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Heterozygous Familial Hypercholesterolemia

Familial hypercholesterolemia is also referred to as hyperlipoproteinemia type 2 and is inherited in an autosomal dominant manner. The underlying mutations interfere with the LDL receptor-mediated uptake of cholesterol. Patients may be homozygous or heterozygous for the respective gene defects, and zygosity determines the severity of the disease. Heterozygous familial hypercholesterolemia (HeFH) is among the most common genetic disorders and is characterized by prominent hypercholesterolemia due to the selective elevation of low-density lipoproteins (LDL), triglyceride levels within reference ranges, and a tendency to develop coronary heart disease. Symptom onset occurs in adulthood, with blood chemical anomalies preceding clinical symptoms by years.


HeFH is the milder variant of familial hypercholesterolemia. Patients don't usually show signs and symptoms until early adulthood, and many would reach the age of retirement not knowing about their condition if it wasn't for abnormal blood tests [1]. Hypercholesterolemia is the hallmark of the disease and may occasionally exceed the threshold for visible lipid deposition in the eye, skin, and other tissues. In this context, patients may develop tendon xanthomas, tuberous xanthomas, xanthelasmas, or arcus senilis corneae. Even though such findings are more commonly made in those suffering from homozygous familial hypercholesterolemia, severe xanthomatosis has been described as an "out of proportion phenotypic expression" in HeFH patients [2] [3].

Despite the virtual absence of complaints or clinical symptoms, functional and morphological changes of the arterial wall do take place and can already be observed in children [4]. The disease follows a progressive course and strongly predisposes for cardiovascular disorders. Symptoms of coronary heart disease develop in more than 50% of males before the age of 50, and about 30% of females before the age of 60 [5]. These patients may present with dyspnea and describe a feeling of pressure and tightness in their chest, or they may be delivered to the emergency room due to myocardial infarction. Less frequently, HeFH manifests in cerebral or peripheral vascular disease.

Coronary Atherosclerosis
  • Effective treatment in heterozygotes and homozygotes can lead to a reduced rate of progression, and, in some cases, an actual regression of coronary atherosclerosis.[ommbid.mhmedical.com]
  • Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth. Circulation. 2000;102:374-9. 11 . Li S, Chen W, Srinivasan SR, et al.[revespcardiol.org]
  • Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation 1996;93:1826–35. Crossref PubMed Wang Y, Blessing F, Walli AK, et al.[ecrjournal.com]
  • Effects on coronary atherosclerosis by targeting low-density lipoprotein cholesterol with statins. Am J Cardiovasc Drugs. 2009;9(2):109–15. pmid:19331439 View Article PubMed/NCBI Google Scholar[journals.plos.org]
  • Due to inhibition of chylomicron synthesis, steatorrhea can also occur, unless individuals adhere to very low-fat diets. Dose titration is purposefully slow in order to foster better tolerability.[read.nxtbook.com]
Family History of Heart Disease
  • Cholesterol screening in children can identify people with probable FH based on an LDL-C level above 160 and a family history of heart disease.[thefhfoundation.org]
Ejection Murmur
  • He had a I-II/VI grade systolic ejection murmur, without aortic valvulopathy or supravalvular pathology on echocardiography.[read.nxtbook.com]
Arcus Senilis
  • In this context, patients may develop tendon xanthomas, tuberous xanthomas, xanthelasmas, or arcus senilis corneae.[symptoma.com]
  • Arcus senilis: A white-colored ring around the cornea Arthralgia (joint pain) Tendonitis (inflamed tendons) History of unusual skin lesions At least one parent with severe hypercholesterolemia The most significant consequence of familial hypercholesterolemia[ada.com]
  • Senilis, Atherosclerosis, Base Pairing, Cholesterol, Cholesterol, LDL, Consanguinity, Constriction, Pathologic, Coronary Disease, Exons, Hypercholesterolemia, Hyperlipoproteinemia Type II, Inheritance Patterns, Leucine, Life Style, Lipoproteins, LDL,[acc.org]
  • Deposits in and around the eye tend to be more specific for HeFH in people younger than 45 years; in elderly people, they are less likely to be associated with blood lipoprotein abnormalities, for instance in the case of arcus senilis.[ncbi.nlm.nih.gov]
  • Sixty-two patients had positive physical examination findings for Achilles tendon xanthomas. Fifty-seven (92%) of these patients had abnormally large tendons ( or 7.1 mm) on sonography.[ajronline.org]
  • Tendinous xanthomas, measured by quantitative xeroradiography, were significantly reduced (P Funding and Disclosures Supported by an Arteriosclerosis Specialized Centers of Research Grant (HLB 14237) from the U.S. Public Health Service.[nejm.org]
  • You may have yellow or orange bumps under your skin, called xanthomas. They often form in tendons like the Achilles tendon in the back of your heel. You might also notice them in your hands, elbows, knees, and feet.[webmd.com]
  • Sitosterolemia and cerebrotendineous xanthomatosis are two rare conditions that can also present with premature atherosclerosis and xanthomas.[en.wikipedia.org]
  • He had bilateral corneal arcus and bilateral xanthomas of his Achilles tendons and the extensor tendons of his hands ( Fig. 1 ).[ncbi.nlm.nih.gov]
  • Tendon xanthomas are seen in 20-40% of individuals with FH and are pathognomonic for the condition. [7] A xanthelasma or corneal arcus may also be seen.[en.wikipedia.org]
  • When xanthomas form on the eyelids, they're called xanthelasmas. Cholesterol can also form deposits around the outside of your cornea -- the clear cover over the front of your eye. This is called corneal arcus, which looks like a silvery blue ring.[webmd.com]
  • C: Xanthelasmas are cholesterol deposits in the eyelids. D: Arcus cornealis results from cholesterol infiltration around the corneal rim (arrow).[ncbi.nlm.nih.gov]
  • Arcus senilis: A white-colored ring around the cornea Arthralgia (joint pain) Tendonitis (inflamed tendons) History of unusual skin lesions At least one parent with severe hypercholesterolemia The most significant consequence of familial hypercholesterolemia[ada.com]
  • […] symptoms Homozygous FH Signs and symptoms of homozygous FH in children include the following: Symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis Articular symptoms such as tendonitis or arthralgias[emedicine.medscape.com]
  • The second type, low density lipoprotein (LDL), is the “bad” cholesterol that candeposit in the blood vessels and narrow or block arteries, leading to heart attacks and strokes.[thefhfoundation.org]
  • Coronary artery disease can lead to heart attacks and other major cardiovascular diseases, including stroke and sudden cardiac death.[ahajournals.org]
  • The researchers found that long-term CHD and atherosclerotic CVD (including stroke) risk rose by approximately fivefold among those with an FH phenotype, even after adjustment for other CHD and CVD risk factors.[healio.com]
  • In those who develop ASCVD, the model characterizes the initial event (cardiac arrest, MI, angina, or stroke) and its sequelae, including cardiovascular death, for 30 days.[jamanetwork.com]


HeFH patients may present symptoms characteristic of hypercholesterolemia or have a family history of xanthomatosis or premature cardiovascular disease, but most are diagnosed incidentally when standard analyses of blood samples reveal elevated levels of total cholesterol and LDL. HeFH is typically associated with LDL levels two to three times greater than those seen in healthy relatives, although the specific threshold concentrations of lipids depend on the age of the patient and their family history [6]. Triglyceride levels are usually within the reference range [5].

The lipid profile in HeFH patients resembles that obtained in secondary hypercholesterolemia, as may be developed in the course of hypothyroidism, Cushing syndrome, or therapy with glucocorticoids and thiazide diuretics, among others. Doubts as to the causes of hypercholesterolemia may be dispelled by comparisons with the lipid profiles of relatives and, even more reliably, by genetic testing [5]. The latter aims at the identification of the underlying mutation of the LDLR gene [7]. Unless the genotype of affected relatives is known, LDLR gene sequencing is usually required to this end. Genes APOB and PCSK9 may be assessed if LDLR mutations are not detected, but despite all efforts, the molecular biological confirmation of HeFH is not universally achieved.

  • The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. Metabolism 2016; 65: 48-53. Turgeon RD, Barry AR, Pearson GJ. Familial hypercholesterolemia: review of diagnosis, screening, and treatment.[termedia.pl]
  • DISEASE Familial hypercholesterolemia Familial hypercholesterolemia (FH) has a rich history in the field of genetic epidemiology.[academic.oup.com]
  • HeFH is the milder variant of familial hypercholesterolemia, a type of autosomal dominant hypercholesterolemia and primary hyperlipidemia.[symptoma.com]
  • Our study suggests that sonography may play an important role in the early diagnosis of heterozygous familial hypercholesterolemia.[ajronline.org]


Most authors recommend initiating treatment as early as possible in order to reduce the incidence of cardiovascular complications later in life. In pediatric patients, lifestyle adjustments focusing on dietary changes, making sports a habit, and discouraging from tobacco smoking are the main preventive and therapeutic measures. LDL levels should be monitored continuously, and the aforementioned approach to therapy should be complemented by pharmacological treatment if LDL concentrations can't be reduced <3.5 mmol/l in patients aged >10 years [4] [5].

Statins, which competitively inhibit the rate-limiting enzyme in cholesterol synthesis, constitute the first choice of cholesterol-lowering drugs in the pediatric and adult population. Ezetimibe, a selective cholesterol absorption inhibitor, should be considered in those who don't respond to or poorly tolerate statins. Bile acid sequestrants may also be used, but they require appropriate dietary supplementation and may have gastrointestinal side effects.

Additional measures may become necessary in case of severe HeFH. Weekly or biweekly adjunctive lipoprotein apheresis is recommended if LDL target levels cannot be achieved by drugs alone, and novel agents as developed to treat homozygous familial hypercholesterolemia may broaden the therapeutic spectrum for those who don't respond satisfactorily to the physical removal of LDL [4].

In any case, HeFH requires lifelong therapy.


HeFH patients are predisposed to atherosclerosis and potentially life-threatening cardiovascular events. Indeed, acute myocardial infarction and sudden cardiac death are the primary causes of mortality among those with HeFH [5] [8]. About 5, 20, and 50% of affected individuals are diagnosed with coronary artery disease at ages 30, 40 and 50 years, respectively [1]. The individual risk of cardiovascular disease correlates with the patient's lifetime exposure to LDL, so the early diagnosis and appropriate management of the disease is essential for improving their prognosis.

Beyond that, hypertension, a family history of cardiovascular disease, diabetes mellitus, elevated lipoprotein(a), smoking, male sex, and low levels of high-density lipoproteins were found to be significant risk factors for cardiovascular complications, and are named here in decreasing order of importance [8]. Advanced age and increased body mass index also have a negative impact on the outcome. Notwithstanding, the adequate treatment of HeFH is assumed to augment the patients' life expectancy by several decades, possibly close to that of the general population [5] [9]. Physical activity may significantly contribute to a more favorable outcome [8].


Familial hypercholesterolemia is caused by mutations of the LDLR gene. This gene is located on the short arm of chromosome 19 and encodes for the LDL receptor, which mediates the uptake of LDL. The life cycle of the LDL receptor comprises LDL binding, the formation and internalization of endocytic vesicles, the dissociation from these vesicles, and the return to the cell surface. Either of these processes may be impaired in HeFH patients, and pathogenic mutations of LDLR are thus classified into distinct groups [9] [10]:

  • Defective intracellular transport
  • Defective ligand binding
  • Defective internalization
  • Defective recycling
  • Null mutations resulting in no detectable protein

More than 1,200 mutations of LDLR have been described to date, and they are associated with different levels of residual LDL receptor activity [7]. Somewhat surprisingly though, LDL receptor activity doesn't correlate with the severity of HeFH and is unsuited to predict the course of the disease in heterozygous individuals, with one exception: Null mutations have been shown to result in more severe disease than any other type of gene defect [9] [10]. Furthermore, there are few pathogenic variants of LDLR that can genuinely be considered "mild", such as those missing exon 15 and double mutant N543H+2393del9 [11] [12]. Beyond that, a combination of genetic modulators and environmental factors seem to considerably affect the outcome, and additional research is required to shed more light on how they interact with the LDL receptor.


The prevalence of HeFH has been estimated at 1 in 500 persons [10]. Particularly high prevalence rates due to founder effects have been described for Finns, Ashkenazi Jews of Lithuanian descent, Christian Lebanese, Druze, French Canadians, and South African Afrikaners [9]. Males and females are affected equally.

Literature contains contradictory data regarding the penetrance of LDLR mutations. Some experts state the penetrance to be almost 100%, while others describe considerable shares of normocholesterolemic carriers in affected families [9] [13]. It has been speculated that the existence of protective factors and cholesterol-lowering gene variants may account for this phenomenon, but evidence has yet to be provided [13].

Sex distribution
Age distribution


LDL consist of apolipoprotein B-100 and other proteins, of triglycerides, phospholipids, cholesteryl esters, and free cholesterol. They are remnants of very-low-density lipoproteins (VLDL) that have delivered triglycerides to peripheral tissues, where they are used as energy substrates. Accordingly, the relative contents of cholesterol and cholesteryl esters increase when VLDL convert to LDL. Cells in need of either lipid enhance the expression of LDL receptors, which are able to bind and internalize circulating LDL. In this context, hepatocytes remove the major portion of LDL from the circulation. After their uptake into cells, LDL are disassembled: Proteins are lysosomally degraded, cholesterol esters are hydrolyzed, and cholesterol is made available for the inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), the rate-limiting enzyme in cholesterol synthesis.

In patients carrying loss-of-function mutations of the LDLR gene, clearing LDL from blood is largely impaired. The regulatory mechanism described above is overridden, and HMG-CoA reductase continues to provide mevalonate for the synthesis of cholesterol. Both conditions contribute to the elevation of blood levels of LDL [10]. Excess lipids are eventually deposited in the cornea, skin, tendons, and arteries. The accumulation of foam cells in the intima of arteries may rapidly progress to occlusive atherosclerosis, plaque formation, coronary ostial stenosis, and myocardial infarction [1].


HeFH patients may be identified long before the onset of symptoms. This is most easily achieved in families known to harbor certain mutations of the LDLR gene. Here, straight-forward analyses for the respective gene defects may be realized to identify those who are carriers of pathogenic variants. These individuals may then be provided nutritional counseling, be educated about the benefits of an active, healthy lifestyle [5]. They may be included in surveillance programs for the early detection of hypertension, diabetes mellitus, and other conditions known to worsen the prognosis. These disorders present vital targets for the prevention of cardiovascular complications and can be addressed through a broad spectrum of therapies [8].


HeFH is the milder variant of familial hypercholesterolemia, a type of autosomal dominant hypercholesterolemia and primary hyperlipidemia. Familial hypercholesterolemia is also referred to as hyperlipoproteinemia type 2 and is characterized by high total cholesterol and LDL, with triglyceride levels within normal ranges. Heterozygosity for mutations of the LDLR gene accounts for the vast majority of cases and allows for partial allelic compensation: The clearance of LDL from the circulation is impaired, and patients are predisposed to cardiovascular complications, but the overall exposure to LDL is significantly lower when compared to homozygous subjects. Thus, symptoms don't usually occur until adulthood.

Notwithstanding, the early diagnosis and appropriate management of the disease remain essential for obtaining a favorable outcome. Blood tests and genetic studies should be realized to identify as-of-yet asymptomatic carriers of LDLR mutations and patients with hypercholesterolemia, and the diagnosis of an index case should prompt a thorough familial workup. The importance of familial hypercholesterolemia for public health is illustrated by the fact that up to 9% of premature cardiovascular diseases are associated with this condition [9].

Patient Information

Heterozygous familial hypercholesterolemia (HeFH) is a very common genetic disorder. It affects about 1 in 500 inhabitants, and there are more than 10 million patients worldwide. HeFH is a hereditary disorder of cholesterol metabolism, and affected individuals have inherited a defective copy of the LDLR gene from one of their parents. The copy provided by the other parent remains unaltered and is able to partially compensate for the malfunction of the former. This is related to a late onset of symptoms.

In detail, the LDLR gene encodes for the receptor of low-density lipoproteins or LDL, which are commonly described as "bad cholesterol". The dysfunction of the LDL receptor interferes with the clearance of LDL from the circulation, so HeFH patients present with increased levels of LDL and total cholesterol. The excess of cholesterol in their blood is not noticed by the patients and does not induce any symptoms until adulthood. Nevertheless, functional and morphological changes of the arterial walls do take place from early childhood and predispose for severe cardiovascular complications. HeFH may eventually lead to coronary heart disease and myocardial infarction.

Luckily, hypercholesterolemia can be detected through standard analyses of blood samples. What's more, HeFH can be diagnosed before the development of hypercholesterolemia - by means of genetic testing. In clinical practice, laboratory and genetic studies complement each other and facilitate the diagnosis of HeFH as well as the familial workup. In order to prevent long-term sequelae as mentioned above, patients should maintain a healthy lifestyle and diet, avoid smoking, and be administered cholesterol-lowering drugs. Treatment is required throughout life but does increase the patients' life expectancy by several decades, close to that of the general population.



  1. Rahalkar AR, Hegele RA. Monogenic pediatric dyslipidemias: classification, genetics and clinical spectrum. Mol Genet Metab. 2008; 93(3):282-294.
  2. Aljenedil S, Ruel I, Watters K, Genest J. Severe xanthomatosis in heterozygous familial hypercholesterolemia. J Clin Lipidol. 2018; 12(4):872-877.
  3. Santos RD, Gidding SS, Hegele RA, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol. 2016; 4(10):850-861.
  4. Wiegman A, Hutten BA. Novel pharmacological treatments for children and adolescents with heterozygous familial hypercholesterolemia. Expert Rev Clin Pharmacol. 2017; 10(9):919-921.
  5. Rynkiewicz A, Cybulska B, Banach M, et al. Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum. J Clin Lipidol. 2013; 7(3):217-221.
  6. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004; 160(5):407-420.
  7. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013; 34(45):3478-3490a.
  8. Akioyamen LE, Genest J, Chu A, Inibhunu H, Ko DT, Tu JV. Risk factors for cardiovascular disease in heterozygous familial hypercholesterolemia: A systematic review and meta-analysis. J Clin Lipidol. 2019; 13(1):15-30.
  9. De Castro-Orós I, Pocoví M, Civeira F. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl Clin Genet. 2010; 3:53-64.
  10. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007; 4(4):214-225.
  11. Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ. Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. Atherosclerosis. 2005; 180(1):93-99.
  12. Koivisto PV, Koivisto UM, Kovanen PT, Gylling H, Miettinen TA, Kontula K. Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia. FH-Espoo. Arterioscler Thromb. 1993; 13(11):1680-1688.
  13. Garcia-Garcia AB, Ivorra C, Martinez-Hervas S, et al. Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family. Atherosclerosis. 2011; 218(2):423-430.

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Last updated: 2019-07-11 19:56