Because FH is a genetic disorder inherited with a dominant trait, familial anamnesis is of utmost importance and possible allows early diagnosis and initiation of treatment.

This applies particularly to those patients suffering from homozygous FH. Both parents are carriers of the defective genes and probably have a history of elevated cholesterol levels, but since homozygous FH manifests in early childhood, parents may be too young to have developed symptoms. Pediatric patients often present with symptoms characteristic for coronary heart disease and cerebrovascular accidents. Homozygous FH is frequently associated with valvular insufficiency, notably with aortic stenosis. Moreover, yellow-orange planar xanthoma, often xanthoma tuberosum, are characteristic for this type of FH and may even be present at birth. Tendon xanthoma develop later and may lead to tendinitis and joint pain. Corneal arcus senilis may be another symptom of the disease although it is less common than in heterozygous FH.

Individuals suffering from heterozygous FH do not develop symptoms during childhood. The majority of patients presents with recurrent tendinitis, arthralgia or premature cardiovascular disorders during their fourth decade of life (men) or after menopause (women). Tendon xanthoma account for the former and are most commonly observed in Achilles tendon and those tendons pertaining to the extensors of hands and wrists. Cholesterol deposition in peripheric tissues is considerable and manifests, for instance, in form of an arcus senilis. In these patients, thorough anamnesis will reveal similar problems in one of their parents and possibly in siblings.

• Coronary Atherosclerosis

  Pediatric patients with familial hypercholesterolemia may present with premature coronary atherosclerosis requiring coronary artery bypass grafting. In situ internal mammary artery grafts should be the graft of choice. [ncbi.nlm.nih.gov]

  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]

  Coronary atherosclerosis has been detected in men with heterozygous FH as young as age 17 years and in women as young as 25 years. [empr.com]

• Hunting

  Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993;72:171-176. 17. [bcmj.org]

  BMJ. 2008; 337 :a1095. [ PubMed : 18753174 ] Williams RR, Hunt SC, Hopkins PN, Wu LL, Hasstedt SJ, Berry TD, Barlow GK, Stults BM, Schumacher MC, Ludwig EH, Elbein SC, Wilson DE, Lifton RP, Lalouel JM. [ncbi.nlm.nih.gov]

  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(2):171–6. [link.springer.com]

  Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993 Jul 15. 72(2):171-6. [Medline]. Patel MD, Thompson PD. [emedicine.medscape.com]

  ^ Williams RR, Hunt SC, Schumacher MC, et al. (1993). "Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics". [en.wikipedia.org]

• Gangrene

  Peripheral artery occlusive disease may occur in smokers who have FH; this can cause pain in the calf muscles during walking that wanes during rest and complications from decreased blood supply to the feet (e.g. gangrene). [clinicaladvisor.com]

  […] 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 [en.wikipedia.org]

• Intermittent Claudication

  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 [en.wikipedia.org]

• Surgical Procedure

  Any major surgical procedure occurring less than 3 months prior to the screening visit, or any planned future surgical procedure within 3 months of baseline. [clinicaltrials.gov]

• Diarrhea

  The latter may manifest with neurological/psychiatric symptoms, cataracts, diarrhea and normal LDL-C levels as distinguishing features. [clinicaladvisor.com]

  Elevation of transaminases ≥ 3 x ULN (34%) Hepatic steatosis (hepatic fat increases by a mean of 8%) Gastrointestinal: Diarrhea (79%), Nausea (65%), Dyspepsia (38%), vomiting (34%); Other GI side effects occurring in ≥ 20% of patients include constipation [pharmacytimes.com]

  The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities. [9] Genetics [ edit ] The most common genetic defects in FH are LDLR mutations ( prevalence 1 in 500, depending on the population [en.wikipedia.org]

• Xanthelasma

  Her mother and maternal grandmother both had a history of hypercholesterolemia and had developed extensive xanthelasma palpebrarum from early adult life. [ncbi.nlm.nih.gov]

  Diagnosis of this pathology is based on laboratory tests and physical examinations where the doctor can find xanthomas and xanthelasma, as well as fat deposits in the eye—corneal arcus. [ihhub.org]

  Possible symptoms include: Fatty skin deposits (xanthomas) around the hands, elbows, knees, ankles and around the cornea of the eye Cholesterol deposits in the eyelids (xanthelasmas) Chest pain ( angina ) or other signs of coronary artery disease ; may [heart.ucla.edu]

• Arcus Senilis

  Corneal arcus senilis may be another symptom of the disease although it is less common than in heterozygous FH. Individuals suffering from heterozygous FH do not develop symptoms during childhood. [symptoma.com]

  Diagnosis of FH is based on high concentrations of low-density lipoprotein cholesterol (LDL-C), family history of hypercholesterolemia, presence of premature CAD, and cholesterol deposition in the form of xanthomas and/or arcus senilis. 3 Early diagnosis [revespcardiol.org]

  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, [en.wikipedia.org]

• Suggestibility

  Family history revealed vertical transmission of hypercholesterolemia from father to patients, thereby suggesting dominant inheritance. Lipid data of their mother did not match the criteria of FH. [ncbi.nlm.nih.gov]

• Psychiatric Manifestation

  The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities. [9] Genetics [ edit ] The most common genetic defects in FH are LDLR mutations ( prevalence 1 in 500, depending on the population [en.wikipedia.org]

• Seizure

  Neurodevelopmental Dosage Sensitivity Subgroup This subgroup evaluates genes and/or genomic regions associated with neurodevelopmental disorders (intellectual disability, autism, seizures, etc.) for evidence for haploinsufficiency and triplosensitivity [clinicalgenome.org]

Anamnesis and laboratory analyses of serum samples are the mainstays of FH diagnosis. As has been indicated above, one or both parents of FH patients usually have a history of elevated cholesterol levels, although FH may never have been diagnosed. TC and LDL levels are typically elevated while HDL concentrations are in or below their physiological ranges. Heterozygous FH is commonly associated with LDL cholesterol levels above 5 mmol/l. In patients suffering from homozygous FH, these values frequently exceed 10 mmol/l. Lower cut-offs may be defined for those patients with a family history of hypercholesterolemia [1]. Because this condition may also result from diabetes mellitus, renal problems or thyroid disorders, the respective parameters should be checked. If altered, serum lipids should be measured regularly [5].

Biopsies should be obtained from nodules suspicious for xanthoma and analyzed histopathologically. In this context, diagnostic imaging may be applied to assess the condition of tendons, particularly of the Achilles tendon.

In order to evaluate disease extent and progress, initial and subsequently annual echocardiographic evaluation is highly recommended. Carotid intima-media thickness has been proven a valuable parameter to monitor FH. Computed tomography scans should be carried out in five-year intervals.

• Hypercholesterolemia

  CONCLUSIONS: Nonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C. [ncbi.nlm.nih.gov]

• LDL Increased

  Serum levels of TC and LDL increase massively. Physiologically, serum LDL levels are primarily regulated by hepatocytic uptake and LDL degradation. [symptoma.com]

Causative treatment for FH cannot be provided. However, dietary and lifestyle adjustments, drug therapy, apheresis and surgical interventions may contribute to lowering TC and LDL levels, decrease the risk for cardiovascular complications and increase life expectancy.

Dietary and lifestyle adjustments

In general, the intake of cholesterol, saturated and trans-unsaturated fatty acids should be restricted. Overweight patients should aim at weight reduction. Moderate physical activity is strongly recommended if cardiovascular symptoms are not yet present or if an exercise test is successfully completed. Compliant heterozygous patients may achieve a significant reduction of TC and LDL levels, but due to genetic differences not all individuals respond equally to this form of treatment. Additional medication is most often necessary [6]. Although such adjustments are also recommended to homozygous patients, significant reductions of TC and LDL levels are rarely observed here.

Drug therapy

HMG-CoA reductase inhibitors inhibit cholesterol synthesis and are first line therapeutics for FH [7] [8] [9]. If target values for TC and LDL cannot be achieved, they may be combined with ezetimibe or bile acid sequestrants that reduce enteral cholesterol absorption. Niacin is able to raise HDL levels. Mipomersen inhibits apoB-100 synthesis and lomitapide inhibits VLDL assembly; both may be administered to supplement the aforementioned therapeutic schemes but have important side effects. Alirocumab and evolocumab avoid LDL receptor degradation and have recently been approved for therapy of hypercholesterolemia.

Post-menopausal women may benefit from estrogen replacement therapy.

Apheresis and surgery

Homozygous patients should undergo regular apheresis from early childhood. In heterozygous patients, apheresis should be applied if medication is insufficient to decrease TC and LDL concentrations.

Most homozygous patients require ileal bypass surgery, portocaval anastomosis or liver transplants. While the former reduces cholesterol absorption and the latter provides functional LDL receptors, the mechanism behind LDL level lowering by means of portocaval anastomosis is still unclear.

Prognosis for homozygous FH is unfavorable. Here, generalized, severe atherosclerosis often manifests in early childhood. Heart valve defects may further aggravate the patient's condition. Sudden death by myocardial infarction due to coronary heart disease may occur in children aged less than two years. Few patients reach the age of 30 years [4].

Prognosis for heterozygous FH is significantly better. While men develop symptoms of premature cardiovascular disease aged 30 years and older, women usually don't manifest such disorders until after menopause.

FH is a genetic disease that affects function and/or density of hepatic LDL receptors. It is almost exclusively inherited with an autosomal dominant trait and is associated with severe reduction of hepatic uptake of LDL and consequently increased serum levels of TC and LDL. Patients may be heterozygous or homozygous for the defective gene.

The gene that encodes for hepatic LDL receptors is located on the p arm of chromosome 19. FH may be triggered by a wide variety of different mutations and indeed, more than 1,700 mutations of the corresponding gene have been described so far [1]. However, up to 30% of all FH cases result from as of yet undefined gene mutations. Thus, unless a specific mutation is known for a determined family, genetic testing for FH is not only cost-intensive but may also yield false-negative results [2].

With regards to LDL receptor metabolism, different types of FH may be distinguished. Some patients do not synthesize LDL receptors at all. Others present disturbances in protein transport from the endoplasmic reticulum to the Golgi apparatus, so cell surface receptor density is significantly decreased. Another group of patients expresses LDL but the receptors affinity to apoB-100 is pathologically diminished. Finally receptor-mediated endocytosis of ligand and receptor may be disturbed or the receptor may not be transported back to the cell surface after uptake.

Of note, other genetic disorders may cause symptoms similar to those manifested by FH patients. For instance, a decreased affinity of LDL towards its receptor may not only be triggered by a mutation affecting the gene encoding for the receptor, but also by a defective apoB-100. This disease is called familial defective apoB-100 [3].

Overall prevalence of heterozygous FH has been estimated to be about 2 per 1,000 individuals. Homozygous FH is rare and only occurs in 1 out of 1,000,000 persons.

Higher prevalence rates have been detected for certain ethnicities. For instance, populations of Finland, Lebanon or French Canada show increased prevalence for FH. According to current knowledge, risk of FH is highest among Ashkenazi Jews. Here, prevalence amounts to 15 per 10,000 individuals.

Although FH is triggered by a mutated gene located on an autosome, there are considerable differences regarding the age of onset in men and women. Both genders are affected with equal frequency, but the heterozygous form of the disease manifests approximately one decade later in females. Presumably, hormonal disparity accounts for this observation. No such differences have been detected for homozygous FH.

FH is a congenital disease, but symptoms are not manifest at birth. The more severe, homozygous form of FH may lead to cardiovascular disturbances already in early childhood. Heterozygous FH is typically detected in adults unless familial history prompts an earlier screen.

LDL account for cholesterol transport to peripheric tissues, but about 70% of circulating LDL are eventually uptaken by hepatocytes themselves. Similar to other cells, hepatocytes use part of this cholesterol to synthesize and maintain their cell membranes. Cholesterol may also be used for bile acid synthesis and be released through bile ducts. Finally, cholesterol may be re-bound in VLDL and be released to the blood stream.

However, cholesterol uptake with LDL also fulfills important functions in cholesterol synthesis regulation. The more LDL is uptaken, the less cholesterol is produced. In FH, LDL uptake is severely restricted and thus this form of negative feedback fails. Hepatocytes synthesize excess cholesterol and VLDL, load the latter with the former and release them into circulation. Subsequently, VLDL become lipoproteins of intermediate and finally low density. Serum levels of TC and LDL increase massively.

Physiologically, serum LDL levels are primarily regulated by hepatocytic uptake and LDL degradation. Here, the scavenger pathway, i.e., unresisted LDL uptake by macrophages, only accounts for a small part of LDL reduction. This is not the case in FH patients. Macrophages have to struggle with severely increased LDL levels, are overloaded and degenerate to foam cells, prototypical cells in atherosclerotic plaques. Thus, severe atherosclerosis can develop very early in FH patients.

FH patients who want to become parents should seek genetic counseling.

Under certain conditions, genetic screens may allow for an early diagnosis of FH [10].

A diet low in cholesterol, saturated and trans-unsatured fatty acids, moderate physical activity and avoidance of atherosclerosis risk factors such as smoking may contribute significantly to maintain lower TC and LDL levels.

Serum cholesterol levels are regulated by a complex metabolic network. Cholesterol is absorbed in the small intestine, bound to chylomicrons and transported to the liver. Hepatocytes use cholesterol to synthesize bile acids, which reach the small intestine and support digestion. However, cholesterol is largely recycled by means of the enterohepatic circulation. Thus, cholesterol excretion is rather tedious.

Cholesterol is an integral part of cell membranes and is therefore needed by peripheric tissues. Thus, hepatocytes not only use this compound for bile acid synthesis, but also release it in form of lipoproteins of very low density (VLDL) into the blood stream. VLDL that release triglycerides become low-density lipoproteins (LDL). Of note, high-density lipoproteins (HDL) deal with reverse transport of excess cholesterol, i.e., from peripheric tissues to the liver, but LDL themselves are also largely uptaken by hepatocytes.

LDL contain considerable quantities of cholesterol and physiologically bind to the LDL receptor. One of LDL's major components, apolipoprotein B-100 (apoB-100), accounts for the LDL's affinity to its receptor that consecutively mediates LDL receptor, LDL and cholesterol uptake into the cell. Intracellularly, LDL is degraded and cholesterol is esterified and stored. The LDL receptor is transported back towards the cell membrane. LDL receptors are expressed by most cell types, but the vast majority of these membrane-bound structures can be found in hepatocytes.

In familial hypercholesterolemia (FH), the gene encoding for the LDL receptor protein is mutated, LDL receptor function is restricted and receptor density is altered. The disease is characterized by increased serum levels of total cholesterol (TC) and LDL. Cardiovascular symptoms typically manifest at an early age.

Familial hypercholesterolemia (FH) is a genetic disorder associated with increased serum levels of total cholesterol and low-density lipoproteins. These conditions predispose affected individuals for early development of cardiovascular diseases such as atherosclerosis.

Causes

Cholesterol levels are regulated by a complex metabolic network. One of its key players is the hepatic LDL receptor. It binds serum cholesterol and mediates reduction of hepatic cholesterol synthesis. In FH, the function of this receptor is severely restricted due to a genetic defect. If a patient inherited defective genes from both of their parents, they suffer from homozygous FH, which is the more severe form of the disease. Heterozygous FH patients will develop less severe symptoms at later times in life.

Symptoms

FH patients are prone to develop atherosclerosis and, consecutively, coronary heart disease, myocardial infarction and stroke. Furthermore, cholesterol may deposit in form of nodules on skin and tendons, particularly on the Achilles tendon.

In homozygous FH, these symptoms may manifest in early childhood. Heterozygous FH patients usually do not present these disorders until their fourth decade of life (men) or after menopause (women).

Diagnosis

The disease is inherited with a dominant trait, i.e., one or both of the patient's parents should have a medical history of elevated cholesterol, too. Besides the above described symptoms, this is the most important hint at FH. Laboratory analyses of blood samples will be carried out to confirm elevated levels of total cholesterol and low-density lipoproteins and to rule out other diseases that may cause hypercholesterolemia, e.g., diabetes mellitus.

Treatment

FH patients should maintain a diet low in cholesterol, saturated and trans-unsatured fatty acids and realize moderate physical activity. Different pharmaceuticals are available that reduce cholesterol absorption, cholesterol synthesis and LDL receptor degradation. If drug therapy does not suffice to reduce cholesterol levels, apheresis may be indicated. This treatment is comparable to dialysis realized in patients suffering from renal failure. In severe cases, only a liver transplant may prolong life expectancy.

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