Familial Hypercholesterolemia, a Widely Underdiagnosed and Undertreated Clinical Entity: The Physician Perspective


Dr Harpreet Singh, Dr Deepak Jain, Dr Kiran B, Dr Ruchi Jagota    09 February 2018


Familial hypercholesterolemia, autosomal dominant genetic disease, atherosclerotic cardiovascular disease, xanthomas, lipid profiles

Familial hypercholesterolemia (FH), also known as autosomal dominant hypercholesterolemia (ADH) type 1, is an autosomal co-dominant disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) in the absence of hypertriglyceridemia, tendon xanthomas and the development of symptomatic cardiovascular disease.1 There are two types of FH: the heterozygous form which has an incidence of 1 out of 500 and in which the patient has one normal allele and one mutated allele, whereas the homozygous form in which the patient has two mutated alleles, considered an autosomal co-dominant disorder is much rarer than heterozygous form with an incidence of approximately 1 in a million.2

FH patients need aggressive treatment to lower plasma levels of LDL-C, that includes initiation of a diet low in saturated and trans fats and drug therapy for effective control of their LDL-C levels.3,4 If medical treatment is inefficient then LDL-C apheresis and liver transplantation are needed.5 Due to the rare prevalence of the condition and the life-threatening complications and the fact that timely aggressive treatment can delay the onset and progression of coronary vascular disease, this article aims to report a case of a 30-year-old male patient who developed xanthomas since the age of 10 years and raised serum LDL-C levels.


The patient, a 30-year-old male, presented to the Dept. of Medicine, PGIMS, Rohtak with chief complaints of multiple nodular swellings over bilateral hands, both elbow and knee joints, nodular swelling over right fibular head and right fifth metatarsophalangeal joint for 20 years. There was no history of coronary artery disease (CAD), stroke, hypertension, hypothyroidism and diabetes mellitus. Patient’s sister and parents were healthy and did not have any skin lesions. Systemic examination of the patient was essentially normal with no cardiovascular abnormality. Respiratory system, per abdomen and cranial nervous system revealed no abnormality.

On local examination, multiple nodular swellings over proximal interphalangeal, distal interphalangeal and metacarpophalangeal joints of both hands, elbow and knee joints were present which were soft, nontender and mobile having smooth surface with regular margins. Multiple papulonodular lesions which were yellow to skin-colored were present in right cubital fossa. Soft yellow thin plaques were seen around both eyelids (Fig. 1).

Investigations showed total cholesterol (TC) of 540 mg/dL, low-density lipoprotein (LDL) of 530 mg/dL, triglycerides (TGs) of 112 mg/dL, very low-density lipoprotein (VLDL) of 22 mg/dL and high-density lipoprotein (HDL) of 40 mg/dL. Serum apolipoprotein A-1 levels were 79 mg/dL and apolipoprotein B levels were 315 mg/dL with ApoB/ApoA1 ratio of 3.97.

Complete hemogram, blood sugar, renal function tests, liver function tests and thyroid function tests were within normal limits. Chest X-ray and electrocardiogram were normal. Echocardiography showed thickened aortic valve. Bilateral carotid Doppler showed plaque of size 0.4 × 0.4 cm in right carotid bulb and of size 0.6 × 0.4 cm in left carotid bulb. Excision biopsy of one of the nodules showed large and small aggregates of xanthoma or foam cells with infiltration by lymphocytes, histiocytes and few polymorphs. Foreign body type and Touton giant cells were seen giving impression of aging tuberous xanthomas. Screening lipid profile of family members also revealed elevated levels of TC and LDL-C, which are shown in Table 1.

Based on the above findings, the diagnosis of FH was considered and the patient was started on low-fat, lowcholesterol diet and treatment with rosuvastatin and ezetimibe was initiated. At present, patient is under our regular follow-up along with cardiovascular clinic.


Familial hypercholesterolemia (FH) is an autosomal dominant genetically inherited lipid disorder caused by more than 900 mutations in the LDL receptor gene present on chromosome 19, leading to the lack of functional receptors for LDL on the cell surface resulting in very high LDL-C levels and causing preventable premature cardiovascular death. FH is classified into, the heterozygous form in which the patient has one normal allele and one mutated allele; and the homozygous form in which the patient has two mutated alleles.5 FH is inherited with a gene dosing effect, in which homozygotes are more adversely affected than heterozygotes.

Patients with homozygous FH have been further classified into patients with virtually no detectable LDL receptor activity (receptor negative) and those patients with markedly reduced but detectable LDL receptor activity (receptor defective). LDL-C levels in patients with homozygous FH range from about 400 to >1,000 mg/dL, with receptor defective patients at the lower end and receptor negative patients at the higher end. TGs are usually normal.5 Untreated patients with homozygous FH rarely survive beyond the second decade. Patients with homozygous FH, present in childhood with cutaneous xanthomas on the hands, wrists, elbows, knees, heels or buttocks.

The devastating consequence of homozygous FH is accelerated atherosclerotic coronary vascular disease (ASCVD), which often presents in childhood or early adulthood and these patients have severe and early functional and structural cardiovascular diseases (CVDs) including clinical CAD, aortic valve disease and atherosclerotic aortic, carotid and peripheral vascular disease. Patients with heterozygous FH have hypercholesterolemia from birth but they are usually asymptomatic and the disease recognition is frequently based on detection of hypercholesterolemia on routine screening, the appearance of tendon xanthomas or the development of symptomatic CVD.

Tendon, xanthomas are essentially pathognomonic for FH; however, they occur in less than half of FH patients, homozygous FH is characterized by xanthomata, particularly in age less than 10 years. They are plaques or nodules consisting of abnormal lipid deposition in foam cells (macrophages with phagocytosed lipid material) and collagen. Xanthomas develop because of lipid leakage from the vascular into the surrounding tissue, where macrophages subsequently phagocytose these lipids. But these can be seen in other rare genetic disorders (e.g., sitosterolemia and cerebrotendinous xanthomatosis).

In addition, juvenile xanthogranulomas (JXG) and other non-Langerhans cell histiocytoses have a similar appearance and may be mistaken for xanthomata. The distribution of the lesions helps to differentiate xanthomata in FH from the lesions in JXG (in FH, xanthomata commonly occur on Achilles tendons, dorsum of the hands and extensor surfaces of the knees and elbows; whereas lesions in JXG typically occur on the head, neck and upper trunk). A definitive distinction is made on the basis of the lipid profile, which is normal in JXG. Other clinical signs include corneal arcus and xanthelasma. Arcus senilis or corneal arcus, is described as a yellowish-white ring around the cornea that is separated from the limbus by a clear zone 0.3-1 mm in width. Xanthelasma palpebrarum or simply xanthelasma, is described as plaque-like yellow lesions near the inner canthus of the eyelids that may emanate from the medial portions of the upper and lower eyelids.

A variety of approaches have been developed for diagnosing FH by applying any one of several validated sets of criteria. The best characterized are the Simon Broome Register Diagnostic Criteria for FH, the Dutch Lipid Clinic Network Diagnostic Criteria for FH and the US Make Early Diagnosis Prevent Early Death (MEDPED) Program Diagnostic Criteria for FH.6-8 Out of these, the Simon Broome Register Diagnostic Criteria is most widely used (Table 2).

In our patient, after detailed review of literature, history, relevant investigations and clinical examination; the diagnosis of FH was made. The diagnosis of homozygous FH in our patient was based on the presence of: serum cholesterol levels >500 mg/dL with normal TG levels, appearance of xanthomas in the first decade of life (at the age of 10 years), presence of hypercholesterolemia in both parents and in the siblings and the presence of premature atherosclerosis.

He was also fulfilling the criteria for homozygous FH according to Familial Hypercholesterolemia of the European Atherosclerosis Society (Table 3).9  But due to financial constraint, nonavailability of test at our center and some technical problems, LDL receptor studies and genetic analysis could not be done in our patient. So, the differentiation into true homozygous and compound heterozygous type could not be made here. It is pertinent to mention that according to National Lipid Association, genetic screening for FH is generally not needed for diagnosis or clinical management but may be useful when the diagnosis is uncertain and moreover importantly, a negative genetic test does not exclude FH, since approximately 20% of clinically definite FH patients will not be found to have a mutation despite an exhaustive search using current methods.

In untreated patients of homozygous FH with markedly elevated LDL-C levels overt atherosclerosis develops before the age of 20 years, and they generally do not survive past 30 years.10 Thus, the primary goals of management are prevention of ASCVD by early and comprehensive control of hypercholesterolemia, and early detection of complications, with specific focus on ostial occlusion and aortic stenosis. Unfortunately, it is typically diagnosed when considerable coronary atherosclerosis has already developed, emphasizing the need for optimization of treatment in childhood.

Treatment consists of dietary, lifestyle modification and drugs like statins and bile acid sequestrants.3,4 New treatment options are required to decrease LDL-C levels beyond those currently achieved. The new classes of pharmacotherapy under investigation to control LDL-C levels include agents which modify LDL-C production, such as inhibitors of apolipoprotein B, or those which affect LDL-C catabolism, such as inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9), a protein which is responsible for the degradation of the LDL receptor. Therapies which raise HDL-C are also being evaluated. In nonresponsive patients to medical therapy; LDL apheresis and liver transplantation can also be considered in such patients.5


Untreated FH can lead to severe atherosclerotic disease resulting in life-threatening complications. FH is both underdiagnosed and undertreated, particularly among children and deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of physician and public. Hence, early diagnosis and appropriate management of the condition is very much necessary to prevent premature deaths. The family members of the patient should also be screened for dyslipidemia.


  1. Nemati MH, Astaneh B. Optimal management of familial hypercholesterolemia: treatment and management strategies. Vasc Health Risk Manag. 2010;6(1):1079-88.
  2. Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M, et al. Preemptive liver transplantation in a child with familial hypercholesterolemia. Pediatr Transplant. 2011;15(2):E25-9.
  3. Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202-7.
  1. Fahed AC, Nemer GM. Familial hypercholesterolemia: the lipids or the genes? Nutr Metab (Lond). 2011;8(1):23.
  2. Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL (Eds.). Harrison’s Principles of Internal Medicine. Volume 2, 19th Edition. McGraw-Hill; 2015. pp. 2435-49.
  3. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004;160(5):421-9.
  4. Civeira F; International Panel on Management of Familial Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004;173(1):55-68.
  5. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ. 1991;303(6807):893-6.
  6. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al; European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. 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 J 2014;35(32):2146-57.
  1. Widhalm K, Binder CB, Kreissl A, Aldover-Macasaet E, Fritsch M, Kroisboeck S, et al. Sudden death in a 4-yearold boy: a near-complete occlusion of the coronary artery caused by an aggressive low-density lipoprotein receptor mutation (W556R) in homozygous familial hypercholesterolemia. J Pediatr. 2011;158(1):167.

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