Lipoproteinemia 5j1p1c

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Hyperlipidemia Hyperlipoproteinemia i. Familial (primary) a. Hyperlipoproteinemia type I b. Hyperlipoproteinemia type IIa c. Hyperlipoproteinemia type IIb d. Hyperlipoproteinemia type III e. Hyperlipoproteinemia type IV f. Hyperlipoproteinemia type V g. Unclassified familial forms

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ii. Acquired (secondary) Hypolipoproteinemia I. Abetalipoproteinemia II. Hypobetalipoproteinemia III.Familial alpha lipoprotein deficiency

IV. Complete apoA-I deficiency V.Complete/partial LCAT deficiency

 Elevated concentration of lipids in the blood

 The major plasma lipids of interest are total cholesterol ( free cholesterol + cholesteryl ester) and the triglycerides. When one or more these major classes of plasma lipids is elevated, a condition referred to as Hyperlipidemia exists.

 Hyperlipoproteinemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood  Lipoprotein abnormalities are regarded as a modifiable risk factor for cardiovascular disease due to their influence on atherosclerosis

o Hyperlipoproteinemia may basically be classified as a) familial (also called primary) caused by specific genetic abnormalities a) acquired (also called secondary) is caused by other diseases, such as: diabetes mellitus, pancreatitis, renal disease, or hypothyroidism.

o Familial hyperlipidemias are classified according to the Fredrickson classification w hich is based on the pattern of lipoproteins on electrophoresis or ultracentr ifugation o It was later adopted by the World Health Organization (WHO).

Definition:

Type1 hyperlipoproteinemia is a group of rare genetic disorders in which a person lacks a protein needed to break down fat molecules. The disorder causes large amounts of fat to build up in the blood.

Alternative

Name:

hyperchylomicronemia

Familial

Causes:  It is due to the deficiency of enzyme lipoprotein lipase or its cofactor apolipoprotein C-II  Without this enzyme, the body cannot break down fat from digested food. Fat particles called chylomicrons build up in the blood. Risk factors include a family history of lipoprotein lipase deficiency.

The disorder affects about 1 out of 1,000,000 people. The condition is usually first seen during infancy or childhood.

Symptoms oAbdominal pain (may appear as colic in infancy) oLoss of appetite oNausea oPain in the muscles and bones (musculoskeletal pain) oVomiting

 Signs of this condition include: o o o o o o o

Enlarged liver Failure to thrive in infancy Fatty deposits in the skin (xanthomas) High triglyceride levels in the blood Pale retinas and white-colored blood vessels in the retinas Pancreatitis that keeps returning Yellowing of the eyes and skin (jaundice)

 Treatment o Diet control

 Definition: Type11a hyperlipoproteinemia is a disorder of high LDL ("bad") cholesterol that is ed down through families, which means it is inherited. The condition begins at birth and can cause heart attacks at an early age.

Alternative Names: Familial hyperbetalipoproteinemia, Familial hypercholesterolemia

 Causes  Familial hypercholesterolemia is a genetic disorder caused by a defect on LDLR gene(chromosome 19), that encodes the LDL receptor protein, which normally removes LDL from the circulation  The defect makes the body unable to remove low density lipoprotein (LDL, or "bad") cholesterol from the blood. This results in high levels of LDL in the blood. High levels of LDL cholesterol make you more likely to have narrowing of the arteries from atherosclerosis at an early age.

 Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40.  Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood.  Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries  homozygous FH is much rarer, occurring in 1 in a million births

Symptoms Symptoms that may occur include: Fatty skin deposits called xanthomas over the elbows, knees, buttocks, tendons, and around the cornea of the eye Cholesterol deposits in the eyelids (xanthelasmas) Chest pain (angina) or other signs of coronary artery disease; may be present at a young age

 Exams and Tests •A physical examination may reveal fatty skin growths called xanthomas and cholesterol deposits in the eye (corneal arcus).

 Individuals from families with a strong history of early heart attacks should have blood tests done to determine lipid levels. 

Blood tests may show: High levels of total cholesterol •Greater than 300 mg/dL in adults •Greater than 250 mg/dL in children High LDL levels •Greater than 170-200 mg/dL in children •Greater than 220 mg/dL in adults Normal level triglycerides

 Treatment  Heterozygous FH is normally treated with statins, bile acid sequestrants or other hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic counseling.  Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

 Definition:

Familial hypercholesterolemia is a disorder of overproduction of VLDL, which leads to high LDL

 Alternative Name: Familial combined hyperlipidemia

 Causes: Decreased LDL receptor and increased ApoB The high VLDL levels are due to overproduction of substrates, including triglycerides, acetyl CoA, and an increase in B-100 synthesis. They may also be caused by the decreased clearance of LDL. The disorder affects about 1 out of 10 people

Treatment Normally treated with Statins, niacin, fibrate

 Definition: Familial dysbetalipoproteinemia is a disorder ed down through families in which there are high amounts of cholesterol and triglycerides in the blood.

 Alternative Names:; Familial dysbetalipoproteinemia : Deficient or defective apolipoprotein E

 Causes A genetic defect causes this condition. The defect results in the buildup of large lipoprotein particles that contain both cholesterol and triglycerides, a type of fat. The disease is linked to defects in the gene for apolipoprotein E Hypothyroidism, obesity, or diabetes can make the condition worse. Risk factors for familial dysbetalipoproteinemia include a family history of the disorder or coronary artery disease. The disorder affects about 1 out of 10,000 people

 Symptoms Symptoms may not be seen until age 20 or older. Yellow deposits of fatty material in the skin called xanthomas may appear on the eyelids, palms of the hands, soles of the feet, or on the tendons of the knees and elbows. Atherosclerosis develops at an early age. There may be early chest pain (angina) or decreased blood flow to specific parts of the body, causing transient ischemic attacks of the brain or peripheral artery disease with claudication.

 Treatment The goal of treatment is to control underlying conditions such as obesity, hypothyroidism, and diabetes.

Reducing calories, saturated fats, and cholesterol may significantly reduce cholesterol levels. Medicine to lower blood triglyceride and cholesterol levels include: o o o o

Bile acid-sequestering resins Fibrates (gemfibrozil, fenofibrate) Nicotinic acid Statins

 Definition Type IV hypertriglyceridemia is a common disorder ed down through families in which the level of triglycerides (a type of fat) in a person's blood are higher than normal. The condition is not associated with a significant increase in cholesterol levels.

 Alternative names: Familial hypertriglyceridemia

 Causes Familial hypertriglyceridemia is caused by a genetic defect, which is ed on in an autosomal dominant fashion. This means that if you get a bad copy of the gene from just one of your parents, you will have the condition. Some people with this condition also have high levels of very low density lipoprotein (VLDL)

Familial hypertriglyceridemia does not usually become noticeable until puberty or early adulthood. Obesity, hyperglycemia (high blood glucose levels), and high levels of insulin are often also present and may cause even higher triglyceride levels. Familial hypertriglyceridemia occurs in about 1 in 500 individuals in the United States. Risk factors are a family history of hypertriglyceridemia or a family history of heart disease before the age of 50.

 Symptoms  No symptoms. People with the condition may have coronary artery disease at an early age.  Treatment Normally treated with Statins, niacin, fibrate

 Hyperlipoproteinemia type V is very similar to type I, but with high VLDL in addition to chylomicrons  It is also associated with glucose intolerance and hyperuricemia  Alternative name: Mixed hyperlipoproteinemia (rare)  Plasma is usually opaque and a floating cream layer above the turbid plasma observed

 Symptoms: Eruptive cutaneous xanthomas

 Treatment: Niacin, fibrate

 Non-classified forms are extremely rare:

• Hyperalphalipoproteinemia : the presence of abnormally high levels of high-density LIPOPROTEINS (α-lipoproteins) in the serum.

• Polygenic

hypercholesterolemia:

Polygenic hypercholesterolemia is the most common cause of elevated serum cholesterol concentrations. Low-density lipoprotein cholesterol (LDL-C) elevations are moderate (140-300 mg/dL) with serum triglyceride concentrations within the reference range. Polygenic hypercholesterolemia is associated with an increased risk for coronary heart disease (CHD)

Acquired hyperlipidemias (also called secondary dyslipoproteinemias) may mimic primary forms of hyperlipidemia and can have similar consequences. They may result in increased risk of premature atherosclerosis or, when associated with marked hypertriglyceridemia, may lead to pancreatitis and other complications of the chylomicronemia syndrome. The most common causes of acquired hyperlipidemia are: • diabetes mellitus • Use of drugs such as diuretics, beta blockers, and estrogens  Other conditions leading to acquired hyperlipidemia include: • Hypothyroidism • renal failure • nephrotic syndrome • alcohol • Some rare endocrine disorders and metabolic disorders

Although low levels of plasma lipids within the normal range may be beneficial to the body, very low lipid levels are undesirable. These are commonly associated with certain abnormalities I. II. III. IV. V.

Abetalipoproteinemia Hypobetalipoproteinemia Familial alpha lipoprotein deficiency Complete apoA-I deficiency Complete/partial LCAT deficiency

 Abetalipoproteinemia, also known as Bassen-Kornzweig Syndrome, is an inherited condition that causes dangerously low cholesterol levels.  It is characterized by a mutation in the gene for a protein called microsomal triglyceride transfer protein ( apo B ). This protein is very important in the formation of lipids like very low-density lipoproteins (VLDL) and chylomicrons.  Characterized by total absence of LDL in plasma

 Symptoms  Abetalipoproteinemia usually appears in infancy. It is an inherited condition that is autosomal recessive. These symptoms would include: • Bloating • Diarrhea • Vomiting • Presence of fatty, pale-colored, foul smelling stools

 Test:  A lipid will be performed to examine the levels of cholesterol and other fats circulating in the blood. This cholesterol test would reveal the following findings: •Undetectable LDL (low density lipoprotein) levels •Triglyceride levels less than 20 mg/dL •Total cholesterol levels less than 40 mg/dL

 These levels are extremely low, and apolipoprotein B, which is the protein attached to LDL cholesterol, will be absent in the blood. These factors, coupled with some of the symptoms that the infant is experiencing, will help to confirm a diagnosis of abetalipoproteinemia.

 Treatment: Vitamin supplementation, especially vitamin E, is extremely important.

 Familial hypobetalipoproteinemia is a rare, inherited condition that causes mild to extremely low LDL cholesterol levels. It is characterized by a mutation in the protein, apolipoprotein b(apoB). This protein is attached to LDL particles and helps transport cholesterol to cells in the body.  There are two types of hypobetalipoproteinemia: homozygous and heterozygous. Individuals who are homozygous for this condition have mutations in both copies of the gene. Symptoms in these individuals will be more severe and will occur earlier in life, typically within the first 10 years of life. Heterozygous individuals, on the other hand, only have one copy of the mutated gene. Their symptoms are mild, and sometimes, the individual may not even he has this condition until he has his cholesterol tested during adulthood.

 Symptoms The severity of symptoms will depend on which type of familial hypobetalipoproteinema. Individuals with homozygous familial hypobetalipoproteinemia have more severe symptoms than the heterozygous type, which would include: o Diarrhea o Bloating o Vomiting o Presence of fatty, pale-colored stools

Test: A lipid will be performed to examine the levels of cholesterol circulating in the blood. A cholesterol test would typically reveal the following findings • Homozygous : Total cholesterol levels < 80 mg/dL LDL cholesterol levels < 20 mg/dL Very low triglyceride levels • Heterozygous:Total cholesterol levels < 120 mg/dL LDL cholesterol levels < 80 mg/dL Triglyceride levels are usually normal (< 150 mg/dL)

 Treatment  Treatment of familial hypobetalipoproteinemia depends upon the type. In people with the homozygous type, vitamin supplementation –- especially vitamins A, K, and E –- is important. If an individual with the heterozygous type of hypobetalipoproteinemia is asymptomatic, he may not need treatment. However, some heterozygous individuals may need to be placed on a special diet or receive supplementation with fat-soluble vitamins if symptoms -- such as diarrhea or bloating -are present.

 ABC 1 (=ATP-binding cassette protein) : facilitates the removal of excess

free cholesterol  Tangier disease

 ApoA-I : LCAT activator  Complete apoA-I deficiency  LCAT (= lecithin:cholesterol acyl transferase) : catalyzes acyl group

transfer from phosphatidylcholine to cholesterol ester 

Complete/partial LCAT deficiency (Fish-eye disease)

 Tangier disease, also known as familial alpha lipoprotein deficiency, is an extremely rare, inherited condition that was first described in a child on Tangier Island, an island located off of the coast of Virginia.  It is characterized by very low HDL cholesterol levels due to a mutation in a gene called ABCA1 (=ATP-binding cassette protein) . This gene codes for a protein that helps get rid of excess cholesterol from inside the cell. When this protein is working properly, cholesterol is shuttled outside of the cell and binds to apolipoprotein A.  This forms HDL, or “good” cholesterol, which will travel to the liver so that cholesterol can be recycled. Without this protein, cholesterol will remain inside of the cells and accumulate.

 Symptoms • Tangier disease is usually noted in childhood and can range from very mild to severe. Individuals who are homozygous for this condition have mutations in both copies of the ABCA1 gene that codes for the protein and have virtually no HDL cholesterol circulating in the blood. These individuals will also have other symptoms as a result of cholesterol accumulation within various cells in the body, including: • Neurological abnormalities (including peripheral neuropathy, decreased strength, loss of pain or heat sensation, muscle pain) • Clouding of the cornea • Abdominal pain, diarrhea • Appearance or yellow patches on the intestinal mucosa, including the rectum • Enlarged, yellow-orange tonsils • Enlarged liver • Enlarged spleen • Premature cardiovascular disease

 Heterozygous individuals, on the other hand, only have one copy of the mutated gene. They also have roughly half of the normal amount of HDL in the blood. Although these individuals usually experience very mild to no symptoms, they are also at risk for premature cardiovascular disease. Additionally, these individuals can this condition on to their children.

 Tests :A lipid will be performed to examine the levels of • • • • •

cholesterol circulating in the blood. A cholesterol test would typically reveal the following findings: HDL cholesterol < 5 mg/dL in homozygous individuals HDL cholesterol between 5 and 30 mg/dL in heterozygous individuals Low total cholesterol levels (ranging between 38 and 112 mg/dL) Normal or elevated triglycerides (ranging between 116 and 332 mg/dL) Levels of apolipoprotein A may also be low to nonexistent. Based upon an abnormal lipid , as well as the symptoms experienced by the individual, a diagnosis of Tangier disease will be made.

 Handbook of clinical biochemistry- Swaminathan

 Clinical biochemistry – Lawrence A K., et al  http://en.wikipedia.org/wiki/Hyperlipidemia  http://reidhosp.adam.com/content.aspx?productId=39&pid= 1&gid=000408

 www.lfhk.cuni.cz/marklova/CEEPUS%5CCEEPUS03lipids.p pt