Familial hypercholesterolemia (FCH) is a rather common genetic disorder characterized by prominent hypercholesterolemia due to the selective elevation of low-density lipoproteins (LDL), triglyceride levels within reference ranges, and a tendency to develop xanthomas and coronary heart disease. It 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 heterozygous or homozygous for pathogenic mutations, with homozygosity implicating an increased severity of the disease.
While those suffering from homozygous FCH generally present in childhood or adolescence, heterozygotes don't usually experience any symptoms until early adulthood . Hypercholesterolemia is the hallmark of both variants and is associated with the deposition of cholesterol-rich material in distinct tissues:
Furthermore, cholesterol-rich lipids are deposited in the arteries. While this is not readily visible, it may induce life-threatening cardiovascular disease. Atherosclerosis and coronary heart disease are frequent findings in FCH patients, and they may be diagnosed at the age of just 3 years . Furthermore, thickening of the aortic valve and aortic root may lead to aortic regurgitation or stenosis . The descending aorta, carotid, renal, and ileo-femoral arteries may also be affected .
Clinical findings should raise suspicion of hypercholesterolemia. This suspicion may be supported by information as to the medical condition of the patient's parents and grandparents: Since FCH is inherited in an autosomal dominant pattern, there may be reports about elevated blood fat levels, xanthomas, and cardiovascular disorders.
In any case, standard analyses of blood samples reveal elevated levels of total cholesterol and LDL. As a rule of thumb, LDL concentrations are about four and two times increased in individuals with homozygous and heterozygous FCH, respectively, when compared to healthy relatives . The specific threshold concentrations of lipids depend on the age of the patient and their family history , and it may not always be possible to confirm or refute the tentative diagnosis on the basis of laboratory results.
A more reliable diagnosis of FCH is based on the identification of the underlying mutation of the LDLR gene . In this context, straight-forward analyses may be carried out if the parents' genotype is known. Otherwise, LDLR gene sequencing is required. Genes APOB and PCSK9 may be assessed if LDLR mutations are not detected, but despite all efforts, the molecular biological confirmation of FCH is not universally achieved. For homozygous FCH, the following criteria may then be applied to make a clinical diagnosis :
Patients who have been diagnosed with FCH should undergo regular screenings for aortic and coronary heart disease .
Cholesterol-lowering drug therapy is the mainstay of treatment and should be initiated as early as possible. In this context, statins, ezetimibe, and bile acid sequestrants are most commonly prescribed. The patients' response to therapy varies largely and cannot be predicted based on the results of genetic studies  . If LDL target levels cannot be achieved, weekly or biweekly adjunctive lipoprotein apheresis is recommended. The following target levels have been defined by the European Atherosclerosis Society :
These values apply to both homozygous and heterozygous FCH.
In any case, medical therapy should be complemented by lifestyle adjustments. Patients are to receive dietary counseling and should be advised on how to reduce the intake of exogenous cholesterol and saturated fats . Regular, moderate exercise is recommended if cardiovascular findings don't suggest an imminent risk of angina pectoris upon exertion . FCH patients should be discouraged from smoking .
Since FCH is associated with an elevated risk to develop coronary heart disease and other life-threatening cardiovascular disorders, the early diagnosis and appropriate management of the disease is essential for obtaining a favorable outcome  . If left untreated, homozygous FCH is generally fatal before the age of 30 years . Those suffering from heterozygous FCH have a 5%, 20% and 50% risk of coronary artery disease at ages 30, 40 and 50 years, respectively . The adequate treatment of FCH is assumed to increase the patients' life expectancy by several decades .
FCH 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 FCH patients, and pathogenic mutations of LDLR are thus classified into distinct groups  :
More than 1,200 mutations of LDLR have been described to date . Certain genotype-phenotype correlations could be established: In patients suffering from homozygous FCH, the residual activity of the LDL receptor correlates with the severity of the disease. Somewhat surprisingly though, LDL receptor activity is unsuited to predict the course of the disease in heterozygous individuals. In general, genetic modulators and environmental factors seem to considerably affect the outcome. Those who are exposed to cigarette smoke are at increased risks of cardiovascular disorders, as are those suffering from diabetes mellitus, males and elder patients  .
The prevalence of heterozygous FCH has been estimated at 1 in 500 persons. Accordingly, the frequency of homozygous FCH may approximate 1 in 1,000,000 inhabitants  . Particularly high prevalence rates due to founder effects have been described for Christian Lebanese, French Canadians, and South African Afrikaners, among others . 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  . 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 .
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 . 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 .
Due to the high prevalence of FCH and the clear benefits of an early diagnosis and initiation of therapy, population screenings have repeatedly been considered. The genetic heterogeneity of FCH, patients, however, imposes severe practical limitations on this proposition. The screening of families known to harbor pathogenic mutations of the LDLR gene is the better approach: It is more cost-effective and may involve straight-forward analyses for those mutations detected in the index case .
The prenatal diagnosis of FCH is feasible if the parents' genotype has been determined.
Owing to its specific features, FCH is considered both a type of autosomal dominant hypercholesterolemia and primary hyperlipidemia. The corresponding classification systems shall be briefly summarized in this paragraph to dispel doubts as to the nomenclature, which may be confusing.
Hyperlipidemias are divided into categories according to the Fredrickson classification . There are six types of primary hyperlipidemias:
Contrary to the other types of primary hyperlipidemia, FCH is not associated with increased levels of triglycerides, but with pure hypercholesterolemia. More than 80 genes have been shown to affect cholesterol levels, and pathogenic mutations of those genes may result in increased levels of cholesterol . Distinct types of hypercholesterolemia may be classified according to the underlying gene defects, the pattern of inheritance, the clinical presentation, or biochemical findings such as the elevated lipoprotein fraction. Because the vast majority of cases may be attributed to mutations of genes LDLR, APOB, and PCSK9, they provide the basis of current classification systems :
As implied above, a minor share of patients diagnosed with autosomal dominant hypercholesterolemia tests negative for any of the aforementioned mutations. Even though mutations may be detected that predispose for hypercholesterolemia, such as anomalies of genes GSBS and ITIH4, these are not usually considered sufficient to induce the disease. The true causes of these cases remain unknown, and they are not covered by the current classification scheme. The need for revision will eventually arise, as the molecular biological background and the pathogenesis of hypercholesterolemia are increasingly better understood.
Hyperlipoproteinemia type 2 is also referred to as familial hypercholesterolemia. It is a hereditary disorder of cholesterol metabolism, and affected individuals present increased levels of total cholesterol and low-density lipoproteins (LDL), whereby LDL are commonly described as "bad cholesterol". Eventually, excess blood fats are deposited in the cornea, skin, tendons, and arteries. The formation of plaques in the arterial walls is least visible but most detrimental; it leads to atherosclerosis and may trigger coronary heart disease and myocardial infarction.
Familial hypercholesterolemia is caused by mutations in the gene encoding for the LDL receptor. About 1 in 500 people has inherited such a mutation from one of their parents and is heterozygous for the pathogenic allele. Homozygosity, i.e., the inheritance of two defective alleles from both parents, occurs about once in a million births. Symptom onset in childhood and severe atherosclerosis by the end of the second decade of life are characteristic of homozygous familial hypercholesterolemia, but in heterozygous individuals, the risk of cardiovascular complications is far from negligible either: By the age of 50 years, 50% of patients have been diagnosed with coronary artery disease.
Although the deposition of blood fats in the arteries does not imply obvious complaints, it should be taken seriously. The life expectancy of people carrying defective LDL receptors largely depends on the early diagnosis and appropriate management of the disease.