Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder that leads to increased risk of stroke, heart attacks and other vascular disorders. Read and know all about the causes, diagnosis, symptoms and treatment of this disorder.

What is Familial Hypercholesterolemia?

It is a genetic disorder characterized by an increase in the level of low density lipoproteins (bad cholesterol) in the body. The condition is also known by other names like:

  • PSCK9
  • LDL receptor disorder
  • Autosomal dominant hypercholesterolemia
  • Homozygous familial hypercholesterolemia

History of Familial Hypercholesterolemia

Dr. C Muller was the first person to associate the characteristics of the disease (high cholesterol levels) with autosomal inheritance in 1938. Later, in 1970, Dr. Joseph L Goldstein and Dr. Michael Brown provided detailed information about the disease and also described genetics as its possible cause. They even won the Nobel Prize in Medicine for their contribution related to the LDL receptor.

Familial Hypercholesterolemia Types

FH is classified into two types:

Picture of Familial hypercholesterolemia

Picture 1 – Familial hypercholesterolemia

Heterozygous FH

It is more common and occurs in 1 out of 500 people. It can be treated with various drugs like statins, bile sequesterants or other medicines that are capable of lowering cholesterol levels in the body.

Homozygous FH

It is much rarer as compared to heterozygous type. It is estimated to occur in 1 out of one million people. Homozygous FH cannot be treated with drugs. Advanced techniques, such as LDL apheresis and liver transplantation, may be required for its treatment.

Familial Hypercholesterolemia Causes

The LDL cholesterol binds to LDL receptor after circulation. Thereafter, it gets digested through a process called Endocytosis. In case of FH, the activity of the LDL receptors gets reduced. As a result, the LDL circulates for longer duration and results in higher levels of LDL cholesterol in the blood. The intensity of the symptoms mainly depends on the functionality of the LDL receptors. Conditions such as smoking, diabetes or high blood pressure also increase the risk of acquiring the disease. An abnormality of a gene called Prothrombin is also associated with increased rate of atherosclerosis.

Familial Hypercholesterolemia and Genetics

The mutations observed in FH include:

1)   LDRR mutations: There are five different types of FH caused to these type of mutations:

  • Class1: It is characterized by an absence of synthesis of LDRR.
  • Class 2: The transport of LDRR from the endosplasmic reticulum to Golgi apparatus is interrupted in this type.
  • Class 3: In this form, the binding of LDRR is affected.
  • Class 4: Clustering of LDRR is affected in this type.
  • Class 5: Recycling of LDRR is affected in this form.

2)   ApoB mutation: The mutation occurs in the part of protein that is involved with the binding function.

3)   PCSK9 mutation: It refers to the mutation in the proprotein convertase subtilisin/kexin type 9.

4)   LDRAP1 mutation: It refers to the mutation of the ARH gene.

Familial Hypercholesterolemia Symptoms

Know about the symptoms of this condition:

Physical signs

An increase in cholesterol levels does not produce any distinct physical sign. However, the extra cholesterol gets deposited at different spots in the body and might be visible from the outside. The deposition typically occurs in areas close to the the eyelids, iris, and tendons of hand, feet and elbow.

Cardiovascular disease

A number of cardiovascular diseases can occur due to enhanced cholesterol in FH. These include coronary artery disease, angina pectoris and heart attacks.  The chances of occurrence of cardiovascular disease increase even more in people who smoke, are diabetic or have a family history of heart disease. The cardiovascular disease are called due to a condition, atherosclerosis. This refers to the deposition of excess cholesterol in the artery walls.

Familial Hypercholesterolemia Diagnosis

Know about the various techniques used for the diagnosis of FH:

Lipid Measurement

Since the LDL cholesterol levels increase in a person suffering from LH, the lipid measurements tests are quite effective. These tests are performed when cardiovascular problems, which are a clear indication of high cholesterol, start appearing. The level of high-density Lipoprotein and Triglycerides remain normal even in such patients.

Mutation Analysis

Genetic testing is also performed to analyze the receptor mutations and ApoB mutations.

Familial Hypercholesterolemia Differential Diagnosis

FH is often mistaken with Familial Combine Hyperlipidemia and Polygenic Hypercholesterolemia. As such, it is necessary to carry out a differential diagnosis of FH. It is based on the estimation of Xanthomata which is found only in case of FH.

Familial Hypercholesterolemia Treatment

The treatment approach is different for both homozygous and heterozygous forms of FH. It includes:

Image of Familial hypercholesterolemia

Picture 2 – Familial hypercholesterolemia Image

Treatment for Heterozygous FH

It is treated with the help of statins. Simvastatin, lovastatin and pravastatin are some of the commonly used statins. Statins relieve the symptoms as it is capable of reducing the LDL and cholesterol levels in the body. The mechanism of action of LDL involves inhibition of the enzyme hydroxymethylglutaryl CoA reductase. The inhibition of this enzyme results in removal of LDL circulating in the blood from the body. In order to achieve faster response, the statins might be used in combination with other drugs like bile acid sequestrants, nicotinic acid and fibrates. Statins have replaced the earlier drugs like thyroxine and is used by majority of the physicians these days. Another drug used by doctors is ezetimibe that controls the cholesterol absorption.

Treatment for Homozygous FH

This form of FH is rare and very hard to treat. This is because of the fact that it does not respond properly to medications. However, very strong doses of statins combines with other drugs can show some positive results. In most of the cases, advanced techniques like LDL apheresis and liver transplant are used. In LDL apheresis, the set up is just like dialysis and it aims to filter out LDL from the blood. In extreme cases, liver transplant may be performed although it is associated with many complications. The Partial Ileal Bypass Surgery is another surgical technique used in this case. In this technique, the absorption of cholesterol is decreased by bypassing a small part of the small bowel. Another operative technique used for bypassing is the portacaval shunt surgery, in which the portal vein is joined with the vena cava. A lot of research and clinical trials are being done to find more effective alternative methods for the treatment of homozygous FH.

The use of statins is not considered to be safe in children. Thus in small children other alternatives like fenofibrate and bile acid sequestrants are used. The bile acid sequestrants commonly used are Questran and colestid. These act by binding to the bile acids which is latter removed as stool. Bile acid consists of cholesterol and thus the removal of bile acids also decreases the cholesterol level in the body.

Familial Hypercholesterolemia Management

Healthy eating habits should also be encouraged in patients, especially those having a family history of FH or cardiovascular disease. It involves avoiding smoking or drinking and performing exercises regularly. Similarly, attempts should be made to keep the blood pressure of the patient to normal as it is another risk factor that fastens the rate of progression of FH. The diet should also provide lower fat calorie as it helps to keep the cholesterol level in check.


If you are suffering from chest pain or other heart attack symptoms, seek medical care on an immediate basis. You should also seek professional medical consultation if you have a family or personal history of elevated cholesterol levels.








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