etc.; perturbations in serum calcium due to malignancy and bone metastases; and the complex mineral and skeletal complications of renal failure. A basis for understanding the pathogenesis of the primary and secondary diseases of bone and its minerals that are discussed in this text is an appreciation of the interplay among hormones, minerals, and organ systems that regulate normal bone and bone and mineral metabolism (Figure 1).

 

The skeleton is the reservoir of calcium for many physiological functions, and it serves a similar but not so unique role for phosphorus and magnesium (Table 2) (2,3). Skeletal calcium is controlled through the regulatory pathways of the gastrointestinal (GI) tract and the kidneys, and in bone by the osteoblast, the bone-forming cell, and the osteoclast, the bone-resorbing cell. Calcium reaches the skeleton by being absorbed from the diet in the GI tract. Unabsorbed calcium passes into the feces, which also contains the small amount of calcium secreted into the GI tract. Minor losses occur through perspiration and cell sloughing. In pregnancy, substantial losses can occur across the placenta to the developing fetus and in the postpartum period through lactation. Absorbed dietary calcium then enters the extracellular fluid (ECF) space and becomes incorporated into the skeleton through the process of mineralization of the organic matrix of bone, osteoid. ECF calcium is also filtered by the kidney at a rate of about 6 grams per day, where up to 98 percent of it is reabsorbed (Figure 1).

 

Figure 1. Schematic Representation of Calcium and Skeletal Metabolism. Abbreviations: A, absorption; S, secretion; ECF, extracellular fluid; GF, glomerular filtration; TR, tubular reabsorption. The dark vertical line between bone and ECF represents bone surface and bone-lining cells. Shaded area represents labile skeletal calcium. The various calcium compartments are not to scale. See text for discussion. (see Acknowledgements).

 

The major regulation of bone and bone mineral metabolism results from the interactions of four hormones – parathyroid hormone (PTH), vitamin D (VD), fibroblast growth factor 23 (FGF23) and to a much lesser extent calcitonin (CT) – at three target organs – bone, kidneys, and GI tract – to regulate three bone minerals – calcium, magnesium, and phosphorus. Other hormones also play a role, and skin is a participating organ system (Table 1). Understanding the normal regulatory mechanisms of this system will aid the clinician in evaluation and management of disorders of mineral metabolism (1-3).

 

CELLULAR AND INTRACELLULAR CALCIUM AND PHOSPHORUS METABOLISM

 

Physicians are most aware of the clinical status of calcium and skeletal metabolism in the patient as revealed by the concentrations of these minerals in biological fluids, especially blood and urine, and by the structural integrity of the skeleton (1). The actions of the calcemic hormones to regulate mineral concentrations in biological fluids are well understood at the target organ level. However, less well understood are the cellular and intracellular mechanisms that underlie the clinically important phenomena.

 

Both calcium and phosphorous, as well as magnesium, are transported to blood from bone, renal, and GI cells, and visa versa (4-6). These transport mechanisms can be through cells (transcellular) and around cells (paracellular). The cellular transport is mediated by the membrane structures illustrated in Figure 2 and by binding transport proteins (7,8). The paracellular transport is generally passive and mediated by mineral gradients. These mechanisms also involve corresponding co-transportation and exchange-transportation with other ions, notably sodium, potassium, chloride, hydrogen, and bicarbonate, some of which are powered by ATP hydrolysis. Similar mechanisms allow for the intracellular distribution of calcium, where it partitions primarily between the mitochondria and cytosol.

 

The details of the regulation of these cellular and intracellular mineral transports are not as well understood as are the whole organ mechanisms that they effectuate. However, some evidence along with inferences lead to the tentative clinical conclusion that changes in ambient concentrations of mineral in extracellular fluids are mirrored by corresponding intracellular changes and redistribution (Figure 2).

 

Figure 2. Schematic representation of cellular transport of bone minerals. The model can be applied to transport of calcium, magnesium, and phosphorus for cells of the renal tubules, gastrointestinal tract enterocytes, and bone cells. The mineral transport can be with (downhill) or against (uphill) a gradient. Lumen refers to GI and renal tracts; for bone, it can refer to bone marrow, blood, and/or matrix space. The site of the indicated membrane transport structures is schematic. Microsomes designate other intracellular organelles such as secretory vesicles and endoplasmic reticulum. See text for details.

 

Figure 2 provides a simplified version of the cellular regulation of bone minerals metabolism and transport. Mineral homeostasis requires the transport of calcium, magnesium, and phosphate across their target cells in bone, intestine, and kidney. This transport can be across cells (transcellular) and around cells (pericellular). The pericellular transport is usually diffusional, down a gradient (“downhill”), and not hormonally regulated. Diffusion can also occur through cell channels, which can be gated. Transport across cells is more complex and usually against a gradient (“uphill”). This active transport is energized by either ATP hydrolysis or electrochemical gradients and involves membrane structures that are generally termed porters, exchangers, or pumps. Three types of porters have been described, uniporters of a single substance; symporters for more than one substance in the same direction; and anti-porters for more than one substance in opposite directions (7,8).

 

Once through the luminal cell membrane, the bone minerals can cross the cell into the extracellular fluid compartment, blood for enterocytes and urine for renal epithelium cells (5,6). For bone cells, the corresponding compartments are marrow and blood (1,2). For calcium, the transcellular transport is ferried by the interaction among a family of proteins that include calmodulin, calbindin, integral membrane protein, and alkaline phosphatase; the latter three are vitamin D dependent in their expression (6). Cytoskeletal interactions are likely important for transcellular transport as well. Exit from the cell is regulated by membrane structures similar to those that mediate entry. There do not appear to be any corresponding binding proteins for phosphorous, so diffusional gradients and cytoskeletal interactions seem to regulate its cellular transport.

 

The molecular details of the hormonal regulation of cellular bone mineral transport have not been fully elucidated. It is reasonable to hypothesize that PTH, vitamin D, FGF23, and CT, regulate these molecular mechanisms through their biological effects on the participating membrane structures and transport proteins. For the enterocyte, vitamin D enhances the movement of calcium into the cell through its stimulation of calbindin synthesis (6). For kidney tubules, PTH and FGF23 are the key regulators for the transport of calcium and phosphate (1,5,9). For bone, PTH and to a lesser extent CT are important regulators of cellular calcium and phosphate transport, while vitamin D provides appropriate concentrations of these minerals through it’s GI and perhaps renal actions (1-3).

 

It is important to note that these mineral translocations not only mediate the mineral metabolism represented in Figure 2, but also the cellular effects summarized in Table 3.

 

Table 2. Distribution of Calcium, Phosphorus, and Magnesium

TOTAL BODY CONTENT, G

% IN SKELETON

% IN SOFT TISSUES

Calcium                 1000

               99

                  1

Phosphorus            600

               85

                  15

Magnesium            25

                65

                 35

 

CALCIUM METABOLISM

 

Serum and extracellular calcium concentrations in mammals are closely regulated within a narrow physiologic range that is optimal for the many cellular functions. (1,2).  More specifically, it is the ionized component of serum calcium that is closely regulated, as it subserves the physiological functions of this divalent cation (Table 3). Ambient calcium is so close to its saturation point with respect to phosphates that deviations in concentrations of either can cause precipitation. Intracellular calcium, which serves as second messenger in many signal transduction pathways, is also tightly controlled, but at concentrations several orders of magnitude lower than extracellular calcium. Extraskeletal calcium accounts for only 1% of the total body calcium, as calcium is primarily sequestered in bone (Table 4-6). The average diet contains about 1 gm of calcium, but there are great variations. About 500 mg undergoes net absorption from the diet, and the unabsorbed and secreted components appear in the stool (Table 6-9). Approximately 10,000 mg/day is filtered at the glomerulus and most is reabsorbed by the renal tubules, with only a few hundred milligrams appearing in urine each day (Tables 10 and 11). The skeleton turns over about 250 mg/day of calcium, but there is wide variation. This turnover is attributed to a labile calcium pool near bone surfaces, but it is difficult to give anatomical assignment to either labile or non-labile calcium compartments. The turnover is mediated by bone-forming osteoblasts and bone-resorbing osteoclasts. In disease states, the turnover can be increased (e.g., hyperparathyroidism) or decreased (e.g., hypoparathyroidism) with corresponding changes in blood and urinary calcium. The primary calcium regulating hormones that control this homeostatic system are PTH and vitamin D, which act at bone, kidney, and GI tract to increase serum calcium and to a lesser extent calcitonin, which decreases bone resorption, but does not appear to have a major effect on serum calcium under normal circumstances (10) (Figure 1).

 

Table 3. Multiple Biological Functions of Calcium

Cell signaling

Neural transmission

Muscle function

Blood coagulation

Enzymatic co-factor

Membrane and cytoskeletal functions

Secretion

Biomineralization

 

Table 4. Distribution of Calcium

Total body calcium- 1kg

       99% in bone

       1% in blood and body fluids Intracellular calcium

               Cytosol

               Mitochondria

               Other microsomes

               Regulated by “pumps”

               Blood calcium – 10mgs (8.5-10.5)/100 mls

                       Non diffusible – 3.5 mgs

                       Diffusible – 6.5 mgs

 

Table 5. Bone Structure (cellular and non-cellular)

Inorganic (69%)

    Hydroxyapatite – 99%

          3 Ca10 (PO4)6 (OH)2

Organic (22%)

    Collagen (90%)

    Non-collagen structural proteins

           proteoglycans

           sialoproteins

           gla-containing proteins

     α2HS-glycoprotein

            Functional components

            growth factor

            cytokines

 

Table 6. Blood Calcium – 10mgs/100 mls (2.5 mmoles/L)

Non diffusible – 3.5 mgs

      Albumin bound – 2.8

      Globulin bound – 0.7

Diffusible – 6.5 mgs

       Ionized – 5.3

       Complexed – 1.2 mgs

                 bicarbonate – 0.6 mgs

                 citrate – 0.3 mgs

                 phosphate – 0.2 mgs

                 other

        Close to saturation point

                 tissue calcification

                 kidney stones

 

Table 7. Diet

Dietary calcium

        Milk and dairy products (1qt ~ 1gm) Dietary supplements

        Other foods

Other dietary factors regulating calcium absorption

        Lactose

        Phosphorus

 

Table 8. Calcium Absorption (0.4-1.5 g/d)

Fastest in duodenum

        15-20% absorption

Adaptative changes

         low dietary calcium

         growth (150 mg/d)

         pregnancy (100 mg/d)

         lactation (300 mg/d)

Fecal excretion

 

Table 9. Mechanisms of GI Calcium Absorption

Vitamin D dependent

Duodenum > jejunum > ileum

Active transport across cells

        calcium binding proteins (e.g., calbindins)

        calcium regulating membranomes

Ion exchangers

Passive diffusion

 

Approximately 50% of the total calcium in serum is ionized, with the rest bound primarily to albumin or complexed with counter-ions, including phosphates (Table 6) (1,2). The ionized calcium concentration averages 1.25 + 0.07 mmol/L and the total serum calcium concentrations range from 8.5 to 10.5 mg/dL. Since ionized calcium has the primary regulatory role, it is in turn the regulated component that maintains homeostasis. This regulation takes place through the complex interactions at their target organs of the primary calcium regulating hormones, parathyroid hormone (PTH) and vitamin D and its metabolites (Tables 4-11). Other hormones participate, most notably gonadal steroids.

 

Table 10. Urinary Calcium

Daily filtered load

10   m (diffusible)

        99% reabsorbed

Two general mechanisms

        Active – transcellular

        Passive – paracellular

Proximal tubule and Loop of Henle reabsorption

        Most of filtered load

        Mostly passive

        Inhibited by furosemide

Distal tubule reabsorption

        10% of filtered load

        Regulated (homeostatic)

                 stimulated by PTH

                 inhibited by CT

                 vitamin D has small stimulatory effect

                 stimulated by thiazides

Urinary excretion

50   – 250 mg/day

        0.5 – 1% filtered load

 

Table 11. Regulation of Urinary Calcium

Hormonal – tubular reabsorption

        PTH – decreases excretion (clearance)

        CT – increases excretion (calciuretic)

        1,25(OH)2D – decreases excretion

Diet

        Little effect

        Logarithmic

Other factors

        Sodium – increases excretion

        Phosphate – decreases excretion

        Diuretics – thiazides vs loop

                   thiazides – inhibit excretion

                   furosemide – stimulate excretion

 

Table 12. Other Routes of Excretion

Perspiration

Lactation

 

PHOSPHORUS METABOLISM

 

Phosphorus is more widely distributed than calcium and also serves a variety of biological functions (Table 2) (3,4). While most of phosphorus is skeletal as hydroxyapatite, 15 % is distributed among extraskeletal sites like phosphoproteins, phospholipids, and nucleic acids (Table 13). In blood, phosphorus exists as the phosphates, H2PO4G and HPO4=, but its concentration is measured as phosphorus, with a normal range of 2.5 – 4.5 mg/100 ml. The regulation is not as tight as it is for calcium, with substantial perturbations due to diet and alimentation.

 

Table 13. Phosphorus Metabolism

General

       Widely distributed

       Multiple biological functions

       Distribution

       Skeletal – Hydroxyapatite:

Ca(PO4)2 o Ca(OH)2

15% extraskeletal

                          Phosphoproteins

                          Phospholipids

                          Nucleic acids

Blood Phosphate:

H2PO4- and HPO4=

Concentration measured as phosphorus: 2.5 – 4.5 mg/100 ml

Regulation

        Not as closely as calcium

        Diet

        Alimentation

        Growth

        Diurnal rhythm

        Hormones

        Other factors

 

 

Table 14. Dietary Phosphorus

Most foods

1 gm per day – variable

Absorption

        Site – distal to duodenum

        Mechanism

               Calcium dependent

               Calcium independent

Regulation

         Diet – 70% absorbed

         Calciotropic hormones

                Vitamin D – increases

                CT – decreases

Other factors

         GH – increases

         Phosphate binders decrease

         Calcium – decreases

         Fecal – non-absorbed and secreted

 

Table 15. Urinary Phosphate

Major route of regulation

Related to diet 90% filtered (? protein binding)

Proximal tubule – 90% reabsorbed

        H2PO4- – active

        HPO4= – passive

Distal tubule – 10% reabsorbed

Regulation

        Diet

        Calciotropic hormones

                  PTH – increases excretion

                  CT – increases excretion

                  Vitamin D – decreases excretion

                   FGF23 and other phosphatonins increase excretion

                   Proximal renal tubular NaPi2a, NaPi2c

 

Dietary phosphorus comes from most foods, averaging about 1 gm per day (Table 14), with the most important sources being dairy products, grains, meats, and food additives (3,4). Absorption takes place at a site distal to duodenum and utilizes both calcium dependent and calcium independent mechanisms that can be active or passive. The most significant quantitatively is post-prandial passive absorption. Approximately 60-80% is absorbed primarily by a diffusional process without a significant saturable component; however, there is regulation by the calciotropic hormones, especially vitamin D, whose active metabolites increases absorption, while PTH and CT have only minor direct effects (6) (Tables 13 and 14). Calcium- and aluminum-containing phosphate binders as well as newer phosphate binders such as sevelamer, lanthanum carbonate, ferric citrate, and sucroferric oxyhydroxide can inhibit absorption and are used to do so in the treatment of the hyperphosphatemia associated with chronic kidney disease (11). Fecal phosphate comprises non-absorbed and secreted components (Table 14).

 

Renal phosphate reabsorption controls the concentration of phosphate in serum, and it is usually quantified as the tubular reabsorption of phosphorus and expressed as the renal phosphate threshold (TmP/GFR), which closely mirrors the normal range of serum phosphorus (5). Although the TmP/GFR can be measured, it is usually estimated by a nomogram from fasting measurements of serum and urinary phosphorus and creatinine. The proximal convoluted tubule reabsorbs about 75 percent of filtered phosphate, and most of the remainder is reabsorbed in the proximal straight tubule; the distal tubule segments may have a limited capacity for reabsorption, about 5 percent of filtered load (1,5).

 

An important role for FGF23 in phosphate metabolism has been elucidated (9). This glycoprotein product of osteocytes and osteoblasts promotes the renal excretion of phosphorus by decreasing expression of NaPi2a and NaPi2c resulting in decreased renal tubular reabsorption. The expression of FGF23 is up-regulated by serum phosphate and 1,25 dihydroxyvitamin D (9,12). 

 

SKELETAL METABOLISM

 

The metabolic function of bone is to provide a homeostatic mineral reservoir, primarily for calcium, but also for other minerals, especially magnesium and phosphorus (1-3). These bone minerals can be mobilized to maintain systemic mineral homeostasis. This metabolic function of bone prevails over its structural function in that calcium and other minerals are removed from and replaced in bone to serve systemic homeostatic needs irrespective of loss of skeletal structural integrity. Bone is also a depository for certain cytokines and growth factors that can be released upon bone resorption and can exert their effects locally and systemically; notable among these is TFG beta.

 

Bone consists of a mineral phase and an organic phase (Table 5) (2). The major component of the mineral phase is hydroxyapatite crystal and the major component of the organic phase is type 1 collagen which, with other bone proteins, comprises the osteoid matrix of bone. The organic components of bone are products of the osteoblast. Bone mineral is present in two forms in the skeleton. Hydroxyapatite crystals, represented by the formula Ca10(PO4)6(OH)2, are the major forms and occur in mature bone. Amorphous calcium phosphate comprises the remainder; it occurs in areas of active bone formation and matures through several intermediate stages to hydroxyapatite. The end result is a highly organized amalgam of protein, primarily collagen, and mineral, primarily hydroxyapatite, that has sufficient structural integrity to serve the mechanical functions of the skeleton. Upon completion of this process, the osteoblast becomes encased in bone and become an osteocyte. Mineralization can occur if there is a functionally adequate local concentration of these ions, if nucleators are present to promote crystallization, and if local inhibitors of mineralization are removed. While vitamin D is key to providing sufficient ambient concentrations of calcium and other minerals to promote mineralization of osteoid, this hormone does not seem to exert a direct regulatory effect on mineralization.

 

Cortical bone comprises approximately 80% of the skeleton and trabecular bone 20% (1,3). However, the surface area of cortical bone is only one fifth that of trabecular bone, so trabecular bone is metabolically more active than cortical bone, with an annual turnover (remodeling) of approximately 20% to 30% for the former and 3% to 10% for the latter. A given skeletal site in the adult is remodeled approximately every 3 years. Bone mass is acquired up to the fourth decade, with a rapid phase during adolescent growth. Much of peak bone mass is genetically determined. Women have approximately 30% less peak bone mass than men and experience an accelerated loss after the menopause. Both genders experience age-related loss of bone mass.

 

A role for the central nervous system role in fat and skeletal metabolism has received much recent experimental support. The adipocyte-derived hormone leptin appears to inhibit bone mass accrual through a brain pathway, while having direct peripheral anabolic effects on bone (13).  Furthermore, calcium metabolism has recently become linked to glucose metabolism through an appreciation of the biological effects of the osteoblast product, osteocalcin. When carboxylated, osteocalcin acts as a structural bone protein. However, in its undecarboxylated state, osteocalcin may act to regulate glucose metabolism by stimulating insulin secretion. Thus, two major metabolic pathways – calcium/bone and glucose/insulin – seem to be linked (14).

 

Table 16. Skeletal Metabolism

Bone cells

        Osteoblast

        Osteoclast

        Osteocyte

        Other – marrow elements

Bone structure

        Cortical bone

        Trabecular bone

        Mix

 

Bone Cells

 

Skeletal metabolism is regulated by bone cells and their progenitors (Figure 3). Among the population of bone cells are osteoblasts, osteocytes, osteoclasts, and lining cells (Table 16) (1-3). Monocytes, macrophages, and mast cells may also mediate certain aspects of skeletal metabolism. Marrow cells contribute to the population of bone cells. The osteoblast forms bone. Osteoblasts express receptors to many bone-active agents such as PTH, PTHrP, vitamin D metabolites, gonadal and adrenal steroids, and certain cytokines and growth factors. The major product of osteoblasts is type 1 collagen, which along with other proteins, forms the organic osteoid matrix that is mineralized to hydroxyapatite.

 

Figure 3. Schematic Representation of Osteoclast and Osteoblast Lineages. Schematic representation of the osteoclast (top) and osteoblast (bottom) lineages. The two lineages are distinct, but there is regulatory interaction among the cells (vertical arrows). Osteoclasts originate from a hematopoietic stem cell that can also differentiate into a macrophage, granulocyte, erythrocyte, megakaryocyte, mast cell, B-cell, or T-cell. Osteoblasts originate from a mesenchymal stem cell that can also differentiate into a chondrocyte, myocyte, fibroblast, or adipocyte. The terminology for these lineages is still evolving and is herein [over] simplified. Many intermediate steps and regulatory factors are involved in lineage development. (see Acknowledgements).

 

Osteocytes are osteoblasts that become encased in bone during its formation and mineralization and reside in the resulting lacuna (2,3). They comprise 90-95% of bone cells in the adult human skeleton (15).  The cells develop processes that communicate as canaliculi with other osteocytes, osteoblasts, and the vasculature. Osteocytes thus present acres of cellular syncytium that permits translocation of bone mineral during times of metabolic activity and can provide minute-to-minute exchanges of minerals from bone matrix.

 

Osteocytes are extremely important in normal skeletal homeostasis.  Their function is reviewed by Bonewald (15).   These cells are the likely transducers through their canaliculi of mechanical forces on bone and mediate the complex remodeling response to mechanical stimuli of the skeleton that causes appropriate changes in formation and resorption in response to skeletal loading. These cells produce sclerostin (SOST gene), which decreases bone formation and increases bone resorption (15).  Defects in sclerostin function either by a mutation in SOST or a mutation downstream to sclerostin cause the high bone mass disorders sclerosteosis and van Buchem disease respectively (15).  Osteocytes are also important endocrine cells that produce enzymes and hormones which affect bone mineralization and regulate phosphate such as Phosphate Regulating Endopeptidase X-Linked (PHEX), Dentin Matrix Acidic Phosphoprotein 1 (DMP1), Matrix Extracellular Phosphoglycoprotein (MEPE), and FGF23 (15).  Sclerostin antagonism represents a therapeutic target for osteoporosis therapy (16,17). FGF-23 antagonism with a monoclonal antibody to FGF23, burosumab, is now used to treat FGF23-mediated disorders causing renal phosphate wasting (18).

 

The osteoclast resorbs bone. It is a terminally-differentiated, large, multinucleated giant cell that arises from hematopoietic marrow precursors under the influences of hormones, growth factors, and cytokines (3). The osteoclast resorbs bone by attachment with a ruffled border through adhesion molecules and by secretion of hydrogen and chloride ions that dissolve mineral and lytic proteases, notably lysosomal proteases active at low pH and metalloproteinases and cysteine proteinases that dissolve matrix. One enzyme involved in bone resorption, (cathepsin K), has been an investigational target for treatment of osteoporosis (19).  In contrast to the receptor-rich osteoblast, the mature osteoclast has few receptors, but it robustly expresses the receptor for CT. After completing its function, the terminally-differentiated osteoclast undergoes apoptosis.

 

Bone-lining cells are flat, elongated cells that cover inactive bone surfaces. Their function is unknown, but they may be osteoblast precursors or function to clean up resorption and formation debris. Mast cells can be seen at sites of bone resorption and may also participate in this process. Cells of the immune system play a key role in bone metabolism, especially resorption, by their interactions with bone cells that are described later.

 

BONE GROWTH, MODELING AND REMODELING

 

Growth, modeling, and remodeling are important processes that allow the skeleton to play its many important roles (1). Bone grows and models under the influence of metabolic, mechanical, and gravitational forces during growth through adolescence, changing its size and shape in the process. Bone growth continues until approximately the third decade. Bone mass continues to increase until the fourth decade (Figure 4).

 

Figure 4. Peak Bone Mass. Schematic representation in relative units of normal skeletal development, demonstrating changes in bone resorption and formation. The crossover of formation/resorption occurs during the fourth decade. In osteoporosis, there is an accelerated loss of bone because of increased resorption and decreased formation. (see Acknowledgements).

 

Bone in adults renews itself by remodeling, a cycle in which old bone is first resorbed and new bone is then formed to replace it (1-3). Both cortical bone and trabecular bone remodel, but the latter is more metabolically active. Bone remodeling can be divided into several stages that include resorption by osteoclasts and formation by osteoblasts. Remodeling serves to repair skeletal microdamage and to improve skeletal strength in response to mechanical forces. Osteoclasts and osteoblasts communicate with each other during remodeling in a process that is referred to as coupling and mediated by local regulatory signals that are discussed subsequently. Coupling assures a balance of bone formation and bone resorption in the adult skeleton. The process of bone formation is thus balanced by the process of bone resorption.

Cortical bone is resorbed by “cutting cones” of osteoclasts that tunnel through it (2).  Trabecular bone remodels on its surface. Most remodeling occurs in trabecular bone and on the endosteal surfaces of cortical bone, with little periosteal remodeling. However, in diseases like hyperparathyroidism, subperiosteal resorption is activated. With aging, periosteal remodeling and expansion seems to compensate (mechanically) for bone loss at other sites.

 

Bone resorption is mediated by the osteoclast, a large, multinucleated cell that is molecularly equipped to dissolve both the mineral and organic phases of bone (1,3). The processes of osteoblast-mediated bone formation and osteoclast-mediated bone resorption can be assessed by measurement in urine and blood of bone markers. The markers of bone formation include osteoblast products (e.g., alkaline phosphatase and osteocalcin) and by-products of collagen synthesis such as procollagen-1 N-terminal peptide (P1NP).  Markers of bone resorption include osteoclasts products such as tartrate resistant acid phosphatase (TRAP) and by products of collagen breakdown such as such as N-terminal telopeptide (NTX) and C-terminal telopeptide (CTX) (20). Approximately 20% of adult bone surface is undergoing remodeling at any time. The homeostatic end-point of skeletal metabolism is to provide the appropriate amount of ambient calcium for the many biological functions that this ion serves, with the structural integrity of the skeleton taking second place. These metabolic activities of bone cells can release into blood and urine certain bone cell and matrix products that can serve as clinically useful markers of skeletal metabolism (Figure 5).

 

Figure 5. Schematic Representation of the Cellular and Skeletal Sources of Serum and/or Urinary Markers of Bone Formation and Bone Resorption. Abbreviations: BGP, bone gamma carboxyglutamic acid (GLA) protein (osteocalcin); PICP, C-terminal propeptide of type I procollagen; P1NP, N-terminal propeptide of ty pe I procollagen; BAP, bone-specific alkaline phosphatase; AP, alkaline phosphate; TRAP, tartrate-resistance acid phosphatase; NTX, N-terminal cross-linked telopeptide of type I collagen; CTX, C-terminal cross-linked telopeptide of type I collagen; OH, hydroxyproline glycoside; OL, hydroxylysine glycoside; PYD, pyridinoline (total, free); DPD, deoxypyridinoline (total, free). (see Acknowledgments).

 

RANKL, RANK, AND OPG

 

The elucidation of this pathway of molecular regulation has provided both a physiologic link among bone cell functions as well as a pathogenic link among cancer cells, the immune system, and bone cells in the regulation of the osteoclastic bone resorption that is the final cellular mediator of most cases of hypercalcemia (Figure 1) (21,22). The molecular participants in this pathway are the membrane-associated protein named RANKL (receptor activator of nuclear factor kappa B ligand,) a member of the tumor necrosis factor family of cytokines; its cognate receptor, RANK, and OPG (osteoprotegerin), a soluble “decoy” receptor for RANKL.

 

In the physiology of bone metabolism, RANKL is expressed on the surface of osteoblastic stromal cells (21). By binding to RANK, its receptor, on osteoclast precursors, RANKL enhances their recruitment into the osteoclastogenesis pathway in the physiology of bone metabolism. RANKL also activates mature osteoclasts to resorb bone. RANKL is considered to be a “coupling factor” through which osteoblasts regulate osteoclasts and bone formation is coupled to bone resorption. In the pathophysiology of hypercalcemia, many of the tumor cell types that are associated with cancer-stimulated bone resorption express a soluble form of RANKL, sRANKL. Furthermore, during the inflammation that can be associated with malignancy, activated T-lymphocytes also express increased amounts of RANKL, which can stimulate osteoclasts. The activated lymphocytes also express interferon gamma (INF), which opposes the effect of RANKL on osteoclast mediated bone resorption. The osteoclastic effects of RANKL can also be attenuated by its soluble decoy receptor, OPG, also produced by osteoblasts and tumor cells. Hypercalcemia results when these opposing regulatory interactions of RANKL, RANK, OPG, and INF allow osteoclastic activation to predominate (Figure 5).

 

These molecular participants in the interaction between bone cells, tumor cells, and the immune system are also regulated by several hormones, growth factors, and cytokines that mediate increased bone resorption, both physiologic and pathophysiologic. They include PTH, PTHrP, TNF, PGE2, vitamin D metabolites, IL-1, and TGF (22).

 

An antibody to RANKL (denosumab) decreases bone resorption, increases bone density, and decreases fractures and is FDA approved for treatment of osteoporosis (23).

 

Furthermore, defects in this system may cause bone diseases.  Loss of function mutations of OPG are responsible for the excess bone resorption in juvenile Paget’s disease and gain of function mutations of RANK cause familial expansile osteolysis and expansile skeletal hyperphosphatasia (24,25).

 

Figure 6. Schematic representation of the cellular and molecular mechanisms of the effects of OPG, RANK, and RANKL on skeletal metabolism. A variety of skeletal and non-skeletal cells can express several cell products [in brackets] that regulate the balance between osteoblastic bone formation (left) and osteoclastic bone resorption (right). They include PTHrP (parathyroid hormone related protein); 1, 25 Vit D (1, 25- dihydroxyvitamin D); prostaglandins, especially of the PGE2 series; cytokines, especially interleukin 1 (IL-1); growth factors, especially TGF beta; RANKL (receptor activator of nuclear factor kappa B ligand), a cell membrane-associated member of the tumor necrosis factor family of cytokines; soluble RANKL (sRANKL); and their cognate receptor, RANK; and OPG (osteoprotegerin), a soluble “decoy” receptor for RANKL. The latter group are also expressed by osteoblast precursors as they develop into osteoblasts in the osteoblastic cascade (left). In addition to OPG, the stimulation of osteoclastic bone resorption by RANKL is opposed by activation of the gamma interferon receptor (INFR) by gamma interferon (INF) production by activated lymphocytes and by the peptide hormone, calcitonin. The relative activity of the osteoclast stimulatory effects of RANKL and sRANKL and the inhibitory effects of OPG and INF determine the balance between bone resorption and formation. Arrows indicate a positive (stimulatory) effect except where indicated by the negative sign, (-). Several growth factors in addition to TGF beta reside in bone matrix and can be released upon resorption to exert their biological effects, often osteoclast stimulation. They include BMP (bone morphogenetic proteins, especially BMP-2); FGF (fibroblast growth factor); PDGF (platelet derived growth factor); and IGFs in (insulin like growth factors). Macrophages may fuse into giant cells and resorb bone. (see Acknowledgements).

 

LIPOPROTEIN RECEPTOR-RELATED PROTEIN (LRP)-5, WNT, BETA CATENIN SYSTEM             

 

Activation of the LRP5/WNT system increases intracellular beta catenin which increases bone formation (26).  Gain-of-function mutations of LRP-5 cause a high bone density phenotype and loss-of-function mutations cause the osteoporosis-glioma syndrome (26).  Dkk1 and sclerostin inhibit this pathway and decrease bone formation and increase bone resorption.  Sclerostin production by osteocytes is increased with acute immobilization; resulting in decreased bone formation (27).  Loss-of-function mutations of sclerostin cause the high bone density conditions sclerosteosis and van Buchem disease (15).  A monoclonal antibody to sclerostin (romosozumab) increases bone formation and decreases bone resorption with resultant increased bone density and decreased fracture risk.  This drug is approved for women with post-menopausal osteoporosis at high risk for fractures (16,17).  Other monoclonal antibodies to sclerostin are being studied for treatment of osteogenesis imperfecta (OI) (28) and hypophosphatasia (29).

 

Figure 7. Wnt/β-catenin signaling pathway. A, In the absence of Wnt ligand, β-catenin is phosphorylated by GSK-3β leading to its degradation and pathway signaling inactivation. B, After Wnt binding to its LRP5/6 and Fz coreceptors, GSK-3β is inactivated. β-Catenin is then stabilized and accumulates in the cytoplasm. β-Catenin will consequently translocate into the nucleus where it affects gene expression. C, The secreted Dkk proteins bridge LRP5/6 and the transmembrane protein Krm. This results in the LRP5/6 membrane depletion by internalizing the receptors. As a consequence, Wnt signaling is inhibited. Sclerostin (Sost) also inhibits Wnt signaling through binding to LRP5/6, but its activity is independent of Krm proteins. Reprinted with permission from Baron, R and Rawadi G. Targeting the Wnt/β-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton. Endocrinology 148: 2635-2643, 2007 Copyright (2007), The Endocrine Society.

 

HORMONAL REGULATION OF SKELETAL AND MINERAL METABOLISM PARATHYROID HORMONE

 

Parathyroid hormone is an 84-amino-acid peptide secreted by two pairs of parathyroid glands located adjacent to the back of the thyroid gland in the neck. There can also be ectopic parathyroid glands along their developmental route between the thyroid gland and mediastinum. The mature PTH is packaged into dense secretory granules for regulated secretion (1,2).

 

Secretory Regulation Of Parathyroid Hormone And The Calcium Sensor

 

PTH is synthesized as a 115 amino acid pre-pro-peptide, however, the 84 amino acid peptide is secreted by the parathyroid glands.  The major regulatory signal for PTH secretion is serum calcium (Table 17) (30). Serum calcium inversely affects PTH secretion, with the steep portion of the sigmoidal response curve corresponding to the normal range of both. An increase in ionized calcium inhibits PTH secretion by increasing intracellular calcium through the release of calcium from intracellular stores and the influx of extracellular calcium through cell membranes and channels. This mechanism differs from most cells, where secretion of their product is stimulated by increased calcium. Intracellular magnesium may serve this secretory function in the parathyroids in that hypermagnesemia can inhibit PTH secretion and hypomagnesemia can stimulate PTH secretion. However, prolonged depletion of magnesium will inhibit PTH biosynthesis and secretion, as it will the function of many cells. Hypomagnesemia also attenuates the biological effect of PTH by interfering with its signal transduction. Serum calcium also inversely regulates transcription of the PTH gene, and increased levels of 1,25-dihydroxyvitamin D (1,25-D) inhibit PTH gene transcription.  The parathyroid gland senses the concentration of extracellular ionized calcium through a cell-surface calcium-sensing receptor (CaSR) for which calcium is an agonist. The same sensor also regulates the responses to calcium of thyroid C cells, which secrete CT in direct relationship to extracellular calcium; the distal nephron of the kidney, where calcium excretion is regulated; the placenta, where fetal-maternal calcium fluxes occur; and the brain and gastrointestinal (GI) tract, where its function is unknown, and bone cells. Loss-of-function mutations of the CaSR cause familial hypocalciuric hypercalcemia (FHH) 1 (31). Two other mutations downstream in this pathway (GNA11 and AP2S1) have been identified that cause FHH2 and FHH3 respectively (31).  Gain-of-function mutations of CaSR and GNA11 cause autosomal dominant hypocalcemia (ADH) type 1 and type 2 respectively (32).

 

Drugs have been identified that allosterically activate the CaSR (calcimimetics) and are useful treatment agents; they are available for treatment of the increased PTH secretion that occurs in secondary hyperparathyroidism of renal failure (oral cinacalcet, intravenous etelcalcetide) (33) severe primary hyperparathyroidism (oral cinacalcet), and parathyroid cancer (oral cinacalcet )(34). Calcilytic agents which antagonize the CaSR are being studied for treatment of ADH (35).

FGF23 may also inhibit PTH secretion, an action that requires binding to the FGF receptor and the co-receptor alphaKlotho (36).  (See below)

 

Table 17. Regulation of PTH Biosynthesis and Secretion

Ambient calcium acting through the calcium sensing receptor (CaSR)

Vitamin D [1,25(OH)2D]

Ambient phosphorus

FGF23

Other

 

Some studies fail to demonstrate a direct effect of serum phosphate on PTH secretion, however, others show that high phosphate increases PTH biosynthesis and visa versa (4). However, serum phosphate has an inverse effect on calcium concentration and low ambient phosphate directly increases 1,25-D production. Thus, serum phosphate may directly and indirectly regulate PTH expression.

 

Metabolism And Clearance Of Parathyroid Hormone

 

Parathyroid hormone has a circulating half-life of less than 5 minutes (2,36). The hormone is metabolized to amino-terminal and carboxyl-terminal fragments primarily in the liver, also in the kidney, and perhaps in the parathyroid gland and blood. The carboxyl-terminal fragments are cleared by glomerular filtration (GF), so they accumulate in renal failure. All of the classic biological effects of PTH are mediated by the amino terminus, PTH1-34, and likely a subpeptide of this sequence, but other fragments may have their own biologic actions. For example, the carboxy terminus may regulate calcium channel flux.

 

As a result of the biosynthesis, secretion, and metabolism of PTH, the circulation contains several forms of the molecule (36). The forms that comprise this heterogenous collection of PTH species include primarily native PTH1-84 and amino terminal, mid-region and carboxy terminal PTH fragments. Overall, 10-20% of circulating PTH immunoreactivity comprises the intact hormone, with the remainder being a heterogeneous collection of peptide fragments corresponding to the middle and carboxy regions of the molecule. Recent studies have demonstrated a PTH 7- 84 fragment that accumulates in renal failure and may even be secreted by the normal as well as abnormal parathyroid gland. While only the amino terminus of PTH can bind to the PTH receptor at a site that mediates its classical biological effects, which result in hypercalcemia, PTH 7 – 84 may act as an antagonist and/or weak agonist to PTH at its receptor. Nevertheless, it should be kept in mind that each of the circulating forms of PTH, regardless of biological activity, contain within them peptide sequences that can be recognized by a variety of immunoassay systems and thus complicate clinical interpretation.  The so-called intact PTH assays do not require the far amino-terminus of the molecule, a sequence need for full biological activity. The intact PTH assays recognize both PTH 1-84 and PTH 7-84.  Newer assays, designated “bio-intact” or “whole” apparently do not recognize PTH 7-84, but there does not appear to be any clear clinical advantage of the “whole” compared to intact PTH assays (37).

 

Biologic Effects Of Parathyroid Hormone

 

Parathyroid hormone regulates serum calcium and phosphorus concentrations through its receptor-mediated, combined actions on bone, intestine, and kidney (3,38). The skeletal effects of PTH on bone are complex. High levels of PTH, as seen in primary and secondary hyperparathyroidism, increase osteoclastic bone resorption. Low levels, especially if delivered episodically, seem to increase osteoblastic bone formation, an effect that has been applicable to osteoporosis treatment by daily injections of teriparatide (PTH 1-34) (39) and the PHTrP analogue, abaloparatide (40). The skeletal effects of PTH are mediated through the osteoblast, since they are the major expressor of the PTH receptor. However, osteoblasts communicate with osteoclasts to mediate PTH effects. This communication seems mediated through the RANK-OPG pathway (21).

 

Any direct gastrointestinal (GI) effect of PTH on intestinal calcium or phosphate absorption is weak. However, PTH through its stimulating effects on the renal production of 1,25-D, discussed later, promotes the absorption of both. In the kidney, PTH increases the reabsorption of calcium, predominantly in the distal convoluted tubule, and inhibits the reabsorption of phosphate in the renal proximal tubule, causing hypercalcemia and hypophosphatemia. PTH also inhibits NA+/H+ antiporter activity and bicarbonate reabsorption, causing a mild hyperchloremic metabolic acidosis.

 

PTH mediates most of its effects through the PTH/PTHrP receptor (PTH1 receptor) (38). This receptor is an 80,000-MW membrane glycoprotein of the G protein receptor superfamily. The classic PTH receptor recognizes the amino-terminus of PTH and the homologous terminus of the parathyroid hormone-related protein (PTHrP) with indistinguishable affinity; it is therefore designated the PTH/PTHrP receptor. Both PTH and PTHrP generate cyclic adenosine monophosphate (cAMP) as a cellular second messenger by activating protein kinase A (PKA), and the phospholipase C effector system increasing cellular IP3 and calcium and activating protein kinase C (PKC). There may be some tissue specificity as to which pathway dominates.

 

In addition to this shared receptor, there is accumulating evidence for the existence of receptors that are respectively specific for PTH and PTHrP and for some of their subpeptides. The PTH2 receptor is activated by PTH but not PTHrP and is expressed in brain and pancreas (41).  For PTH, a carboxy-terminal peptide seems to mediate cellular calcium flux; for PTHrP, a nuclear localizing sequence (NLS) has been identified (38).

 

Table 18. Effects of Parathyroid Hormone on Calcium and Skeletal Metabolism

 

Bone

       Increases resorption

       Increases formation, especially at low and intermittent concentrations

Kidney

       Decreases calcium excretion (clearance)

       Increases phosphorus excretion

Gastrointestinal Tract

       Increases calcium and phosphorus absorption

       Indirect effect via 1,25-D production

Blood

       Increases calcium

       Decreases phosphorus

 

 

PTHrP is a major humoral mediator of the hypercalcemia of malignancy (1,3,22). The polypeptide is a product of many normal and malignant tissues (22). PTHrP is secreted by many types of malignant tumors, notably by breast and lung cancer, and produces hypercalcemia by activating the PTH/PTHrP receptor. PTHrP is produced in many fetal tissues, but as development proceeds its expression becomes restricted. PTHrP expression reappears in adult tissues when injury or malignancy occurs (22).

 

The PTHrP gene expresses three native forms of the polypeptide through alternate mRNA splicing, PTHrP 1-141, a truncated 139 residue form, and a 173 residue form expressed primarily in humans (37). Whereas PTHrP 1-139 is quite similar to PTHrP 1-141, PTHRP 1-173 completely diverges from both at its own carboxy terminus. The amino-terminus of PTHrP reacts with the shared PTH/PTHrP receptor and has the potential to produce most of the biological effects of native PTH, including hypercalcemia. Other cell products, such as cytokines and growth factors, are also likely to play a casual role in the hypercalcemia because of their direct and indirect skeletal actions.   As discussed later, these can be produced by the tumor cells or immune cells. TGF beta can also participate in pathogenesis by stimulating PTHrP production from tumors or immune cells as it is released from its skeletal reservoir upon resorption.

 

PTHrP is required for normal development as a regulator of the proliferation and mineralization of cartilage cells and as a regulator of local calcium transport. The amino terminus of PTHrP reacts with the PTH/PTHrP receptor and produces most of the biological effects of native PTH, including hypercalcemia. The PTHrP gene expresses three forms of polypeptide through alternate messenger ribonucleic acid (mRNA) splicing. In addition to mRNA splicing, processing of PTHrP into peptides is an important regulatory mechanism. Distinct biological properties have been attributed to the different PTHrP peptides, and specific receptors and effects have been identified.

 

Although multiple, the functions of PTHrP in malignant and normal tissues seem to be growth- and proliferation-related (22). In most physiologic circumstances, PTHrP carries out local rather than systemic actions. When produced in excess by malignancy, PTHrP has systemic effects, especially hypercalcemia. Because of its protean and developmental effects, PTHrP can be considered an oncofetal protein.

 

Malignancy and PTHrP

 

The hypercalcemia of malignancy is usually due to increased bone resorption that is caused by skeletal metastases or the production by the tumor of a “humour” that stimulates osteoclasts (22). It is likely that the first mechanism also involves the second, since most tumor cells do not have the capacity to directly resorb bone and more likely stimulate the neighboring osteoclast to do so through their “humours.” Many cell types and their products participate in and many tumor products have been implicated in the pathogenesis of the hypercalcemia of malignancy (Figure 5). The most common seems to be PTHrP, especially in solid tumors where abnormal PTHrP expression can be implicated in up to 80% of patients. Originally discovered as a product of malignant cells that produce hypercalcemia, PTHrP has been demonstrated to be a product of many normal and malignant tissues. The growing appreciation of the key role of PTHrP in the pathogenesis of the hypercalcemia of malignancy has revealed that ectopic PTH production by cancer cells is a rare event.

 

PTHrP expression was initially noted to be common in squamous cell cancers, but it has been subsequently shown that many other cancer types can overexpress PTHrP.  PTHrP production and secretion by breast and prostate cancers is especially common, occurring in more than half of the cases, with even a higher incidence in breast when the patient is hypercalcemic. Breast tumors that produce PTHrP are more likely to metastasize to bone, and breast cancers that metastasize to bone are even more likely to produce PTHrP. PTHrP is commonly expressed in lung cancer, especially in those lung cancers that metastasize to bone. While breast and lung cancer are among the most common PTHrP producing tumors that cause hypercalcemia, this pathway has been described in many cancers. PTHrP production that often accompanies prostate cancer does not usually cause hypercalcemia, perhaps because this tumor processes the polypeptide to a non-hypercalcemic peptide. It is notable that some non-malignant PTHrP-producing tumors can also be associated with hypercalcemia (42).

 

While PTHrP is the most common humour produced by malignant cell to cause osteoclast-mediated hypercalcemia, increased 1,25-dihydroxy vitamin D is causal in lymphomas and some leukemias.  Furthermore, certain cytokines, notably IL-1, and growth factors, notably TGF beta, can also produce hypercalcemia by stimulating osteoclastic bone resorption; but excess prostaglandin production is no longer considered an important hypercalcemic humour in malignancy.

 

VITAMIN D

 

Metabolism and Activation

 

Vitamin D is a secosterol hormone that is present in humans in an endogenous (vitamin D3) and exogenous (vitamin D2) form (43, 44). The endogenous form of vitamin D, cholecalciferol (vitamin D3), is synthesized in the skin from the cholesterol metabolite 7-dehydrocholesterol under the influence of ultraviolet radiation. Vitamin D3 is also available in oral supplements. An exogenous form of vitamin D (vitamin D2) (ergocalciferol) is produced by ultraviolet irradiation of the plant sterol ergosterol and is available through the diet. Both forms of vitamin D require further metabolism to be activated, and their respective metabolism is indistinguishable. Vitamin D metabolites are solubilized for transport in blood by specific vitamin D-binding proteins.

 

Figure 8. The Metabolic Activation of Vitamin D. Abbreviations: 25-D, 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; VDR, vitamin D receptor. Vitamin D from the diet or the conversion from precursors in skin through ultraviolet radiation (light) provides the substrate of the indicated steps in metabolic activation. The pathways apply to both the endogenous animal form of vitamin D (vitamin D3, cholecalciferol) and the exogenous plant form of vitamin D (vitamin D2, ergocalciferol), both of which are present in humans at a ratio of approximately 2:1. In the kidney, 25-D is also converted to 24-hydroxylated metabolites which seem generally inactive but may have unique effects on chondrogenesis and intramembranous ossification. The many effects (Table 8) of vitamin D metabolites are mediated through nuclear receptors or effects on target-cell membranes (see Acknowledgments).

 

In the liver, vitamin D is converted by a hydroxylase to 25-hydroxyvitamin D (25-D), the principal fat storage form of vitamin D (45). Thus, the serum level of 25-D is the best measure of overall vitamin D status. In the proximal tubule of the kidney, 25-D is 1alpha-hydroxylated to produce 1,25-D, the most active form of the hormone. The animal form is referred to as 1,25-dihydroxycholecalciferol. This hydroxylation step is up-regulated by several factors, the most important of which are PTH and low ambient concentrations of calcium, phosphorus, and 1,25-D itself. The 1alpha-hydroxylase that mediates this conversion in the kidney is also produced in the placenta and in keratinocytes. In certain disease states, macrophages (e.g., in sarcoidosis) and lymphocytes (e.g., in lymphoma) overexpress 1alpha-hydroxylase and produce hypercalcemia (46).

 

The normal serum concentration of 1,25-D is about 20-60 pg/ml. The kidney can also convert 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D. Although this metabolite circulates at 100-fold higher than the concentration of 1,25-D, its biologic role is unclear. Some studies suggest that it is a degradation product with no important biological effects; others suggest that it is important in chondrogenesis and bone formation, especially intramembranous. Vitamin D and its metabolites are inactivated in the liver by conjugation to glucuronides or sulfates and oxidation of their side chains. Mutations of the 24-hydroxylase enzyme (CYP24A1) have been shown to cause hypercalcemia and hypercalciuria in infants and adults (47).  In this condition, 1,25(OH)vitamin D levels are elevated because of inadequate metabolism of 1,25(OH)2D (47).  Studies also suggest the presence of the C-3 epimer of 25(OH)D in serum (48).  The biologic importance of this epimer is unknown.

 

There is controversy about the optimal 25(OH) vitamin D level.  The Institute of Medicine (IOM) has suggested that a 25(OH) vitamin D > 20 ng/ml is adequate (49), while The Endocrine Society suggests that > 30 ng/ml is optimal (50).  The IOM suggests that supplements of 600-800 IU daily will produce adequate levels in most adults, with an upper safe dose of 4000 IU daily (49).

 

Biological Effects of Vitamin D and It’s Mechanism of Action

 

Vitamin D mediates its biological effects through its own member of the nuclear hormone receptor superfamily, the vitamin D receptor (VDR) (43). The receptor binds many vitamin D metabolites with affinities that generally mirror their biological effects, and 1,25-D thus has the highest affinity. The VDR regulates gene transcription by homodimerization and by heterodimerization to a retinoic acid X receptor (RXR). The complex binds to target DNA sequences and regulates the transcription of several genes important in mediating vitamin D’s effects on calcium and skeletal metabolism and its diverse biological effects. Vitamin D metabolites, as well as other steroid hormones, may also act through a membrane receptor to produce rapid changes in cellular calcium flux (Figure 7) (51).

 

There continues to be debate about the relative importance of Vitamin D2 and Vitamin D3 in human health and disease.  Administration of vitamin D3 may result in more persistent elevation of 25(OH)D than administration of vitamin D2 (52-54).

 

Intestinal Calcium Absorption

 

Vitamin D increases intestinal calcium absorption, primarily in the jejunum and ileum, by increasing calcium uptake through the brush border membrane of the enterocyte (Tables 8, 9, and 19). For this action, vitamin D induces the calcium-binding calbindins, which participate in calcium transport across the cell, and through its action on calcium transporting membrane structures (Figure 2), it promotes the efflux of calcium from the basolateral side of the enterocyte into the circulation. The initial effects of vitamin D on intestinal calcium absorption occur within minutes, so the actions of vitamin D on intestinal calcium transport may be also mediated by a membranous nongenomic receptor. The net result is an increase in the efficiency of intestinal calcium transport. In a vitamin D-deficient state, only 10 to 15% of dietary calcium is absorbed by the gastrointestinal tract, but with adequate vitamin D adults absorb approximately 30% of dietary calcium. During pregnancy, lactation, and growth, increased circulating concentrations of 1,25-D promote the efficiency of intestinal calcium absorption by as much as 50% to 80%. Vitamin D also regulates skeletal metabolism through the RANK pathway (Figure 6). 1,25-D also increases the efficiency of dietary phosphorus absorption by about 15 to 20%.

 

Table 19. Mechanisms of GI Calcium Absorption

Vitamin D Dependent

Duodenum > jejunum > ileum

Active transport across cells

        calcium binding proteins (calbindins)

        calcium channels and pumps

Na exchanger

Passive diffusion

 

Bone

 

The effects of vitamin D metabolites on bone are complex (1). By providing sufficient ambient calcium and/or through some other unappreciated direct effect, vitamin D promotes the mineralization of osteoid. Vitamin D causes bone resorption by mature osteoclasts, but this effect is indirect, requiring cell recruitment and interaction with osteoblasts. Vitamin D also promotes the fusion of monocytic precursors to osteoclasts. Vitamin D regulates the expression several bone proteins, notable osteocalcin. It promotes the transcription of osteocalcin and has bidirectional effects on type I collagen and alkaline phosphatase gene transcription

 

Kidney

 

The VDR is robustly expressed in the kidney, and acting through it, 1,25-D stimulates renal proximal phosphate reabsorption and maintenance of normal calcium reabsorption. However, compared to PTH, these effects are relatively weak (43).

 

Other Tissues

 

Vitamin D and its metabolites have protean effects on cell function and signaling (45). Although vitamin D has many in vitro effects on the immune system, no major immune defect is apparent in individuals who are deficient or who lack vitamin D or its receptor. Vitamin D also inhibits proliferation and stimulates maturation of epidermal keratinocytes, which robustly express the VDR. This antiproliferative effect is being used for the treatment of psoriasis, a hyperproliferative skin disorder. Since many persons who lack vitamin D receptors have lifelong alopecia totalis, vitamin D may play a role in the maturation of the hair follicle (55).

 

Many studies have suggested the association of low 25(OH)D levels with a variety of diseases including cardiovascular, metabolic, autoimmune, malignant, and neurologic disorders.  Thus far, these largely observational findings have not been confirmed in randomized trials (56).

 

Table 20. Effects of 1,25-D (1,25-dihydroxyvitamin D) on Mineral Metabolism

Bone

        Promotes mineralization of osteoid

        Increases resorption at high doses

Kidney

        Decreases calcium excretion

        Decreases phosphorus excretion

Gastrointestinal Tract

        Increases calcium absorption

        Increases phosphorus absorption

Blood

        Increases calcium

        Increases phosphorus

 

FGF23

 

FGF23 is a 251 amino acid peptide hormone produced by osteoblasts, osteocytes and flattened bone-lining cells.  O-glycosylation of FGF23 by UDP-N-acetyl-alpha-D-galactosmanine;  polypeptide N- acetylgalactosaminyl transferase 3 (GALNT3) at specific sites is required to prevent intracellular degradation of the intact active molecule.  The action of FGF23 is mediated by binding an FGF receptor (FGFR) with it’s coreceptor alphaKlotho (9,12).

 

FGF23 decreases production of the sodium phosphate cotransporters, Npt2a and Npt2c.  As these cotransporters increase phosphate reabsorption in the renal proximal tubule, FGF23 increases renal phosphate wasting.  FGF23 also decreases 1,25(OH)2D levels probably by decreasing the expression of the 1 alphahydroxylase enzyme and increasing production of the 24-hydroxylase enzyme (9,12).). 

 

FGF23 expression is regulated by phosphorus and by 1,25(OH)2D.  Although regulation by 1,25(OH)2D is believed to be via the vitamin D receptor, the mechanism of phosphate sensing is unknown.  Iron deficiency also increases FGF23 transcription and translation.  In normal subjects, however, increased processing of FGF23 prevents hypophosphatemia.  Patients with autosomal dominant hypophosphatemic rickets (ADHR), however, who have an abnormal FGF23 which is resistant to degradation may not be able compensate particularly when iron deficiency is present (57). 

.

X-linked hypophosphatemic rickets (XLH) (PHEX gene), autosomal dominant hypophosphatemic rickets (ADHR) (FGF23 gene), autosomal recessive hypophosphatemic rickets (ARHR) (DMP1, ENPP1, FAM20C genes), and tumor-induced osteomalacia (TIO) are associated with excessive FGF23 (58).  Interestingly, intravenous iron (especially iron carboxymaltose) may cause FGF23 mediated renal phosphate wasting, hypophosphatemia, and osteomalacia (59). Recently, a monoclonal antibody to FGF23 (burosumab) was approved for treatment of XLH and TIO (18). Loss-of-function mutations of GALNT3, FGF23, and alpha Klotho result in decreased intact FGF23 levels or decreased FGF23 action and result in hyperphosphatemia and tumoral calcinosis. (9, 58)

 

FGF23 is elevated in chronic kidney disease.  Elevations of FGF23 may be associated with progression of renal disease, left ventricular hypertrophy, cardiovascular events, and mortality.  It is not known whether these associations are due to FGF23 or are related to more severe underlying disease (9,12) FGF23 may be measured by a c-terminal assay which measures full-length FGF23 in addition to c-terminal fragments as well as by an intact assay.  FGF23 in both assays is elevated or inappropriately normal in XLH, ADHR, ARHR, and TIO.  In tumoral calcinosis due to FGF23 and GALNT3 mutations, these assays may be discordant with elevated C-terminal FGF23 and reduced intact (active) FGF23.  FGF23 measured by both assays is elevated in TC caused by Klotho mutations (58) because of resistance to FGF23.

 

Table 21. FGF23 Secretion and Action

FGF23 Secretion

            Increased by high phosphate

            Increased by high 1,25(OH)2D

 

FGF23 Action

            Mediated via FGF receptor and Klotho

            Increases renal phosphate wasting

            Decreases production of 1,25(OH)2D

            Lowers serum phosphate

 

CALCITONIN

 

Calcitonin is a 32-amino acid peptide whose main effect is to inhibit osteoclast-mediated bone resorption (60). CT is secreted by parafollicular C cells of the thyroid and other neuroendocrine cells. Hypercalcemia increases secretion of hypocalcemia-inducing CT while hypocalcemia inhibits secretion (61). CT secretion is controlled by serum calcium through the same CaSR that regulates PTH secretion, but in an inverse manner and at higher concentrations of calcium. CT directly inhibits bone resorption by inactivating the CT-receptor rich osteoclast. CT also inhibits the renal reabsorption of phosphate, thus promoting renal phosphate excretion. CT also induces a mild natriuresis and calciuresis, the latter contributing to its hypocalcemic effect. However, calcitonin does not appear to have a major effect on human calcium metabolism as evidenced by normocalcemia in thyroidectomized patients as well as patients with medullary thyroid cancer and very high calcitonin levels (10,60).  Calcitonin in pharmacologic doses has been used to decrease bone resorption in osteoporosis, Paget’s bone disease, and hypercalcemia of malignancy (10).   It is unclear whether long-term use of calcitonin is associated with increased cancer risk (62).

 

Table 22. Regulation of Calcitonin Secretion

Calcium and related ions (CaSR)

Age and gender

Gastrointestinal factors

 

The CT receptor, like the PTH and calcium-sensing receptor, is a heptahelical G protein-coupled receptor coupled to the PKA, PKC, and Ca++ signal transduction pathways (63, 64).

 

The CT gene through alternative exon splicing and polypeptide processing ultimately encodes two peptide products, CT in thyroid C-cells which is processed from a 141-amino acid precursor, and a 37-amino peptide called gene-related peptide (CGRP) in neural tissues which is processed from a 128-amino acid precursor (1,65). CGRP is weakly recognized by the CT receptor and thereby has a CT-like effect on osteoclasts and osteoblasts. CGRP also acts through its own receptor to produce vasodilation and to act as a neurotransmitter. In addition to its role in calcium and skeletal metabolism, CT is important as a tumor marker in medullary thyroid carcinoma and other neuroendocrine tumors. The receptor that mediates the effects of the peptide products of the CT gene can be modulated by accessory proteins to alter binding characteristics (65).

 

Table 23. Effects of Calcitonin on Mineral Metabolism

Bone

·       Inhibits resorption

Kidney

·       Increases calcium excretion

·       Increases phosphorus excretion

Gastrointestinal Tract

·       ? Inhibitory effect on calcium/phosphorus absorption

Blood

·       Decreases calcium

Decreases phosphorus

 

OTHER HORMONES

 

In addition to the primary calcemic hormones, other hormones play an important role in calcium and skeletal metabolism (1-3). Gonadal steroids maintain skeletal mass.  Estrogen deficiency is a major factor in the development of postmenopausal osteoporosis by permitting increased bone resorption.  There is controversy about whether the elevation in FSH that accompanies menopause also contributes to increased bone resorption (66).  In an animal model, a blocking antibody to the beta subunit of FSH decreased bone resorption (67).  Glucocorticoids have significant deleterious effects on the skeleton including decreased bone density, increased fracture risk, and increased risk of avascular necrosis (68). Glucocorticoids transiently increase bone resorption, chronically decrease bone formation and cause osteoblast and osteocyte apoptosis (68). Insulin, growth hormone, and thyroid hormones promote skeletal growth and maturation. Excess production of the latter can cause hypercalcemia (Table 24).

 

Table 24. Effects of Calcitonin on Mineral Metabolism

Decrease Bone Resorption

         Calcitonin

         Estrogens

Increase Bone Resorption

         PTH/PTHrP

         Glucocorticoids (early)

         Thyroid Hormones

         High dose vitamin D

         ? FSH

Increase Bone Formation

        Growth Hormone

         Vitamin D Metabolites

         Androgens

         Insulin

         Low-dose PTH/PTHrP

Decrease Bone Formation

         Glucocorticoids (also increase osteocyte apoptosis)

 

SUMMARY

 

Through their actions and interactions on bone, kidney and the gastrointestinal (GI) tract, the calciotropic hormones, parathyroid hormone (PTH), FGF23, and vitamin D metabolites, especially 1,25-D, act to maintain serum (and extracellular fluid) calcium within a normal range, a range that optimally subserves many calcium-requiring physiological functions such as neural transmission and muscle contraction.  Perturbations in serum calcium, which plays an important role in regulating the concentrations of the calciotropic hormones, will cause a homeostatically appropriate and reciprocal change in the secretion of PTH by the parathyroid glands. These responses are designed to return the serum calcium, and, to a lesser extent, the serum phosphorus and magnesium to normal, with the skeleton acting as a reservoir for these minerals that can be emptied or filled.  During the last several years, a more physiologically integrated view of calcium metabolism has emerged. The metabolism of the skeleton has been linked to the metabolism of glucose in a manner that coordinates the regulation of bone mass with energy expenditure. And in addition to peripheral hormone regulation, the CNS exerts important regulatory effects on both systems, which encompass calcium and glucose metabolism, body and skeletal mass regulations, and energy expenditure and appetite.

 

The patient with hypoparathyroidism will have hypocalcemia with an inappropriately normal or low PTH and low 1,25(OH)2D.

 

The patient with nonparathyroid hypocalcemia will have an increased serum PTH and1,25-D (unless vitamin D stores are severely reduced). This will result in increased GI absorption of calcium, increased bone resorption, and decreased renal calcium excretion all acting to increase the serum calcium toward normal.

 

The patient with primary hyperparathyroidism will have hypercalcemia and inappropriately normal or elevated PTH.  The patient with PTH-independent hypercalcemia (e.g., due to bone metastases) will have a decreased serum PTH and 1,25-D (unless the hypercalcemia is PTHrP-mediated or calcitriol-mediated). This will result in decreased GI absorption of calcium, decreased bone resorption, and increased renal calcium excretion all acting to decrease the serum calcium toward normal.  Although these compensatory mechanisms act to restore serum calcium to normal, the homeostasis will not be complete until the primary abnormality has been corrected. In addition to these calciotropic hormones, other hormones, cytokines, and growth factors play an important role in calcium metabolism. Among the other important hormones are insulin, growth hormone, and the gonadal and adrenal steroids and thyroid hormone (Table 20).  They are discussed in other chapters.

 

FGF23 is an important phosphate regulator with excess action causing renal phosphate wasting, hypophosphatemia, and low 1,25(OH)2D and decreased action causing renal phosphate retention, hyperphosphatemia, and inappropriately high 1,25(OH)2 D levels.

 

CLINICAL IMPLICATIONS

 

The clinician can consider a simplified scheme when confronted with a patient with a disorder of calcium and skeletal metabolism – the serum or urinary calcium can be abnormally high or low and bone density can be increased or decreased.

 

In practical terms, when the serum calcium is high, primary hyperparathyroidism, granulomatous and inflammatory conditions causing unregulated 1,25D production, and malignancy are at the top of the diagnostic list.  When the serum calcium is low, hypoparathyroidism, malabsorption, vitamin D deficiency, and kidney disease should be considered.

 

Chronically abnormal phosphate levels in the non-acutely ill patient may be caused by renal failure, renal tubular defects, and abnormalities of FGF23 action.

When bone density is decreased, it is usually due to osteoporosis or osteomalacia; when increased, osteopetrosis and other osteosclerotic disorders should be considered.

These diagnostic categories can be properly assigned when one considers the interaction among the calcium regulating hormones that have been described in this chapter and orders the appropriate diagnostic tests. In most cases, the correct diagnosis is readily made.

 

ACKNOWLEDGEMENTS

 

The authors substantially and expressly relied on the following publications for the information presented in this text: Deftos, LJ: Immunoassays for PTH and PTHrP In: The Parathyroids, Second Edition, JP Bilezikian, R Marcus, and A Levine (eds.), Chapter 9, pp.143-165, 2001. Deftos LJ and Gagel R: Calcitonin and Medullary Thyroid Carcinoma In: Cecil Textbook of Medicine, Twentieth First Edition, JB Wyngarden and JC Bennett, Chapter 265, pp.1406-1409, 2000. Deftos, LJ: Clinical Essentials of Calcium and Skeletal Metabolism, Professional Communication Inc, First Edition, pp. 1-208, (Figures 1,3-5 and Table 2) 1998 (Published on-line at Medscape.com). The following Chapters in Felig, P and Frohmer, LA. Endocrinology and Metabolism, 4th Edition, McGraw-Hill, 2001: Chapter 22, Mineral Metabolism, Bruder, Guise, and Mundy. Chapter 23, Metabolic Bone Disease, Singer. Chapter 27. Multiglandular Endocrine Disorders, Deftos, Sherman, and Gagel. Deftos, LJ: Hypercalcemia in malignant and inflammatory diseases. Endocrinology and Metabolism Clinics of North America, 31:1-18, (Figure 2) 2002.

 

This work was supported by the National Institutes of Health and the Department of Veterans Affairs (Dr. Deftos). Drs. Shaker and Deftos have no relevant conflicts of interest.

 

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Definitions, Classification, and Epidemiology of Obesity

ABSTRACT

 

Recent research has established the physiology of weight regulation, the pathophysiology that leads to unwanted weight gain with establishment of a higher body-weight set point, and the defense of the overweight and obese state even when reasonable attempts in lifestyle improvement are made. This knowledge has informed our approach to obesity as a chronic disease. The assessment of adiposity risk for the foreseeable future will continue to rely on cost-effective and easily available measures of height, weight, and waist circumference. This risk assessment then informs implementation of appropriate treatment plans and weight management goals. Within the United States, prevalence rates for generalized obesity (BMI > 30 kg/m2), extreme obesity (BMI > 40 kg/m2), and central obesity continue to rise in children and adults with peak obesity rates occurring in the 5th-6th decades. Women may have equal or greater obesity rates than men depending on race, but less central obesity than men. Obesity disproportionately affects people by race and ethnicity, with the highest prevalence rates reported in Black women and Hispanic men and women. Increasing obesity rates in youth (ages 2-19 years) are especially concerning. This trend will likely continue to fuel the global obesity epidemic for decades to come, worsening population health, creating infrastructural challenges as countries attempt to meet the additional health-care demands, and greatly increasing health-care expenditures world-wide. To meet this challenge, societal and economic innovations will be necessary that focus on strategies to prevent further increases in overweight and obesity rates.

 

INTRODUCTION

 

Unwanted weight gain leading to overweight and obesity has become a significant driver of the global rise in chronic, non-communicable diseases and is itself now considered a chronic disease. Because of the psychological and social stigmata that accompany developing overweight and obesity, those affected by these conditions are also vulnerable to discrimination in their personal and work lives, low self-esteem, and depression (1). These medical and psychological sequelae of obesity contribute to a major share of health-care expenditures and generate additional economic costs through loss of worker productivity, increased disability, and premature loss of life (2-4).

 

The recognition that being overweight or having obesity is a chronic disease and not simply due to poor self-control or a lack of will power comes from the past 70 years of research that has been steadily gaining insight into the physiology that governs body weight (homeostatic mechanisms involved in sensing and adapting to changes in the body’s internal metabolism, food availability, and activity levels so as to maintain fat content and body weight stability), the pathophysiology that leads to unwanted weight gain maintenance, and the roles that excess weight and fat maldistribution (adiposity) play in contributing to diabetes, dyslipidemia, heart disease, non-alcoholic fatty liver disease, obstructive sleep apnea, and many other chronic diseases (5,6).

 

Expression of overweight and obesity results from an interaction between an individual’s genetic predisposition to weight gain and environmental influences. Gene discovery in the field of weight regulation and obesity has identified several major monogenic defects resulting in hyperphagia accompanied by severe and early-onset obesity (7) as well as many more minor genes with more variable impact on weight and fat distribution, including age-of-onset and severity. Several of these major obesity genes now have a specific medication approved to treat affected individuals (8). However, currently known major and minor genes explain only a small portion of body weight variations in the population (7). Environmental contributors to obesity have also been identified (9) but countering these will likely require initiatives that fall far outside of the discussions taking place in the office setting between patient and provider since they involve making major societal changes regarding food quality and availability, work-related and leisure-time activities, and social and health determinants including disparities in socio-economic status, race, and gender.

 

Novel discoveries in the fields of neuroendocrine (6) and gastrointestinal control (10) of appetite and energy expenditure have led to an emerging portfolio of medications that, when added to behavioral and lifestyle improvements, can help restore appetite control and allow modest weight loss maintenance (8). They have also led to novel mechanisms that help to explain the superior outcomes, both in terms of meaningful and sustained weight loss as well as improvements or resolution of co-morbid conditions, following metabolic-bariatric procedures such as laparoscopic sleeve gastrectomy and gastric bypass (11,12). 

 

Subsequent chapters in this section of Endotext will delve more deeply into these determinants and scientific advances, providing a greater breadth of information regarding mechanisms, clinical manifestations, treatment options, and prevention strategies for those with overweight or obesity.

 

DEFINITION OF OVERWEIGHT AND OBESITY

 

Overweight and obesity occur when excess fat accumulation (globally, regionally, and in organs as ectopic lipids) increases risk for adverse health outcomes.  Like other chronic diseases, this definition does not require manifistation of an obesity-related complication, simply that the risk for one is increased. This allows for implementation of weight management strategies targeting treatment and prevention of these related conditions. It is important to point out that thresholds of excess adiposity can occur at different body weights and fat distributions depending on the person or population being referenced.

 

Ideally, an obesity classification system would be based on a practical measurement widely available to providers regardless of their setting, would accurately predict health risk (prognosis), and could be used to assign treatment stategies and goals. The most accurate measures of body fat adiposity such as underwater weighing, dual-energy x-ray absorptiometry (DEXA) scanning, computed tomograpy (CT), and magnetic resonance imaging (MRI) are impractical for use in everyday clinical encounters. Estimates of body fat, including body mass index (BMI, calculated by dividing the body weight in kilograms by height in meters squared) and waist circumference, have limitations compared to these imaging methods, but still provide relevant information and are easily obtained in a variety of practice settings.

 

It is worth pointing out two important caveats regarding cuurent thresholds used to diagnose overweight and obesity. The first is that although we favor the assignement of specific BMI cut-offs and increasing risk (Table 1), relationships between body weight or fat distribution and conditions that impair health actually represent a continum. For example, increased risk for type 2 diabetes and premature mortality occur well below a BMI of 30 kg/m2 (the threshold to define obesity in populations of European extraction) (13). It is in these earlier stages that preventative strategies to limit further weight gain and/or allow weight loss will have their greatest health benefits. The second is that historic relationships between increasing BMI thresholds and the precense and severity of co-morbidities have been disrupted as better treatments for obesity-complications become available. For example, in the past several decades, atherosclerotic cardiovascular (ASCVD) mortality has steadily declined in the US population (14) even as obesity rates have risen (see below). Although it is generally accepted that this decline in ASCVD deaths is due to better care outside the hospital during a coronary event (e.g., better coordination of “first responders” services such as ambulances and more widespread use by the public of cardiopulmonary resusitation and defibrillator units), advances in intensive care, smoking cessation, and in the office (increased use of aspirin, statins, PCSK9 inhibitors, and blood pressure medications) (15), these data have also been cited to support the claim that being overweight might actually protect against heart disease (16). In this regard, updated epidemiological data on the health outcomes related to being overweight or having obesity should include not just data on morbidity and mortality, but also health care metrics such as utilization and costs, medications used, and the number of treatment-related procedures performed.

 

CLASSIFICATION OF OVERWEIGHT, OBESITY, AND CENTRAL OBESITY

 

Fat Mass and Percent Body Fat

 

Fat mass can be directly measured by one of several imaging modalities, including DEXA, CT, and MRI, but these systems are impractical and cost prohibitive for general clinical use. Instead, they are mostly used for research. Fat mass can be measured indirectly using water (underwater weighing) or air displacement (BODPOD), or bioimpedance analysis (BIA). Each of these methods estimates the proportion of fat or non-fat mass and allows calcutation of percent body fat. Of these, BODPOD and BIA are often offered through fitness centers and clinics run by obesity medicine specialists. However, their general use in the care of patients who are overweight and with obesity is still limited. Interpretation of results from these procedures may be confounded by common conditions that accompany obesity, especially when fluid status is altered such as in congenstive heart failure, liver disease, or chronic kidney disease. Also, ranges for normal and abnormal are not well established for these methods and, in practical terms, knowing them will not change current recommendations to help patients achieve sustained weight loss.

 

Body Mass Index

 

Body mass index allows comparison of weights independently of stature across populations. Except in persons who have increased lean weight as a result of intense exercise or resistance training (e.g., bodybuilders), BMI correlates well with percentage of body fat, although this relationship is independently influenced by sex, age, and race (17). This is especially true for South Asians in whom evidence suggests that BMI-adjusted percent body fat is greater than other populations (18). In the United States, data from the second National Health and Nutrition Examination Survey (NHANES II) were used to define obesity in adults as a BMI of 27.3  kg/m2 or more for women and a BMI of 27.8  kg/m2 or more for men (19). These definitions were based on the gender-specific 85th percentile values of BMI for persons 20 to 29 years of age. In 1998, however, the National Institutes of Health (NIH) Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults adopted the World Health Organization (WHO) classification for overweight and obesity (Table 1) (20). The WHO classification, which predominantly applied to people of European ancestry, assigns increasing risk for comorbid conditions—including hypertension, type 2 diabetes mellitus, and cardiovascular disease—to persons with higher a BMI relative to persons of normal weight (BMI of 18.5 - 25  kg/m2) (Table 1). However, Asian populations are known to be at increased risk for diabetes and hypertension at lower BMI ranges than those for non-Asian groups due largely to predominance of central fat distribution and higer percentage fat mass (see below). Consequently, the WHO has suggested lower cutoff points for consideration of therapeutic intervention in Asians: a BMI of 18.5 to 23  kg/m2 represents acceptable risk, 23 to 27.5 kg/m2 confers increased risk, and 27.5  kg/m2 or higher represents high risk (21,22).

 

Table 1 Classification of Overweight and Obesity by BMI, Waist Circumference, and Associated Disease Risk. Adapted from reference (20).

 

BMI (kg/m2)

Obesity Class

Disease Risk* (Relative to Normal Weight and Waist Circumference)

 

 

 

Men ≤40 inches (≤ 102 cm) Women ≤ 35 inches (≤ 88 cm)

> 40 in (> 102 cm)

> 35 in (> 88 cm)

 

Underweight

 

< 18.5

 

 

-

 

-

Normal†

18.5–24.9

 

-

-

Overweight

25.0–29.9

 

Increased

High

Obesity

30.0–34.9

35.0–39.9

1

2

High

Very High

Very High

Very High

Extreme Obesity

≥ 40

3

Extremely High

Extremely High

*Disease risk for type 2 diabetes, hypertension, and cardiovascular disease.

†Increased waist circumference can also be a marker for increased risk even in persons of normal weight.

 

Fat Distribution (Central Obesity)

 

In addition to an increase in total body weight, a proportionally greater amount of fat in the abdomen or trunk compared with the hips and lower extremities has been associated with increased risk for metabolic syndrome, type 2 diabetes mellitus, hypertension, and heart disease in both men and women (23,24). Abdominal obesity is commonly reported as a waist-to-hip ratio, but it is most easily quantified by a single circumferential measurement obtained at the level of the superior iliac crest (20). For the practioner, waist circumference should be measured in a standardized way (20) at each patient’s visit along with body weight. The original US national guidelines on overweight and obesity categorized men at increased relative risk for co-morbidities such as diabetes and cardiovascular disease if they have a waist circumference greater than 102 cm (40 inches) and women if their waist circumference exceeds 88 cm (35 inches) (Table 1) (20). These waist circumference thresholds are also used to define the “metabolic syndrome” by the most recent guidelines from the American Heart Association and the National Lipid Association (e.g., triglyceride levels > 150 mg/dL, hypertension, elevated fasting glucose (100 – 125 mg/dL)) or prediabetes (hemoglobin A1c between 5.7 and 6.4%) (25,26). Thus, an overweight person with predominantly abdominal fat accumulation would be considered “high” risk for these diseases even if that person does not meet BMI criteria for obesity. Such persons would have “central obesity.” It is commonly accepted that the predictive value for increased health risk by waist circumference is in patients at lower BMI’s (< 35 kg/m2) since those with class 2 obesity or higher will nearly universally have waist circumferences that exceed disease risk cut-offs.

 

However, the relationships between central adiposity with co-morbidities are also a continuum and vary by race and ethnicity. For example, in those of Asian descent, abdominal (central) obesity has long been recognized to be a better disease risk predictor than BMI, especially for type 2 diabetes (27). As endorsed by the International Diabetes Federation (28) and summarized in a WHO report in 2008 (29), different countries and health organizations have adopted differing sex- and population-specific cut offs for waist circumference thresholds predictive of increased comorbidity risk. In addition to the US criteria, alternative thresholds for central obesity as measured by waist circumference include > 94 cm (37 inches) and > 80 cm (31.5 inches) for men and women of European anscestry and > 90 cm (35.5 inches) and > 80 cm (31.5 inches) for men and women of South Asian, Japanese, and Chinese origin (28,29), respectively. 

 

EPIDEMIOLOGY OF OVERWEIGHT AND OBESITY IN THE UNITED STATES

 

In the United States (US), data from the National Health and Nutrition Examination Survey using measured heights and weights shows that the steady increase in obesity prevalence in both children and adults over the past several decades has not waned, although there are exceptions among subpopulations as described in greater detail below. In the most recently published US report (2017-2020), 42.4% of adults (BMI ≥ 30 kg/m2) (30) and 20.9% of youth (BMI ≥ 95th percentile of age- and sex-specific growth charts) (31) have obesity, and the age-adjusted

prevalence of severe obesity (BMI ≥ 40 kg/m2) was 9.2% (30) (Figure 1).

 

Figure 1. Trends in age-adjusted obesity (BMI ≥ 30 kg/m2) and severe obesity (BMI ≥ 40 kg/m2) prevalence among adults aged 20 and over: United States, 1999–2000 through 2017–2018. Taken from reference (30).

 

Obesity and Severe Obesity in Adults:  Relationships with Age, Sex, and Demographics

Figure 2. Age-Adjusted Prevalence of Obesity and Severe Obesity in US Adults. National Health and Nutrition Examination Survey data, prevalence estimates are weighted and age-adjusted to the projected 2000 Census population using age groups 20-39, 40-59, and 60 or older. Significant linear trends (P < .001) for all groups except for obesity among non-Hispanic Black men, which increased from 1999-2000 to 2005-2006 and then leveled after 2005-2006. Data taken from reference (31).

 

On average, the obesity rate in US adults has nearly tripled since the 1960’s (Reference (32) and Figure 2). These large increases in the number of people with obesity and severe obesity, while at the same time the level of overweight has remained steady (32,33), suggests that the “obesogenic” environment is disproportionately affecting those portions of the population with

the greatest genetic potential for weight gain (34). This currently leaves slightly less than 30% of the US adult population as having a healthy weight (BMI between 18.5 and 25 kg/m2).

 

Men and women now have similar rates of obesity and the peak rates of obesity for both men and women in the US occur between the ages of 40 and 60 years (Figures 2 and 3). In studies that have measured body composition, fat mass also peaks just past middle age in both men and women, but percent body fat continues to increase past this age, particularly in men

because of a proportionally greater loss in lean mass (35-37). The menopausal period has also been associated with an increase in percent body fat and propensity for central (visceral) fat distribution, even though total body weight may change very little during this time (38-41).

 

The rise in obesity prevalence rates has disproportionately affected US minority populations (Figure 2). The highest prevelance rates of obesity by race and ethnicity are currently reported in Black women, native americans, and Hispanics (Figure 2 and reference (42)). In general, women and men who did not go to college were more likely to have obesity than those who did, but for both groups these relationships varied depending on race and ethnicity (see below). Amongst women, obesity prevelance rates decreased with increasing income in women (from 45.2% to 29.7%), but there was no difference in obesity prevalence between the lowest (31.5%) and highest (32.6%) income groups among men (43).

 

Figure 3. Prevalence of obesity among adults aged 20 and over, by sex and age: United States, 2017–2018. Taken from reference (30).

 

The interactions of socieconomic status and obesity rates varied based on race and ethnicity (43). For example, the expected inverse relationship between obesity and income group did not hold for non-Hispanic Black men and women in whom obesity prevelance was actually higher in the highest compared to lowest income group (men) or showed no relationship to income by racial group at all (women) (43). Obesity prevalence was lower among college graduates than among persons with less education for non-Hispanic White women and men, Black women, and Hispanic women, but not for Black and Hispanic men.  Asian men and women have the lowest obesity prevelance rates, which did not vary by eduction or income level (43).

 

Central Obesity

 

As discussed above, central weight distribution occurs more commonly in men than women and increases in both men and women with age. In one of the few datasets that have published time-trends in waist circumference, it has been shown that over the past 20 years, age-adjusted waist circumferences have tracked upward in both US men and women (Figure 4). Much of this likely reflects the population increases in obesity prevelance since increasing fat mass and visceral fat track together (52).

 

Figure 4. Age-adjusted mean waist circumference among adults in the National Health and Nutrition Examination Survey 1999-2012. Adapted from (51).

 

Pediatrics

 

Childhood obesity is a risk factor for adulthood obesity (44-46). In this regard, the similar tripling of obesity rates in US youth (ages 2-19 years old)  (Figure 5) to 20.9% in 2018 (31) is worrisome and will contribute to the already dismal projections of the US adult population approaching 50% obesity prevelance by the year 2030 (47). Obesity prevalence was 26.2% among Hispanic children, 24.8% among non-Hispanic Black children, 16.6% among non-Hispanic White children, and 9.0% among non-Hispanic Asian children (48). Like adults, obesity rates in children are greater when they are live in households with lower incomes and less education of the head of the household (49). In this regard, these obesity gaps have been steadily widening in girls, whereas the differences between boys has been relatively stable (49).

 

Figure 5. Trends in obesity among children and adolescents aged 2–19 years, by age: United States, 1963–1965 through 2017–2018. Obesity is defined as body mass index (BMI) greater than or equal to the 95th percentile from the sex-specific BMI-for-age 2000 CDC Growth Charts. Taken from reference (50).

 

With regard to socieconomic status, the inverse trends for lower obesity rates and higher income and education (of households) held in all race and ethnic origin groups with the following exceptions:  obesity prevalence was lower in the highest income group only in Hispanic and Asian boys and did not differ by income among non-Hispanic Black girls (49).

 

 

Historically, international obesity rates have been lower than in the US, and most developing countries considered undernutrition to be their topmost health priority (53). However, international rates of overweight and obesity have been rising steadily for the past several decades and, in many countries, are now meeting or exceeding those of the US (Figure 6) (54,55). In 2016, 1.3 billion adults were overweight worldwide and, between 1975 to 2016, the number of adults with obesity increased over six-fold, from 100 million to 671 million (69 to 390 million women, 31 to 281 million men) (54). Especially worrisome have been similar trends in the youth around the world (Figure 6), from 5 million girls and 6 million boys with obesity in 1975 to 50 million girls and 74 million boys in 2016 (54), as this means the rise in obesity rates will continue for decades as they mature into adults. 

 

The growth in the wordwide prelance of overweight and obesity is thought to be primarily driven by economic and technological advancements in all developing societies (56,57). These forces have been ongoing in the US and other Western countries for many decards but are being experienced by many developing countries on a compressed timescale. Greater worker productivity in advancing economies means more time spent in sedentary work (less in manual labor) and less time spent in leisure activity. Greater wealth allows the purchase of televisions, cars, processed foods, and more meals eaten out of the house, all of which have been associated with greater rates of obesity in children and adults. More details and greater discussion of these issues can be found in Endotext Chapters on Non-excercise Activity Thermogenesis (58) and Obesity and the Environment (9).

 

Regardless of the causes, these trends in global weight gain and obesity are quickly creating a tremendous burden on health-care systems and cost to countries attempting to respond to the increased treatment demands (59). They are also feuling a rise in global morbity and mortality for chronic (non-communicable) diseases, especially for cardiovascular disease and type 2 diabetes mellitus, and especially in Asian and South Asian populations where rates of type 2 diabetes are currently exploding (15,60-63). Efforts need to be made to deliver adequate health care to those currently with obesity and, at the same time, find innovative and alternative solutions that allow economies to prosper and to incorporate technologies that will reverse current trends in obesity and obesity-related complications.

 

Figure 6: Trends in the number of adults, children, and adolescents with obesity and with moderate and severe underweight by region. Children and adolescents were aged 5–19 years. (Taken from (54)).

 

SUMMARY

 

Obesity is both a chronic disease in its own right and a primary contributor to other leading chronic diseases such as type 2 diabetes, dyslipidemia, hypertension, and cardiovascular diseases. In the clinic, obesity is still best defined using commonly available tools, including BMI and waist circumference; although it is hoped that newer imaging modalities allowing more precise quantification of amount and distribution of excess lipid depots will improve obesity risk assessment. The general rise in obesity taking place in the US over the past 50 years is now occurring globally. In the US, the prevalence rates of obesity in adult men and women are now similar at 40%, and minorities are disproportionately affected, including Blacks, Native Americans, and Hispanics, with obesity rates of 50% or higher. Particularly worrisome is the global increase in obesity prevalence in children and adolescents as these groups will continue to contribute to a rising adult obesity rates for several decades to come. As important as finding solutions that address the global logistical and financial challenges facing health-care systems attempting to meet current demands of obesity and weight-related co-morbidities will be finding innovative solutions that prevent and reverse current population weight gain trends.

 

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Non-Invasive Techniques In Pediatric Dyslipidemia

ABSTRACT

 

Symptomatic and overt atherosclerosis in children is rare. The earliest lesion of atherosclerosis develops in childhood, but may not correlate with traditional markers of atherosclerosis. Children are considered low risk populations for atherosclerosis. The use of non-invasive imaging can have a role to identify early subclinical vascular changes. Imaging techniques are becoming useful adjuncts in conjunction with traditional lipid markers. These techniques have been extensively used in children and have provided indirect evidence for premature atherosclerosis, risk stratification, treatment effectiveness, and longitudinal tracking of adult cardiovascular risk. Use of imaging may be a useful adjunct in combination with traditional cardiovascular risk factors to assess dyslipidemia in children.

 

INTRODUCTION

 

Medical imaging is an important modality used to create visual representation of the body for clinical analysis and interventions. The use of imaging in children can play an important role identifying subclinical disease of dyslipidemia. Identification can be clinically useful for risk stratification and treatment intervention.  The use of imaging in children was previously reserved for research but with improved methodologies have been shown to be a prospective clinical tool for children with dyslipidemia. The combination of imaging and traditional risk assessment has improved our knowledge of the natural history of atherosclerosis in children and adolescents.    

 

Symptomatic atherosclerosis rarely occurs in children with the exception of children with homozygous familial hypercholesterolemia. Vascular progression in children with atherosclerosis is usually minor and clinically asymptomatic.  Longitudinal studies have demonstrated that the atherosclerosis process can be accelerated in individuals with multiple risk factors or high-risk conditions. Early identification would allow for early intervention to delay the natural process of atherosclerosis.     

 

Multiple non-invasive imaging modalities have been used in children for the assessment of subclinical vascular changes, such as vessel endothelium thickening (cIMT), mechanical changes (pulse wave velocity), physiological changes (flow-mediated dilation), and arterial structure changes (CT and MRI). Non-invasive techniques do not require radiation exposure and is preferred over imaging techniques that utilize radiation. 

 

Table 1. Imaging Modalities to Assess for Subclinical Atherosclerosis

Technique

Abbreviation

Principle

Invasive

Radiation

Carotid intimal & medial thickness

cIMT

Arterial wall thickness

No

No

Pulse-waved velocity

Pulse-wave analysis

PWV

 

PWA

 

Stiffness in arteries

No

No

Flow mediated dilation

FMD

Endothelial function

No

No

Echocardiogram

ECHO

Anatomical changes

No

No

Ultrasound

U/S

Velocity, Size

No

No

Coronary artery calcification

CAC

Plaque composition

No

Yes

Computed Tomography

CT

Stenosis, composition

No

Yes

Magnetic Resonance Imaging

MRI

Stenosis, composition

No

No

Coronary Angiography

CA

Stenosis

Yes

Yes

 

The use of non-invasive methods has improved our knowledge and ability to risk stratify children and track longitudinal vascular changes into adulthood. It has been established that children that enter adulthood with multiple risk factors will have premature progression of atherosclerosis as a young adults and adults. The i3C meta-analysis demonstrated the number of abnormal childhood CV risk factors was predictive of elevated adult cIMT measurements.

 

SUBCLINICAL ATHEROSCLEROSIS IN CHILDREN

 

Autopsy studies have demonstrated that atherosclerosis substrate begins in childhood (1).  The initial process is microscopic lesions and transitions to macroscopic changes particularly in places that are prone to the development of atherosclerosis. Areas are predisposed to atherosclerosis include arterial bifurcation sites in the common carotid, coronaries, and abdominal aorta. The accumulation of lipid substrate is deposited in the intima of arteries and forms the fatty streak. These early lesions are generally non-occlusive lesions.  The Bogalusa heart study demonstrated the prevalence of fatty streak in coronary arteries in children 2-15 years of age with 50% of surface vessel involvement (2).  The degree of progression increased with greater number of risk factors in the Pathological Determinants of Atherosclerosis in Youth (PDAY) study (3).   

 

Subclinical atherosclerotic changes in children can manifest as dysfunctional arterial vasodilation, alterations of arterial elasticity (compliance and distensibility), and thickening of arterial walls.  

 

The arterial wall consists of three layers (figure 1). The tunica externa or tunica adventitia (outermost layer) is composed of connective tissue and collagen. The tunica media (middle layer) is made up of smooth muscle cells and elastic tissues. The pediatric arterial vessel is composed of more elastin than collagen. The tunica intima (innermost layer) consists of endothelial cells. The endothelium is a single cell layer lining the vascular lumen and has an important role in maintaining vascular integrity.  

 

Figure 1. Components of the endothelial arterial wall. (Reprinted): Reference 38.

Atherosclerosis is characterized by the formation of lipid substrates, calcium, and other substances in the arterial wall that results in arterial wall thickening and progression to arterial plaques (figure 2). The pathological substrate for vascular dysfunction is mediated by endothelial dysfunction. Endothelial changes are a complex mechanism, but is composed of oxidative stress, loss of vasoactive substrates, inflammatory substances, and prothrombotic state. This cluster of harmful stimuli accelerates and compounds the mechanism of endothelial dysfunction. This process is the underlying mechanism of clinical myocardial infarctions and stroke.  

 

Figure 2. Arterial progression model of atherosclerosis. Earliest substrate manifest as “fatty streak” in children. Further progression is accelerated by additional cardiac risk factors.

 

The substrate of atherosclerosis develops in childhood as the fatty streak. Development of the fatty streak can be evident by 3 years of age. Premature progression can be accelerated by additional risk factors.

 

Our understanding of the atherosclerotic natural process in children is based on imaging studies in individuals with autosomal dominant Familial Hypercholesterolemia (FH).  Familial hypercholesterolemia is a disease of increased LDL cholesterol plasma concentrations that accumulates in the arterial vessel wall. This process has been accelerated in children with homozygous FH.  Children with homozygous FH manifest as early endothelial dysfunction and have been observed to have increased carotid intimal-media thickness. Carotid intimal thickness has been used as a surrogate end-point marker with statin intervention in children with FH.

 

RISK FACTORS FOR PREMATURE ATHEROSCLEROSIS

 

The prevalence of obesity in children has stabilized over the recent years. However, the rate of morbid obesity continues to increase (4). Obesity is associated with an increased metabolic demand. Arterial stiffness is impacted by increased blood volume (preload) and alterations of afterload.  Previous studies have demonstrated a linear relationship between obesity in childhood and increased cIMT in young adults (5).  Indirect measure of subclinical atherosclerosis measured by cIMT and FMD have been observed in obese adolescents and young adults (6). Individuals with the largest increase in BMI during childhood and adolescents that remained obese had greatest changes in cIMT (7).  

 

Chronic elevated blood pressure has an important role in vascular changes. Elevated blood pressure is a complex relationship that is affected by several factors including the sympathetic nervous system, renin-angiotensin-aldosterone system, and stimulation of vascular smooth muscle proliferation.  Children with hypertension have evidence of left ventricular hypertrophy (LVH), increased LV mass, carotid intima-medial thickening (CIMT), and vascular endothelial dysfunction. Increased LV mass is a prominent imaging marker for clinical evidence of target-organ damage (8). A left ventricular mass index above 51 g/m2.7 has been associated with a greater risk of adverse cardiovascular outcome (9).  

 

The combination of insulin resistance and hyperglycemia are linked with endothelial dysfunction and mediators of inflammation. Children with diabetes compared with those without diabetes are at increased risk for other atherogenic factors, such as hypertension and dyslipidemia. Mixed dyslipidemia pattern is characterized by high Apo-B (increased small dense LDL particles and cholesterol ester rich VLDL remnants) and low Apo-A (low HDL particles) (11). The TG/HDL-c ratio is a surrogate atherogenic index of mixed dyslipidemia.  TG/HDL-c ratio was shown to be an independent determinant of arterial stiffness in obese adolescents using brachial artery distensibility (BrachD) and carotid-femoral pulse wave velocity (PWV) (10).

 

Metabolic syndrome (MS) has been established as a cluster of CV risk factors including hypertension, overweight/obesity, dyslipidemia (high triglycerides, low HDL), and insulin resistance.  However, the relationship between childhood metabolic syndrome and CVD events are not well characterized and there has been no consensus in the pediatric population (11). The components of MS are considered independent risk factors associated with vascular dysfunction (12).       

 

NON-INVASIVE IMAGING TECHNIQUES

 

Carotid Intima-Media Thickness (CIMT)

 

The use of cIMT technique is a useful surrogate technique to assess vessel intimal thickness in children with dyslipidemia. Subclinical changes in children are manifested as diffuse thickening of the intima-media space rather than a discrete lipid core or an advance lipid lesion.   

 

The imaging method utilizes high resolution B-mode 2-dimensional (2D) ultrasonography with a high-frequency (7 to 12-MHz) linear array transducer for assessment of carotid intimal and medial vessel. Imaging measurements are traditionally conducted on the common carotid artery at the far-wall of the vessel. Changes to the intimal-medial thickness in the far-wall have correlated with direct histological examination.  Most pediatric studies have focused on assessment of the carotid artery far wall. The distance between the leading edge of the first echo-bright line (lumen-intima interface) and the leading edge of the second echo-bright line (media-adventitia interface) is defined as the carotid intimal-media interface (figure 3) (13). An abnormal cIMT is a thickened sub-intimal layer due to atherogenic particle deposition and inflammatory process.

 

Figure 3. Carotid endothelial structures by B-mode ultrasound.

 

Imaging acquisition is obtained with 2D grayscale imaging along the longitudinal axis of the artery.  Measurement values should be recorded at end diastole and calculated by mean IMT measurement.  Reproducibility of the fall-wall in the carotid artery has been validated and reproducible in previous pediatric studies.

 

Several studies have demonstrated indirect evidence for early development of atherosclerosis in children. Increased cIMT has been demonstrated in pediatric patients with familial hypercholesterolemia (FH), hypertension, obesity, diabetes, and metabolic syndrome (14,15,16, 17,18). The use of cIMT has been used to evaluate cardiovascular risk in pediatric populations with high-risk conditions and chronic medical conditions, such as juvenile rheumatoid arthritis, end-stage renal disease, and Kawasaki disease (19,20,21).

 

The use of cIMT has been utilized to show treatment effectiveness of statins in children with familial hypercholesterolemia. In a study of 214 children with heterozygous FH who were 8-18 years of age, were randomly assigned to the pravastatin treated group and compared with the placebo group. After 2 years of treatment with a statin, cIMT showed significant regression in the pravastatin group. Longitudinal follow-up of 186 children with early initiation of statin in children with FH after 4.5 years delayed the progression of cIMT changes. Data indicated that early treatment with a statin delayed the progression of atherosclerosis in adolescents and young adults (22). The CHARON study assessed the effect of 2-year treatment with rosuvastatin on cIMT in children with HeFH. The result of the study showed a significant reduction in the progression of atherosclerosis, as assessed by cIMT in children with HeFH compared with untreated, unaffected siblings (23).

 

Numerous longitudinal studies have demonstrated the association between CV risk factors developed in childhood and premature atherosclerotic changes into adulthood. In the Bogalusa study, childhood measurements of LDL-C levels and BMI positively predicted increased cIMT in a cohort of 486 adults aged 25-37 years (24).  The Muscatine study demonstrated childhood total cholesterol levels and BMI predicted cIMT changes in a cohort of 725 adults (25). In a meta-analysis of i3C study (International Childhood Cardiovascular Cohort Consortium), a combined analysis of prospective studies showed the number of abnormal childhood CV risk factors (i.e., cholesterol, triglycerides, blood pressure, BMI) were longitudinally predictive of adult cIMT. This process was the greatest in children with risk factors developed at 9 years of age or greater (26).

 

Arterial Stiffness

 

There are several indices of arterial stiffness measurements. Functional measurement such as pulse wave velocity (PWV), pulse wave analysis (PWA), ambulatory arterial stiffness index (24-hour ambulatory blood pressure monitoring), and assessment of endothelial dysfunction (flow-mediated dilation).

 

Stiffer arterial vessels require greater force to expand and accommodate flow to perfuse tissues and organs. Arterial distensibility and compliance changes are a complex mechanism of hemodynamic factors, extrinsic factors and intraluminal influences.  

 

Pulse wave velocity measures the speed of the pressure pulse from the heart as it circulates through the blood vessels. Measurement of the pulse wave (indicator of blood flow) to travel a given distance between 2 sites (carotid to femoral) in the arterial system is measured and recorded (figure 4). A faster PWV is an indicatory of stiffer arterial vessel. PWA is an indirect measure of arterial stiffness that analyzes arterial waveform reflections. PWA is a supplement to PWV analysis. Augmentation index is a parameter derived from systolic peak differences. Risk factors associated with higher PWV include BMI, blood pressure, heart rate, dyslipidemia (27).

 

Figure 4. Tonometric pulse wave velocity. The arterial time difference between two sites is calculated as the PWV.

 

Arterial stiffness is associated with traditional CV risk factors and metabolic alterations including obesity, impaired glucose tolerance, and dyslipidemia. Risk stratification using triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) was tested as an independent predictor of arterial stiffness in obese children. The cohort of 893 subjects aged 10 to 26 years old that demonstrated higher TG/HDL-C ratio had the stiffest vessels measured by brachial artery distensibility (BrachD), augmentation index, and carotid-femoral pulse-wave velocity (28). In young individuals with T1DM with poor glycemic control, higher levels of traditional CV risk factors were independently associated with accelerated arterial aging using PWV and augmentation index (29).

 

Flow-mediated dilation (FMD) is a technique used to assess peripheral macrovascular endothelial function. Endothelial dysfunction is characterized by a complex imbalance of proatherogenic factors such as vasoconstriction, platelet alterations, cellular dysfunction, and inflammation. Endothelial changes are an early reversible stage in the progression of atherosclerosis.

 

The technique measures the nitric oxide-mediated vasodilation produced by increased blood flow after a period of ischemia (Reactive hyperemia). The method requires inflating upper extremity blood pressure at suprasystolic pressures for a short period of time that occludes blood flow. After a period of time, the occlusion is released and functional increased shear stress is generated as signal amplitude.  Both diameter and blood velocity are assessed before and after occlusion with results being reported as a percent change from baseline. A lower index measurement indicated poor endothelial function. A lower artery reactivity has been identified in children with obesity, family history of premature coronary disease and type I DM (30, 31, 32).  A study of 50 children (aged 9 to 18 years) with FH were randomized to simvastatin or placebo for 28 weeks. A control group of 19 non-FH children were matched. Baseline FMD was impaired in the children with FH compared to non-FH group. After treatment there was a significant improvement of endothelial dysfunction towards normal values after short term statin therapy (33).

 

Echocardiography

 

Traditionally transthoracic echocardiography is an image modality that utilizes an ultrasound beam to acquire anatomical images through m-mode imaging and 2D imaging. The use of echocardiogram can be useful to assess subclinical changes of epicardial fat mass, valvular changes, and aortic vessel stenosis. 

 

Subclinical adipose changes to epicardial thickness may have a role in the development of cardiovascular disease.  Studies in children with greater epicardial adipose tissue is associated with larger left ventricular mass, higher blood pressures, and atherogenic lipid profiles (34) Epicardial fat thickness can be visualized using standard parasternal long-axis and short-axis imaging planes of the right ventricle (figure 5). The epicardial fat is the echo-free space between the outer wall of the myocardium and visceral layer of the pericardium. The thickness is measured perpendicularly on the free wall of the right ventricle at end-systole. Echocardiographic measurement might serve as a simple tool for the assessment of cardio-metabolic risk stratification (35).

 

Figure 5. Epicardial fat thickness by 2D echocardiogram in modified parasternal view. (Dashed lines represent epicardial fat structure).

 

A cohort of 33 young patients with homozygous FH were found to have subclinical FH valvulopathy present in 64% of patients (36). Most commonly on the aortic valve and mitral valve. The majority of the patients with valvular changes did not have valvular calcification. Isolated case studies in homozygous FH individuals have presented with heart failure and new systolic murmurs. Echocardiogram is useful in demonstrating supravalvular aortic stenosis due to endothelial dysfunction.  Some cases required surgical aortic root replacement (37). Stenosis occurred despite patients receiving aggressive statin treatment and apheresis.  

 

Advance Imaging Modalities

 

Advance imaging modalities such as cardiac magnetic resonance imaging (C-MRI) and computed tomography (CT) imaging are useful methods in understanding anatomical changes and tissue characterization.  Clinical decision to utilize CT or MRI in pediatrics is debated on the risk of radiation exposure (CT imaging) and the imaging resolution limitations of each modality. The use of CT or MRI is generally not a useful tool to assess subclinical changes in the pediatric population with dyslipidemia. MRI has demonstrated abdominal aorta atheroma formation in adolescents with severe dyslipidemia (38). The use of MRI is being considered as potential research technique for assessment of subclinical abdominal aortic wall changes.    

 

Coronary artery calcification with electron-beam computed tomography (CT) is used to assess the presence and extent of calcified plaque in the coronary arteries that is associated with atherosclerosis. The coronary artery calcium (CAC) score is a helpful prognostic tool and used as a method to assess risk classification for adult atherosclerosis cardiovascular disease (ASCVD). The use of CAD is not recommended as a subclinical technique since the development of calcification generally does not occur until the fourth decades of life. CAC has been utilized in a study of children with familial hypercholesterolemia (39). The use of CAC technique has been limited in pediatrics.

 

Myocardial perfusion imaging is reserved for adults with advanced cardiovascular risk and disease. The use of perfusion imaging in children is not recommended. Myocardial perfusion is helpful in children with Kawasaki (40) and congenital heart defects with coronary artery manipulation.    

 

Invasive coronary angiography is the “gold standard” and direct assessment of coronary arterial stenosis. Utilization of angiography should be reserved to children with presumed advance atherosclerosis, such as homozygous FH or rare genetic dyslipidemia. Angiography technique is not a useful modality for subclinical evaluation in children.

 

Ultrasound Imaging

 

The use of sound waves is a useful non-invasive imaging modality in the evaluation of pediatric subclinical atherosclerosis. Ultrasound can contribute to early detection of renal artery changes and risk stratification attributed to atherosclerosis. Early atherosclerosis stress and inflammation affect the proximal renal arteries causing increased velocity shear stress and longitudinal narrowing. Long term pathological changes develop into atherosclerotic renal artery stenosis (ARAS) in the adult population. Arterial vascular changes are characterized by increased systolic blood pressure an indicator of preclinical atherosclerosis in children.

 

Renal size (length) is a marker of kidney mass and renal function. Carotid-IMT has been shown to be a surrogate maker for renal function. Ultrasound parameters in 515 prepubertal children (lean, overweight, obese) demonstrated renal size and associated carotid-IMT and systolic BP may play a role in the assessment of renal vascular function and early assessment of cardiovascular risk in children (41).  

 

SUMMARY

 

Utilizing imaging techniques in children with dyslipidemia has been extensively used and a valuable tool in our understanding of atherosclerosis process in children. Imaging has been shown to be safe, reliable, and reproducible. With further developments and research, imaging may provide a useful practical tool in the general evaluation of children with dyslipidemia. In combination with family history, traditional CV risk factors, and biochemical markers the use of imaging techniques will refine our clinical awareness for better cardiovascular health metrics and promotion of ideal cardiovascular health in children.  

 

REFERENCES

 

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Secondary Hypertriglyceridemia

ABSTRACT

 

Hypertriglyceridemia (HTG) is often secondary to obesity-related insulin resistance (1,2), which is caused by excessive intake of fats and carbohydrates without compensatory utilization of these calories, but other common and rare causes should be considered (3,4,5). Genetic influences, gestational conditions, and nutrition in infancy and childhood contribute to HTG associated with formation of an atherogenic dyslipidemia profile consisting of high TG, low high-density lipoprotein-cholesterol (HDL-C), increased LDL particle number, smaller LDL size and density, and elevated apolipoprotein B. Very high TG levels generally result from defective disposal by lipoprotein lipase and can cause pancreatitis. Defining and treating the underlying cause are necessary to restore the lipids and lipoproteins to normal. Renal, hepatic, endocrine, immune, and pharmacological causes are in the differential diagnosis. Rare diseases such as lipodystrophy and glycogen storage disease are particularly challenging and require specific management strategies. Prevention of acute pancreatitis by lowering TG is a priority when TG is very high (> 1000 mg/dl), and lifestyle modification is the basis of management for all cases with high and moderately high levels. Since TG metabolism is associated with generation of an atherogenic dyslipidemia profile, predictors of coronary artery disease (CAD) such as LDL-C and non-HDL-C become targets when they exceed cut points.

 

INTRODUCTION

 

This chapter is an overview of causes of hypertriglyceridemia (HTG) that begin during gestation and present in childhood and adolescence, either interacting with genetic background or directly contributing to the TG levels. These disorders are common, such as obesity, or less common such as glycogen storage disease and lipodystrophy for which treatment can be more challenging. Also, both common and unique pharmaceutical agents need to be considered as causes since treatment modification can contribute to reversing the HTG. Dyslipidemia presenting in adolescence is often associated with one or more components of the metabolic syndrome, i.e., obesity, hypertension, and impaired glucose tolerance, and presents with high TG and low HDL-C (6,7,8, 9,10) however, a wide variety of other causes can contribute to the differential diagnosis of HTG. Genetic background, gestational factors, nutrition during infancy and childhood, demographic, and environmental factors are important considerations. Also, understanding how TG is distributed among lipoproteins and how it influences lipoprotein composition and subsequent lipolysis, uptake by receptors and the arterial wall provides important background for understanding associations with specific diagnoses and when treatment can be effective.

 

DIET

 

Although the Cardiovascular Health Integrated Lifestyle Diet (CHILD 1) (11) recommends a balanced diet of carbohydrates (50%), which includes fiber, fat (30%) of which no more than 10% of total calories come from saturated fats, and protein (20%), these guidelines are often not well adhered to. Nutritional intake by many individuals comprises additional consumption of nonessential calories consisting of fats, both saturated and trans fats, as well as carbohydrates such as High-Energy Fructose Corn Syrup (HFCS) and sucrose. This coupled with a decrease in physical activity and increased time spent in leisure activities (i.e., screen time) leads to excessive weight gain, often starting at a young age, metabolic syndrome, and insulin resistance. In an active pediatric preventive cardiology program, the number of children referred because of secondary hypertriglyceridemia and obesity is approximately twice that of children referred for Familial Hypercholesterolemia (12). As excessive consumption of fat and sugar will result in increased levels of triglycerides, it is important to understand both these metabolic pathways and nutritional management is the first step in any treatment algorithm (13).

 

Because of the 2011 NHLBI recommendations for universal screening between 9 and 11 years of age, pediatric medical providers are encouraged to evaluate patients at this time with a non-fasting non-HDL cholesterol (14). However, children with additional risk factors notably including a BMI >95th %ile, should be screened with a fasting lipid profile as early as 2 years of age. Other children in this category include those whose parent or grandparent have a known history of a cardiac event such as myocardial infarction (mother or grandmother <65 years of age; father or grandfather <55 years of age), children with diabetes or hypertension.

 

Dietary consumption of HFCS has increased rapidly since its discovery in 1965 (15). It is a low-cost sweetener, similar in taste to granulated sugar (sucrose), made from cornstarch and is commonly used in two forms. The first form HFCS is widely used commercially in some beverages, processed foods, cereals, and baked goods; the second HFCS is used in manufacturing of soft drinks (the numerical values reflect the percent fructose) (16). Although there is some dispute whether HCFS has led to the increase in obesity (17), it is apparent that both forms are consumed in larger quantity in the American diet. In 2018, the average American consumed approximately 22.l pounds of HFCS and 40.3 pounds of refined cane and beet sugar (18).

 

Both sucrose and HFCS are rapidly absorbed during digestion and hydrolyzed by the enzyme sucrase to form glucose and fructose in the microvilli lining the duodenum (19). Unlike fat metabolism which is slow, both fructose and glucose are usually metabolized within two hours in individuals who are not diabetic (20). Whereas most dietary glucose will pass through the liver and be used by skeletal muscle to form ATP for cell energy or processed by fat cells to glycerol

phosphate for triglyceride synthesis and stored energy, fructose is almost exclusively metabolized in the liver (Figure 1). The first step of fructose metabolism is the conversion to fructose 1-phosphate (F-1-P) by the enzyme fructokinase. F-1-P can then form either glycerol or dihydroxyacetone (DHAP). Whereas glycerol will form glycerol-3 Phosphate (G3P), DHAP can either form G3P or be isomerized to glyceraldehyde 3-phosphate (Ga-3-P). Ga-3-P will be oxidized to form pyruvate and reduced to lactate or be decarboxylated to form acetyl CoA. Acetyl CoA is a central intermediate in metabolism and can form a variety of byproducts including cholesterol, ATP, and fatty acids. G3P can then combine with fatty acids to form triglyceride which the liver packages as VLDL, the latter circulated in the blood stream. Hepatic glucose can either undergo glycogenesis which forms glycogen or glycolysis which can form DHAP. Like fructose metabolism, DHAP can form either G3P or Ga-3-P. From here the two pathways are similar to fructose metabolism with the ultimate formation of triglyceride which is then released from the liver within VLDL.

Figure 1. Fructose and Glucose Metabolism.

TG-RICH LIPOPROTEIN COMPOSITION

 

Triglyceride (TG) is normally located in the core of spherical circulating plasma lipoproteins. In the fasting state, VLDL is typically composed of 55% TG and 22% cholesterol, LDL has 5% TG and 50% cholesterol, and HDL has 5% TG and 20% cholesterol (21). Increases in hepatic

production of VLDL account for the majority of HTG cases resulting in a disproportionate increase in TG. However, VLDL is 22% cholesterol, which also is increased when VLDL production is excessive or when its disposal is defective leading to an elevation of the total cholesterol. In contrast, intestinally derived chylomicrons increase after meals and contain 90% triglyceride and only 3% cholesterol, but are efficiently catabolized by lipoprotein lipase, and their resulting remnant particles are taken up by hepatic receptors. Normally, TG reaches a peak 3 to 6 hours after a fat-containing meal and declines until there are no chylomicrons after ten hours of fasting. However, when disposal mechanisms are defective, chylomicrons account for very high TG levels and VLDL particles compete for lipolysis by lipoprotein lipase. Under these conditions the ratio of triglyceride to cholesterol approaches 10 to1, whereas the ratio is closer to 5 to1 when VLDL predominates. Excessive cholesterol enrichment of VLDL approaching a 1:1 ratio occurs when disposal of chylomicron and VLDL remnants are delayed – a defect usually presenting in adulthood and termed familial dysbetalipoproteinemia, a disorder attributed to variation in the amino acid sequence of Apo E (22).

 

NON-HDL CHOLESTEROL IN HTG

 

Since increased TG levels are often associated with atherogenic dyslipidemia, early plaque formation can occur. The Bogalusa Heart Study found that TG, total cholesterol and LDL-C in children and young adults aged 2 to 39 years of age were associated with post-mortem lesions in the coronary arteries and aorta (23), findings supported by the autopsy-based Pathological Determinants of Atherosclerosis in Youth (PDAY) study (24). While HTG has long been known as a biomarker associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) (25), the role for TG in atherosclerosis has remained less clear than for LDL-C but recent data supports a compelling role for TG and TG-rich lipoproteins as a cause of ASCVD rather simply as a biomarker (26,27,28). Consistently stronger prediction by non-HDL-C than LDL-C indicates that the cholesterol content of TG-rich lipoproteins (VLDL, IDL) represented by non-HDL-C can be regarded as a better predictor of risk than TG. This is also supported by the PDAY study in which non-HDL-C was associated with fatty streaks and raised lesions (29), and risk factors, including non-HDL-C and low HDL-C, accelerated progression of flat fatty streaks to raised lesions in the second decade. Childhood non-HDL-C, TG, Apo B, and Apo B:Apo A-I ratio all predicted carotid IMT after more than 20 years of follow-up, with non-HDL-C being superior to TG. (30) Therefore, targeting non-HDL-C in cases with intermediate triglyceride levels is a useful and productive strategy endorsed by the 2011 NHLBI (National Heart Lung and Blood Institute) Expert Panel’s recommendations (14).

 

TG METABOLISM IN THE SETTING OF INSULIN RESISTANCE

 

Common secondary HTG occurs in insulin resistant states such as obesity and type 2 diabetes (T2D) and can often become modified or exacerbated by other secondary causes. Since the abnormal lipid metabolism in insulin resistance has been extensively studied it serves as a foundation for understanding secondary dyslipidemia and potential for exacerbation by other causes (Figure 2).

 

Figure 2. Lipoprotein Metabolism in Insulin Resistance. A combination of excess production and disposal processes results in secondary HTG and atherogenic dyslipidemia in the insulin resistant state. Chylomicrons and VLDL production originating from the intestine and liver are increased. Mobilization of free fatty acids (FFA) from fat cells by hormone sensitive and TG lipases (HSL/TGL) provides the liver with substrate for VLDL formation. Dietary intake of fat provides the intestine with TG for chylomicron formation, which is upregulated in insulin resistance. Hepatic VLDL containing excess Apo C-III relative to Apo E is increased; Apo C-III delays receptor-mediated hepatic uptake of VLDL and chylomicron remnants resulting in formation of intermediate density lipoproteins (IDL, not shown) and smaller and denser low-density lipoproteins (LDL). Lipoprotein lipase (LPL) is inhibited by Apo C-III and decreased by insulin resistance and/or deficiency. Cholesterol ester transfer protein (CETP) is upregulated resulting in exchange of TG and cholesterol ester (CE), leading to TG enrichment of LDL and HDL. Both become substrates for hepatic triglyceride lipase (HTGL), which is upregulated and acts on TG-enriched HDL and LDL to make them smaller, atherogenic and dysfunctional. Apolipoproteins A-I, B-48, B-100, C-I, C-II, C-III (C), and E are labelled and play important roles in lipoprotein metabolism.

 

HTG PREVALENCE

 

In the U.S., the latest prevalence data for HTG comes from the 1999 - 2006 NHANES study, which found prevalence rates of 5.9% in normal weight children, 13.8% in overweight children and 24.1% in obese children (31). Given that Skinner et al found a positive linear trend for all definitions of overweight and obesity among children 2-19 years old, most prominently among adolescents and children aged 2 to 5 years (32), the current prevalence of HTG is almost

 

certainly significantly higher. Abnormal TG levels for children are generally classified on the basis of cut points based on population norms recommended by the American Academy of Pediatrics and the American Heart Association (33). The 50th to 95th percentile values for TG in children are presented in Table 1. Acceptable levels in children defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health (14) are summarized in Table 2.

 

Table 1. Triglyceride Levels for Males and Females 5-19 Years of Age

Percentile

Males

Females

5-9 yrs

10-14 yrs

15-19 yrs

5-9 yrs

10-14 yrs

15-19 yrs

50th

48

58

68

57

68

64

75th

58

74

88

74

85

85

90th

70

94

125

103

104

112

95th

85

111

143

120

120

126

Mean concentration of triglycerides (mg/dL). Adapted from: Tamir I, Heiss G, Glueck CJ,

Christensen B, Kwiterovich P, Rifkind B. Lipid and lipoprotein distributions in white children ages 6–19 yrs: the Lipid Research Clinics Program Prevalence Study. J Chronic Dis. 1981; 34(1):27– 39.

 

Table 2. Acceptable Lipid levels for Children - Expert Panel on Integrated Guidelines for Cardiovascular Health (14)

 

Acceptable

Borderline

High

Total Cholesterol

<170

170-199

≥200

LDL-C

<110

110-129

≥130

Non-HDL-C

< 120

 

 

Triglycerides

 

0-9 years

<75

75-99

≥100

10-19 years

<90

90-129

≥130

 

The non-HDL-C which is equally accurate when measured on a fasting or non-fasting lipid panel reflects the sum of all apolipoprotein (Apo)-B-containing, triglyceride-rich lipoprotein subfractions (LDL, VLDL, Intermediate-Density Lipoprotein (IDL), lipoprotein (a), and chylomicron remnants. As triglycerides increase, there is a corresponding increase in the non–HDL-C level which correlates with Apo B much better than LDL-C. Hypertriglyceridemia can be diagnosed if TG level is ≥100 mg/dL in children (<10 year) or ≥130 mg/dL in adolescents (10–19 years) based on an average of two fasting measurements. Severe secondary hyper-TG, defined as levels above 1000 mg/dL, presents a risk for acute pancreatitis, especially when lipoprotein lipase-mediated clearance is saturated (> 800 mg/dL) causing the triglyceride to attain very high levels often exceeding 1000 mg/dL, with appearance of chylomicrons on standing plasma. Moderate HTG, defined as levels 150-499 mg/dL, is a risk factor for CVD. These children tend to be undertreated despite potential for reversal and primary prevention of cardiovascular disease (34).

 

MEASUREMENT ASPECTS

 

Although the non-HDL-cholesterol does not require fasting, the standard lipid profile which includes total cholesterol (TC), LDL-C, HDL-C, TG, and very low-density lipoprotein-cholesterol (VLDL-C) should be performed in pediatric patients in the fasting state (at least 8 hours) and guideline directed therapy is based on fasting values. Currently, some laboratories still use a calculated value for VLDL-C and LDL-C based on the Friedewald Formula (35) which estimates the VLDL-C by a fixed ratio of 5 (VLDL-C = TG/5). Because of the significant deviation from linearity at high TG levels (typically 400 mg/dL is used as a cut-point), VLDL-C and LDL-C values are not reported. This is especially important in dyslipidemias where both the TG and LDL-C can be elevated (i.e., familial combined hyperlipidemia) or where the TG level is severely elevated as a result of genetic and/or nutritional factors because it can lead to an under appreciation of the extent of the LDL-C elevation, the latter being especially important for guideline-directed therapy to lower cholesterol and in particular, LDL-C. Recently several equations have been developed that improved the accuracy of the calculated LDL-C. The Martin-Hopkins equation uses an adjustable factor based on lipid profiles from the Very Large Database of Lipids where TG levels were directly measured on samples separated using vertical spin density-gradient ultracentrifugation rather than a fixed ratio to calculate VLDL-C and subsequently the LDL-C (36). While this equation is more accurate than the Friedewald equation at high TG levels, there is still significant error for TG> 400 mg/dL addressed by the extended Martin/Hopkins calculation (37) and the Sampson equation (38). The Sampson equation was derived using beta quantification LDL-C values (the “gold standard” for LDL-C values) using multiple least squares regression analysis to derive a fixed equation to calculate the LDL-C value. All three equations have been proven to be superior to the Friedewald equation and many laboratories have already incorporated these equations when reporting lipid measures. Several pediatric studies have specifically addressed these improved methods to calculate VLDL-C and LDL-C (39,40,41).

 

GENETIC BACKGROUND

 

Commonly encountered HTG is usually multigenic and results from small-effect variants (single nucleotide polymorphisms) in many genes or heterozygotes in genes such as APOA5, GCKR, LPL, and APOB that have larger effects and together, more than 20% of susceptibility is accounted for by common and rare variants (42). The population frequency of the HTG phenotype was shown in the Copenhagen General Population Study in which a small percentage have a non-fasting TG level greater than 1000 mg/dL, whereas the majority have intermediate levels ranging from greater than the 95th percentile to 500 mg/dL and higher, often secondary to an underlying disorder (43).

 

Gene-Environment Interaction

 

Heterozygous relatives of cases with autosomal recessive familial chylomicronemia carry loss-of-function mutations in genes such as LPL, APOC2, APOA5, LMF1, and GPIHBP are generally

 

asymptomatic. Although they have close to normal lipids they may develop severe HTG (44) when exposed to exogenous factors such as alcohol, oral estrogen treatment, obesity, and pregnancy posing a risk for acute pancreatitis (45,46). These observations suggest that adolescent carriers, such as siblings of severely affected homozygotes, should be identified by genotyping to detect carriage of a single allele. If identified as carriers, they should be advised on avoiding risk factors such as alcohol and pharmaceutical agents discussed further in this review.

 

Susceptibility to environmental factors is common; for example, a typical case scenario occurs in a child with a mild increase in LDL-C who develops an increase in triglyceride and non-HDL-C during adolescence. The HTG is worsened by the onset of obesity and participation in social activities involving alcohol consumption and taking oral estrogens as birth control pills. Since insulin resistance and T2D have become more common in adolescence, the gene-environment interaction results in mixed dyslipidemia (47) with variable elevations in TG and cholesterol (48). The interaction is common in cases with a pedigree suggestive of familial combined hyperlipidemia (FCHL) reported to have a prevalence of 1 per 100 and characterized by variable lipid profiles among family members with apparent dominant inheritance, but some have a high cholesterol and others have a high triglyceride or elevations in both. The phenotype has also been defined as having elevated Apo B and TG levels in at least two affected family members, and has been associated with several variants including USF1, supporting a multigenic rather than a monogenic origin as originally thought (49).

 

Mendelian Randomization

 

The important role of genetics in determining HTG associated risk is highlighted by recent Mendelian randomization studies in which individuals carrying a protective mutation were compared to unaffected carriers over a lifetime. Recent studies on loss of function APOC3 mutations are a classic example. As compared with non-carriers, carriers of APOC3mutations had 39% lower TG levels, 16% lower LDL-C levels, and 22% higher HDL-C levels (50). The risk of coronary heart disease was reduced by 40% and was attributed to the lifetime effect of the normal or low levels. These remarkable findings were replicated in a Danish study with similar reductions in TG and cardiovascular disease in individuals with the protective APOC3 mutations (51). Randomization occurs in populations when sorted according to genotype and provides study design analogous to that used in pharmaceutical trials, but with the added benefit that exposure to lower levels of atherogenic lipoproteins in the genetically protected arm of the study begins at birth and continue over the lifespan. These landmark studies contribute evidence that a low TG and an associated improved lipid profile is beneficial, and supports interventions such as lifestyle, and pharmaceutical lowering when indicated, beginning at young ages.

 

DEVELOPMENTAL FACTORS

 

A sequence of factors, beginning during gestation, influence the development of hypertriglyceridemia (HTG) later in life (Figure 3).

 

Figure 3. Developmental Influences. Metabolic processes are programmed during gestation and early childhood and are influenced by disease states and environmental factors such as dietary excess and inactivity. The HTG is associated with atherogenic dyslipidemia consisting of increased non-HDL-C (non-high-density lipoprotein-cholesterol), LDL-P (LDL particle number), Apo B (apolipoprotein B), decreased HDL-C (high density lipoprotein cholesterol) and decreased Apo A-I.

 

Maternal nutrition and placental function affect nutrient supply for fetal growth and influence subsequent development of the metabolic syndrome (52). Overweight children who were small for gestational age (SGA) have increased risk for components of the metabolic syndrome compared to overweight children who were appropriate for gestation age (AGA). These effects on growth are attributed to restriction in intrauterine growth (53). After gestational programming, nutritional and endocrine factors play a role during childhood and affect development of risk factors including dyslipidemia (Figure 3). Preterm infants have higher meal frequency than older children and adults, but less efficient fat digestion and absorption, making it difficult to cope with a high fat intake relative to their body weight (54). Consequently, HTG is a frequent occurrence. Since pancreatic lipase and bile salt secretion is often inadequate for facilitating absorption of fat and its utilization as a source of energy, premature babies often fail to thrive and need exogenous fat as a component of total intravenous parenteral nutrition titrated according to the TG level (55). If lipoprotein lipase is genetically defective plasma clearance is even more compromised and severe HTG occurs during lipid infusions. If clinical circumstances necessitate that fats be restricted, essential omega-3 and omega-6 fatty acids are supplied for development of the brain and retina, and medium chain TG are an effective energy source without raising TG levels since they are directly transported to the liver via the portal system (56).

 

Increases in obesity, particularly as abdominal fat, during childhood predict the metabolic syndrome and compound the effect of an abnormal birth weight (57). Also, low adiponectin has been associated with insulin resistance, particularly in African American youth and compounds dyslipidemia (58). The adrenal axis may be involved; urinary free cortisol is associated with the metabolic syndrome in children (59), but the role of cortisol is controversial. Conversion of cortisone to cortisol by 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1) results in cortisol excess leading to insulin resistance, hypertension, and dyslipidemia. Inhibition of the enzyme results in reversal of metabolic syndrome criteria providing potential for pharmaceutical intervention (60). Normal puberty causes a transient increase in insulin resistance, attributed to maturational increases in sex and growth hormones, and may increase prevalence of both the metabolic syndrome and type 2 diabetes (61).

 

SECONDARY CAUSES OF HYPERTRIGLYCERIDEMIA

 

While primary HTG is associated with relatively rare monogenic and more common polygenic forms, there are many secondary non-genetic factors. The lipid abnormalities associated with these causes are summarized in Table 3.

 

Table 3. Secondary HTG Causes, Lipid Effects and Mechanism

 

Disease

TG

Chol

HDL-C

Mechanism

 

a). HTG (variable hypercholesterolemia)

 

Obesity

++

sdLDL + Apo B

-

Hepatic production

 

Type 2 diabetes

++

sdLDL + Apo B

-

Hepatic production and deficient disposal

 

Type 1 diabetes

+ or

++

+

-

Hepatic production and deficient disposal

 

NAFLD

++

sdLDL

_

Hepatic production of large VLDL

 

GSD 1

++

++

 

Hepatic production

 

Bile duct obstruction

 

+++

 

LpX formation from albumin, globulin & lipids.

 

Cushing’s disease

+

+

-

Insulin resistance effects

 

Lipodystrophy

++

 

-

Secondary LPL deficiency and diabetes

 

Stress and trauma

+

+

 

Increased stress hormones

 

Pregnancy

+

+

 

Progesterone effects

 

CRI

++

+

-

Similar to metabolic syndrome

 

HIV

+

+

 

Inflammation, treatments, lipodystrophy

 

Rheumatoid arthritis

+

+

 

Inflammation, cytokines

 

Lupus

+

+

 

Inflammation, cytokines

 

Gammopathies

+

+

 

Antibodies to LDL-R and LPL

 

b) Hypercholesterolemia (variable HTG)

 

 

Lysosomal acid lipase def.

 

++

-

Excess cholesterol synthesis (high liver enzymes and excess cholesterol storage),

 

Bile duct obstruction

 

+++

 

LpX formation from albumin, globulin & lipids.

 

Hypothyroidism

+

++

 

LDL receptor deficiency

 

Growth hormone deficiency

 

+

 

LDL receptor deficiency

 

Nephrotic syndrome

+

++

 

Increased synthesis (low fatty acids)

 

Saturated and trans fats

 

+

 

Dietary excess and LDL-R down-regulation

 

Anorexia nervosa

 

+

 

Nutrient deficiencies
                     

 

Endocrine

 

OBESITY

 

In early 2023, the AAP published a clinical pathway guideline aimed at treatment interventions for the 14.4 million children and adolescents who are now obese, noting that it is the most common chronic pediatric disease in the United States (62). It focuses on the child’s health status, family system, community context, and the resources for treatment to create the best evidence-based treatment plan. These include 13 Key Action Statements some of which pediatricians and other children healthcare providers are already engaged in including assessing for overweight/obesity, various screening including social determinants of health, and diagnostic studies. As with all children and adolescents, universal lipid screening is recommended but screening should also include screening for pre-diabetes and a hepatic profile to evaluate for the presence of fatty liver disease. Intervention can take place in the medical home or using the chronic care model, engaging in a family-centered non-stigmatizing approach. Referrals for overweight and obese children as young as 2 years-of-age may be referred for intensive health behavior and lifestyle treatment. Pharmacotherapy can be initiated by the pediatric healthcare provider at age 12 as an adjunct to health behavior and lifestyle treatment. At age 13, adolescents with BMI ≥ 120% of the 95th percentile for age and sex may be referred to metabolic and bariatric surgery programs.

 

Obesity has prevailed as the most prominent cardiovascular risk factor beginning in childhood and associated with dietary factors such as excessive consumption of refined carbohydrates, saturated fat and trans fatty acids which not only contribute to weight gain but also cause dyslipidemia (32). Children and adolescents are increasingly referred for obesity associated with dyslipidemia constituting HTG coupled with small dense LDL and low HDL-C (63,64), and with resistance to insulin in muscle and adipose tissue leading to increased plasma insulin and free fatty acids (65). Consumption of high amounts of carbohydrate and fat, being physically unfit, and having close relatives with similar presentations and progression to T2D or manifestations of the metabolic syndrome is often evident (66). Physical characteristics include being overweight or obese; the distribution of fat is generalized but consistently associated with an increased waist circumference, the latter strongly predicting adolescent-onset risk factors (67,68). The skin is hyper-pigmented and thickened at characteristic locations around the neck, knees, elbows, and sites of friction. This condition, called acanthosis nigricans, is associated with insulin resistance (69) and thought by many to be a central component of the metabolic syndrome for which American Indian and Hispanic ethnic groups are particularly predisposed, but Caucasians and African Americans also have high rates (69).

 

Resistance to insulin action results in mobilization of adipocyte TG and increased fatty acid availability for uptake by muscle and an inverse association with insulin resistance (70). The increased hepatic supply of fatty acids coupled with insulin-stimulated hepatic TG synthesis results in increased VLDL formation and HTG (71) constituting a component of Apo B-containing VLDL particles (72, 73); and increased chylomicron production contributes to the TG level (Figure 2) (74). The effect on lipoproteins is significant since it alters function in favor of atherogenesis. An entropic mechanism involves TG-rich particles exchanging their TG for cholesterol ester via cholesterol-ester transfer protein (CETP) thereby enriching LDL and HDL with TG; a process that is increased by insulin resistance (75). Both LDL and HDL become substrates for hepatic TG lipase, which is up-regulated (76) leading to formation of small dense LDL and small HDL prone to degradation (77, 78).

 

TYPE 2 DIABETES

 

Atherogenic dyslipidemia with increased triglyceride and low HDL-C precedes the onset of prediabetes and T2D in association with persisting insulin resistance (79). LDL glycation and oxidation is increased (80, 81) accounting for increased atherogenesis (82). In the Treatment Options for T2D in Adolescents and Youth (TODAY) trial, 699 adolescents were studied in three treatment groups receiving metformin alone, metformin with rosiglitazone, and metformin with intensive lifestyle. Twenty one percent (21%) had a high triglyceride or were on a lipid-lowering medication at baseline and 23 % had a high level after three years. During this same period Apo B increased from a mean value of 76.6 mg/dl to 80.1 mg/dl associated with deterioration in glycemic control attributed to a decline in β-cell function. However, the intensive lifestyle arm had significantly lower TG levels after three years (83). The data indicate that T2D in youth is associated with significant cardiovascular risk and difficult to control requiring a multidisciplinary approach (84).

 

TYPE 1 DIABETES

 

Children with type 1 diabetes (T1D) tend to have elevations in TG and cholesterol when insulin is insufficient, reflecting the dependence of lipoprotein lipase on insulin for synthesis and secretion. Increased triglyceride and cholesterol correct after two weeks of intensified insulin delivery (85), and the low HDL-C increases after two months (86). When cases present with severe insulin deficiency and ketoacidosis, TG and cholesterol attain very high levels but normalize on standard treatment with insulin and intravenous fluids (87, 88). These changes reflect the role of insulin in lipoprotein lipase transcription, synthesis, and secretion. Intensified insulin delivery increases Apo A-I and HDL-C even when control of the diabetes reflected by glycosylated hemoglobin remains unchanged (89). However, the relatively normal lipid profiles seen in treated patients with T1D is a paradox since the risk for CVD persists and remains a frequent cause of death (90), but development of renal complications plays a compounding role (91). Subcutaneous insulin bypasses physiological insulin delivery to the liver, and also results in a delayed plasma insulin peak compared to physiological insulin secretion from the pancreas (92), but the resulting delay in chylomicron clearance was not found to be associated with glucose control or elevated fasting TG in adolescents. However, potentially atherogenic apoB-48 containing remnants are increased after a meal challenge (93) and increases in free fatty acids, a correlate of post-prandial TG (94), are harmful to the endothelium by inducing pro-inflammatory effects (95).

 

Apo C-III, a correlate of triglyceride, has been implicated in the pathogenesis of atherosclerosis (96) in hyperglycemic and insulin resistant states and may have an atherosclerotic role in T1D. The Apo C-III promoter contains both a carbohydrate response element that is responsive to glucose fluctuations (97) and an insulin response element (98) making it susceptible to both glucose fluctuations and insulin deficiency since it is normally down-regulated by insulin. Observations in patients with T1D provide supportive evidence that increased Apo C-III is associated with poor glucose control (99, 100) and being overweight (101). In the DCCT/EDIC T1D cohort with a significant adolescent aged population at onset, Apo C-III was associated with retinopathy (102) and albuminuria (103), implicating Apo C-III and associated TG-rich lipoproteins in microvascular disease (104).

 

LIPODYSTROPHY

 

Congenital and autoimmune lipodystrophies (105) are a group of genetic and acquired disorders characterized by loss of body fat, either partial or generalized (106). The degree of fat loss determines the severity of metabolic complications such as HTG, ectopic fat accumulation, insulin resistance, and progression to diabetes. Loss of adipocytes results in progressive LPL deficiency and chylomicronemia. Reduction in fat intake is effective in reducing risk for pancreatitis; however, insulin resistance and high carbohydrate intake may result in excess VLDL production requiring the use of prescription omega-3 fatty acids and fibrates. Metformin is the drug of choice for diabetes but trial evidence is lacking for the specific use of glucose-lowering agents in lipodystrophy (106). Loss of adipocytes also leads to acquired leptin deficiency and severe hyperphagia making dietary management of HTG, glucose intolerance, and overt diabetes difficult. Recent approval of recombinant leptin (metreleptin, Amylin Pharmaceuticals) has greatly improved outcomes and quality of life; treatment trials for children are in process. Although formation of leptin antibodies has attenuated the effects (107), follow-up studies suggest that low titers may not result in significant decline in the clinical response.

 

HYPOTHYROIDISM

 

Overt hypothyroidism, either autoimmune or congenital, commonly presents in childhood and at onset may be characterized by an increase in LDL-C and Apo B because of a reduced number of LDL receptors (85). In subclinical hypothyroidism the lipid profile is characterized by normal or slightly elevated total cholesterol levels and LDL-C in adults (108) but this observation has been less evident in children (109).

 

GROWTH HORMONE

 

Growth hormone deficiency and excess are both causes of hyperlipidemia. GH deficiency down-regulates the LDL receptor (110) and can result in elevations in total cholesterol and LDL-C that are reduced by treatment (111); whereas excess GH tends to mobilize fatty acids and increase VLDL triglyceride (112, 113), as seen in cases with acromegaly or gigantism in childhood.

 

Heptic

 

NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

 

NAFLD, manifesting as ectopic fat deposition in the liver, is observed in obese children and adolescents in association with increased visceral fat and features of metabolic syndrome (114). The condition is associated with insulin resistance and high TG independent of intra-myocellular fat.

 

HEPATITIS C

 

Hepatitis C is associated with steatosis and a unique dysmetabolic syndrome characterized by insulin resistance, inflammation-induced atherosclerosis but a low cholesterol level.(115) The virus interferes with distal steps in cholesterol synthesis and with Apo B secretion. Risk for atherosclerosis is attributed to vascular inflammation (116, 117).

 

GLYCOGEN STORAGE DISEASE (GSD)

 

GSDs are associated with HTG (118, 119) and present as significant diagnostic and therapeutic challenges since the onset is at an early age. Type I GSD is caused by a recessively inherited defect in glucose-6-phosphatase, and accounts for more than 60% of the GSD types involving the liver and results in the highest TG levels due to excessive VLDL production. It presents during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of hepatic glycogen. Increased VLDL production is associated with TG-rich particles containing excess Apo C-III and Apo E (120). In addition, the metabolic consequences of impeded glucose formation and excessive anaerobic glycolysis manifest as hypoglycemia with lactic acidemia, hyperuricemia and dyslipidemia. Impaired growth factor production and acidosis result in poor growth and delayed puberty. Many of these effects, including impaired growth, can be reversed by sustained correction of hypoglycemia with dietary sources of complex carbohydrate. Restoration of euglycemia results in less stress-hormone induced stimulation of metabolic excesses derived from activated anaerobic glycolysis. Continuous complex carbohydrate feeding regimens are prescribed as frequent meals and supplementation with corn-starch. However, to effectively normalize the TG, frequent corn-starch dosing is needed to achieve blood glucose levels continuously above 75 mg/dL, especially at night. This approach involves high carbohydrate intakes, which in the long term may increase VLDL production often resulting in requirement for lipid lowering medications.

 

Renal

 

Nephrosis is associated with increased cholesterol synthesis and increased TG attributed to lipoprotein lipase inhibition (121). A two-phase dyslipidemia occurs in which TG hydrolysis by lipoprotein lipase is impaired when albumin levels are too low to remove fatty acids at an adequate rate after hydrolysis (122). Association with atherosclerosis is in part attributed to increases in Lp(a) and Apo C-III (123,124). Findings in chronic kidney disease in children resemble those in adults and simulate atherogenic dyslipidemia seen in the metabolic syndrome.

 

Immune

 

Immune causes are rare in adults and children but should be considered in specific clinical situations. HIV (human immunodeficiency virus) is associated with partial lipodystrophy and insulin resistance. The lipid profile before treatment shows a high triglyceride, low HDL-C, and small dense LDL (125), and subsequent treatment with protease inhibitors can make the situation worse (126). In gammopathies such as in Hodgkin’s disease, antibodies can sequester factors required for LPL activity (127) or they can impede lipoprotein uptake by receptors (128). Although less frequent than in adults, monoclonal or oligoclonal gammopathies, predominantly IgG mediated, occur in children with various autoimmune diseases, hematologic diseases, malignancies, transplantations, and immunodeficiencies (129).

 

PHARMACOLOGICAL CAUSES

 

Pharmacological agents have significant effects on plasma lipids. In some cases the mechanism is known but is frequently uncertain or unknown. The potential for causing dyslipidemia is particularly important in a patient that has an underlying genetic predisposition. Changing the offending medication or treating the dyslipidemia are both options, especially when the disease requires long term management and alternative medications are limited or not available. Each medication class has characteristic effects on the lipid profile but some, such as glucocorticoids, oral estrogens, and alcohol, may increase HDL-C and others may increase both cholesterol and triglyceride (Table 4).

 

 

Table 4. Classes of Medications and Examples Causing Hypertriglyceridemia in Childhood

 

Medication Class

TG

TC

HDL-C

Examples

 

Glucocorticoids

++

+

+

prednisone, hydrocortisone

 

Oral estrogens

+

+

+

ethinyl estradiol

 

Anabolic steroids

+

+

-

depo-testosterone, oxandrolone

 

Estrogen receptor blockade

+

 

 

tamoxifen

 

Retinoids

+

 

-

isotretinoin

 

Immune suppressants

+

+

 

cyclosporine, sirolimus, tacrolimus

Protease inhibitors

+

 

-

ritonavir, nelfinovir and indinivir

 

Diuretics

++

 

-

chlorthiazide, diuril

 

Antipsychotics

+

 

-

clozapine, olanzapine, cimetidine

 

Beta blockers

+

 

-

propranolol, labetelol

 

Bile acid sequestrants

+

 

 

cholestyramine, colestipol, cholesevelam

 

Alcohol

+

 

+

spirits, wines, beers

 
                     

 

Glucocorticoids

 

Glucocorticoids, especially in high doses, cause significant combined dyslipidemia and the effects on lipids may be compounded by other medications, the disease itself, or the patient’s genetic background. Lipid changes during treatment of chronic illnesses show elevations in triglyceride and LDL-C due to increased production, with variable changes in HDL-C but often increases (130). The effects may depend on the preparation used, dose and disease being treated (131). Combination drug therapy with L-asparaginase, an inhibitor of lipoprotein lipase, used for the induction phase in leukemia therapy can cause marked elevations in TG and is also diabetogenic (132). Lipid-lowering to prevent acute pancreatitis and thrombotic events is possible without stopping the chemotherapy.

 

Estrogens

 

Oral estrogens such as ethinyl estradiol usually prescribed with progestogen as oral contraceptives increase the production rate of Apo B-containing lipoproteins but the increase is counterbalanced by an increased catabolic rate (133). This finding accounts for only a slight increase in cholesterol and triglyceride within the normal range in adolescent girls (134), however interaction with obesity is possible with respect to LDL-C and fasting glucose (135). Reducing the dose of estrogen from the previously prescribed high dose preparations was effective in offsetting cardiovascular risk, however interactions with other risk factors such as smoking may occur (136).

 

Estrogen receptor blockade with tamoxifen has been associated with mild hyper-TG in women treated for breast cancer or its prevention, but it has rare use in childhood except for treatment of pubertal gynecomastia.

 

Retinoids

 

Retinoids such as isotretinoin (Accutane, 13-cis-retinoic acid) is indicated for treatment of severe nodular acne and can be prescribed for as long as 20 weeks, but careful monitoring is required. Severe HTG resulting from lipoprotein lipase inhibition frequently occurs, and can cause acute pancreatitis (137, 138). It acts via retinoic acid and retinoid x receptors (116) and there is also ongoing interest in use for cancer therapy and chemoprevention (139, 140).

 

Immune Suppressants

 

Cyclosporine (141), sirolimus (142), and tacrolimus are used in transplant patients and immune-mediated diseases in children requiring long term treatment and monitoring when indicated (143, 144). The mechanism is via down-regulation of hepatic 7alpha-hydroxylase and myocyte and adipocyte lipoprotein lipase down-regulation (145).

 

Protease Inhibitors

 

Protease inhibitors are associated with HTG and low HDL-C and add to the effects of the lipodystrophy syndrome occurring before anti-retroviral treatment of human immunodeficiency virus infections in pediatric cases, particularly during adolescence (146). Drugs such as ritonavir, nelfinovir and indinivir cause more severe dyslipidemia than others (147).

Nucleoside reverse transcriptase inhibitors can also cause TG and cholesterol elevations (148).

 

Bile Acid Sequestrants

 

Bile acid sequestrants should be avoided in cases with mixed dyslipidemia since they elevate TG (149). Fibrates or omega-3s, although effective in lowering TG, may transiently raise LDL-C during lipolysis of VLDL and conversion to LDL.

 

Diuretics

 

Diuretics including thiazides and loop diuretics such as furosemide alone or as combination therapy for hypertension raise cholesterol and TG and lower HDL-C in a dose dependent manner and more so in African Americans (150).

 

Beta-Blockers

 

Beta-blockers increase TG and lower HDL-C especially preparations without alpha-blocking activity but have rare indication in childhood since combination therapy for hypertension does not have trial evidence, (151) but they are used for management of arrhythmias.

 

Antipsychotics

 

Antipsychotics have pediatric psychiatric indications and agents such as clozapine and olanzapine induce HTG. However, it is not clear if the effect is independent of HTG induced by increased appetite and resulting weight gain typical of this class of medications and may require prescription changes or behavioral modification when possible (152).

 

Anabolic Steroids

 

Covert use of anabolic steroids in adolescent athletes and should be suspected with HTG and unusually low HDL-C levels. Medical use of oxandrolone for growth or androgens for aplastic anemia is rare and seldom has an indication.

 

Alcohol

 

Alcohol consumption has dyslipidemic effects, particularly with chronic use (153), and promotes development of fatty liver disease and associated HTG (154), particularly in susceptible Hispanic adolescents or in those with underlying genetic predisposition. As with steroids and estrogens, a typical presentation is with a markedly increased TG level with a higher-than-expected HDL-C (Table 4).

 

MANAGEMENT

 

General

 

Obesity and insulin resistance associated with dietary excess and inactivity should be assessed as potential targets in the therapeutic plan. If the identifiable cause(s) of secondary HTG cannot be corrected or optimally managed, as in patients with severe disorders or on essential drug therapy for their underlying diseases, lifestyle management is a priority. A six month trial of weight management by restricting excessive calories, saturated fat, and refined carbohydrate in the diet is recommended by the NHLBI Expert Panel (14). There is also consensus that diet, exercise and behavioral modalities should be used in combination for successful outcomes in children (155), which are dependent on self-motivation, family support, and access to skilled instruction, preferably provided by a dietitian with pediatric experience. A comprehensive team approach for use of exercise and behavioral modalities is considered optimal. Successful programs serve as role models for providers, particularly from centers with resources for team approaches similar to those designed for obesity management (156).

 

Drug Therapy

 

Treatment of the primary disorder is the first priority, i.e., treating HTG associated with T2D diabetes requires specific therapies based on the severity of the TG elevation and response to lifestyle. Rare disorders require specific therapies such as complex carbohydrates for maintaining euglycemia in GSD, and leptin therapy for lipodystrophy (discussed above). If pharmaceutical agents are the cause, modification of the treatment plan can be considered in consultation with the primary specialist. Sunil et al recently summarized medications targeted for HTG (157) as well as hypercholesterolemia and the former are summarized in figure 4 and several are discussed in detail herein, Unfortunately, none of these medications are approved below age 18 years-of-age, therefore treatment of HTG in children and adolescents is largely restricted to lifestyle changes. The most important aspect of dietary counseling is also discerning if the HTG is associated with insulin resistance where lowering simple sugars and carbohydrates is key or hyperchylomicronemia where fat restriction is paramount or where these disorders overlap.

 

Figure 4. Triglyceride lowering medications. From Ref. 157.

 

STATINS

 

Statins which are not described in figure 4 lower cholesterol, specifically LDL-C and have minimal effect on HTG. However, for commonly encountered dyslipidemia there is good reason to follow established guidelines to reduce the future CVD risk through the use of statin therapy (14). If a six-month trial of intensive lifestyle is not effective in reaching the recommended goal, the LDL-C and non-HDL-C become targets using appropriate agents such as statins. As discussed previously, non-HDL-C is a preferred target for individuals with mild to moderate TG elevations (150-499 mg/dl) as recommended by the 2011 expert NHLBI panel (14). For LDL-C and non-HDL-C above 95thpercentiles in the presence of HTG and at least one other risk factor, statin therapy is indicated selecting from approved statins for children over age 10 years (15). The reported statin association with type 2 diabetes (158,159) should be considered when obesity and associated genetic risk for diabetes is present.

 

It should be emphasized that when statin treatment is indicated for drug-induced hypercholesterolemia, care should be taken to avoid interactions with drugs that are metabolized by pathways utilizing cytochrome P450 enzymes, such as CYP3A4 for atorvastatin, lovastatin and simvastatin and CYP2C9 for fluvastatin and rosuvastatin (159). Drugs such as clarithromycin, cyclosporine A, diltiazem, erythromycin, ketoconazole, itraconazole, mibefradil, midazolam, nefazodone, nifedipine, protease inhibitors, quinidine, sildenafil, terbinafine, verapamil and warfarin are CYP3A4 utilizers and will raise the statin levels when used together, thus increasing risk of toxicity. Likewise, alprenolol, diclofenac, fluconazole, hexobarbitoal, n-desmethyldiazepan, tolbutamide and warfarin are CYP2C9 utilizers and will be incompatible with fluvastatin and rosuvastatin. Several of these drugs have common pediatric usage including certain antibiotics and antifungal agents.

 

FIBRATES

 

Based on adult evidence of harmful effects of TG-rich lipoproteins, small dense LDL, and remnant lipoproteins derived from VLDL and chylomicrons (160) and the metabolic effects of TG and associated increase in fatty acids (161), pharmacological TG lowering in childhood is indicated for selected cases resistant to lifestyle (14). Individuals with severe isolated HTG at risk for acute pancreatitis should have a trial of a TG-lowering agent such as a fibrate (i.e., gemfibrozil or fenofibrate), beginning with the lowest available dose while monitoring for adverse effects. Fibrates, approved for use over age 18 years, have limited trial evidence in children but a fibrate (bezafibrate, not available in the United States) was shown to be safe when used for children with familial hypercholesterolemia before statins were available for use (162). It is however notable that few adult trials have shown benefit of fibrates on cardiovascular event reduction. Niacin while historically used (163), no longer has a place in the management of dyslipidemia.

 

OMEGA-3 FATTY ACIDS

 

Omega-3-fatty acids have appeal as a potential TG-lowering agent for children because of their relatively low adverse effect profile and recent availability as a prescription grade preparation following purification to remove heavy metals and fatty acids (164). Although adults have had up to 30% TG lowering with 4-gram doses, 2 gram doses are less effective and increased LDL-C is a recognized adverse effect (165,166). but the LDL-C to HDL-C ratio is unchanged (167). A retrospective survey of children treated for TG lowering with omega-3 fatty acids at a dose of 0.5 to 1 gram per day, did not show significant TG lowering suggesting that prescription of relatively low doses may not be helpful. The study supports use of higher doses in combination with lifestyle measures. A high purity prescription form of icosapent ethyl (eicosapentaenoic acid ethyl ester), lowers TG while lowering LDL particle concentration and LDL-C in cases with TG over 500mg/L (168, 169), but it is not yet available for use under 18 years of age, however it appears to be a reasonable consideration for testing in pediatric settings. The free fatty acid form as shown in the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial is effective for TG-lowering (170), but not yet available for use in children. Non-prescription marine omega-3s can be safely used if patients are instructed on what to look for on the label (e.g., distilled, USP approved) and specific marine sources with high concentrations are recommended (171).

 

SEVERE SECONDARY HTG

 

Treatment for HTG with levels above 1000 mg/dl in patients with partial defects in chylomicron clearance by LPL or its co-factors requires total dietary fat restriction for 72 hours followed by dietary management in the longer term. The approach is similar to the management of homozygous familial chylomicronemia for which there is more information (172) (reviewed in another chapter). It should be recognized that small increments in fat can cause striking increases in plasma TG because when TG levels saturate LPL activity, any additional TG entering the plasma will face zero order kinetics and increase the TG in a non-linear fashion. TG can be substantially lowered by restricting dietary fat to less than 15% of the total daily caloric intake and cases vary in their response to fibrates depending on their effect on residual lipoprotein lipase and on suppression of hepatic TG production. Adherence to a very low-fat diet requires supplementation with linoleic acid and fat-soluble vitamins (A, D, E and K), but frequent monitoring is advised. Supplemental medium chain triglycerides (MCT) may be beneficial in providing additional calories and improving compliance. Fenofibrate can be helpful in cases with residual lipoprotein lipase activity and also may reduce hepatic TG production. New agents are being developed to increase clearance and/or reduce the production of triglyceride-rich lipoproteins, but their clinical efficacy, cost effectiveness, and indications, especially in children, are yet to be established (173).

 

CONCLUSION

 

In addition to obesity accompanied by metabolic syndrome, other common and rare causes of secondary dyslipidemia require diagnosis-specific management strategies. Identification and prioritization of reversible causes and risk factors, use of comprehensive lifestyle approaches, and optimal choice of medications based on guidelines can lead to improved outcomes. Lifestyle modification with selective prescription of medications designed to reduce risk of cardiovascular disease is indicated for individuals with intermediate TG levels ranging from 150­499 mg/dL, but severely elevated levels imposing risk for acute pancreatitis, require more intense dietary restriction combined with TG-lowering medications. The results of AAP’s recent recommendation of a more aggressive approach to treatment of childhood obesity await outcome data. Since non-HDL-C is a known predictor of cardiovascular disease and represents an estimate of all atherogenic lipoprotein particles TG-rich lipoproteins, it is recommended as a preferred target especially in most cases with intermediate elevations of TG.

 

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Nutritional Management of Pediatric Dyslipidemia

ABSTRACT

 

Lifestyle therapies are important in helping to reduce risk of premature cardiovascular disease. A family-centered, behavioral approach to lifestyle modification is generally the most successful approach for children and adolescents. A registered dietitian nutritionist plays a pivotal role in implementing therapeutic lifestyle changes, uniquely trained to fully assess the child's nutrition status as well as outlining practical strategies to obtain the desired behavioral changes.  For all children and adolescents one year of age and older, the Cardiovascular Health Integrated Lifestyle Diet (CHILD-1 diet) is the first step in helping achieve the goal of a healthy lifestyle.  Key to this initial dietary recommendation is restricting saturated fat intake to <10% of daily calorie intake and reducing cholesterol consumption to <300 mg/day.  Those unable to achieve the desired goals while following a CHILD-1 diet should be advanced to the CHILD-2 diet after a three-month trial.  The CHILD-2 diet includes further restriction of saturated fat and cholesterol.  In addition to the CHILD-2 diet, supplementation with plant sterol and stanol esters, water-soluble psyllium fiber, or omega-3 fatty acids may help a child achieve the desired lipid goals.  Nutrition recommendations vary according to age, and parents/caregivers should be counseled accordingly. Each individual age range provides unique challenges, making ongoing nutrition counseling an important part of maintaining modifications in those following a lipid-lowering diet. Regular follow-up visits with appropriate monitoring of the child's understanding of, and satisfaction with, the diet, test results, readiness to change, and growth parameters is important for continued success.  The use of motivational interviewing during visits is frequently helpful in enhancing knowledge, maintaining interest, identifying barriers, and setting short- and long-term goals.

 

ROLE OF MEDICAL NUTRITION THERAPY IN PEDIATRIC DYSLIPIDEMIA

 

The National Lipid Association (NLA), American Heart Association (AHA), and American College of Cardiology (ACC) all regard lifestyle therapies as an important component in helping reduce risk of premature cardiovascular disease, alone or in conjunction with pharmacotherapies (1-4). Research of cardiovascular disease risk reduction has shown improper diets, especially those with excess energy intake, to be major contributors to hypercholesterolemia and obesity in children and adolescents (5).  Counseling of those at risk of premature atherosclerotic cardiovascular disease (ASCVD) focuses on (1) altering diet composition; (2) increasing physical activity; (3) calorie reduction for weight loss in those who are overweight and obese; (4) global reduction of risk factors associated with metabolic syndrome; and (5) cessation/avoidance of tobacco use (1). A behavioral approach to lifestyle modification provided by a registered dietitian nutritionist has been identified as the most consistently effective approach to evoke dietary change (5). In the pediatric population, both the child and family should be engaged in counseling efforts.

 

NUTRITION ASSESSMENT

 

Prior to providing recommendations for lipid-lowering diets, it is important to gather a comprehensive assessment of the child’s current nutritional status and the entire family's readiness to change. Identification of a family’s current healthcare beliefs and practices, nutritional status, and eating patterns can be a valuable resource in estimating future success in implementing and sustaining therapeutic lifestyle changes.  Growth charts, if available, should be reviewed to determine nutrition risks such as malnutrition or obesity. Anthropometric measures of note include the child's age- and sex- appropriate height, weight, body mass index (BMI), and BMI Z-score.  Although generally not formally assessed, the body weight and body mass index of the parent/caregiver as well as other family members should also be taken into account.  Food insecurity or financial barriers to diet modification should also be addressed, including use of the food assistance programs such as the Supplemental Nutrition Assistance Program (SNAP), Supplemental Nutrition Program for Women, Infants, and Children (WIC), National School Lunch Program (NSLP), and food pantries.  This allows modification of dietary recommendations to better align with child and family needs.

 

A diet recall or discussion regarding typical daily dietary intake is generally the most useful information to determine areas of dietary improvement (6). Special attention should be paid to the child’s main sources of meals, frequency of eating meals outside of the home, between-meal snacks, and baseline level of physical activity. Identifying use of nutritional supplements, herbal remedies, and dietary restrictions is also important, as these may affect baseline and follow-up lipid levels.

 

NUTRITION INTERVENTIONS

 

Dietary Guidelines

 

CHILD-1 (STEP 1 DIET)

 

The CHILD-1 diet (Table 1) is the first step in diet modification for all children 1 year of age and older, including those with a family history of early cardiovascular disease, obesity, dyslipidemia, diabetes mellitus, primary hypertension, or exposure to smoking at home. Parameters of this diet include restricting total fat intake to 25-30% of daily calories, saturated fat intake to less than 10% of daily calories, and limiting daily cholesterol intake to 300mg or less (5).  Polyunsaturated fatty acids should constitute up to 10% of daily caloric intake, while targeting a monounsaturated fatty acid intake of 10-15% of daily caloric intake (5). Trans fats should be avoided as they have been shown to increase LDL-C as well as decrease HDL-C. Common sources of saturated and unsaturated fats are outlined in Table 2. Reduction of sugar-sweetened beverage intake should be encouraged, as this has been associated with decreased obesity measures (5). In addition, a daily dietary fiber intake of at least the child’s age + 5g for young children and up to 14g per 1000 calories for older children should be encouraged (7). The American Academy of Pediatrics (AAP) recommends at least 1 hour of moderate-to-vigorous physical activity daily for children 5 years and older (8). This diet has shown to decrease total cholesterol and LDL-C, while lowering the incidence of obesity and insulin resistance. The CHILD-1 diet has been shown to be safe and effective, and may decrease LDL-C by an average of 12% from baseline values. Any resulting decrease in body weight for those who are overweight or obese may also increase levels of HDL-C and decrease triglyceride concentrations (9).

 

TABLE 1. EVIDENCE-BASED DIET FOR CHILDREN AND ADOLESCENTS: CHILD-1

 

Birth to 6 months

All babies should be exclusively breastfed until 6 months of age. Donor breast milk or iron-fortified infant formula may be utilized if maternal breastmilk is unavailable or contraindicated. No supplemental food is recommended.

 

6 to 12 months

Breastfeeding should be continued until at least 12 months of age while gradually adding solids; transition to iron-fortified infant formula until 12 months if if maternal breastmilk is unavailable or contraindicated.

Fat intake should not be restricted unless medically indicated.

No sweetened beverages should be offered; Limit other beverages to 100% fruit juice (≤4oz/day); Encourage water.

 

12 to 24 months

Transition to unflavored, reduced-fat cow’s milk. Fat content (2% to fat free) should be based on child’s growth, intake of other nutrient-dense foods, total fat intake, and family history of obesity or

cardiovascular disease

Avoid sugar-sweetened beverages; Limit 100% fruit juice to ≤4oz/day; Encourage water

Offer table foods with:

Total fat 30% of daily kcal intake

Saturated fat 8-10% daily kcal intake

Avoid trans fats

Mono- and polyunsaturated fat up to 20% daily kcal intake

Cholesterol <300mg/day

Limit sodium intake

 

2 to 10 years

Primary beverage should be unflavored, fat-free milk

Limit/avoid sugar-sweetened beverages; Limit 100% fruit juice to ≤4oz/day; Encourage water

Dietary fat:

Total fat 25-30% of daily kcal intake

Saturated fat 8-10% daily kcal intake

Avoid trans fats

Mono- and polyunsaturated fat up to 20% daily kcal intake

Cholesterol <300mg/day

Encourage high dietary fiber intake

Encourage at least 1 hour of moderate-to-vigorous physical activity daily for children >5 years

 

11 to 21 years

Primary beverages should be fat-free unflavored milk and water

Limit/avoid sugar-sweetened beverages; Limit 100% fruit juice to ≤4oz/day

Dietary fat:

Total fat 25-30% of daily kcal intake

Saturated fat 8-10% daily kcal intake

Avoid trans fats

Mono- and polyunsaturated fat up to 20% daily kcal intake

Cholesterol <300mg/day

Encourage high dietary fiber intake

Encourage at least 1 hour of moderate-to-vigorous physical activity daily

Encourage healthy eating habits such as daily breakfast, limiting fast-foods, and eating meals as a family.

 

 TABLE 2. COMMON DIETARY FAT SOURCES

Saturated Fat

Trans Fat

Monounsaturated Fat

Polyunsaturated Fat

Red meats

Poultry skin

Full fat dairy products

Butter

Deep fried food

Margarine

Shortening

Lard

Pastries

Processed foods

Fried or processed foods

Shortening

Pastries

Donuts

Baking mixes

Vegetable oils (olive, canola, sunflower, sesame, peanut)

Avocados

Natural peanut butter

Many nuts/seeds

Vegetable oils (corn, safflower, soybean)

Fatty fish (salmon, trout, mackerel)

Some nuts/seeds

*Note: Above lists are intended to provide examples and are not all-inclusive.

 

CHILD-2 (STEP 2 DIET)

 

If elevated levels of LDL-C and non-HDL-C persist after adequate compliance to the CHILD-1 diet for 3 months, transition to the CHILD-2 diet should be recommended (Table 3). Parameters of the CHILD-2 diet include further restriction of saturated fat intake to less than 7% of daily calories and a decrease in daily cholesterol intake to 200mg or less. This diet may be further modified, if necessary, to more specifically address elevated LDL-C, non-HDL-C, and elevated triglycerides (TG).  

 

TABLE 3. EVIDENCE-BASED NUTRITION RECOMMENDATIONS FOR PEDIATRIC DYSLIPIDEMIA

 

Nutrition Recommendations for LDL-Lowering

Indication:  Children and adolescents with familial hypercholesterolemia or persistent hypercholesterolemia.

 

Refer to a registered dietitian nutritionist for family-centered medical nutrition therapy.

Dietary fat:

Total fat 25-30% of daily kcal intake

Saturated fat ≤7% daily kcal intake

Avoid trans fats

Monounsaturated fat ~10% daily kcal intake

Cholesterol <200mg/day

Familial hypercholesterolemia patients may benefit from plant sterol and stanol esters up to 2g/day as a replacement for usual dietary fat sources.

Water-soluble fiber psyllium can be added to the CHILD-2 diet at a dose of 6g/day for children 2-12 years of age, and 12g/day for children ≥12 years of age.

Encourage at least 1 hour of moderate-to-vigorous physical activity daily while limiting sedentary screen time to <2 hours/day.

 

 

Nutrition Recommendations for TG-Lowering

Indication:  Children and adolescents with hypertriglyceridemia or persistent hypertriglyceridemia.

 

Refer to a registered dietitian nutritionist for family-centered medical nutrition therapy.

Dietary fat:

Total fat 25-30% of daily kcal intake

Saturated fat ≤7% daily kcal intake

Avoid trans fats

Monounsaturated fat ~10% daily kcal intake

Cholesterol <200mg/day

Reduce sugar intake.

Replace simple carbohydrates with complex carbohydrates.

Avoid sugar-sweetened beverages.

Increase dietary fish to increase omega-3 fatty acid intake.

Omega-3 fatty acid supplementation can be added at 1-4g/day for TG >200-499mg/dL.

 

The CHILD-2 LDL lowering diet places additional emphasis on dietary fiber intake and use of plant sterol/stanol esters, as appropriate. Dietary fiber, specifically soluble fiber intake, may help further reduce LDL-C. Supplemental water-soluble psyllium fiber may be added, though efficacy of supplementation varies in published trials. In children and adolescents with familial hypercholesterolemia, plant sterol and stanol esters may be safely incorporated at 2g/day to enhance LDL-C lowering effects (5). (See the nutrition supplementation section of this chapter for more information on supplemental therapies).

 

The CHILD-2 TG-lowering diet may be utilized in children and adolescents with moderate hypertriglyceridemia.  Dietary recommendations should encourage choosing complex carbohydrates, limiting simple carbohydrates, and restricting dietary fat intake. Sugar sweetened beverages should be discouraged. If overweight or obese, a gradual weight loss should be encouraged (5). Omega-3 supplementation may be beneficial in those with TG >200-499 mg/dL. (See Omega-3 supplementation section below).

 

In children and adolescents with severe hypertriglyceridemia or familial hypertriglyceridemia, the CHILD-2 TG-lowering diet, as well as restriction as low as 10-15% daily calories from fat, may be helpful in lowering TG and avoiding pancreatitis. It is imperative these children and adolescents be closely followed by a registered dietitian nutritionist to ensure all essential fatty acid and micronutrient needs are met, as well as maintaining a proper balance of calories from carbohydrates, fat, and protein (10,11).

 

NUTRITION SUPPLEMENTATION

 

Plant Sterol and Stanol Esters

 

Children and adolescents who have been unable to achieve lipid-lowering goals with dietary modification alone may utilize plant sterol and stanol esters for further LDL-C lowering. Recommended dose for children 2 years of age and older is 2g/day as a replacement for usual fat sources (5). As long-term studies on effectiveness have not been completed, plant sterol and stanol supplementation should be reserved for children and adolescents who do not achieve the desired LDL-C and non-HDL-C goals with diet modification alone (1). Therapeutic doses of plant sterol and stanol esters can be achieved through fortified foods or nutrition supplements, and appear to have increased efficacy when administered throughout the day rather than in a single dose (12,13).

 

Omega-3-Fatty Acids

 

In children and adolescents with fasting triglyceride levels >200-499 mg/dL, a trial of CHILD-2 TG-lowering diet and increased intake of fatty fish or omega-3 fatty acid supplementation may be beneficial (3). When increasing fatty fish in the diet, seafood choices high in EPA and DHA, but low in mercury are recommended (5). While research into the effects of fish oil supplementation is limited in the pediatric population, no safety concerns have been identified as yet. In adults, omega-3 supplementation has been shown to lower triglycerides by 30-40%, though some may cause an increase in LDL-C (14-18). Therapeutic doses of omega-3 fish oils are 1-4 g/day of the active ingredients (EPA+DHA).  If fish-oil supplementation is utilized, prescription formulas are recommended rather than over-the-counter fish-oil capsules, which are not FDA regulated (3,18).

 

Psyllium Fiber

 

This water-soluble fiber can be added to the CHILD-2 LDL-lowering diet to aide in lowering total and LDL-C cholesterol. While evidence for efficacy of psyllium fiber is insufficient for specific recommendation, many studies show significant reductions in total and LDL cholesterol when psyllium fiber is added to a CHILD-2 LDL-lowering diet.  Recommended doses are 6 g/day for children 2-12 years; 12 g/day for children 12 years and older. (5) Soluble fiber has been shown to be well-tolerated and safe for hypercholesterolemic children and adolescents 2 years of age and older (20-22).

 

AGE-BASED NUTRITION RECOMMENDATIONS

 

Birth to 12 Months

 

Fat plays a pivotal role in brain development, and should not be restricted in children <12 months, unless medically necessary.  If implementing, it is imperative that a knowledgeable and experienced dietitian nutritionist be involved in the child's care.  The American Academy of Pediatrics (AAP), Surgeon General’s Office, and World Health Organization (WHO) recommend that all babies be exclusively breastfed until 6 months of age (6). Breastfeeding should be continued until at least 12 months of age, with gradual addition of supplemental foods to the child’s diet. Iron-fortified formula may be utilized until 12 months of age if breastfeeding is reduced or discontinued. No sugar-sweetened beverages should be offered, and 100% fruit juice should be limited to 4 oz or less daily.  While extensive diet modification is not recommended at this age, previous studies have shown repeated dietary counseling, beginning as early as 7 months of age, decreases lipid risk factors of premature coronary heart disease (CHD) in children (23).

 

12-24 Months

 

The 2020-2025 Dietary Guidelines for Americans recommends a diet consisting of 30-40% calories from fat for children aged 1-3 years (7). Toddlers with family history of heart disease and hypercholesterolemia may transition to milk with reduced fat at 12 months of age to decrease saturated fat intake. This should be done only if the overall diet consistently supplies 30% daily calories from fat. Diets with less than 30% daily calories from fat should only be utilized when medically indicated and closely followed by a registered dietitian nutritionist. Nutrient-rich table foods should be offered, while avoiding concentrated sweets and trans fats (5).  Sugar-sweetened beverages should be avoided, while limiting 100% fruit juice consumption to 4 oz or less daily and encouraging water intake (5).

 

2-10 Years

 

At this age, focus should be placed on introducing a wide variety of vegetables, fruits, lean proteins, and complex carbohydrates.  Dietary recommendations include a total fat intake of 25-30% of daily calorie intake, limiting saturated fats, and avoiding trans fats (5). As milk is a main source of saturated fat at this age, fat-free unflavored milk is recommended.  Intake of sugar-sweetened beverages should be limited or avoided, limiting 100% fruit juice to 4 oz or less daily, and encouraging water intake.  For children with persistent elevations in LDL-C, the CHILD-2 diet described earlier in this chapter may be utilized (5).

 

This age presents unique challenges due to selective eating habits and increased consumption of foods prepared at day care facilities and school. The AHA notes that, at this age, regular breakfast consumption begins to decrease, while there is often an increase in foods prepared away from home, increased percent daily calories from snack foods, and an increased consumption of foods that are fried and of low-nutrient value (24). Families should be counseled on choosing nutritionally-dense foods, and encouraging dietary fiber intake (age + 5g daily). Physical activity with limited sedentary time should be encouraged, with a goal of at least 1 hour of moderate-to-vigorous activity daily for children 5 years and older (7).

 

10-21 Years

 

Recommendations for this population are similar to children 2-10 years of age.  Dietary recommendations remain the same with 25-30% of daily calorie intake from fat, limiting saturated fat to 8-10% of daily calories, and avoiding trans fats. The CHILD-2 diet can be utilized for children and adolescents with persistent elevations in LDL-C and TG (5). Intake of fat-free unflavored milk and water should be encouraged, while limiting or avoiding sugar-sweetened beverages. 100% fruit juice should also be limited to 4 oz or less daily. Foods high in dietary fiber are encouraged with a goal of 14g fiber per 1000 calories (7).

 

At this age, many children consume meals or snacks at school, after-school programs, restaurants, convenience stores, or vending machines. There is often an increase in choosing foods at home that require minimum preparation. Identifying a child’s main sources of nourishment is helpful in the counseling process (24). Family-centered education is helpful as parental role modeling is important to establish healthy eating at younger ages. As children and adolescents mature, education may be focused on maintaining healthy habits, such as eating breakfast daily, choosing a healthy lunch, and limiting fast food intake (5). Special considerations should also be made regarding the approach to discussions on weight and disordered eating patterns (3).

 

MONITORING AND EVALUATION

 

After the initial visit and nutritional counseling, it is recommended that children, adolescents, and their parent/caregiver continue to meet frequently with specially trained cardiovascular disease risk reduction healthcare professionals, including a lipid specialist and registered dietitian nutritionist to monitor the child's progress and efficacy of the lipid-lowering diet. Growth charts and updated laboratory studies should be reviewed with each visit to guide subsequent recommendations for diet modification or supplementation. In children and adolescents who are overweight or obese, moderate, gradual weight reduction has been shown to improve dyslipidemia and decrease insulin resistance. Regular follow-up visits, tracking growth, and evaluating the child’s and family’s readiness to change can help guide the dietitian nutritionist in providing appropriate and timely counseling. A family-centered approach, transitioning to a patient-centered focus in late adolescence, helps ensure the recommended therapeutic lifestyle changes are followed throughout life stages (3).

 

REFERENCES

 

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  2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63(25 Pt B):2889-934.
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