ABSTRACT

Cerebrotendinous xanthomatosis is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the CYP27A1 gene. These patients lack mitochondrial sterol 27-hydroxylase enzyme, which is responsible for conversion of cholesterol to cholic acid and chenodeoxycholic acid (CDCA) in bile acid synthesis pathway. CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues, including brain, leading to progressive neurological dysfunction marked by dementia, spinal cord paresis, and cerebellar ataxia. Deposition in other tissues causes tendon xanthomas, premature atherosclerosis, and cataracts. The clinical manifestations usually start at infancy and develop during the first and second decades of life. The diagnosis of CTX is based on clinical findings, biochemical testing, and neuroimaging. Molecular genetic analysis although not necessary for initiation of treatment, provides definitive confirmation of CTX. Early initiation of CDCA is the treatment of choice for neurological and non-neurological symptoms of CTX and treatment with cholic acid has also been shown to be effective for non-neurological symptoms.

INTRODUCTION

Cerebrotendinous xanthomatosis (CTX; OMIM#213700) is a rare autosomal recessive disorder of bile acid metabolism and lipid storage characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues. It is caused by homozygous or compound heterozygous mutation in the CYP27A1 gene located on chromosome 2q33-qter. CYP27A1 gene encodes sterol 27-hydroxylase which is involved in bile acid synthesis. Over 100 different mutations (missense, deletions, insertions, splice site, and nonsense mutations) of the CYP27A1 gene have been reported worldwide in patients of different ethnic origin (1,2). About 50% of these mutations were found in the region of exons 6–8 of the CYP27A1 gene, however here is no genotype phenotype correlation (3,4). The metabolic pathway for bile acids synthesis is shown in the figure 1.

Figure 1. Bile acids are synthesized from cholesterol in the liver through two pathways: the classic pathway and the alternative pathway. The bile acid synthesis mainly produces two primary bile acids, cholic acid and chenodeoxycholic acid (CDCA). In the classic pathway, the mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes the steroid side-chain oxidation in both CA and CDCA synthesis. In the alternative pathway, CYP27A1 catalyzes the first step to convert cholesterol to 27-hydroxycholesterol which eventually is converted to CDCA.

CTX was first described by Van Bogart, Scherer and Epstein in 1937 as a condition characterized by early development of cataracts and large tendon xanthomas and later by progressive neurologic impairment (5,6). The incidence of CTX is estimated to be 3 to 5 per 100,000 people (1,7). The prevalence is estimated to be highest in Asians (1:44,407-93,084), intermediate in Europeans, Americans, and Africans/African Americans (1:70,795-233,597) and lowest in the Finnish population (1:3,388,767) (8). 

ETIOLOGY AND PATHOGENESIS

Patients with CTX lack mitochondrial sterol 27-hydroxylase, which is an important enzyme in both the alternative and classic bile acid synthesis pathways (9). The biochemical defect prevents the synthesis of chenodeoxycholic acid (CDCA) and cholic acid (10).The absence of the negative feedback mechanism of CDCA on 7a-hydroxylase, the rate limiting step, leads to the accumulation of cholestanol and its precursor 7α-hydroxy-4-cholesten-3-one (Figure 1) (9-11). Bile acid alcohols are glucoronidated and can be found in significantly increased amounts in blood, urine, and feces of untreated CTX subjects. It has been hypothesized that the increased bile alcohol levels may lead to disruption of the blood–brain barrier (BBB), and that increased permeability of BBB may be caused by circulating bile alcohol glucuronides (12). Cholestanol and cholesterol accumulate in many tissues, including brain (primarily white matter), leading to progressive neurological dysfunction marked by dementia, spinal cord paresis, and cerebellar ataxia. Deposition in other tissues causes tendon xanthomas, premature atherosclerosis, and cataracts (13).

CLINICAL FEATURES

Patients with CTX present diverse manifestations with multi-organ involvement and a broad range of neurological and non-neurological symptoms (Table 1). The clinical manifestations usually start at infancy and develop during the first and second decades of life. Neonatal cholestatic jaundice and infantile-onset diarrhea with failure to thrive may be the earliest clinical manifestation (14-16). Childhood-onset cataracts are a common early symptom, described in 92% patients with CTX. Cataracts precede neurological signs and tendon xanthoma, and if present, are considered useful for early diagnosis (14,16,17). Tendon xanthomas have been documented in 71% patients with CTX and can appear in first, second or third decade. They are common in Achilles tendon, but can also be seen in fingers, tibial tuberosity, and triceps (17,18). Pes cavus deformity has also been described (19,20). Neurological dysfunction is almost always present in patients with CTX and usually occurs in late adolescents and early adulthood. The range of symptoms are wide and include intellectual disability; dementia; psychiatric symptoms (i.e., behavioral changes, depression, agitation, hallucination, and suicide attempts); pyramidal signs (spasticity, hyperreflexia, extensor plantar responses); cerebellar signs (progressive ataxia, dysarthria); movement disorder (parkinsonism, dystonia, myoclonus, postural tremor); seizures; and peripheral neuropathy (1,4,21-23). Osteoporosis, heart involvement, and premature atherosclerosis have also been described later in life (19,24-26).

DIAGNOSIS

The diagnosis of CTX is mainly based on clinical features, biochemical testing, neuroimaging, and molecular genetic analysis. Since clinical presentation can be variable in type, severity, and timing, diagnosis is often delayed. Patients with CTX include having high plasma cholestanol concentration (five- to ten-fold greater than normal), normal-to-low plasma cholesterol concentration, elevated urine bile alcohol concentration, elevated plasma bile alcohol concentration, decreased CDCA level, and increased levels of cholestanol and apolipoprotein B in cerebrospinal fluid (10,17). Cholesterol concentration in tissue is increased but plasma cholesterol levels are low to normal (27). Brain MRI features are strongly suggestive of diagnosis and include bilateral hyperintensity of the dentate nuclei, diffuse cerebral and cerebellar atrophy, and white matter signal abnormalities. Brain MRI spectroscopy shows decreased n-acetylaspartate and increased lactate signals, suggestive of widespread axonal damage and cerebral mitochondrial dysfunction (20). Although not necessary for initiation of treatment, molecular testing provides definitive confirmation of CTX. Various mutations in all nine exons and in introns 2,4,6,7 and 8 of the CYP27A1 gene have been described worldwide (8). Mignarri et al (22) developed a suspicion index to be used by clinicians to calculate CTX prediction score. They proposed using family history, systemic and neurologic features as diagnostic indicators, classified as very strong (score of 100; e.g., tendon xanthoma or, sibling with CTX); strong (score of 50; e.g., juvenile cataract, chronic diarrhea, prolonged neonatal cholestasis, ataxia, MRI alterations, intellectual disability and/or psychiatric disturbances); or moderate (score of 25; e.g., early osteoporosis, epilepsy, parkinsonism or polyneuropathy. A total score ≥ 100 warrants serum cholestanol assessment, and elevated cholestanol or total score ≥ 200, with one very strong or four strong indicators, warrants CYP27A1 gene analysis (22). Quantification of bile acid precursor 7α-hydroxy-4-cholesten-3-one has been proposed to be a rapid, convenient diagnostic test for CTX (28). Early detection of ketosterol bile acid precursors can play important role in early detection through newborn screening (29).

MANAGEMENT

Early initiation of oral chenodeoxy-cholic-acid (CDCA) therapy at a dose of 250 mg given 3 times daily for adults and 15 mg/kg/d for children is the treatment of choice for neurological and non-neurological symptoms such as diarrhea (30-32), however it still does not have U.S. Food and Drug Administration approval for CTX. FDA has granted it an orphan drug designation for use in CTX.  CDCA has been approved in the European Union to treat adults and children with CTX over 1 month of age. This treatment suppresses synthesis of cholesterol, cholestanol, bile alcohols, and bile acids and alleviates clinical symptoms if started at an early age (33,34); however it has not been shown to improve bone mineral density in affected patients (35). The treatment is most effective when started early (31), and patients diagnosed later in life with significant neurological disease may progress despite CDCA therapy. A retrospective cohort study in 79 Dutch patients with CTX showed that the MRI brain remained normal even after 25 year of follow-up treatment if therapy was started in young patients with a normal MRI at diagnosis. Treatment with cholic acid has also been shown to be effective, especially in patients with side effects to CDCA therapy (36,37). HMG-CoA-reductase-inhibitors along with CDCA can improve lipoprotein metabolism, inhibit cholesterol synthesis, and reduce plasma levels of cholestanol (38). Surgical excision of bilateral tendon may worsen the gait imbalance and cannot prevent the deterioration of neurologically affected patients (39). Lumbreras et al (40) showed that adeno-associated virus (AAV) vectors expressing CYP27A1 restored bile acid metabolism and normalized the concentration of most bile acids in plasma in a CTX mouse model, making gene therapy a feasible option.

SCREENING

Screening of all first-degree relatives, when feasible, should be considered as early detection and treatment are the most important aspects for preventing morbidity and mortality (41). A recent pilot study has also shown promising option of screening for CTX as part of newborn screening (42). A recent study on de-identified dried blood spots of 20,076 newborns from the 2019 cohort of the biobank of the Dutch newborn screening program (Dutch National Institute for Puublic Health and the Environment, Bilthoven, The Netherlands) showed that metabolite ratios bile alcohol cholestanetetrol glucuronide (GlcA-tetrol)/ tauro-chenodeoxycholic acid (t-CDCA) to be informative biomarker, paving way for introduction of CTX newborn screen (43).

CONCLUSIONS

Cerebrotendinous xanthomatosis is a rare autosomal recessive disorder of bile acid metabolism and lipid storage characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues. Clinical manifestations include neonatal cholestatic jaundice, infantile-onset diarrhea with failure to thrive, childhood-onset cataracts, tendon xanthomas, and progressive neurological dysfunction including intellectual disability, dementia, and psychiatric symptoms. Treatment with CDCA is treatment of choice, however cholic acid, HMG-Co-A reductase inhibitors, and surgical excision also play a role in management. Timely detection and treatment are the key to prevent severe morbidity and mortality in these patients.

REFERENCES

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ABSTRACT

In evaluating a patient with dyslipidemia the initial step is to decide which particular lipid/lipoprotein abnormalities need to be evaluated and whether they need treatment. These disorders can be divided into elevations of LDL-C, triglycerides, non-HDL-C, and Lp(a) and decreases in plasma HDL-C. Frequently a patient can have multiple lipid/lipoprotein abnormalities. The next step is to rule out secondary causes that could account for the abnormal lipid/lipoprotein levels. These secondary causes can be due to diet, various disease states, or drug therapy. One should be suspicious of a secondary cause if a patient suddenly develops a lipid/lipoprotein abnormality or the lipid/lipoprotein profile suddenly worsens. Next one should consider the possibility of a genetic disorder and therefore ask whether relatives have either premature cardiovascular disease, lipid disorders, or are receiving lipid lowering medications. If the triglyceride levels are markedly elevated one should inquire about a family history of pancreatitis. When the lipid/lipoprotein abnormality is markedly abnormal or begins at a young age, the likelihood of a genetic disorder is increased and the family history assumes even greater importance. In most circumstances a routine lipid panel consisting of plasma triglycerides, total cholesterol, HDL-C, and calculated LDL-C and non-HDL-C provides sufficient information to appropriately decide on who to treat and the best treatment approach. However, it should be recognized that there are certain situations where more sophisticated and detailed laboratory studies can be helpful. The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. Several guidelines have been published that discuss in detail cardiovascular risk assessment and provide recommendations on treatment strategies. Additionally, calculators are available on-line to determine an individual patient’s risk of developing cardiovascular disease in the next 10 years or their lifetime risk. In the prevention of cardiovascular disease, the main priority is to lower the LDL-C levels. Reductions in other apolipoprotein B containing lipoproteins may be instituted if LDL-C levels are at goal. Depending on the specific guideline the percent reduction in LDL-C and/or the goal LDL-C will vary depending upon the patient profile. When LDL-C levels are at goal but triglyceride and non-HDL-C levels are still elevated a recent study suggests further treatment with icosapent ethyl may be beneficial. Whether decreasing Lp(a) is beneficial in preventing cardiovascular disease is uncertain and further studies are in progress. Lifestyle changes are the initial treatment but in most patients’ drug therapy will be necessary.

INTRODUCTION

The initial step is to decide which particular lipid/lipoprotein abnormalities need to be evaluated and whether they need treatment. These disorders can be divided into elevations of LDL-C, triglycerides, non-HDL-C, and Lp(a), and decreases in HDL-C. An increase in non-HDL-C accompanies an increase in LDL-C and/or triglycerides levels. Often a patient can have multiple lipid/lipoprotein abnormalities. For example, it is not uncommon for a patient to have high triglycerides with low HDL-C levels or high LDL-C and high Lp(a) levels.

From a clinical point of view, one is not usually concerned if the LDL-C, Lp(a), or triglyceride levels are low or if the HDL-C level is high. Very low levels of LDL-C and/or triglycerides suggest the presence of other medical issues such as hyperthyroidism, malabsorption, liver disease, chronic infections, cancer, etc. On rare occasions very low LDL-C levels or triglyceride levels can be due to genetic disorders (1). Very high HDL-C levels can also be due to genetic causes (2).

RULE OUT SECONDARY CAUSES

The next step is to rule out secondary causes that could account for the abnormal lipid/lipoprotein levels. These secondary causes can be due to diet, various disease states, or medications. One should be suspicious of a secondary cause if a patient suddenly develops a lipid/lipoprotein abnormality or the lipid/lipoprotein profile suddenly worsens. Patients with genetic abnormalities causing dyslipidemia can have their disorder worsen if they develop secondary causes that further adversely affect lipid/lipoprotein levels.

The key is that if one corrects the secondary cause the lipid/lipoprotein abnormality can often markedly improve or even disappear. For example, hypothyroidism can be accompanied by striking increases in LDL-C levels and the treatment of hypothyroidism can result in a large decrease in LDL-C, often to normal levels (3). Likewise, an improvement in glycemic control in a patient with poorly controlled diabetes may result in a large decrease in serum triglyceride levels (4). Occasionally, the presence of dyslipidemia leads to the discovery of an unrecognized secondary disorder that requires treatment.

Similarly stopping certain drugs can greatly improve the lipid profile (5). For example, in some postmenopausal women with hypertriglyceridemia stopping oral estrogen therapy can result in a marked decrease in triglyceride levels (3). The disorders and drugs that cause lipid/lipoprotein abnormalities are shown in tables 1-7. It should be noted that many disorders and drugs can cause multiple lipid abnormalities. The effects of disorders and drugs in an individual patient can vary depending on genetic background and the presence of other disorders and drugs that effect lipid/lipoprotein levels. For an extensive discussion of the secondary disorders that alter lipid and lipoprotein metabolism please refer to the individual Endotext chapters on these disorders. For additional information on the effect of drugs on lipid and lipoprotein metabolism please see the Endotext chapter on this topic (5).

In a patient with an elevated LDL-C level, one should take a diet history, review the medication list, and check a TSH level to rule out hypothyroidism. Most of the disorders that cause elevations in LDL-C levels, other than hypothyroidism, should be obvious on routine history, physical examination, and laboratory screening. In a patient with an elevated triglyceride level, one should take a diet history and in particular focus on the ingestion of simple sugars and ethanol. One should review the medication list and recognize that many common disease states can adversely impact triglyceride levels including obesity, poorly controlled diabetes, chronic renal failure, HIV, and inflammatory disorders (4,6-9). Weight loss, improvements in glycemic control in patients with diabetes, and a reduction of inflammation can all result in a decrease in triglyceride levels (4,6,7). In a patient with a low HDL-C level one should review the medication list and diet, recognizing that diets very low in fat can result in low HDL-C levels, which are often accompanied by low LDL-C and triglyceride levels (10). In young or very fit males with very low HDL-C levels a careful history directed at anabolic steroid use is essential (3).

THINK ABOUT GENETIC CAUSES

One should always consider the possibility of a genetic disorder and therefore ask whether relatives have either premature cardiovascular disease, lipid disorders, or are taking lipid lowering medications (11). If the triglyceride levels are markedly elevated one should inquire about a family history of pancreatitis. When the lipid/lipoprotein abnormality is markedly abnormal or begins at a young age, the likelihood of a genetic disorder is increased and the family history assumes even greater importance. It is essential to think about the possibility of a genetic disorder because many of the common lipid disorders, such as familial hypercholesterolemia and elevations in Lp(a), have an autosomal codominant genetic transmission and therefore will be present in approximately 50% of family members (12-15). The recognition of the possibility of a genetic disorder will lead to screening family members and if abnormalities are found early treatment can be initiated, which may prevent the adverse consequences of hyperlipidemia. The monogenetic disorders that cause elevations in LDL-C and triglycerides levels and low HDL-C levels are shown in tables 8-11.

In autosomal codominant disorders heterozygotes have lipid abnormalities approximately half as severe as homozygotes

In autosomal codominant disorders heterozygotes have lipid abnormalities approximately half as severe as homozygotes

Very frequently hypertriglyceridemia and/or hypercholesterolemia are due to polygenic inheritance secondary to combinations of common small effect genes that regulate the production or catabolism of lipoproteins (16). In addition, lifestyle, other disease states, and medications can interact with genetic susceptibilities to result in marked dyslipidemia and therefore even when a genetic disorder is present one should not ignore reversible factors where appropriate treatment can have marked effects on lipid levels. Often secondary factors facilitate the expression of genetic variations to result in an abnormal lipid phenotype. One of the best examples of the interaction of secondary factors and genetic variants is familial dysbetalipoproteinemia (17,18). The apolipoprotein E2/E2 polymorphism occurs in approximately 1% of individuals whereas the clinical disorder only occurs in 1-5/5000 and is frequently associated with other disorders, such as obesity, hypothyroidism, and diabetes, which also perturb lipid metabolism (17,18). A detailed discussion of the genetic disorders that effect plasma lipid and lipoprotein levels can be found in the individual Endotext chapters that focus on these disorders.

ORDERING SPECIAL LABORATORY STUDIES

In most circumstances a routine lipid panel consisting of triglycerides, total cholesterol, HDL-C, and calculated LDL-C and non-HDL-C provides sufficient information to appropriately decide on who to treat and the best treatment approach. In a patient with high fasting triglycerides (>200-400mg/dl) where the LDL-C cannot be accurately calculated measurement of direct LDL-C maybe very helpful. However, it should be recognized that there are certain situations where more sophisticated and detailed laboratory studies can be helpful (19). For example, in a young patient with atherosclerotic vascular disease and no obvious risk factors and a normal lipid profile obtaining specialized lipid/lipoprotein studies including measurement of Lp(a) would be indicated. Indications for measuring Lp(a) are shown in Table 12 (19,20). Note, it is the opinion of some experts that Lp(a) should be measured once in all individuals. The various specialized lipid and lipoprotein studies and their appropriate use are discussed in detail in the Endotext chapter “Utility of Advanced Lipoprotein Testing in Clinical Practice” (19). 

Note: It is the opinion of some experts that Lp(a) should be measured once in all individuals

DECIDING WHO TO TREAT

The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. A number of guidelines have been published that discuss in detail cardiovascular risk assessment and provide recommendations on treatment strategies (21-24). It should be noted that while these guidelines are similar there are significant differences between their recommendations. Additionally, several calculators are available on-line to determine an individual patient’s risk of developing cardiovascular disease in the next 10 years or their lifetime risk. These issues are discussed in detail in the chapters on Risk Assessment and Guidelines for the Management of High Blood Cholesterol and Triglycerides (25-27). In addition to cardiovascular complications, marked elevations in triglycerides can lead to pancreatitis (26). The National Lipid Association recommends treating triglyceride levels greater than 500mg/dl while the Endocrine Society recommends treating triglycerides if they are greater than 1000mg/dl to lower the risk of pancreatitis (28,29).

GOALS OF THERAPY

The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines do not emphasize specific lipid/lipoprotein goals of therapy but rather to just treat with the statins to lower LDL-C by a certain percentage (21). An exception is that they do recommend in patients with very high-risk ASCVD, to use an LDL-C threshold of 70 mg/dL to consider addition of non-statins to statin therapy. In contrast, other groups, such as the National Lipid Association, International Atherosclerosis Society, European Society of Cardiology/European Atherosclerosis Society, and AACE, do recommend lowering the LDL and non-HDL cholesterol levels to below certain levels depending upon the cardiovascular risk in a particular patient but the recommendations from these organizations are not identical (22,24,29,30).

A detailed discussion of lipid/lipoprotein goals is provided in the chapter on Risk Assessment and Guidelines for the Management of High Blood Cholesterol (25). It should be noted that many lipid experts would recommend trying to achieve an LDL-C levels less than 70mg/dl and non-HDL-C levels less than 100mg/dl in patients with cardiovascular disease or patients at very high risk for the development of cardiovascular disease. In other patients, an LDL-C level less than 100mg/dl and non-HDL-C level less than 130mg/dl is a reasonable goal. AACE and European Society of Cardiology/European Atherosclerosis Society have recommended LDL-C levels less than 55mg/dl in patients at very high risk (22,24). With the results of the IMPROVE-IT trial and PCKS9 inhibitor studies, which showed that adding ezetimibe or a PCSK9 inhibitor to statin therapy resulted in an additional decrease in LDL-C levels and a further reduction in cardiovascular events, the arguments in favor of trying to reach lower lipid/lipoprotein goals has been greatly strengthened  (31-33). Moreover, the results of these and other studies provide strong support that the lower the LDL-C level the greater the reduction in cardiovascular events (34,35).     

TREATMENT TO REDUCE COMPLICATIONS OF DYSLIPIDEMIA

The first priority in treating lipid disorders is to lower the LDL-C levels to goal, unless triglycerides are markedly elevated (> 500-1000mg/dl), which increases the risk of pancreatitis. LDL-C is the usual first priority because the data linking lowering LDL-C with reducing cardiovascular disease are extremely strong and we now have the ability to markedly decrease LDL-C levels. Dietary therapy is the initial step but in the majority of patients’ dietary modifications will not be sufficient to achieve the LDL-C goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL-C levels but this seldom occurs in clinical practice. Additionally, the dietary changes need to be sustained for a long period of time to be effective and many patients while able to follow an LDL-C lowering diet in the short term are unable to follow the diet for an extended period of time.

Primary Prevention Patients

The first step is determining the risk for developing atherosclerotic cardiovascular disease. There are a number of different calculators for determining risk. In the US the most popular is the ACC/AHA risk calculator (http://www.cvriskcalculator.com/) whereas in Europe the SCORE (Systematic Coronary Risk Estimation) is popular (SCORE2 and SCORE2-OP (escardio.org)). The ACC/AHA recommendations are shown in Figure 1 and the European Society of Cardiology/European Atherosclerosis Society recommendations are shown in Figure 2.

Figure 1. ACC/AHA Recommendations for Patients without ASCVD, Diabetes, or LDL-C greater than 190mg/dl. Risk enhancers are listed in table 13. (Note the risk is for MI and stroke, both fatal and nonfatal).

Figure 2. European Society of Cardiology/European Atherosclerosis Society Recommendations for Primary Prevention Patients. Risk categories are shown in table 14. (Note that the SCORE risk is for a fatal event). There are different tables for different European countries.

A few caveats are worth noting. First, in patients less than 60 years of age it is very helpful to calculate the life-time risk of ASCVD events. Often one will find that the 10-year risk is modest but the life-time risk is high and this information should be included in the risk discussion to help in the decision process. Second, patients should be made aware of the natural history of ASCVD i.e., that it begins early in life and slowly progresses overtime with high LDL-C levels accelerating the rate of development of atherosclerosis and low LDL-C leading to a slower progression of atherosclerosis (35,36). Third, patients should be made aware of genetic studies demonstrating that variants in genes that lead to lifetime decreases in LDL-C levels (for example the HMG-CoA reductase gene, NPC1L1 gene, PCSK9 gene, ATP citrate lyase gene, and LDL receptor gene) result in a decreased risk of cardiovascular events. In a recent study it was reported that a 10mg/dL lifetime decrease in LDL-C with any of these genetic variants was associated with a 16-18% decrease in cardiovascular events whereas a 10mg/dl reduction in LDL-C with lipid lowering therapy results in only approximately a 5% decrease in cardiovascular events (34,37,38). The combination of the natural history and the results observed with genetic variants strongly suggests that early therapy to lower LDL-C levels will have greater effects on reducing the risk of ASCVD events than starting therapy later in life. This information needs to be discussed with the patient. Fourth, if the patient or health care provider are uncertain of the best course of action obtaining a cardiac calcium scan can be very helpful in the decision-making process, particularly in older individuals. A score of 0, particularly in an older patient would indicate that statin therapy is not needed whereas a score > 100 would indicate a need for statin therapy (21). A score of 1-99 favors the use of a statin (21).

In most primary prevention patients, statin therapy is sufficient to lower LDL-C levels to goal (< 100mg/dl). One can usually start with moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg) and increase the statin dose, if necessary, to achieve LDL-C goals. Statins are available as generic drugs and therefore are relatively inexpensive. If a patient does not achieve their LDL-C goal on intensive statin therapy, cannot tolerate statin therapy, or is able to take only a low dose of a statin one can use ezetimibe (generic drug), bempedoic acid, bile acid sequestrants, or PCSK9 inhibitors to further lower LDL-C levels (for detailed discussion of cholesterol lowering drugs see (39)). It should be noted that the addition of ezetimibe or a PCSK9 inhibitor to statin therapy has been shown to reduce cardiovascular events (31-33). In most situations, ezetimibe is the drug of choice given its low cost, ability to reduce ASCVD events, and long-term safety record. If LDL-C is not close to goal PCSK9 inhibitors can be used. Once LDL-C is at goal if the non-HDL-C remains high one can consider the approaches described in the section describing the approach to patients with LDL-C at goal with elevated triglycerides.

Patients with LDL Cholesterol Greater than 190mg/dl

When the LDL-C is greater than 190mg/dl the patient should be started on intensive statin therapy (atorvastatin 40-80mg per day or rosuvastatin 20-40mg per day). If the LDL-C goal is not achieved (usually < 100mg/dl) additional lipid lowering medications should be added. If the LDL-C is relatively close to goal one can use ezetimibe but if the LDL-C is far from the goal the use of a PCSK9 inhibitor should be employed. Because of the potential for a genetic disorder, either monogenic or polygenic, one should check family members for lipid abnormalities. If possible genetic testing for monogenic disorders causing hypercholesterolemia is recommended (40).

Patients with Diabetes

Most patients with diabetes (age 40-75) without risk factors should be started on moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg). In young individuals (< age 40) and older individuals (> age 75) one needs to use clinical judgment Patients with diabetes with ASCVD or risk factors should be started on intensive statin therapy. In my opinion reasonable goals are shown in table 15 (similar to AACE and ADA guidelines) (24,41). If intensive statin therapy does not achieve LDL-C goals additional drugs can be added. If reasonably close to the LDL-C goal the initial drug added should be ezetimibe. If far from goal one could add a PCSK9 inhibitor. Once LDL-C is at goal if the non-HDL-C remains high one can consider the approaches described in the section describing the approach to patients with LDL-C at goal with elevated triglycerides.

Secondary Prevention Patients

Patients with ASCVD (secondary prevention patients) should be started on intensive statin therapy (atorvastatin 40-80mg per day or rosuvastatin 20-40mg per day). Given the extensive data showing that the lower the LDL-C the greater the reduction in ASCVD events most secondary prevention patients would benefit from the addition of ezetimibe to maximize LDL-C lowering without markedly increasing costs (34,35). The goal LDL-C in this patient population is an LDL<70mg/dl but many experts and some guidelines would prefer an LDL-C<55mg/dl if possible. If on intensive statin therapy and ezetimibe treatment the LDL-C is far above goal one could consider adding a PCSK9 inhibitor (this is particularly necessary if the LDL-C is greater than 100mg/dl or the patient is at very high risk due to other factors (diabetes, cerebral vascular disease, peripheral vascular disease, recent MI, history of multiple MIs) (34,35).

Patients with LDL Cholesterol at Goal but High Triglycerides (>150mg/dl to <500mg/dl)

Patients with an LDL-C at goal but high triglyceride levels (>150mg/dl to <500mg/dl) will often have increased non-HDL-C levels. Numerous studies have shown that the risk of ASCVD events is increased in this patient population (42). The initial step should be to improve lifestyle, treat secondary disorders that may be contributing to the increase in triglycerides, and if possible, discontinue medications that increase triglyceride levels. Studies have not demonstrated a reduction in cardiovascular events when niacin is added to statin therapy and given the side effects of niacin enthusiasm for using niacin in combination with statins to reduce ASCVD is limited (43,44). Additionally, the ACCORD-LIPID trial failed to demonstrate that adding fenofibrate to statin therapy (45) and the PROMINENT trial failed to demonstrate that adding pemafibrate to statin therapy (46) reduces cardiovascular disease. Thus, there is little evidence that adding either niacin or a fibrate to statin therapy will be beneficial in reducing cardiovascular events.

The REDUCE-IT trial demonstrated that adding the omega-3-fatty acid icosapent ethyl (EPA; Vascepa) to statin therapy in patients with elevated triglyceride levels reduced the risk of ASCVD events by 25% while decreasing triglyceride levels by 18% (47). Similar results were seen in the JELIS trial (48). In these trials the reduction in triglyceride levels was relatively modest and would not have been expected to result in the magnitude of the decrease in cardiovascular disease observed in the JELIS and REDUCE-IT trials. Other actions of EPA, such as decreasing platelet function, anti-inflammation, decreasing lipid oxidation, stabilizing membranes, etc. could account for or contribute to the reduction in cardiovascular events (49). Based on these results the National Lipid Association has recommended “that for patients aged ≥45 years with clinical ASCVD, or aged ≥50 years with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting TGs 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (±ezetimibe), treatment with icosapent ethyl is recommended for ASCVD risk reduction” (50). However, it should be recognized that the STRENGTH trial using a carboxylic acid formulation of EPA and DHA failed to reduce cardiovascular events despite reducing triglyceride levels to a similar degree as in the REDUCE-IT trial (51). Whether EPA has special properties that resulted in the reduction in cardiovascular events in the REDUCE-IT trial or there were flaws in the trial (the use of mineral oil as the placebo) is debated (49,52). For a detailed discussion of triglyceride lowering drugs see the Endotext chapter on this topic (53).

Patients with Very High Triglyceride Levels (>500-1000mg/dl)

The main aim is to keep triglyceride levels below 500 mg/dL to prevent triglyceride-induced pancreatitis (17,54,55).

FAMILIAL HYPERCHYLOMICRONEMIA (FCS)

FCS is a rare autosomal recessive disorder due to an abnormality in the genes listed in table 9 that result in the absence of functional lipoprotein lipase (LPL) activity (17,54,55). Patients with FCS respond poorly to most triglyceride lowering drugs (fibrates, omega-3-fatty acids, niacin) (17,54,55). A very low-fat diet (5-10% of total calories) is the most effective treatment but can be difficult for many patients to comply with (17,54,55). Volanesorsen, a drug that is approved in Europe but not in the US, lowers ApoC-III levels and is effective in lowering triglyceride levels in patients with FCS (53).

MULTIFACTORIAL CHYLOMICRONEMIA SYNDROME (MCS)

MCS is due to the coexistence of a genetic predisposition (polygenic or heterozygous for genes that cause FCS) to hypertriglyceridemia with 1 or more secondary causes of hypertriglyceridemia (see tables 3 and 4) (17,54,55). Initial treatment is a very low-fat diet to reduce triglyceride levels into a safe range (<1000mg/dl). Treating secondary disorders that raise triglyceride levels and when possible, stopping drugs that increase triglyceride levels is essential (17,54,55). If the triglyceride levels remain above 500mg/dl the addition of fenofibrate or omega-3-fatty acids is indicated. Many patients with MCS are at high risk for ASCVD and therefore after triglyceride levels are controlled the patient should be evaluated for cardiovascular disease risk and if indicated statin therapy initiated.   

Patients with High Lp(a) Levels

Life style changes do not significantly lower Lp(a) levels (56). The effect of lipid lowering drugs on Lp(a) levels is shown in Table 16. In patients with elevations in Lp(a) the initial therapy is to aggressively control the other cardiovascular disease risk factors. In some instances, one can use niacin, PCSK9 inhibitors, or in postmenopausal women estrogen to lower Lp(a) levels but the effect of these drugs on preventing cardiovascular events by lowering Lp(a) levels is uncertain (57). Studies of an antisense oligonucleotide or small interfering RNA (both not yet approved) directed at apo(a) have shown that these drugs can lower Lp(a) by >75% without effecting other lipoprotein levels (58). Lipoprotein apheresis can be employed to lower Lp(a) in patients with very high Lp(a) levels who continue to have cardiovascular events despite optimal medical management (59).  

*only approved for the treatment of Homozygous FH; **not currently available

Decreased HDL Cholesterol Levels

Despite epidemiologic studies consistently showing that high HDL-C levels are associated with a decreased risk of cardiovascular disease there are no studies demonstrating that increasing HDL-C levels reduces cardiovascular disease (60). It should be recognized that the crucial issue with HDL may not be the HDL-C levels per se but rather the function of the HDL particles (60). Assays have been developed to determine the ability of HDL to facilitate cholesterol efflux from macrophages and these studies have shown that the levels of HDL-C do not necessarily indicate the ability to mediate cholesterol efflux (61). Similarly, the ability of HDL to protect LDL from oxidation may also play an important role in the ability of HDL to reduce ASCVD (62). Thus, the functional capability of HDL may be more important than HDL-C levels (60-62).

CONCLUSION

In summary, modern therapy demands that we aggressively evaluate and when indicated treat lipid disorders to reduce the risk of atherosclerotic cardiovascular disease and in those with very high triglycerides to reduce the risk of pancreatitis.

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ABSTRACT

Lipoprotein apheresis involves the physical removal of lipoproteins from the blood and is employed only in patients where lifestyle and pharmacologic treatment is not capable of decreasing lipoproteins to acceptable levels. There are a number of different guidelines for the use of lipoprotein apheresis. In general, apheresis is indicated for patients with homozygous or heterozygous Familial Hypercholesterolemia (FH) and LDL cholesterol levels >300mg/dl, patients with heterozygous FH and high cardiovascular disease risk characteristics with an LDL cholesterol > 200mg/dl, patients with heterozygous FH and cardiovascular disease or diabetes with an LDL cholesterol > 160mg/dl, or patients with progressive cardiovascular disease and Lp(a) concentrations > 60 mg/dl. Lipoproteins may be removed from the circulation by precipitation, adsorption, or filtration. A number of different systems are currently available for lipoprotein apheresis (heparin precipitation, binding to polyacrylate anions or dextran sulfate, filters that remove lipoproteins based on size, and columns containing antibodies to apolipoprotein B or lipoprotein (a)). The effect of these different lipoprotein apheresis methods on LDL cholesterol and lipoprotein (a) (Lp(a)) levels are very similar with LDL cholesterol and LP(a) levels decreasing by 50-75%. Over 8-13 days the LDL cholesterol and Lp(a) levels increase and may return to baseline levels but in some patients the baseline levels are reduced below the starting values. Triglyceride levels decrease by approximately 50% and HDL cholesterol levels may also decrease depending on the method of apheresis. Triglyceride and HDL cholesterol levels return to baseline levels by 24 hours. Lipoprotein apheresis is generally well tolerated. There are no large randomized studies examining the effect of apheresis on cardiovascular events but there are other types of studies demonstrating the benefits of lipoprotein apheresis on atherosclerosis and cardiovascular disease including observational studies in patients with homozygous FH, studies examining the effect of apheresis on the progression of atherosclerosis, and studies comparing rates of cardiovascular events pre-apheresis and during apheresis. While these studies do not definitively demonstrate that lipoprotein apheresis decreases cardiovascular events, the results of these studies coupled with the randomized studies of LDL cholesterol lowering with drugs makes it extremely likely that lowering LDL cholesterol levels with lipoprotein apheresis will reduce the risk of cardiovascular events. Whether lowering Lp(a) levels with lipoprotein apheresis will reduce cardiovascular events is less certain but given the epidemiology data, genetic studies, basic science experiments, and animal experiments it is very likely that lowering elevated Lp(a) will also have beneficial effects on cardiovascular outcomes. Thus, in carefully selected patient’s lipoprotein apheresis is a useful procedure to lower LDL cholesterol and Lp(a) levels thereby reducing the risk of cardiovascular events. Finally, plasmapheresis has been utilized to rapidly decrease plasma triglyceride levels in patients with very high triglyceride levels and pancreatitis.

INTRODUCTION

Lipoprotein apheresis involves the physical removal of lipoproteins from the blood and is employed in patients where lifestyle and pharmacologic treatment is not capable of decreasing lipoproteins to acceptable levels (1-4). Lipoprotein apheresis is not widely used but in selected patients can have dramatic effects on lipoprotein levels and clinical benefit (1-4).

INDICATIONS

Lipoprotein apheresis is only recommended after maximal lifestyle and drug treatment fails to achieve acceptable lipoprotein levels. There are a number of guidelines and recommendations for the use of lipoprotein apheresis. In the United States the Food and Drug Administration has approved the use of lipoprotein apheresis for a limited number of patient categories (Table 1).

In other countries the guidelines are more liberal. For example, in Germany lipoprotein apheresis is accepted for additional indications (Table 2) (5).

In Japan lipoprotein apheresis is approved for patients with coronary artery disease and a total cholesterol level > 250mg/dl (6). The National Lipid Association Recommendations are shown in Table 3 (7).

In general, patients with homozygous Familial Hypercholesterolemia who do not have an adequate response to lipid lowering drugs are candidates for lipoprotein apheresis and this should be initiated as soon as possible. Additionally, apheresis can be considered in patients with elevated cholesterol levels if atherosclerotic vascular disease is present and progressive and if LDL cholesterol treatment goals are not achieved despite maximal drug therapy. The use of lipoprotein apheresis solely for the lowering of Lp(a) is uncertain.

In the United States the widespread use of lipoprotein apheresis is limited by the high expense of this treatment and by the small number of centers that perform this procedure (in the US fewer than 60 centers with approximately 600 patients) (2). In contrast, in Germany there are over 350 centers that perform lipoprotein apheresis and the number of patients treated is over 3,000 (4,8).

In pregnant women with homozygous or heterozygous Familial Hypercholesterolemia lipoprotein apheresis when available can be utilized to lower LDL cholesterol levels as the use of many drugs is relatively contraindicated during pregnancy (9). In children with homozygous familiar hypercholesterolemia and very high LDL cholesterol levels lipoprotein apheresis treatment can be initiated prior to puberty (10,11).    

It is likely that in the future the need for lipoprotein apheresis will be markedly diminished by the recent development of new drugs for lowering LDL cholesterol levels (12). For example, in patients with heterozygous FH the use of PCSK9 inhibitors will markedly reduce the need for lipoprotein apheresis (12). In patients with heterozygous Familial Hypercholesterolemia on lipoprotein apheresis treatment with a PCSK9 inhibitor resulted in 63% to 77% being able to discontinue lipoprotein apheresis (12,13). In patients with homozygous FH the availability of PCSK9 inhibitors, lomitapide, and  evinacumab might also decrease the need for lipoprotein apheresis (12). Additionally, in the future drugs that specifically and markedly lower Lp(a) may become available (14,15). Thus, the number of patients that require lipoprotein apheresis should be limited with the majority of patients having homozygous FH.

LIPOPROTEIN APHERESIS METHODS

Lipoproteins may be removed from the circulation by precipitation, adsorption, or filtration (Table 4) (2-4,8). A number of different systems are currently available for lipoprotein apheresis (Table 4) (2-4,8).

Lipoprotein apheresis is typically carried out on a weekly or biweekly schedule. A typical session is 1.5 – 4 hours. Venous blood is utilized and anticoagulation is required. Some methods utilize plasma (immunoadsorption, filtration, dextran sulfate (Liposorber), HELP) while others utilize whole blood (DALI and dextran sulfate (Liposorber D)) (2-4,8). In the United States HELP precipitation and dextran sulfate adsorption (Liposorber) are approved by the FDA (2). A schematic of the Liposorber system is shown in Figure 1.

Figure 1. Liposorber System (http://www.accessdata.fda.gov/cdrh_docs/pdf12/H120005b.pdf)

EFFECT OF LIPOPROTEIN APHERESIS ON LIPOPROTEINS

While there are several different lipoprotein apheresis methods (see table 4), the effect of these different methods on plasma lipoprotein levels are similar except for modest differences in their effect on HDL cholesterol levels (2-4,16-18). Soon after lipoprotein apheresis, LDL cholesterol and lipoprotein (a) (Lp(a)) levels are decreased by 50-75% (2-4,16). Over 8-13 days the LDL cholesterol and Lp(a) levels increase such that they may be only modestly decreased or return to baseline prior to the next lipoprotein apheresis session (2,4,19,20). Lp(a) levels tend to rebound more slowly than LDL (2,4,20). After chronic lipoprotein apheresis the pretreatment levels of LDL and Lp(a) in some patients may be reduced by 20 to 40% (2,4,20). Weekly apheresis is more effective in lowering baseline lipoprotein levels than biweekly apheresis. The concomitant use of drug therapy is beneficial, slowing the rebound in lipoprotein levels, even in patients with homozygous FH (2,4,20). In a systemic review of children with homozygous familiar hypercholesterolemia lipoprotein apheresis resulted in a 60-70% reduction in LDL cholesterol (21).

Triglyceride levels may decrease by 50% with lipoprotein apheresis but the plasma triglyceride levels return to baseline levels by 24 hours (2,4). HDL cholesterol levels also may transiently decrease by 5-20% but return to baseline within 24 hours (2,4). The explanation for the decrease in HDL cholesterol is uncertain, but may be due to hemodilution, activation of hepatic triglyceride lipase, or the decreased activity of LCAT (2). Notably the acute decrease in HDL cholesterol is greater than the decrease in apolipoprotein A-I (2).

The commonly used lipoprotein apheresis methods are not typically used to remove chylomicrons. Instead in patients with markedly elevated triglycerides and severe pancreatitis plasma exchange may be used to rapidly remove chylomicrons and lower plasma triglyceride levels (22,23). 

TARGET LEVELS OF LIPOPROTEINS DURING LONG TERM LIPOPROTEIN APHERESIS

The following goals of therapy have been suggested (Table 6) (20). It should be recognized that these goals are not based on randomized controlled outcome trials but are suggestions by experts.

*Compared with baseline off all lipid lowering treatment

⁺Baseline levels are immediately before apheresis and interval mean is the level obtained by integrating the area under the post apheresis rebound curve.

PLEOTROPIC EFFECTS OF LIPOPROTEIN APHERESIS

In addition to decreasing lipoprotein levels, lipoprotein apheresis has other effects (Table 7) (1,2,24).

It should be noted that the levels of these proteins rapidly return towards normal and the clinical significance of these changes is unknown.

EFFECT OF LIPOPROTEIN APHERESIS ON ATHEROSCLEROSIS AND CARDIOVASCULAR OUTCOMES

There are no large randomized outcome studies examining the effect of lipoprotein apheresis on cardiovascular event rates. Performing such a study would be very difficult and given the abundance of evidence that marked hypercholesterolemia causes cardiovascular events randomizing patients with very high levels of LDL cholesterol to a group that is not treated would raise ethical concerns. However, there are a large number of other types of studies that provide insights into the benefits of lipoprotein apheresis on atherosclerosis and cardiovascular events.

Observational Studies in Patients with Homozygous FH

In 1985 Thompson and colleagues reported that plasma exchange for a mean of 8.4 years decreased peak serum cholesterol levels by 37% in five patients with homozygous FH and resulted in 5.5 year longer survival than their five respective homozygous siblings (25). In a larger group of patients with homozygous FH, Keller also reported that survival was improved in the patients treated with lipoprotein apheresis compared to those treated only with drug therapy (26). Additionally, angiographic studies demonstrated that plasma exchange delays the rate of progression of coronary atherosclerosis in homozygotes FH patients (27).

Studies Examining the Effect of Lipoprotein Apheresis on Atherosclerosis

Several studies have examined the effect of apheresis on atherosclerosis. In 1992 Tatami and colleagues reported that lipoprotein apheresis for greater than one year in 37 patients with hypercholesterolemia (7 homozygote and 25 heterozygote FH patients and 5 undefined patients) had favorable effects on coronary artery stenosis (28). As expected, lipoprotein apheresis decreased LDL cholesterol levels. Definite regression was observed in 14 patients, including 4 homozygotes and 10 heterozygotes and regression was observed in patients with severe or mild atherosclerosis. Moreover, the greater the difference in pre and post LDL cholesterol levels the greater the regression in atherosclerosis. Interestingly patients with other risk factors in addition to hypercholesterolemia had less regression.

In 1994 Schuff-Werner and colleagues prospectively determined the efficacy of lipoprotein apheresis in 39 patients with elevated LDL cholesterol levels (286mg/dl) not on statin therapy over a 2 year period (29). Lipoprotein apheresis resulted in a rapid decrease in LDL cholesterol levels from 286mg/dl to 121mg/dl one day after apheresis. Moreover, after one and two years of lipoprotein apheresis the baseline LDL cholesterol levels decreased to 203mg/dl and 205mg/dl, respectively. Angiographic studies were obtained in 33 patients before and after 2 years and demonstrated that the mean degree of stenosis of all segments decreased from 32.5% to 30.6% over the 2 years of apheresis treatment (p=0.02). Additionally, regression > 8% was observed in 50/187 (26.7%) segments, 29/187 (15.5%) segments showed progression, and 108/187 (57.8%) segments were stable (< 8% deviation) over 2 years. Finally, the percentage of patients with angina decreased with lipoprotein apheresis.

Waidner and colleagues determined the effect of 3 years of lipoprotein apheresis on coronary artery disease in 32 patients with drug refractory FH (30). Apheresis did not significantly improve exercise tolerance. However, quantitative measurement of 111 circumscribed coronary stenoses showed a mean stenosis of 45 +/- 26% at baseline and 43 +/- 22% after apheresis demonstrating no significant improvement with lipoprotein apheresis.

In 1998 Richter and colleagues described the effect of lipoprotein apheresis in 34 patients with coronary heart disease and heterozygous FH not adequately responsive to lipid-lowering drugs (31). Baseline LDL cholesterol levels were 269 +/- 62 mg/dl and the calculated-on treatment interval mean LDL cholesterol was 129 +/- 23mg/dl. Coronary angiography revealed regression of lesions in 4 patients (11.8%) and no progression in 19 patients (55.8%).

In a multicenter study Stefanutti et al reported on the effect of lipoprotein apheresis on the progression of coronary artery lesions in 19 patients (32). The levels of LDL cholesterol decreased from 130mg/dl pre-apheresis to 41mg/dl post apheresis. Similarly, Lp(a) levels pre-apheresis decreased from 125mg/dl to 34mg/dl post apheresis. Of note, during apheresis both the pre-apheresis LDL cholesterol and Lp(a) levels were lower than baseline values (LDL: 152mg/dl decreasing to 130mg/dl; Lp(a) 172mg/dl decreasing to 125mg/dl). Coronary catheterization revealed that 94.5% of the lesions were stable over 3.1 years.

In 2022 Safarova et al reported the results of lipoprotein apheresis for 10 plus years on carotid intima medial thickness (CIMT) in 10 patients with severe hypercholesterolemia (33). Pretreatment LDL cholesterol was 214mg/dL and 40% of the patients had an Lp(a) >60 mg/dL. As expected, LDL cholesterol and Lp(a) levels decreased (over 70% decrease immediately after apheresis). The percentage of patients with CIMT above their "vascular age" decreased from 80% to 30% over the treatment course and the estimated annual rate of change in mean common CIMT was  minus 4 µm/year.

In general, these angiographic studies suggest that lipoprotein apheresis has beneficial effects on coronary artery atherosclerosis. It should be recognized that in many of the patients in the studies described above one would expect worsening of coronary atherosclerosis and therefore the lack of progression in these patients suggests benefit. That these studies demonstrate either regression or decreased progression in these high-risk patients indicates lipoprotein apheresis is having beneficial effects on atherosclerosis.

Studies Comparing Pre-Lipoprotein Apheresis Cardiovascular Event Rates to Cardiovascular Event Rates During Lipoprotein Apheresis

A number of small studies have compared the rate of cardiovascular events prior to the initiation of lipoprotein apheresis with the rate of cardiovascular events during lipoprotein apheresis treatment. These studies have consistently shown that the rate of cardiovascular events is reduced during apheresis. A larger German Registry study also found evidence supporting a reduction in cardiovascular events during apheresis.

STUDIES FOCUSING ON LDL CHOLESTEROL

Gordon and colleagues reported the long term effects of lipoprotein apheresis in 49 patients with homozygous (n=10) or heterozygous FH (n=39) (34). As expected, there was a 76% decrease in LDL cholesterol levels immediately following apheresis and in patients with homozygous FH there was a progressive decrease in pretreatment LDL cholesterol levels. In patients with heterozygous FH there was no change in pretreatment LDL cholesterol levels. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy (P=0.17).

Sachais and colleagues retrospectively studied 34 FH patients treated with biweekly lipoprotein apheresis at the Hospital of the University of Pennsylvania (35). As expected, there was a marked reduction of LDL cholesterol level after apheresis and in some but not all patients there was a long-term reduction in their pre-apheresis LDL cholesterol levels. There was a marked decrease in cardiovascular events (3.2-fold decrease) defined as myocardial infarction, stroke, transient ischemic attack or rupture of aortic aneurysm. Similarly, there was also a 20-fold decrease in the need for cardiovascular interventions (coronary artery bypass surgery, carotid endarterectomy, and coronary artery angioplasty or stent placement).

Berent et al in an observational study of 30 patients reported that the incidence of cardiovascular disease 2 years after initiating apheresis compared to the 2 years prior to was reduced by 78% (36).

STUDIES FOCUSING ON LDL CHOLESTEROL AND LP(a)

In a single center study Koziolek and colleagues determined the incidence of major cardiovascular events in 38 patients who were treated during a 20 year period (37). LDL cholesterol and Lp(a) were reduced by approximately 60%. Major cardiovascular events were decreased from 7.02% events per patient per year at the start of lipid apheresis to 1.17% during lipid apheresis. Similarly, the rate of myocardial revascularization decreased from 22.8% to 3.8% per patient per year.

A multicenter study by von Dryander and colleagues examined the occurrence of cardiovascular events before apheresis and during apheresis in three groups defined by their lipid patterns at the start of an apheresis treatment: Group 1 (LDL-C ≥ 133mg/dl and Lp(a) ≤ 60 mg/dl; n = 35), Group 2 (LDL-C ≤ 133mg/dl and Lp(a) ≥ 60 mg/dl n = 37), and Group 3 (LDL-C ≥ 133mg/dl and Lp(a) ≥ 60 mg/dl; n = 15) (38). LDL cholesterol and Lp(a) levels were decreased by 55-70% by lipoprotein apheresis. Comparisons of the two years before the start of apheresis treatment with the first two years of apheresis treatment revealed the following reductions in the rates of cardiovascular events: Group 1- 54%; Group 2- 83%; Group 3- 83.5%.

In a single center study, Heigl and colleagues examined the effect of lipoprotein apheresis on cardiovascular events in 118 patients with either severe hypercholesterolemia or isolated increases in Lp(a) (39). Medium interval between the first cardiovascular event and apheresis treatment was 6.4 ± 5.6 years and the average apheresis treatment period was 6.8 ± 4.9 years. In patients with severe hypercholesterolemia (n=83) baseline LDL cholesterol levels were 176mg/dl and decreased by 67% following apheresis leading to an interval mean value of 120mg/dl. In patients with isolated elevations in Lp(a) (n=35), the baseline Lp(a) was 127mg/dl and decreased by 67% following apheresis leading to an interval mean value of 60mg/dl. After the initiation of lipoprotein apheresis, the annual rate of major cardiovascular events decreased by 80% (p<0.0001). Subgroup analysis showed a 73.7% decrease in patients with severe hypercholesterolemia (p<0.0001) and a 90.4% decrease in patients with isolated elevated Lp(a) levels (p< 0.0001).

Jaeger and colleagues in a longitudinal, multicenter, cohort study determined the effect of lipoprotein apheresis on major coronary events in 120 patients on maximal medical therapy with elevated LDL cholesterol (127mg/dl) and Lp(a) levels (>2.14micromol/l) (40). The mean duration of lipid-lowering therapy alone was 5.6 years and that of apheresis was 5.0 years. Median Lp(a) concentration was reduced from 4.00 micromol/l to 1.07 micromol/l (73% decrease) with apheresis treatment (P<0.0001) while LDL cholesterol levels decreased from 127mg/dl to 86mg/dl. Most importantly, major cardiovascular events were reduced by 86% during the lipoprotein apheresis phase (Annual rate 1.056 per patient during the pre-apheresis phase vs. 0.144 per patient during the apheresis phase; p < 0.0001).

In a review of data from the German Lipoprotein Apheresis Registry, the effect of lipoprotein apheresis in 991 patients was described (41). As expected, lipoprotein apheresis reduced both LDL cholesterol and Lp(a) levels by greater than 60%. Moreover, there was a 90% decrease in major adverse coronary events as well as a decrease in major adverse non-coronary events by 69 %. An update from the German Lipoprotein Apheresis Registry with 2028 reported similar results (42). Similarly, data from the United Kingdom registry reported a reduction in LDL cholesterol and Lp(a) of approximately 40% with a 62.5% reduction in major adverse cardiovascular events between the 2 years prior to, and the first 2 years following introduction of lipoprotein apheresis (43).

STUDIES FOCUSING ON LP(a)

Rosada and colleagues compared the occurrence of cardiovascular events in 37 patients with elevated Lp(a) levels (112mg/dl) and normal LDL cholesterol levels (84mg/dl) before the initiation of apheresis and during apheresis treatment (44). As expected, lipoprotein apheresis resulted in a marked decrease in LDL cholesterol levels (-60%) and Lp(a) levels (-68%). Event-free survival rate after 1 year in the pre-apheresis period was 38% vs. 75% during the apheresis period (P < 0.0001). These results suggest that lowering LDL cholesterol and Lp(a) levels in patients with normal LDL levels and elevated Lp(a) levels by lipoprotein apheresis reduces the number of cardiovascular events.

Leebmann, Roeseler and colleagues carried out a five year prospective observational multicenter study that compared cardiovascular events before and after lipoprotein apheresis in 170 patients with normal LDL cholesterol levels (99mg/dl) and elevated Lp(a) levels (108mg/dl) (45,46). As expected, apheresis reduced Lp(a) levels 68%. Moreover, there was a significant decline of the mean annual cardiovascular event rate from 0.58±0.53 2 years before initiating lipoprotein apheresis to 0.11±0.15 thereafter (P<0.0001). These results further support the hypothesis that lowering Lp(a) levels by apheresis in patients with elevated Lp(a) levels and reasonable LDL cholesterol levels will decrease cardiovascular events.

Grob et al studied 59 patients with elevated Lp(a) levels who were treated with lipoprotein apheresis (47). Lp(a) levels were acutely reduced by approximately 70% by apheresis and pre-apheresis Lp(a) levels were decreased by 22.8% compared to baseline. Moreover, cardiovascular events were reduced by approximately 83% during lipoprotein apheresis. Recently, Bigazzi reported in 23 patients with elevated Lp(a) levels and LDL cholesterol levels less than 100mg/dl that lipoprotein apheresis also resulted in a 74% reduction in cardiovascular events during apheresis compared to prior to apheresis (48).

Moriarty et al compared cardiovascular events pre and on lipoprotein apheresis in 14 patients with a mean of LDL cholesterol 80mg/dl and Lp(a) level of 138mg/dl pre-lipoprotein apheresis (49). On lipoprotein apheresis LDL cholesterol decreased to 29mg/dl and Lp(a) to 51mg/dl. Notably there was a 94% reduction in major adverse cardiovascular events over a mean treatment period of 48 months.

Finally, in a small study Poller and colleagues determined the effect of lipoprotein apheresis in 10 patients with peripheral artery disease who had recently undergone a revascularization procedure and had isolated elevations in Lp(a) (Lp(a) 156mg/dl; LDL cholesterol 85mg/dl) (50). After 12 months it was noted that the ankle-brachial-index increased from 0.5 ± 0.2 to 0.9 ± 0.1 (P < 0.001), the mean pain level decreased from 7.0 ± 1.5 to 2.0 ± 0.8 (P < 0.001) as determined using the visual analog scale, and that walking distance increased from 87 ± 60 m to 313 ± 145 m (P < 0.001). Moreover, the frequency of revascularization procedures was decreased (35 revascularizations within the 12 months prior to initiating apheresis vs. 1 revascularization procedure after starting apheresis P<0.001).

While the results of these studies are impressive and demonstrate a consistent reduction in cardiovascular events with the initiation of lipoprotein apheresis in patients with elevations in LDL cholesterol and/or Lp(a) levels it should be recognized that these studies did not include control groups. The absence of a control group is a major limitation. The patients included in these studies were likely selected for treatment with lipoprotein apheresis because they were having progressive cardiovascular events. The decrease in cardiovascular events following the initiation of lipoprotein apheresis could simply represent “regression to the mean” rather than a beneficial effect of apheresis. The inclusion of matched controls who were not treated with lipoprotein apheresis would have increased the significance and the reliability of the above observations. Of course, whether it would be ethical to include such a control group is debatable.

Controlled Trials

STUDIES FOCUSING ON LDL CHOLESTEROL

Koga et al determined the effect of the combination of lipoprotein apheresis plus drug therapy in 2 patients with homozygous FH and 9 patients with heterozygous FH compared to 10 heterozygous FH patients maintained on medication only on carotid intima-media thickness over a greater than 5 year period (51). It should be noted that the medication only group was significantly older than the apheresis group. The annual rate of progression of mean maximum intima-media thickness in the common carotid artery was -0.0023+/-0.0246 mm year in heterozygous FH patients treated with LDL apheresis plus drugs while in heterozygote FH patients treated with drugs alone the mean change was +0.0251+/-0.0265 mm year. These results suggest that the long-term treatment with combined lipoprotein apheresis and drugs may delay the progression of the atherosclerotic process and prompt the stabilization of atheromatous plaque in severe FH patients. However, it should be recognized that this was a small non-randomized study and the lipoprotein apheresis plus medication group was not perfectly matched with the medication only group.

Nishimura and colleagues compared angiographic changes after 2.3 years in 25 patients with heterozygous FH treated with lipoprotein apheresis and lipid lowering drugs and 11 patients who declined apheresis and were treated only with drugs (52). The apheresis plus drug therapy group was very similar to the lipid lowering drug therapy group. During the trial LDL-cholesterol levels were 140 +/- 34 mg/dl in the apheresis group and 170 +/- 58 mg/dl in the control group (P < 0.05). The mean changes in minimal lumen diameter of lesions were +0.19 +/- 0.30 mm (improved) in the apheresis group (n = 76) and -0.44 +/- 0.40 mm (worsened) in the control group (n = 37) (P < 0.0001). When progression and regression were defined as a change in minimal lumen diameter of +/- 0.67 mm, in the apheresis group, two patients (8%) had progression, 19 (76%) remained unchanged and four (16%) demonstrated regression. In contrast, in the control group seven patients (64%) had progression and four (36%) stayed unchanged. The frequency of regression or no change was greater in the apheresis group than in the control group (P < 0.004). It should be recognized that this was not a randomized study and there may have been subtle differences between the two groups.

Mabuchi and colleagues described the effects of lipoprotein apheresis on coronary artery disease in 43 patients with heterozygous FH treated with cholesterol lowering drug therapy plus apheresis vs. 87 patients with heterozygous FH treated with drug therapy alone (53). The patients were not randomized and there were differences in smoking, baseline LDL levels, and percent of patients with coronary artery bypass surgery between the apheresis vs. the drug only group. In the patients treated with apheresis the decrease in LDL cholesterol was 58% (LDL cholesterol on treatment 122mg/dl) while in the drug only group the decrease in LDL cholesterol was 28% (LDL cholesterol on treatment 168mg/dl). Major cardiovascular events including nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and death from coronary heart disease were 72% lower in the lipoprotein apheresis group (10%) compared to the drug therapy alone group (36%) (p=0.0088). The lack of randomization and differences in the treatment groups limit the conclusions of this study.

Matsuzaki et al determined the effect of lipoprotein apheresis for one year in 18 patients with heterozygous FH on minimal lumen diameter (MLD) measured by coronary angiogram and plaque area (PA) measured by intravascular ultrasound (IVUS) (54). All patients were offered lipoprotein apheresis therapy and 11 patients elected to be treated with medication plus apheresis and 7 patients elected medications alone. The two groups were similar. The apheresis group showed a 34.3% reduction in LDL cholesterol from 213 +/- 25 mg/dl to 140 +/- 27 mg/dl) after one-year. The medication alone group showed no change in LDL cholesterol levels (174mg/dl at baseline and 181mg/dl at one year). Analysis of minimal lumen diameter (MLD) by coronary angiogram revealed an increase in MLD in the apheresis group and a decrease in the medication only group (P=0.008). Analysis of plaque area (PA) by IVUS revealed a decrease in the apheresis group and an increase in the medication only group (p=0.017). Once again, the lack of randomization and the potential for subtle differences in the two groups limit the conclusions of this study.

While the four studies described above were not randomized controlled trials, they nevertheless suggest that lipoprotein apheresis has beneficial effects on the progression of atherosclerosis and the occurrence of cardiovascular events.

In a 2-year randomized trial by Kroon and colleagues 42 men with severe coronary atherosclerosis were randomized to simvastatin 40mg daily (n=21) or simvastatin 40mg daily plus lipoprotein apheresis (n=21) (55). Baseline LDL cholesterol levels were approximately 300mg/dl and were reduced by 47% in the simvastatin group and 63% in the simvastatin plus apheresis group. No significant differences in quantitative coronary angiographic end points were observed between the two groups. However, in the simvastatin plus apheresis group bicycle exercise testing revealed a 39% increase in the time to 0.1 mV ST-segment depression and the maximum level of ST depression decreased significantly by 0.07 mV versus no changes in the simvastatin only group. Moreover, regional myocardial perfusion improved in the LDL apheresis group and remained unchanged in the medication group (56). Additionally, mean intima-media thickness decreased by 0.05 +/- 0.34 mm in the apheresis group and increased by 0.06 +/- 0.38 mm in the simvastatin-only group (P < 0.001) while the number of patients with hemodynamically significant stenosis in the aorta-tibial vessels decreased from 9 to 7 in the apheresis group and increased from 6 to 13 in the simvastatin alone group (P = 0.002) (57). Thus, this study showed that apheresis resulted in functional improvements and a decrease in atherosclerosis in non-coronary vessels. Atherosclerosis in the coronary arteries was not improved by apheresis during this 2-year study. Nevertheless, this randomized trial demonstrates that lipoprotein apheresis has benefits in patients with marked elevations in LDL cholesterol levels.

STUDIES FOCUSING ON LP(a)

Ezhov and colleagues studied 30 patients who had coronary heart disease with Lp(a) levels ≥50 mg/dL and LDL cholesterol levels ≤ 100 mg/dL on chronic statin therapy (58). Subjects were allocated to treatment with weekly apheresis with an immunoadsorption column specific for Lp(a) ("Lp(a) Lipopak"(®), POCARD Ltd., Russia) plus atorvastatin (n=15) or atorvastatin monotherapy (n=15). As expected in the apheresis group Lp(a) level decreased by an average of 73 ± 12% to a mean of 29 ± 16 mg/dL while there was no significant change in the atorvastatin monotherapy group. Moreover, carotid intima-media thickness (CIMT) did not change in the atorvastatin alone group but in the apheresis group CIMT at 9 and 18 months decreased from baseline by -0.03 ± 0.09 mm (p = 0.05) and -0.07 ± 0.15 mm (p = 0.01), respectively. Additionally, clinical status was improved, with less angina in the apheresis group. This controlled trial demonstrates that lowering Lp(a) by apheresis has beneficial effects on atherosclerosis as determined by measuring CIMT.

In contrast, a study by Thompson and colleagues did not demonstrate a benefit of lowering Lp(a) by lipoprotein apheresis (59). In this trial patients with heterozygous FH were randomized to simvastatin 40mg daily plus apheresis (n=20) or simvastatin plus colestipol (n=19). LDL cholesterol levels were slightly lower in the apheresis group (125mg/dl vs. 133mg/dl, p= 0.03) while Lp(a) levels were reduced by 33% (14mg/dl vs. 21mg/dl, p=0.03). After a mean of 2.1 years there were no differences in quantitative coronary angiography between the two groups. The results of this study suggest no benefit to lowering Lp(a) levels. However, it should be noted that in this study the Lp(a) levels were not very high and therefore this study did not examine the effect of lowering Lp(a) levels in patients with elevated levels.

Finally, in a small study by Khan and colleagues randomized 20 patients with refractory angina and elevated Lp(a) >500 mg/L (normal <300 mg/L) and an LDL cholesterol level less than 156mg/dl (4.0 mmol/L), despite optimal lipid lowering drug therapy to lipoprotein apheresis or a sham procedure (60). The reported that total carotid wall volume, a marker of atherosclerosis, increased in the sham group but decreased in the lipoprotein apheresis group (P < 0.001 between groups) suggesting that apheresis reduces atherosclerotic burden.

Summary

In conclusion, while the studies described above are not perfect and do not definitively demonstrate that lipoprotein apheresis decreases cardiovascular events, the results of the lipoprotein apheresis studies coupled with the randomized studies of LDL cholesterol lowering with statins and other drugs makes it extremely likely that lowering LDL cholesterol levels with lipoprotein apheresis will reduce the risk of cardiovascular events (12). Whether lowering Lp(a) levels with lipoprotein apheresis is somewhat less certain, as to date no intervention to lower Lp(a) levels has been shown to reduce events. Nevertheless given the epidemiology data, genetic studies, basic science experiments, and animal experiments it is very likely that lowering elevated Lp(a) will have beneficial effects on cardiovascular outcomes in patients with high Lp(a) levels (61,62).

OTHER BENEFITS OF LIPOPROTEIN APHERESIS

Randomized controlled trials have shown that a single lipoprotein apheresis was beneficial in restoring hearing in patients with acute hearing loss (63,64). Additionally, lipoprotein apheresis has been shown to induce remission in approximately 50% of patients with drug-resistant nephrotic syndrome (1,65). The FDA has approved lipoprotein apheresis for new onset focal segmental glomerulosclerosis in pediatric patients who are resistant to standard treatment (1). A meta-analysis has also reported benefit in adult patients with focal segmental glomerulosclerosis (66)

SIDE EFFECTS AND CONTRAINDICATIONS

Lipoprotein apheresis in general is well tolerated. During apheresis a decrease in blood pressure may occur in some patients (2,3,8,16). Additionally, with long standing apheresis iron deficiency anemia may occur (67).

Lipoprotein apheresis using polyacrylate and dextran sulfate columns converts kininogen to bradykinin leading to marked increases in bradykinin levels (68). Angiotensin converting enzyme (ACE) inactivates bradykinin and therefore treatment with ACE inhibitors is contraindicated in patients receiving lipoprotein apheresis with polyacrylate or dextran sulfate as the resulting very high levels of bradykinin may lead to severe hypotension and an anaphylactoid reaction (2,3,68,69). However, in these patient’s angiotensin receptor blockers can be safely used.

CONCLUSION

Lipoprotein apheresis is a well-tolerated procedure that markedly lowers LDL cholesterol and Lp(a) levels in patients who do not obtain acceptable levels with maximal lifestyle and drug therapy. Studies strongly suggest that lipoprotein apheresis will decrease the progression of atherosclerosis and reduce cardiovascular events. Therefore, lipoprotein apheresis is a potential treatment in selected patients with drug resistant elevations in LDL cholesterol and/or Lp(a) levels. Studies have shown that lipoprotein apheresis safely reduces LDL cholesterol levels and xanthomas in children with homozygous Familial Hypercholesterolemia (21).

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