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Spectrum of cardiovascular manifestations in homozygous familial hypercholesterolemia

1 Department of Cardiology, AICTS, Pune, Maharashtra, India
2 Department of Cardiology, 7 Air Force Hospital, Kanpur, Uttar Pradesh, India
3 Department of Cardiology, INHS Aswini Hospital, Mumbai, Maharashtra, India
4 Department of Cardiology, General Hospital, Guwahati, Assam, India

Date of Submission24-Feb-2022
Date of Decision13-Mar-2022
Date of Acceptance14-Mar-2022
Date of Web Publication05-Oct-2022

Correspondence Address:
Balbir Singh,
Department of Cardiology, 7 Air Force Hospital, Kanpur, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_30_22


Homozygous familial hypercholesterolemia (HoFH) is a rare, primarily an autosomal dominant genetic disorder that causes markedly elevated low-density lipoprotein (LDL) cholesterol levels predisposing patients to risk of developing premature atherosclerotic cardiovascular diseases. Disease manifestations usually develop in 1st or 2nd decade of life and severity depends on the duration of exposure to elevated LDL cholesterol levels. The mainstay in management is early recognition and treatment with various lipid-lowering agents including lipid-apheresis in severe cases not responding to drug therapy. We report three cases of HoFH presenting to our institute in their 2nd decade of life with different cutaneous and cardiovascular manifestations and discuss challenges in their management.

Keywords: Atherosclerotic cardiovascular diseases, homozygous familial hypercholesterolemia, lipid-lowering therapies

How to cite this URL:
Bajaj N, Singh B, Ramamoorthy A, Ghosh AK. Spectrum of cardiovascular manifestations in homozygous familial hypercholesterolemia. J Mar Med Soc [Epub ahead of print] [cited 2023 Apr 2]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=357919

  Introduction Top

Homozygous Familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by very high levels of circulating LDL cholesterol from birth. Deposition of this cholesterol at different sites results in skin and cardiovascular manifestations early in life. Premature development of atherosclerotic disease leads to detrimental outcomes such as myocardial infarction and death occurring early in life in patients with HoFH, especially in those who are not or inadequately treated. Despite several effective cholesterol-lowering drugs now being available, a main gap in the management of this disease is the lack of early detection and aggressive pharmacological intervention of HoFH subjects. Thus, the early identification of these subjects is crucial to reduce the burden of cholesterol exposure and the incidence of cardiovascular events. We would like to discuss clinical presentation, evaluation and management of three of our cases of HoFH [Table 1].
Table 1: Clinical features, lab characteristics and cardiovascular manifestations of cases

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Learning objective

  1. This report highlights the various cardiovascular manifestations in patients presenting primarily with cutaneous manifestations of familial hypercholesterolemia, and the importance to look for sinister diseases such as aortic stenosis (AS) or premature coronary artery disease
  2. It also discusses the various modalities of treatment and understands the limitations of management of homozygous familial hypercholesterolemia (HoFH).

  Case Reports Top

Case 1

A 15-year-old boy came to medical attention with a history of multiple xanthomatous eruptions on both knees, extensor surface of both arms and legs, which had been gradually increasing in size for the last 6 years. He gave significant family history of similar eruptions in one of his elder sisters and one paternal uncle. Both these relatives had a sudden death in the second decade of life. He was symptomatic with dyspnea and angina on exertion NYHA class 2 for the past 1 year. Clinical examination revealed multiple xanthomas on knees, elbows, dorsal aspect of hands, calves, and polydactyly of the right hand [Figure 1]. Systemic examination revealed a grade 2 mid systolic murmur in the aortic area. Investigations showed a deranged lipid profile with total cholesterol of 560 mg/dL, triglyceride (TG) of 100 mg/dL, low-density lipoprotein (LDL) cholesterol of 552 mg/dL and high-density lipoprotein (HDL) cholesterol of 42 mg/dL.
Figure 1: Various cutaneous manifestations in our patients (a) Xanthomas and polydactyly of right hand of case 1. (b) Xanthelema on left eye of case 2. (c) Tuberous xanthomas on buttock of case 2. (d-f) Xanthomas on leg and knee of the patients

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In view of significant family history of sudden cardiac death and HoFH, he was evaluated for cardiovascular effects of familial hypercholesterolemia (FH). Electrocardiography (ECG) showed normal sinus rhythm with no ST-T changes. Echocardiography showed normal left ventricular function with no evidence of any valvular dysfunction. His carotid and renal arterial Doppler were normal. In view of significant symptoms, a coronary angiogram was done which showed 90% stenosis of ostial left main, left anterior descending (LAD), and left circumflex (LCX) coronary artery [Figure 2].
Figure 2: Coronary angiogram of case 1. (a) AP view demaonstrating Ostial left main stenosis. (b) LAO caudal view demaonstrating left main, ostial LAS and ostial LCX 90% stenosis

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He was treated with lipid-lowering therapy with high-dose atorvastatin 80 mg/day and ezetimibe 10 mg/day, and was subjected to coronary artery bypass graft (CABG) surgery with grafts from left internal mammary artery to LAD and left radial artery to LCX coronary arteries. The postoperative period was uneventful and he is asymptomatic after surgery. Post CABG he is on regular follow-up and his lipid profile after 1 year follow-up revealed total cholesterol of 420 mg/dL and LDL of 321 mg/dL (40% reduction). A follow-up computed tomography (CT) coronary angiogram done after 12 months of CABG showed patent grafts.

Case 2

A 14-year-old boy presented with a history of chest pain, dyspnea, and episodes of presyncope on exertion of 6 months' duration. He also gave a history of multiple cutaneous swellings on his buttocks and left knee for the past 6 years. There was no significant past or family history.

Clinical examination revealed a thinly built individual with a body mass index of 14.9 kg/m2, multiple tuberous xanthomas on buttocks, left knee, and xanthelasmas on both eyelids [Figure 1]. Cardiovascular examination revealed a sustained heaving apical impulse in the left 5th intercostal space in the midclavicular line and a systolic thrill on palpation. Auscultation revealed a soft first heart sound and a grade 4/6 mid systolic murmur over the aortic area with radiation to the carotids.

Investigations revealed deranged lipid profile with total cholesterol of 516 mg/dL, LDL cholesterol 511 mg/dL, TG 60 mg/dL and HDL cholesterol of 68 mg/dL. His mother and brother had normal lipid levels. Father's lipid levels could not be done as he does not stay with the family and could not be contacted. ECG showed left ventricular hypertrophy (LVH). Chest X-ray was normal. Echocardiography confirmed concentric LVH with normal LV systolic function, the aortic valve was tricuspid, had thickened leaflets, and restricted opening. Continuous-wave Doppler revealed severe AS with peak and mean pressure gradient of 149 and 90 mm Hg, respectively [Figure 3]. The aortic valve annulus was 17 mm. There was no dilatation of the aortic root or aortic regurgitation.
Figure 3: Echocardiography of case 2: Contious wave Doppler across the aortic value in apical 5 chamber view, shows a serve aortic stenosis, with a V max of 609 cm/s and a mean pressure gradient across the aortic value of 90 mm Hg

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A left heart catheterization was done which revealed a pullback gradient of 100 mm Hg at the aortic level. There was a pullback gradient of 30 mm Hg in the supravalvular area. CAG revealed normal epicardial coronaries. He was initiated on lipid-lowering therapy with atorvastatin 80 mg and ezetimibe 10 mg once daily. His LDL cholesterol level with treatment has reduced to 338 mg/dl (33.8% reduction). He underwent aortic valve balloon dilatation for severe AS with a 16 mm size Tyshak balloon. Postprocedure the result was suboptimal, his peak gradient reduced to 70 mm Hg. On follow-up, his symptoms had improved significantly. He is on close medical follow-up with intensive lipid-lowering therapy and planned for an aortic valve replacement in the future.

Case 3

A 13-year-old girl came to medical attention with a history of multiple xanthomatous eruptions present on knees, buttocks, and arms for 5-year duration. Parents gave a history of the sudden death of an elder sibling at 10 years of age. She had no cardiovascular symptoms. Clinically other than the skin eruptions she had a grade 3 mid systolic murmur in the aortic area. Investigations showed a deranged lipid profile with total cholesterol of 540 mg/dL, TG of 100 mg/dL, LDL of 520 mg/dL, and HDL of 42 mg/dL.

Echocardiography revealed moderate AS with a peak gradient of 60 mm Hg and mean Gradient of 36 mmHg, and an aortic annulus of 16 mm. CT coronary angiogram was normal. For evaluation for atherosclerotic disease in other vascular territories, magnetic resonance (MR) angiogram of the aorta and its branches was done which showed stenosis of bilateral internal carotid arteries, left subclavian artery, and diffuse narrowing of the abdominal aorta and common iliac arteries [Figure 4] She was put on tablet atorvastatin 80 mg plus ezetimibe 10 mg daily. Her latest LDL cholesterol level is 332 mg/dl (36.1% reduction) with lipid-lowering therapy. She is on regular follow-up with a plan of aortic valve dilatation or replacement later on.
Figure 4: Magnetic resonance angiogram of case 3 (a) 90% stenosis of left internal carotid artery (black arrow), mild narrowing of right cervical internal carotid artery (blue arrow) and 70% stenosis of left subclavian artery (yellow arrow) (b) diffuse narrowing of the abdominal aorta (white arrow)

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  Discussion Top

HoFH is a rare disorder characterized by markedly elevated plasma cholesterol levels extensive xanthomas, and premature atherosclerotic cardiovascular disease (ASCVD). These patients have a severe defect in the ability to bind and internalize LDL particles, caused predominantly by mutations in both alleles of the gene encoding the LDL receptor (LDLR). Other mutations causing HoFH are in alleles of genes encoding for apolipoprotein (APO) B, Proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR adaptor protein1 (LDLRAP1). Without treatment, most patients develop signs of atherosclerosis with involvement of the coronary ostia and aortic valve apparatus being the most common site of involvement in the first or second decade of life and may not survive beyond 30 years of age.[1]

The frequency of HoFH has been estimated at 1 in million people and for heterozygous FH (HeFH) 1 in 500.[2] Cutaneous and tuberous xanthomas are the hallmarks of these patients. The age of presentation of these cutaneous manifestations may vary depending upon the underlying mutations.

The diagnostic criteria of HoFH are based on either genetic confirmation of mutant alleles at LDLR, APOB, PCSK9, or LDLRAP1 gene locus or clinical criteria wherein a level of LDL cholesterol > 500 mg/dL with cutaneous or tendon xanthomas in first decade of life should be present.[3] The MEDPED criteria from the United States,[4] the Dutch Lipid Clinic criteria,[5] and the British Simon Broome Registry criteria[6] are validated diagnostic systems for FH but none of them is specific for HoFH. The European Atherosclerosis Society has recommended specific diagnostic criteria for HoFH [Box 1]. Our patients met the clinical criteria of diagnosis of HoFH.

FH patients usually develop dermatological and ocular (Corneal arcus) manifestations early in life - tendon xanthomas, and interdigital xanthomas are pathognomic of HoFH. Tendon xanthomas are frequently missed on visual inspection alone and hence careful palpation is mandatory in the Achilles, biceps, and triceps tendons for early detection.[7] Cardiovascular manifestations are predominantly due to accelerated atherosclerosis, the most common sites being the aortic root involving the coronary ostia and Aortic valve. The other major arteries which may be involved are the carotids, descending thoracic aorta, iliofemoral and renal arteries.[8] Cholesterol deposits lead to inflammation, fibrosis, and sometimes calcification at the aortic valvular site causing both valvular, and supravalvular AS.[9] HoFH patients usually develop cardiovascular symptoms during adolescence baring some cases which may have angina or myocardial infarction and even sudden death during the first decade, especially LDLR negative patients. All our cases had cutaneous manifestations in the first decade of life but were diagnosed during the second decade of life as they reported only when they became symptomatic.

Patients of HoFH have a high incidence of premature ASCVD and hence they need to be evaluated for any subclinical disease at the time of presentation and subsequently at regular intervals. The European Atherosclerosis Society recommends that patients receive a comprehensive cardiovascular evaluation at diagnosis, with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, and, if available, CT coronary angiography (CTCA) every 5 years. In patients who have high clinical suspicion due to symptoms of ischemia, a stress test or invasive coronary angiogram may be done to look for coronary ostial involvement.[3] A transeosophageal echocardiography or an MR angiogram may also be done to assess the involvement of the aorta.[10],[11]

Lipid-lowering therapy should be started as early as possible since treatment can delay the onset of clinically evident ASCVD. As per the European Atherosclerosis Society Guidelines, LDL-cholesterol (LDL-C) targets in HoFH are <100 mg/dL (<135 mg/dL in children), or <70 mg/dl in adults with clinical ASCVD. Though these targets are ambitious but necessary efforts with dietary restrictions, lifestyle changes, and drug therapy must be made to achieve them. Statins form the mainstay of drug therapy but provide only a modest decrease in LDL levels. Cholesterol absorption inhibitors (Ezetimibe) provide additional reduction in LDL levels.

Despite the above treatment, most patients cannot achieve therapeutic goals. Our patients could achieve only 33%–40% reductions in LDL cholesterol with high-dose statin and Ezetimibe. As the response to drug therapy is generally suboptimal, lipid apheresis has emerged as a promising treatment modality. A single treatment can lead to lowering LDL levels by about 50%, but it is a very expensive modality and has got limited availability, especially in developing countries. The frequency of lipid apheresis required is generally once or twice a week. It has shown to result in regression in size of xanthomas and a reduction in mortality rates. It should be started as early as possible usually between 5 and 8 years of age.[12]

Various newer drugs have been developed and tried for HoFH but their availability and cost remain a concern. Lomitapide and mipomersen have been approved by the Food and Drug Administration as an adjunct therapy for HoFH in patients aged ≥18 and ≥12 years, respectively. Mipomersen is a second-generation antisense oligonucleotide that blocks the translation of messenger ribonucleic acid and inhibits the synthesis of apoB100. It is administered subcutaneously at the dose of 200 mg once weekly. In a placebo-controlled double-blind trial in HoFH patients, mipomersen (weekly 200 mg, on top of standard lipid-lowering therapy), at 26 weeks has resulted in further reductions in plasma levels of LDL-C (mean 25%), apoB (27%), and Lipoprotein (a) (31%) vs. placebo.[13] Lomitapide is an oral inhibitor of the microsomal TG transport protein, which reduces various lipoprotein levels in circulation by inhibiting the transfer of TGs and phospholipids onto chylomicron and very LDL during their assembly in the intestine and the liver, respectively. In an open-label trial in HoFH patients, lomitapide at maximally tolerated doses, in addition to the standard of care including LDL apheresis, reduced plasma LDL-C and apoB levels by 50% and Lp(a) by 15% at 26 weeks, with durable LDL-C lowering over a further 12 months' follow-up.[14]

PCSK9 inhibitors have been the most recent addition in the armamentarium against HoFH. They were first tried in the TESLA trial which showed a 30% reduction in LDL cholesterol levels.[15] Recent studies have proven long-term safety also in this group.[16] Our both patients are on follow-up with high-dose atorvastatin and ezetimibe, they have achieved modest reductions in cholesterol and LDL levels though the response is still suboptimal. They were offered treatment with PCSK9 inhibitors as well as lipid apheresis too but could not take it due to financial constraints.

  Conclusion Top

HoFH is a rare genetic disorder of lipid metabolism. HoFH patients commonly present in their first decade of life with cutaneous manifestations and diligent evaluation early in life and prompt initiation of treatment can delay the development of cardiovascular manifestations which are the sole cause for morbidity and mortality in these patients. We report these cases to highlight the various cardiovascular manifestations of HoFH. In previous reports from India single cases with aortic valve involvement, coronary ostia involvement, and descending aortic involvement have been reported,[17],[18] but to our knowledge, this is the first series from India with multiple patients showing premature ASCVD in patients of HoFH. It is an eminently treatable lipoprotein disorder with currently available lipid-lowering therapies including drugs, dietary modifications, and lipid apheresis in cases with inadequate response.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaud AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill Information Services Company; 2001. p. 2863-913.  Back to cited text no. 1
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Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart Journal 2014;35:2146-57.  Back to cited text no. 3
Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993;72:171-6.  Back to cited text no. 4
Civeira F; International Panel on Management of Familial Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004;173:55-68.  Back to cited text no. 5
Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ 1991;303:893-6.  Back to cited text no. 6
Schaefer EJ, Santos RD. Xanthomatoses and lipoprotein disorders. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Dermatology in General Medicine. McGraw-Hill Professional; 2012. p. 1601.  Back to cited text no. 7
Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment. Atherosclerosis 2012;223:262-8.  Back to cited text no. 8
Rallidis L, Nihoyannopoulos P, Thompson GR. Aortic stenosis in homozygous familial hypercholesterolaemia. Heart 1996;76:84-5.  Back to cited text no. 9
Koh TW. Aortic root involvement in homozygous familial hypercholesterolemia – Transesophageal echocardiographic appearances of supravalvular aortic stenosis. Echocardiography 2005;22:859-60.  Back to cited text no. 10
Summers RM, Andrasko-Bourgeois J, Feuerstein IM, Hill SC, Jones EC, Busse MK, et al. Evaluation of the aortic root by MRI: Insights from patients with homozygous familial hypercholesterolemia. Circulation 1998;98:509-18.  Back to cited text no. 11
Schuff-Werner P, Fenger S, Kohlschein P. Role of lipid apheresis in changing times. Clin Res Cardiol Suppl 2012;7:7-14.  Back to cited text no. 12
Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, 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;375:998-1006.  Back to cited text no. 13
Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, 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;381:40-6.  Back to cited text no. 14
Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341-50.  Back to cited text no. 15
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  [Full text]  
Kumar P, Devgan A, Kumar G, Shahbaz H. A rare case of hypercholesterolemia in a young girl. Med J Armed Forces India 2014;70:293-6.  Back to cited text no. 18


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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