• Familial hypercholesterolemia:

·         Familial hypercholesterolemia:

·     It is a genetic disorder characterized by high cholesterol levels, specifically very high levels of LDL and early cardiovascular disease.

·     FH is classified as a type II familial dyslipidemia.

·     About 1 in 500 cases, people have mutation in LDLR Gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (apoB), which is the part of LDL that binds to receptor.

·     People with one abnormal copy of the LDLR gene may develop CVD prematurely at age of 30-40. Having two mutant copies cause severe CVD in childhood (rare).

·     Heterozygous FH is common and inherited in autosomal dominant pattern.

·     Signs and symptoms:

·     Yellow deposit of cholesterol rich fat may be seen in various parts such as eyelids, (xanthelasma palpebrarum), tendons of hands, elbows, knees etc.

·     Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of CVD.

·     Development of coronary artery disease which may lead to angina pectoris or heart attacks.

·     Arteries of brain are affected, rarely leads to transient ischemic attacks or strokes.

·     Peripheral artery occlusive disease.

·     Diagnosis:

·     Lipid measurements:

·     Raised level of total cholesterol (350-550 mg/dl for heterozygous) (650-1000 mg/dl for homozygous).

·     Raised LDL

·     Normal level of HDL and triglycerides.

·     Mutation analysis : on the basis of isolated high LDL and clinical criteria, genetic testing for LDL receptor mutations and apoB mutation can be performed.

·     Differential diagnosis: FH needs to be distinguished from familial combined hyperlipidemia.

·     Genetics:  LDL receptor gene is located on short arm of chromosome 19. The plasma LDL levels are inversely related to the activity of LDLR.

·     There are 5 classes of FH due to LDLR mutations:

·     Class I : LDLR nit synthesized at all.

·     Class II : LDLR not properly transported from ER to golgi.

·     Class III : LDLR not bind LDL on cell because of defect in apolipoprotein.

·     Class IV : LDLR bound to LDL does not cluster.

·     Class V : LDLR is not recycled.

·     Pathiophysiology:

·     LDL-cholesterol normally circulates in the body and subsequently the apoB portion of LDL binds to LDLR on liver cells, triggering its uptake and digestion. This process results in the removal of LDL from circulatory system. Synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway.

·     In FH, LDL receptor function is absent or reduced, resulting in high levels of LDL cholesterol in blood. In mutations of apoB, reduced binding of LDL particles cause high LDL cholesterol.

·     Treatment:

·     Statins : act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA) in the liver. Thus liver produces more LDL receptors, which removes circulating LDL From blood.

·     Bile acid sequestrants (cholestryramine), nicotinic acid.

·     Ezetimibe: inhibits cholesterol absorption.

·     Liver transplant, gene therapy.

·     Lomitapide : inhibitor of microsomal triglyceride transfer protein.