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Familial apoprotein CII deficiency

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Title: Familial apoprotein CII deficiency  
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Subject: Apolipoprotein C2, Familial hypercholesterolemia, Lipoprotein lipase deficiency, Familial hypertriglyceridemia
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Familial apoprotein CII deficiency

Classification and external resources
10 9 DiseasesDB MeSH D006949

Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia (British English) involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.[1] It is the most common form of dyslipidemia (which includes any abnormal lipid levels).

Lipids (fat-soluble molecules) are transported in a protein capsule. The size of that capsule, or lipoprotein, determines its density. The lipoprotein density and type of apolipoproteins it contains determines the fate of the particle and its influence on metabolism.

Hyperlipidemias are divided in primary and secondary subtypes. Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein), while secondary hyperlipidemia arises due to other underlying causes such as diabetes. Lipid and lipoprotein abnormalities are common in the general population, and are regarded as a modifiable risk factor for cardiovascular disease due to their influence on atherosclerosis. In addition, some forms may predispose to acute pancreatitis.


Hyperlipidemias may basically be classified as either familial (also called primary[2]) caused by specific genetic abnormalities, or acquired (also called secondary)[2] when resulting from another underlying disorder that leads to alterations in plasma lipid and lipoprotein metabolism.[2] Also, hyperlipidemia may be idiopathic, that is, without known cause.

Hyperlipidemias are also classified according to which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Elevated levels of Lipoprotein(a) may also be classified as a form of hyperlipidemia.

Familial (primary)

Familial hyperlipidemias are classified according to the Fredrickson classification which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation.[3] It was later adopted by the World Health Organization (WHO). It does not directly account for HDL, and it does not distinguish among the different genes that may be partially responsible for some of these conditions. It remains a popular system of classification, but is considered dated by many.

Fredrickson classification of Hyperlipidemias
OMIM Synonyms Defect Increased lipoprotein Main symptoms Treatment Serum appearance Estimated prevalence
Type I a 238600 Buerger-Gruetz syndrome or familial hyperchylomicronemia Decreased lipoprotein lipase (LPL) Chylomicrons Acute pancreatitis, lipemia retinalis, eruptive skin xanthomas, hepatosplenomegaly Diet control Creamy top layer 1 in 1,000,000[4]
b 207750 Familial apoprotein CII deficiency Altered ApoC2
c 118830 LPL inhibitor in blood
Type II a 143890 Familial hypercholesterolemia LDL receptor deficiency LDL Xanthelasma, arcus senilis, tendon xanthomas Bile acid sequestrants, statins, niacin Clear 1 in 500 for heterozygotes
b 144250 Familial combined hyperlipidemia Decreased LDL receptor and increased ApoB LDL and VLDL Statins, niacin, fibrate Clear 1 in 100
Type III 107741 Familial dysbetalipoproteinemia Defect in Apo E 2 synthesis IDL Tubo-Eruptive Xanthomas & Palmar Xanthomas Fibrate, statins Turbid 1 in 10,000[5]
Type IV 144600 Familial hypertriglyceridemia Increased VLDL production and Decreased elimination VLDL Can cause pancreatitis at high triglyceride levels Fibrate, niacin, statins Turbid 1 in 100
Type V 144650 Increased VLDL production and Decreased LPL VLDL and Chylomicrons Niacin, fibrate Creamy top layer & turbid bottom

Hyperlipoproteinemia type I

Type I hyperlipoproteinemia exists in several forms:

Type I hyperlipoproteinemia usually presents in childhood with eruptive xanthomata and abdominal colic. Complications include retinal vein occlusion, acute pancreatitis, steatosis and organomegaly, and lipaemia retinalis.

Hyperlipoproteinemia type II

Hyperlipoproteinemia type II, by far the most common form, is further classified into type IIa and type IIb, depending mainly on whether there is elevation in the triglyceride level in addition to LDL cholesterol.

Type IIa

This may be sporadic (due to dietary factors), polygenic, or truly familial as a result of a mutation either in the LDL receptor gene on chromosome 19 (0.2% of the population) or the ApoB gene (0.2%). The familial form is characterized by tendon xanthoma, xanthelasma and premature cardiovascular disease. The incidence of this disease is about 1 in 500 for heterozygotes, and 1 in 1,000,000 for homozygotes.

HLPIIa is a rare genetic disorder characterized by increased levels of LDL cholesterol in the blood due to the lack of uptake (no Apo B receptors) of LDL particles. This pathology however is the second most common disorder of the various hyperlipoproteinemias, with individuals with a heterozygotic predisposition of 1 in every 500 and individuals with homozygotic predisposition of 1 in every million. These individuals may present with a very unique set of physical characteristics such as: Xanthelasma’s (yellow deposits of fat underneath the skin often presenting in the nasal portion of the eye), tendon and tuberous xanthomas, Arcus juvenilis (the graying of the eye often characterized in older individuals), Arterial bruits, claudication, and of course atherosclerosis. Lab findings for these individuals are obvious and yet interesting in the fact that their Serum cholesterol is 2-3 times greater than normal as well as increased LDL cholesterol but their triglycerides and VLDL values fall in the normal ranges. To manage person’s with HLPIIa drastic measures may need to be taken especially if their HDL cholesterol is less than 30mg/dl and their LDL cholesterol is greater than 160mg/dl. A proper diet for these individuals requires a decrease in total fat to less than 30% of total calories with a ratio of mon:poly:saturated fat of 1:1:1. Cholesterol should be reduced to less than 300mg/day thus the avoidance of animal products and to increase fiber intake to more than 20g/day with 6g of soluble fiber/day. Of course exercise should be promoted as exercise can increase HDL. The overall prognosis for these individuals is in the worst case scenario if uncontrolled and untreated individuals may die before the age of 20, however if one seeks a prudent diet with correct medical intervention the individual my see an increased incidence of xanthomas with each decade, Achilles tendinitis will occur, and accelerated atherosclerosis.

Type IIb

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. Prevalence in the population is 10%.

  • Familial combined hyperlipoproteinemia (FCH)
  • Lysosomal acid lipase deficiency, often called (Cholesteryl ester storage disease)
  • Secondary combined hyperlipoproteinemia (usually in the context of metabolic syndrome, for which it is a diagnostic criterion)

Hyperlipoproteinemia type III

This form is due to high chylomicrons and IDL (intermediate density lipoprotein). Also known as broad beta disease or dysbetalipoproteinemia, the most common cause for this form is the presence of ApoE E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). Its prevalence has been estimated to be approximately 1 in 10,000.[5]

Hyperlipoproteinemia type IV

Familial hypertriglyceridemia is an autosomal dominant condition occurring in approximately 1% of the population.[11]

Hyperlipoproteinemia type V

Hyperlipoproteinemia type V,also known as mixed hyperlipoproteinemia familial or mixed hyperlipidemia[12] , is very similar to type I, but with high VLDL in addition to chylomicrons.

It is also associated with glucose intolerance and hyperuricemia

In medicine, combined hyperlipidemia (or -aemia) (also known as "Multiple-type hyperlipoproteinemia") is a commonly occurring form of hypercholesterolemia (elevated cholesterol levels) characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL.[1]:534 On lipoprotein electrophoresis (a test now rarely performed) it shows as a hyperlipoproteinemia type IIB. It is the most common inherited lipid disorder, occurring in approximately one in two hundred persons. In fact, almost one in five individuals who develop coronary heart disease before the age of sixty will have this disorder. The elevated triglyceride levels (>5 mmol/l) are generally due to an increase in VLDL (very low density lipoprotein), a class of lipoprotein that is prone to cause atherosclerosis.


  1. Familial combined hyperlipidemia (FCH) is the familial occurrence of this disorder, probably caused by decreased LDL receptor and increased ApoB.
  2. Acquired combined hyperlipidemia is extremely common in patients who suffer from other diseases from the metabolic syndrome ("syndrome X", incorporating diabetes mellitus type II, hypertension, central obesity and CH). Excessive free fatty acid production by various tissues leads to increased VLDL synthesis by the liver. Initially, most VLDL is converted into LDL until this mechanism is saturated, after which VLDL levels elevate.

Both conditions are treated with fibrate drugs, which act on the peroxisome proliferator-activated receptors (PPARs), specifically PPARα, to decrease free fatty acid production. Statin drugs, especially the synthetic statins (atorvastatin and rosuvastatin) can decrease LDL levels by increasing hepatic reuptake of LDL due to increased LDL-receptor expression.

Unclassified familial forms

Non-classified forms are extremely rare:

Acquired (secondary)

Acquired hyperlipidemias (also called secondary dyslipoproteinemias) often mimic primary forms of hyperlipidemia and can have similar consequences.[2] 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.[2] The most common causes of acquired hyperlipidemia are:

Other conditions leading to acquired hyperlipidemia include:

Treatment of the underlying condition, when possible, or discontinuation of the offending drugs usually leads to an improvement in the hyperlipidemia. Specific lipid-lowering therapy may be required in certain circumstances.

Another acquired cause of hyperlipidemia, although not always included in this category, is postprandial hyperlipidemia, a normal increase following ingestion of food[13]


For treatment of type II, dietary modification is the initial approach but many patients require treatment with statins (HMG-CoA reductase inhibitors) to reduce cardiovascular risk. If the triglyceride level is markedly raised, fibrates may be preferable due to their beneficial effects. Combination treatment of statins and fibrates, while highly effective, causes a markedly increased risk of myopathy and rhabdomyolysis and is therefore only done under close supervision. Other agents commonly added to statins are ezetimibe, niacin and bile acid sequestrants. Dietary supplementation with fish oil is also used to reduce elevated triglycerides, with the greatest effect occurring in patients with the greatest severity.[14] There is some evidence for benefit of plant sterol-containing products and ω3-fatty acids[15]

For the other types see the treatment column in the Fredrickson classification table above.

See also


  1. The American Heritage Medical Dictionary. 2007, 2004 by Houghton Mifflin Company.

External links

  • The Fredrickson papers (with photos from early lipoprotein research)
  • GPnotebook
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