Welcome to the NORD Physician Guide to Homozygous Familial Hypercholesterolemia (HoFH). The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was written by Dr. Dirk Blom, Head of Division of Lipidology, Department of Medicine, University of Cape Town. (see acknowledgements for additional information).
HoFH: The Patient Experience
At age 11, after running laps at top speed in his sixth grade gym class, Jesse Spychalla had a heart attack and later underwent triple coronary artery bypass surgery at Saint Joseph’s Hospital in Marshfield, Wisconsin. Until that happened, Jesse had thought of himself as “a normal kid with no medical issues.”
Testing when he was first admitted to the hospital showed Jesse’s total cholesterol to be 694, as compared to the norm of less than 170. His LDL was approximately 500. Jesse’s family history included an uncle who had died at age 39 and other relatives who had experienced cardiovascular disease while young. After he was diagnosed with homozygous familial hypercholesterolemia (HoFH), Jesse began a treatment regimen that, over the years, included cholesterol-lowering medication and plasmapheresis.
Jesse, who is now 30, responded well to treatment but the need to have pheresis every two weeks limited his career and lifestyle options. Today, treatment is available specifically for HoFH patients that controls Jesse’s cholesterol levels and makes it possible for him to pursue his chosen career of travel nursing. He has also found it helpful to connect with other patients who have this extremely rare disease. “I’ve never been a person to dwell on the bad things in life,” he says. “But meeting other HoFH patients and learning that I am not alone has been very helpful to me.”
HoFH is usually diagnosed in infancy or childhood but occasionally the diagnosis may be delayed until later in life in patients who are not as severely affected as in the description of ‘classical HoFH’ given above.
Diagnosis of HoFH requires a careful clinical, laboratory, and family evaluation followed by molecular genetic testing.
The treatment of HoFH is complex and patients should be referred to a specialized lipid unit that is experienced in the treatment of such patients.
What Is HoFH?
HoFH is an inherited disorder of lipoprotein metabolism characterized by marked elevation of low density lipoprotein cholesterol (LDL-C), xanthomata and premature cardiovascular disease. In most cases the underlying genetic abnormality is mutation of both alleles of the LDL-receptor (LDLR) gene.
LDL is generated in the circulation by the delipidation and modification of very low density lipoproteins (VLDL) secreted by the liver. Apolipoprotein B100 (apoB100) is the major structural apoprotein of VLDL and LDL. LDL is cleared from the circulation by hepatic LDLR with apoB100 acting as the ligand for the receptor. The major pathophysiological abnormality in HoFH is decreased LDL clearance although hepatic overproduction of apoB100-containing lipoproteins may further exacerbate the hyperlipidaemia.
The worldwide prevalence of HoFH across populations is generally estimated to be 1 in 160,000 to 1in 1 million while the prevalence of heterozygous familial hypercholesterolaemia (HeFH) is estimated to be 1 in 250 to 500 people, making the latter one of the commonest severe monogenic disorders in medical practice. The prevalence of HoFH is markedly increased in certain regions of the world and may be as high as one in thirty thousand in some populations. Populations with a very high prevalence of HoFH include Afrikaners in South Africa, French Canadians, Christian Lebanese and Japanese from the Hokuriku district. These regions are characterized by a high prevalence of HeFH (estimated to be one in seventy to a hundred for Afrikaners in South Africa) which results from founder effects that occur when small, isolated populations increase in size rapidly with little outside genetic admixture.1
HoFH is usually inherited in an autosomal co-dominant fashion but on occasions may also be inherited recessively. The HoFH phenotype may result from mutation of a single gene or more rarely may be the consequence of mutations in several different genes involved in lipoprotein metabolism. Currently four genes have been associated with the FH phenotype. All of these genes are critical to LDLR function and mutations result in impaired LDL clearance.
The commonest underlying molecular cause of the HoFH phenotype is mutation of both LDLR alleles. The inheritance of HoFH due to mutations in the LDLR is autosomal co-dominant. When HoFH is due to LDLR mutations, both parents contribute one mutated allele. Patients may be true homozygotes (the same mutation is found in both alleles) or compound heterozygotes (a different mutation is found in each allele). Mutation of only one LDLR allele causes heterozygous familial hypercholesterolaemia (HeFH). The severity of the HeFH phenotype may vary considerably even amongst patients carrying identical mutations as multiple other genetic and environmental influences also influence LDLC concentration. The risk of a couple who both carry one mutated LDLR allele of having a child with HoFH is 25%, while the risk of a child with HeFH is 50% and the chance that a child will not inherit a LDLR mutation is 25%.
Mutations in both alleles of the autosomal recessive hypercholesterolaemia (ARH) adaptor protein 1 gene may also result in the HoFH phenotype. The ARH adaptor protein 1 plays an important role in the clustering and internalization of the LDLR from clathrin coated pits. HoFH secondary to ARH adaptor protein mutations is an autosomal recessive disorder and mutation carriers do not express the HeFH phenotype. The risk of two gene carriers having an affected child is 25%. ARH adaptor protein 1 mutations were first described in patients from Sardinia, where there is likely a founder effect, but have subsequently been identified in patients from all over the world.
ApoB100 is the ligand for the LDLR and mutations that change the conformation of the apoB100 binding region are associated with decreased LDL binding and clearance. Mutation of one apoB allele is associated with the HeFH phenotype. Homozygosity or compound heterozygosity for apoB mutations is often associated with a less severe phenotype than that seen with mutations of both LDLR alleles. 3,4
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzymatically inactive serine protease that is predominantly secreted by hepatocytes. PCSK9 targets LDLR for intracellular degradation and prevents their recirculation. Gain-of-function mutations in PCSK9 are associated with LDL hypercholesterolaemia while loss-of-function lower LDLC. Gain-of-function PCSK9 mutations are associated with the HeFH phenotype in heterozygote carriers. A few homozygotes and compound heterozygotes for PCSK9 mutations have been identified, but generally at least one of the mutations is relatively mild and the identified phenotypes have not been extremely severe.4
Occasionally patients may have mutations in several genes involved in LDL metabolism. For example the combined inheritance of a mutated LDLR allele and a mutated PCSK9 allele has been described in association with the HoFH phenotype.
The majority of the literature on HoFH describes patient cohorts that were identified using clinical definitions of HoFH. One of the important objectives of clinical definitions was to distinguish severe HeFH from HoFH. The advent of novel genetic techniques that can screen multiple genes rapidly for mutations have broadened our understanding of HoFH indicating that, not surprisingly, clinical definitions generally identify the more severely affected patients within the HoFH spectrum. It is thus important to realize that there are patients with genetic HoFH who are not as severely affected as in the description of ‘classical HoFH’ given below.
The three cardinal clinical manifestations of HoFH are markedly elevated levels of LDLC (often, but not invariably, exceeding 13 mmol/L (500 mg/dL)), cutaneous as well as tendinous xanthomata and premature cardiovascular disease.
HoFH is often diagnosed in children, adolescents or young adults, but occasionally the diagnosis may be delayed until later in life in patients who are not as severely affected. The commonest childhood presentation is with cutaneous xanthomata. If the diagnosis was missed in childhood the first presentation may be with atherosclerotic cardiovascular disease either in adolescence or as a young adult.
The physical signs of HoFH can be quite variable, but cutaneous xanthomata are often noted in the first years of life. Most clinical definitions of HoFH include the presence of cutaneous xanthomata before the age of ten years as a diagnostic criterion. Planar xanthomata are often found in skin creases or at other points of friction. Common sites for planar xanthomata include the wrist, ankle, cubital fossa, popliteal fossa and natal cleft. Planar xanthomata in the interdigital webspaces on the dorsum of the hand (interdigital xanthomata) are pathognomonic of HoFH. Xanthelasma are also commonly found in HoFH but are not diagnostically useful due to their non-specific nature. Tuberous xanthomata are commonly found at the elbows but can occur at other sites such as the knees or ankles as well. Tendon xanthomata occur most commonly in the Achilles tendons and the extensor tendons of the hands but can occur in other tendons as well. Tendon xanthomata manifest later than cutaneous xanthomata and are usually not found in infants and children. Arcus cornealis is a common but non-specific finding in HoFH.
Some of the physical features of HoFH are illustrated in Figure 1:
Premature cardiovascular disease is a hallmark of HoFH. Patients may develop ischemic heart disease in childhood. Survival beyond the second or third decade was rare before the advent of statins and the addition of apheresis to the therapeutic armamentarium. Supravalvular aortic stenosis due to cholesterol deposition in the aortic root is a common complication of HoFH and may require surgical correction. Coronary ostial stenosis is a frequent finding at angiography in patients with HoFH. Although diffuse atherosclerotic vascular damage is often seen on vascular imaging studies, clinically overt disease in the non-coronary vasculature is relatively uncommon. The clinical findings in the vasculature depend on the age of the patient, the level of LDLC control achieved and a history of previous interventions or complications. Frequent findings include an aortic outflow murmur and bruits in multiple vascular territories.
Patients with suspected HoFH, including patients with what clinically appears to be severe HeFH with a poor response to lipid lowering therapy, should be referred to a specialist lipid center so that an accurate diagnosis can be made. Historically, the diagnosis of HoFH was based on the clinician identifying the ‘HoFH phenotype’ – what is now sometimes called ‘classical HoFH’. Although there are no universally accepted clinical criteria for the diagnosis of HoFH a common clinical definition of HoFH included the following:
The clinical diagnosis of HoFH could historically be confirmed by determining LDL uptake in fibroblasts (or lymphocytes) or by identification of pathogenic mutations in both alleles of the LDLR. Outside of specialized centers the clinical diagnosis of HoFH was often not confirmed by specialized investigations, as the required investigations were complex and not routinely available. LDL uptake studies in cultured fibroblasts are complex and labor intensive while early molecular genetics techniques were not able to screen genes for mutations rapidly and efficiently. There are for instance more than 1500 reported pathogenic mutations in the LDLR alone. The advent of modern genetic techniques that allow rapid and simultaneous screening of multiple genes has changed the diagnostic paradigm for HoFH and a molecular genetic diagnosis should now be sought in every suspected case. However, HoFH can still be diagnosed using clinical criteria and treatment should not be withheld because of lack of access to genetic testing or a delay in obtaining results as not all health systems reimburse genetic testing.
Modern molecular genetic testing has confirmed that the spectrum of severity of HoFH is wider than initially thought. A substantial proportion of patients with genetically confirmed HoFH do not fulfill the clinical criteria for diagnosis of ‘classical HoFH’, and genetic HoFH is likely underdiagnosed. Without molecular genetic testing many patients with genetic HoFH may be labeled by clinicians as patients with ‘severe HeFH’. Most of the available HoFH literature describing cardiovascular outcomes and response to treatment is based on HoFH cohorts that were identified clinically and may thus not always be representative of patients with less severe phenotypes. The FDA recently licensed two novel agents for the treatment of HoFH (see below) based on trials where HoFH could be diagnosed clinically, although the diagnosis was in fact confirmed by genetic testing in the vast majority of patients.
Patients who carry mutations that render the LDLR completely non-functional (receptor negative HoFH) often have a more severe phenotype and worse prognosis than patients in whom there is some residual LDLR function (receptor defective HoFH). Receptor negative patients also tend to respond poorly if at all to therapies that act mainly by upregulating the LDLR. Knowing the genotype and the functional impact of the mutation(s) may thus be useful when selecting therapy based on the mechanism of action (requires residual LDLR function or not).
Diagnosing HoFH requires a careful clinical, laboratory and family evaluation followed by molecular genetic testing. Conditions that on occasions may cause diagnostic difficulties for the non-expert include dysbetalipoproteinaemia, sitosterolaemia, cerebrotendinous xanthomatosis and secondary hyperlipidaemia. Dysbetalipoproteinaemia is characterized by remnant accumulation and although the total cholesterol may be markedly elevated there is concomitant hypertriglyceridaemia (often the molar ratio of total cholesterol to triglycerides is around 2:1) and more detailed analysis of the lipoprotein phenotype will reveal low levels of LDL with an accumulation of remnant lipoproteins. It is also very unusual for dysbetalipoproteinaemia to manifest in childhood. Sitosterolaemia is characterized by the accumulation of plant sterols (phyosterols) and may present with cutaneous xanthomata and high total cholesterol in childhood. It is a recessive disorder and normal lipid levels in the parents of a child with HoFH should alert the clinician to this diagnosis. The diagnosis can be confirmed by measuring plant sterols. Cerebrotendinous xanthomatosis is associated with prominent tendon xanthomata but the diagnosis is usually obvious as LDLC is not markedly elevated in the face of early-onset cataracts and neurological degeneration.
The treatment of HoFH is complex and patients should be referred to a specialized lipid unit that is experienced in the treatment of such patients. Referral to a specialized unit also offers patients the best chance of access to novel therapies. Atherosclerotic complications tend to be proportional to the duration and severity of LDL hypercholesterolaemia (‘cholesterol-year score’). Because LDLC is so high in patients with HoFH they may reach the ‘cholesterol exposure burden’ at which atherosclerosis is likely to occur in childhood or early adolescence. Early and aggressive LDLC control is therefore the major therapeutic goal when treating patients with HoFH.
Treatment for HoFH is usually started at the time of diagnosis and may be started in infants as young as one year. No lipid-lowering therapies are licensed for use in such young patients and parents should thus always be informed and counseled about the risks and benefits of off-label prescribing. Statins remain the backbone of therapy in HoFH although they are less effective than in patients with HeFH or other forms of hypercholesterolaemia. Individual responses may vary widely and can range from virtually no response to a 50% reduction in LDLC. Receptor defective patients generally achieve a 25% LDLC reduction while the average reduction in receptor negative patients is usually only around 15%. The main mechanism by which statins lower LDLC is LDLR upregulation but high dose statins also decrease hepatic lipoprotein synthesis due to decreased availability of cholesterol in the hepatocyte. This second mechanism probably accounts for the response seen in receptor negative patients. HoFH patients are generally prescribed high to maximal doses (adjusted for body mass) of potent statins such atorvastatin or rosuvastatin.
Ezetimibe lowers LDLC by a further 10-20% in patients with HoFH on statins. 6 It is generally safe and well tolerated and is routinely prescribed in combination with statins even in very young patients. Other lipid lowering therapies such as bile acid sequestrants, niacin, omega-3 fatty acids and fibrates are used on occasions but there is little published evidence to support their use. When multiple lipid-lowering therapies are prescribed concomitantly patients should be monitored carefully for adverse effects and drug interactions. Therapies that do not lower LDLC further should be discontinued.
LDLC levels are inadequately controlled in almost all HoFH patients receiving conventional lipid-lowering therapy. In a recent review of a large cohort of HoFH patients from South Africa the mean on-treatment LDLC was 11.7 mmol/L (a 26% reduction from the untreated baseline). 2 Until December 2012 when lomitapide and subsequently mipomersen (January 2013) were approved for use in HoFH by the FDA the only other therapeutic options were apheresis or liver transplantation. Partial ileal bypass, portocaval shunting and gene therapy were utilized in the past but have been abandoned due to poor efficacy and/or unacceptable side effects.
The first apheresis therapy was plasma exchange but techniques that remove lipoproteins more specifically (lipoprotein apheresis) have replaced plasma exchange in most areas of the world. Lipoprotein apheresis typically lowers LDLC by about 45%, but results may vary considerably depending on the plasma volume treated and the frequency at which the procedure is performed. There are no controlled cardiovascular outcome trials of apheresis in patients with HoFH, but cohort and retrospective studies suggest that outcomes are improved and apheresis is considered standard of care for HoFH in most parts of the world. 7 Because apheresis is costly, imposes a significant treatment burden on patients and is often only available in specialized centers, not all patients have access to this therapy. Apheresis only reduces LDLC transiently and LDLC rebounds relatively rapidly in the first few days following the procedure. If apheresis is performed infrequently (once every two weeks or less) the vasculature continues to be exposed to significant amounts of LDL.
Advances in surgical techniques and immunosuppression have resulted in significantly improved survival rates for liver transplant recipients. Because the liver is the major site of LDL uptake transplantation may normalize or reduce LDLC levels very significantly. The limited availability of donor organs and concerns about long term immunosuppression has restricted the numbers of patients receiving liver transplants.
Lomitapide and mipomersen are two novel therapies for HoFH that reduce lipoprotein production and do not rely on functional LDLR for their effect. Lomitapide is an oral inhibitor of microsomal triglyceride transfer protein (MTP). MTP is required for the production of apoB-containing lipoproteins in the intestines and liver. Mutation of both MTP alleles causes abetalipoproteinaemia – a condition characterized by fat malabsorption, very low or absent levels of apoB-containing lipoproteins and neurological damage secondary to vitamin E deficiency in peripheral tissues which depend on vitamin E transported in apoB-containing lipoproteins. MTP inhibition was first explored as a therapeutic option for lowering lipids more than 30 years ago, but subsequently abandoned in favor of statins. More recently there has been renewed interest in MTP inhibition and in a pilot study with six HoFH patients lomitapide monotherapy reduced LDLC by 51%. 8 This study was followed by a larger phase 3 study in which patients remained on their baseline lipid-lowering therapy including apheresis. In this single-arm, open-label study involving 29 HoFH patients older than 18 years lomitapide reduced LDLC by a further 50% on top of baseline therapy at week 26. 9
The side effects of lomitapide relate to its mechanism of action. Inhibition of MTP in the intestines may result in nausea, bloating and diarrhea especially if oral fat intake is high. Gastrointestinal symptoms were frequent in the initial phases of the trial but decreased in severity and frequency as the trial progressed. Hepatotoxicity is one of the complications of lomitapide therapy. Specifically, hepatic inhibition of MTP may result in hepatic steatosis and transaminitis. In the phase 3 study hepatic fat measured by magnetic resonance spectroscopy increased from 1% at baseline to 8.3% at week 78 with large individual variations. Transaminitis with alanine aminotransferase (ALT) greater than five times the upper limit normal was seen in four patients and was managed successfully in all patients either by dose reduction or by temporary interruption of lomitapide dosing.
Lomitapide, as an adjunct to a low-fat diet and other lipid-lowering treatments including LDL apheresis, is currently approved for use in adult patients with HoFH in the United States, Europe, Canada and Mexico.
In countries where lomitapide has been approved regulatory authorities have imposed conditions (risk mitigation programs) on the prescription of lomitapide. Although there are variations in the labels among the countries where the drug has been approved, the general principles are that lomitapide should only be prescribed for patients with HoFH who are older than 18 years and physicians prescribing lomitapide need to be knowledgeable about its use and potential adverse effects. Hepatic function needs to be monitored closely; patients should receive dietary advice and vitamin E and essential fatty supplements; and patients should restrict intake (1 drink/ day) or avoid alcohol completely. In addition, because lomitapide is a substrate of cytochrome (CYP) 450 3A4, very close attention should be paid to possible drug interactions with concomitant medications. A registry study (Lomitapide Observational Worldwide Evaluation Registry, or LOWER) is being conducted to evaluate the long-term effects of lomatipide.
Mipomersen is an antisense oligonucleotide that targets apoB100 mRNA. ApoB100 mRNA that is bound to mipomersen is degraded by ribonuclease H and less apoB100 protein is synthesized which in turn inhibits hepatic production of apoB100-containing lipoproteins. Mipomersen was studied in a double-blind, placebo controlled of 51 HoFH patients older than 12 years not receiving apheresis. The dose of mipomersen was 200 mg once a week by subcutaneous injection except for patients weighing less than 50 kg who received 160 mg once a week. The mean LDLC reduction was 25% although responses ranged from no response to more than 80% LDLC reduction. 10 The major adverse effects of mipomersen are injection site reactions, transaminitis, flu-like symptoms and hepatic steatosis. Mipomersen was licensed for use in adult HoFH by the FDA (subject to a risk mitigation program) but not by the EMA. Because mipomersen was studied in a HoFH population not receiving apheresis its use in conjunction with apheresis is not recommended. Patients receiving mipomersen require regular liver function monitoring and alcohol intake should be restricted to a maximum of 1 drink per day.
There is as yet no cardiovascular outcome data for lomitapide and mipomersen. These drugs were licensed based on their ability to lower LDLC, the very high and poorly responsive levels of LDLC that characterize HoFH and the known association between LDLC lowering and improved cardiovascular outcomes. Hepatic steatosis is a complication intrinsic to the mechanism of action of both drugs and they should thus not be prescribed together. The long term outcome of the hepatic steatosis associated with lomitapide and mipomersen is as yet unknown and careful long term follow up of each patient is required. Potential complications of hepatic steatosis may include steatohepatitis and ultimately cirrhosis. However, the substantial LDLC lowering and expected cardiovascular benefit outweighs the potential risks in patients with HoFH.
Despite optimal therapy many patients require cardiac interventional procedures. Such procedures should ideally only be performed by cardiologists and surgeons experienced in the management of patients with HoFH. Aortic root and valve surgery in patients with HoFH poses particular technical challenges due to the extensive cholesterol deposits that may be present.
PCSK9 inhibition is a novel lipid lowering strategy and increases the number of LDLR on hepatocytes by reducing PCSK9 mediated lysosomal degradation of internalized LDLR. Several approaches to PCSK9 inhibition are currently being explored in clinical trials with monoclonal antibodies, the furthest advanced along the development pathway. The trials completed thus far have shown large (>50%) and consistent reductions in LDLC with good tolerability in multiple populations including patients with HeFH. 11 Antibodies have mostly been given by subcutaneous injection once every two to four weeks. The results of a small pilot study involving eight patients with HoFH were reported recently. In this study evolocumab 420 mg two weekly reduced LDLC by 26% in the six receptor defective patients. The two receptor negative patients did not respond at all. 12 A larger double-blind study is currently ongoing and results are expected in mid-2014.
The predominant effect of cholesterol ester transfer protein (CETP) inhibitors is to raise high density lipoprotein cholesterol (HDLC) but some CETP inhibitors also lower LDLC. An ongoing study is evaluating the use of anacetrapib in patients with HoFH. Other therapeutic approaches that are being evaluated for HoFH include infusion of apolipoprotein A1 mimetic peptides and mesenchymal stem cell transplantation.
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2. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202-2207.
3. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the netherlands: Prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. First published online: February 28, 2014.
4. Mabuchi H, Nohara A, Noguchi T, et al. Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the hokuriku district of japan. Atherosclerosis. 2011;214(2):404-407.
5. Rader DJ, Kastelein JJ. Lomitapide and mipomersen: Two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129(9):1022-1032.
6. Gagne C, Gaudet D, Bruckert E, Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105(21):2469-2475.
7. Thompson GR. The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease. Atheroscler Suppl. 2013;14(1):67-70.
8. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356(2):148-156.
9. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: A single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40-46.
10. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: A randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998-1006.
11. Stein EA, Raal F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9. Annu Rev Med. 2014;65:417-431.
12. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128(19):2113-2120.
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Dr. Dirk Blom
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This NORD Physician Guide was made possible by an educational grant from Aegerion Pharmaceuticals.
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