Familial hypercholesterolemia

Are you suffering from small, waxy and elevated yellowish deposits on the arms, legs, or around the eyelids along with severe chest pain? Watch out, for these are signs of Familial hypercholesterolemia that may prove detrimental for your heart. Read and know all about the types, symptoms, causes diagnosis and treatment of this disorder.

Familial hypercholesterolemia Definition

The condition is marked by elevated levels of low-density lipoprotein (LDL) – a compound that regulates the synthesis and transport of cholesterol in the body. Increased amount of this group of lipoprotein causes high cholesterol levels in the blood. This may put individuals at an increased risk for heart attacks. LDL is generally referred to as “bad cholesterol”. The disorder is often abbreviated as FH.

Familial hypercholesterolemia Synonyms

The condition is referred to by various other names, such as:

Picture 1 – Familial hypercholesterolemia

  • Type II hyperlipoproteinemia
  • Hypercholesterolemic xanthomatosis
  • Low density lipoprotein receptor mutation

Familial hypercholesterolemia Incidence

Heterozygous FH affects 1 in 500 individuals whereas Homozygous FH occurs in 1 in a million births.

Familial hypercholesterolemia Types

The two major forms of FH are:

Heterozygous Familial hypercholesterolemia

It is generally the most common type of FH that is known to cause cardiovascular disorders by the age of 50 in about 40% of cases. The condition is capable of causing severe atherosclerosis in young children.

Homozygous Familial hypercholesterolemia

It is a rare as well as a serious form of FH and the leading cause of heart attacks before the age of 30. Failure in recognizing the disorder at an early stage may cause sudden cardiac death.

Familial hypercholesterolemia Symptoms

Abnormal increase in the cholesterol levels does not normally give rise to any major symptoms. Affected patients, however, may show signs like:


Cholesterol-containing yellowish nodules or bumps may appear in various parts of the body that are easily noticeable. The most commonly affected sites of the condition include:

  • Hands
  • Creases of the palms and fingers
  • Knees
  • Ankles
  • Elbows
  • Buttocks


The skin condition is marked by yellowish deposits of fatty cholesterol on or around the upper and lower eyelids that often disfigures the face.

Corneal arcus

Unusually high levels of LDL may often affect the eyes. In this condition, a white, gray, or blue opaque ring appears on the margins of the cornea. The ring may even appear at the periphery of the iris.


Excessive accumulation of cholesterol plaque along the coronary arterial walls of the heart may cause acute chest discomfort. The pain arises due to decreased supply of oxygen in blood to the cardiac muscles.

Familial hypercholesterolemia Causes

FH is an inherited disorder that begins at birth and is typically passed down through families in an autosomal dominant pattern. The genetics of the disorder involves the following components:

LDL receptor (LDLR)

This is a cell-surface receptor that initiates the endocytosis of LDL cholesterol. The gene of this receptor is located on chromosome 19. Heterozygous FH develops when the LDLR gene possesses two different, abnormal copies. In this type, a patient normally inherits one form from the male parent and the other from the female parent. In Homozygous FH, on the other hand, the receptor gene has two identical, abnormal copies, one inherited from each parent. Defects in the LDL receptor are functionally divided into five classes depending on the impact of the mutation.

Class 1

The receptor is not synthesized.

Class 2

Mutation in LDLR retards its transportation from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface.

Class 3

The receptor has difficulty in binding to the LDL on the cell surface. The problem arises due to a defect in either LDLR or in apolipoprotein B100.

Class 4

LDLR binds to LDL, but does not cluster in clathrin-coated vesicles for receptor-mediated endocytosis.

Class 5

The receptor does not circulate back to the cell surface.

Apolipoprotein B (ApoB)

It is the primary apoprotein, or protein segment of the lipoprotein particle. ApoB gene is located on the second chromosome (2p24-p23). FH occurs when the amino acid called arginine is replaced by glutamine at position 3500, resulting in mutation of R3500Q. The section of the protein that binds with the LDL receptor undergoes mutation in this disorder and eventually inhibits the process of binding. The condition gets more severe with increase in the number of abnormal copies of ApoB.

Proprotein convertase subtilisin/kexin type 9 (PCSK9)

This enzyme has several variants which play a crucial role in reducing the circulating cholesterol in the body. PCSK9 gene encodes a 666 amino acid protein that is expressed in the liver. The gene is located on chromosome 1. The enzyme increases the cholesterol levels by decreasing the number of LDL receptors on liver cells.

Low density lipoprotein receptor adapter protein 1 (LDLRAP1)

Although its exact function remains undefined, it has been found to play an essential role in receptor-mediated endocytosis. Defects in the protein gene curtail the length of LDLRAP1. Unlike the other two forms of the disorder, here, two copies of an abnormal LDLRAP1 gene is responsible for causing autosomal recessive FH. In this case, affected individuals usually develop complicated health issues.

Familial hypercholesterolemia Pathophysiology

Under normal conditions, LDL cholesterol undergoes circulation in the body for 2.5 days and later binds to the LDL receptors on the liver cells. LDL is then absorbed by these cells through a process called endocytosis for its complete elimination from the body. The synthesis of cholesterol by the liver is blocked in the HMG-CoA reductase pathway- a cellular metabolic pathway that is essential for the production of few hydrophobic molecules. However, in FH the function of LDL receptor is completely impaired, causing the LDL to circulate for more than 4.5 days. The level of LDL cholesterol subsequently increases in the blood, leading to the development of severe cardiac problems.

Familial hypercholesterolemia Diagnosis

Fatty skin deposits all over the body as well as around the eyes are indicative of FH that are normally revealed during physical examination. The family medical history of an affected patient is crucial for health care providers to track the ailment by knowing the exact genetic makeup. A few clinical tests and exams for critical diagnosis of the condition include:

Blood test

The test may reveal the following features in individuals suffering from FH.

  • Increased levels of total cholesterol, normally above 300 mg/dl in adults and 250 mg/dl in children
  • Elevated levels of LDL, usually above 220 mg/dl in adults and greater than 170-200 mg/dl in children
  • Normal triglyceride levels

Factors like age, weight, kidney abnormalities and decreased metabolism should be taken into account while testing the blood sample of a patient.

Genetic testing

It is a sophisticated technique that confirms the mutations in LDL and ApoB. The medical test greatly influences a patient’s choices about proper health care and management of the disorder.

Heart tests

Associated disorders such as coronary heart disorder and atherosclerosis can be assessed, using some common cardiac tests like:

  • Echocardiography
  • Electrocardiogram
  • Cardiac MRI
  • Cardiac catheterization and angiography
  • Stress testing

Familial hypercholesterolemia Differential diagnosis

During differential diagnosis, a few specific tests are conducted to distinguish FH from ailments like:

  • Polygenic hypercholesterolemia
  • Familial combined hyperlipidemia
  • Sitosterolemia
  • Cerebrotendineous xanthomatosis

Familial hypercholesterolemia Treatment

Some of the most commonly used treatment options for the disorder include:

Picture 2 – Familial hypercholesterolemia Image

Drug therapy

Statins are a class of drugs, typically used to lower the cholesterol levels in the HMG-CoA reductase pathway. Simvastatin, Atorvastatin and Rosuvastatin are some of the regularly administered statins.

Non-statin cholesterol-lowering medication such as ezetrol is an effective way of normalizing the lipid levels in patients who encounter serious side-effects, owing to statin intake. The drug functions as a cholesterol absorption inhibitor and is given on a daily basis.

Anion-exchange resins or bile acid sequestrants such as Questran accelerates the elimination of LDL cholesterol by preventing its reabsorption by the intestine.

LDL apheresis

The medical technology closely resembles the process of dialysis where the LDL cholesterol is removed from the bloodstream. An apparatus is used in this method through which a patient’s blood is passed to separate the lipoprotein from it. The remainder is then returned to the circulation.

Surgical interventions

Partial ileal bypass surgery is a surgical procedure that involves shortening the length of the small intestine to reduce the absorption of nutrients and cholesterol.

Portacaval shunt surgery involves a direct connection between the portal vein of the liver and the vena cava of the heart. This form of system enables the blood with nutrients from the intestine to bypass the liver. In this way, the reabsorption of cholesterol is inhibited.

Diet change

Physicians generally recommend the patients to modify their dietary intake. The LDL levels can be checked by following a diet that is low in cholesterol and saturated fat, but rich in unsaturated fat.

Familial hypercholesterolemia is manageable by a combined treatment of medication and proper dietary behavior. A good exercise regimen may aid in lowering the abnormal levels of cholesterol. Symptoms like intense chest pain, or heart attack should not be ignored and must be given prompt medical attention.

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