Familial hypercholesterolemia

Physical signs High cholesterol levels normally do not cause any symptoms. Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known as xanthelasma palpebrarum), the outer margin of the iris (known as arcus senilis corneae), and in the tendons of the hands, elbows, knees, and feet, particularly the Achilles tendon (known as a tendon xanthoma). Cardiovascular disease Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in FH is the development of coronary artery disease (atherosclerosis of the coronary arteries that supply the heart) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest pain or tightness on exertion) or heart attacks. Less commonly, arteries of the brain are affected; this may lead to transient ischemic attacks (brief episodes of weakness on one side of the body or inability to talk) or occasionally stroke. Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who smoke; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased blood supply to the feet (such as gangrene). Atherosclerosis risk is increased further with age and in those who smoke, have diabetes, high blood pressure and a family history of cardiovascular disease. ==Diagnosis==

Approximately 85% of individuals with this disorder have not been diagnosed and consequently are not receiving lipid-lowering treatments. Differential diagnosis FH needs to be distinguished from familial combined hyperlipidemia and polygenic hypercholesterolemia. Lipid levels and the presence of xanthomata can confirm the diagnosis. Sitosterolemia and cerebrotendineous xanthomatosis are two rare conditions that can also present with premature atherosclerosis and xanthomas. Generally, cholesterol measurement will not differentiate patients with FH and sitosterolemia, in which the plant stanol is accumulated instead of animal-source cholesterol. The treatment of the condition is highly effective with a class of lipid-lowering agents: Ezetimibe. Polygenic hypercholesterolemia can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities. This condition does not have increased blood cholesterol but the accumulation of cholesterol derivative in the tendon can mimic FH. ==Genetics==

The most common genetic defects in FH are LDLR loss of function mutations (prevalence 1 in 250, depending on the population), • Class I: LDLR is not synthesized at all. • Class II: LDLR is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface. • Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R. • Class IV: LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis (pathway step 2). • Class V: LDLR is not recycled back to the cell surface (pathway step 5). Apolipoprotein B Apolipoprotein B, in its ApoB100 form, is the main apolipoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is 46.2 kb long. FH is often associated with the mutation of R3500Q, which causes the replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia. PCSK9 Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report. The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells. LDLRAP1 Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in 1973. In contrast to the other causes, two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relationship between the LDL receptor and clathrin-coated pits. People with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes. ==Pathophysiology==

. LDL cholesterol normally circulates in the body for 2.5 days, and subsequently, the apolipoprotein B portion of LDL cholesterol binds to the LDL receptor on the liver cells, triggering its uptake and digestion. In FH, LDL receptor function is reduced or absent, In addition to the classic risk factors such as smoking, high blood pressure, and diabetes, genetic studies have shown that a common abnormality in the prothrombin gene (G20210A) increases the risk of cardiovascular events in people with FH. Several studies found that a high level of lipoprotein(a) was an additional risk factor for ischemic heart disease. The risk was also found to be higher in people with a specific genotype of the angiotensin-converting enzyme (ACE). ==Screening==

Cholesterol screening and genetic testing among family members of people with known FH is cost-effective. Other strategies such as universal screening at the age of 16 were suggested in 2001. The latter approach may, however, be less cost-effective in the short term. Screening at an age lower than 16 was thought likely to lead to an unacceptably high rate of false positives. "The use of total cholesterol alone may best discriminate between people with and without FH between the ages of 1 to 9 years." Genetic counseling can help assist in genetic testing following a positive cholesterol screen for FH. ==Treatment==

Heterozygous FH Heterozygous familial hypercholesterolemia (HeFH) is usually treated with statins. Prior to the introduction of the statins, clofibrate (an older fibrate that often caused gallstones), probucol (especially in large xanthomas) and thyroxine were used to reduce LDL cholesterol levels. More controversial is the addition of ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called the intima-media thickness. Whether this means that ezetimibe is of no overall benefit in FH is unknown. There are no interventional studies that directly show the mortality benefit of cholesterol lowering in FH. Rather, evidence of benefit is derived from several trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, a 1999 observational study of a large British registry showed that mortality in people with FH had started to improve in the early 1990s when statins were introduced. A cohort study suggested that treatment of FH with statins leads to a 48% reduction in death from coronary heart disease to a point where people are no more likely to die of coronary heart disease than the general population. However, if the person already had coronary heart disease the reduction was 25%. The results emphasize the importance of early identification of FH and treatment with statins. Alirocumab and evolocumab, both monoclonal antibodies against PCSK9, are specifically indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, who require additional lowering of LDL cholesterol. More recently Inclisiran has been approved for the treatment of HeFH. Although monoclonal antibodies against PCSK9 are highly effective for patients with FH, the parenteral administration makes it less acceptable to the patient. There are many oral PCSK9 studies in the clinical trials (phase 2 and phase 3) and will be soon adopted as the treatment of hypercholesterolemia. Homozygous FH Homozygous familial hypercholesterolemia (HoFH) is harder to treat. The LDL (Low-Density Lipoprotein) receptors are minimally functional, if at all. Only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels. Probucol, which enhances LDL removal independently of the LDL receptor, is currently used in Japan too, though clinical trials on this indication are old (1988). If medical therapy is not successful at reducing cholesterol levels, LDL apheresis may be used; this filters LDL from the bloodstream in a process reminiscent of dialysis. Other surgical techniques include partial ileal bypass surgery, in which part of the small bowel is bypassed to decrease the absorption of nutrients and hence cholesterol, and portacaval shunt surgery, in which the portal vein is connected to the vena cava to allow blood with nutrients from the intestine to bypass the liver. Lomitapide, an inhibitor of the microsomal triglyceride transfer protein, was approved by the US FDA in December 2012 as an orphan drug for the treatment of homozygous familial hypercholesterolemia. In January 2013, The US FDA also approved mipomersen, which inhibits the action of the gene apolipoprotein B, for the treatment of homozygous familial hypercholesterolemia. Gene therapy is a possible future alternative. Evinacumab, a monoclonal antibody inhibiting angiopoietin-like protein 3, was approved in 2021 for adjunct therapy. Children Given that FH is present from birth and atherosclerotic changes may begin early in life, it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many physicians prefer to use bile acid sequestrants and fenofibrate as these are licensed for children. Nevertheless, statins seem safe and effective, and in older children may be used as in adults. ==Epidemiology==

The global prevalence of FH is approximately 10 million people. In most populations studied, heterozygous FH occurs in about 1:250 people, but not all develop symptoms. Homozygous FH occurs in about 1:1,000,000. LDLR mutations are more common in certain populations, presumably because of a genetic phenomenon known as the founder effect—they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The Afrikaner, French Canadians, Lebanese Christians, and Finns have high rates of specific mutations that make FH particularly common in these groups. APOB mutations are more common in Central Europe. ==History==

The Norwegian physician Dr Carl Müller first associated the physical signs, high cholesterol levels, and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas. Initially, they found increased activity of HMG-CoA reductase, but studies showed that this did not explain the very abnormal cholesterol levels in people with FH. The focus shifted to the binding of LDL to its receptor, and effects of impaired binding on metabolism; this proved to be the underlying mechanism for FH. Subsequently, numerous mutations in the protein were directly identified by sequencing. An important tool in the research of FH is the Watanabe heritable hyperlipidemic (WHHL) rabbit, named after its discoverer Yoshio Watanabe. The original mutant was found in 1973. The strain was established in 1976. Subsequent selection and breeding produced forms with heightened susceptibility of coronary atherosclerosis and myocardial infarction, as hypercholesterolemia alone in rabbits was not sufficient to cause this issues frequently enough. Watanabe died in 2008. == See also ==