• Information
  1. Types
  2. Hyperlipidemia Phenotypes
  3. Homozygous Familial Hypercholesterolemia
  4. Heterozygous FH
  5. Familial Hypertriglyceridemia
  6. Familial Combined Hyperlipidemia
  7. Familial Dysbetalipoproteinemia
  8. Familial Hypoalphalipoproteinemia
  9. Other Low HDL Syndromes
  10. Autosomal Recessive Hypercholesterolemia
  11. Rare Disorders of Lipid Metabolism

A. Types [2]
[Figure] "Cholesterol Transport"

1. Homozygous FH
2. Heterozygous FH
3. Other Familial Dyslipidemias
   1. Familial hypertriglyceridemia (Familial chylomicronemia)
   2. Familial combined hyperlipidemia
   3. Familial dysbetalipoproteinemia (remnant removal disease)
   4. Familial hypoalphalipoproteinemia (low HDL syndrome)
   5. Autosomal recessive hypercholesterolemia (see below)
4. Other Low-HDL Syndromes
5. Rare Lipid Disorders (autosomal recessive; some with very low serum cholesterol)
6. In general, very aggressive lipid lowering is preferred over conventional therapy [8]

B. Hyperlipidemia Phenotypes

1. These phenotypes are designated by World Health Organization
2. Type 1: chylomicronemia, elevated triglycerides
3. Type 2a: LDL elevation (high cholesterol)
4. Type 2b: LDL and VLDL (high cholesterol and triglycerides, usually low HDL)
5. Type 3: chylomicronemia (high triglycerides and cholesterol)
6. Type 4: VLDL and triglyceride elevations
7. Type 5: chylomicronemia and VLDL (high triglycerides and cholesterol)
8. Variety of genetic mutations have been discovered

C. Homozygous Familial Hypercholesterolemia

1. Most cases are autosomal inheritance, ~1:1 million births
2. Genetic Abnormalities
   1. Dysfunctional LDL receptors - most common cause [1]
   2. Apolipoprotein B (ApoB) mutations that affect binding of LDL to its receptor [3]
   3. Ornithine transcarbamoylase deficiency (usually considered separately from FH)
3. Presentation at young age
4. Symptoms and Signs
   1. Tuberous, planar, tendinous xanthomas
   2. Arcus corneae
   3. Accelerated atherosclerosis - including large vessels (for example, aorta)
5. Clinical Course
   1. Invariably reduced lifespan despite treatment (difficulty reducing LDL adequately)
   2. Atorvastatin (Lipitor®) 80mg qd appears to prevent atherosclerosis progression [4]
   3. Pravastatin (Pravachol®) 20-40mg qd for 2 years in children was safe and reduced carotid atherosclerosis [9]
   4. Simvastatin (Zocor®) + ezetimibe (Zetia®), in combination pill (Vytorin®) reduced LDL, triglycerides and C-reactive protein (CRP) better than simvastatin alone [12]
   5. Vytorin showed no reduction over simvastatin on carotid and femoral intima-media thickness [12]
   6. Optimal therapy is unclear, but generally, lower LDL and CRP levels are superior
   7. Liver transplantation is only current definitive therapy
6. Gene therapy may cure disease in near future

D. Heterozygous FH [5]

1. About 1:500 persons
2. LDL receptor activity 2-25% of normal (LDL receptor mutations)
3. Serum cholesterol levels are about 2X normal
4. Early Coronary Artery Disease (CAD) is major morbidity
   1. Clinical CAD is 5% by age 30
   2. 20% by age 40
   3. 50% by age 50
   4. About 25% of untreated patients die from CAD events by age 50
5. Treatment
   1. Aggressive Diet and weight loss
   2. HMG Co-A reductase inhibitors (statin) - lovastatin is safe for 1 year, age 10-17 [5]
   3. Niacin
   4. Caution when combining statin and niacin - may cause myositis and/or severe hepatitis
   5. Plasmapheresis
   6. Despite increases in HDL by 30mg/dL and reductions in LDL, torcetrapib (a CTEP inhibitor) added to atorvastatin did not reduce carotid atherosclerosis in heterozygous FH [11]
6. Gene therapy may cure disease in near future

E. Familial Hypertriglyceridemia (Chylomicronemia) [2,6]

1. Mechanism
   1. Reduced lipoprotein lipase (LPL) activity due to mutations in LPL gene
   2. LPL functions to reduce serum triglyceride levels
   3. Increased hepatic secretion of triglyceride-rich VLDL also occurs
   4. Net result is highly elevated chylomicron numbers and triglyceride levels
2. Lipid Profile
   1. Hypertriglyceridemia - average over 200mg/dL
   2. Reduced HDL levels - average <20mg/dL
   3. Highly reduced LDL levels - average 28mg/dL
3. Complications
   1. Pancreatitis - usually with triglyceride levels >2000mg/dL
   2. Premature atherosclerosis is unusual
4. Treatment
   1. Diet and weight loss
   2. Fibrate - such as gemfibrozil
   3. Nicotinic acid (niacin)
   4. N-3 fatty acids
   5. Oxandrolone
5. Inhibition of Microsomal Triglyceride Transfer Protein (MTTP; Experimental) [10]
   1. BMS-201038 is an inhibitor of MTTP
   2. At 1.0 mg/kg/day, provided 50% reduction in LDL chol and apoB levels
   3. Elevated liver aminotransaminase levels and increased hepatic fat accumulation

F. Familial Combined Hyperlipidemia [2]

1. Mechanism
   1. Increased hepatic secretion of ApoB containing VLDL and conversion to LDL
   2. Accumulation of VLDL and/or LDL
2. Lipid Profile
   1. Elevated VLDL
   2. Elevated LDL
3. Complications
   1. Increased risk for CAD
   2. Increased risk for stroke
   3. Increased risk for peripheral vascular disease (PVD)
4. Treatment
   1. Diet and weight loss
   2. Statin
   3. Nicotinic acid
   4. Fibrate

G. Familial Dysbetalipoproteinemia [2]

1. Mechanism
   1. Remnant removal disease due to reduced ApoE-e2 activity
   2. May have homozygous or heterozygous ApoE-e2 alleles
2. Lipid Profile
   1. Increases in VLDL
   2. Increased total cholesterol
3. Complications
   1. CAD increased
   2. PVD increased
   3. Increased stroke risk
4. Treatment
   1. Diet, weight loss
   2. Fibrate
   3. Nicotinic acid
   4. Statin

H. Familial Hypoalphalipoproteinemia [2]

1. Mechanism
   1. Diminished apolipoprotein AI (ApoAI) formation
   2. Increased removal of ApoAI
   3. Increased cholesterol ester transferase protein (CETP)
   4. Increased hepatic lipase activity
2. Lipid Profile
   1. Low HDL Syndrome: HDL <30mg/dL
   2. Hypertriglyceridemia
3. Complications
   1. CAD increased
   2. PVD increased
4. Treatment
   1. Exercise and weight loss
   2. Nicotinic acid
   3. Fibrate
   4. Statin

I. Other Low HDL Syndromes [3]

1. About 50% of patients with myocardial infarction have low HDL chol levels
2. Apo AI-CIII mutations is most common genetic cause
3. Lipoprotein lipase mutations
4. Cholesterol ester transport protein (CETP) mutations
5. Hepatic lipase mutations
6. Lecithin-cholesterol acyltransferase mutations
7. Mutations in ABC1 gene cause familial HDL deficiency [3]
   1. ABC1 (ATP binding cassette) gene codes for cholesterol efflux regulatory protein (CERP)
   2. ABC1 mutations also cause Tangier Disease (see below)
   3. Mutations in ABC1 which cause familial HDL deficiency are more common than those that cause Tangier Disease

J. Autosomal Recessive Hypercholesterolemia (ARH) [8]

1. Very rare autosomal recessive disorder
2. Reduced rates of plasma LDL clearance
3. ARH gene is 308 aminoacid protein probably involved in signalling and transport
4. Two major ARH mutations present in Sardinia and Italian mainland
5. Clinically behave as intermediate between homozygous and heterozygous FH

K. Rare Disorders of Lipid Metabolism

1. These are autosomal recessive disroders, very rare
2. Abetalipoproteinemia
   1. Very low plasma levels of cholesterol and triglycerides
   2. Fat malabsorption is main problem, along with neuropathy
   3. Caused by defective apoprotein B synthesis
   4. Treat with Vitamin E
3. Tangier Disease [7]
   1. Low cholesterol levels, normal or increased triglycerides
   2. Large, orange or yellow tonsils, corneal opacities, relapsing polyneuropathy
   3. Absence of HDL from plasma
   4. No current therapy
4. Lecithin:Cholesterol Acetyltransferase Deficiency
   1. Elevated VLDL, decreased esterified cholesterol, increased unesterified cholesterol
   2. Corneal opacities, hemolytic anemia, renal dysfunction, premature atherosclerosis
   3. Decreased LCAT activity
   4. Treat with fat restricted diet, supportive for other organs
5. Cerebrotendinous Xanthomatosis
   1. No plasmid lipid abnormality
   2. Progressive cerebellar ataxia, dementia and spinal cord paresis, tendon xanthomas
   3. Defective synthesis of primary bile acids
   4. No current therapy
6. Sitosterolemia
   1. Elevated levels of plant sterols in plasma, elevated or normal cholesterol
   2. Tendon xanthomas are main symptom
   3. Increased intestinal cholesterol and sitosterol absorption
   4. Treat with diet low in plant sterols and cholesterol

References

1. Durrington P. 2003. Lancet. 362(9385):717
2. Knopp RH. 1999. NEJM. 341(7):499
3. Tybjaerg-Hansen A, Steffensen R, Meinertz H, et al. 1998. NEJM. 338(22):1577
4. Smilde TJ, van Wissen S, Wollersheim H, et al. 2001. Lancet. 357(9256):577
5. Stein EA, Illingworth DR, Kiwterovich PO Jr. 1999. JAMA. 281(2):137
6. Benlian P, de Gennes JL, Foubert L, et al. 1996. NEJM. 335(12):848
7. Siao PTC, Cros DP, Lees RS. 1996. NEJM. 334(21):1389
8. Arca M, Zuliani G, Wilund K, et al. 2002. Lancet. 359(9309):841
9. Wiegman A, Hutten BA, de Groot E, et al. 2004. JAMA. 292(3):331
10. Cuchel M, Bloedon LT, Szapary PO, et al. 2007. NEJM. 356(2):148
11. Kastelein JJ, van Leuven S, Burgess L, et al. 2007. NEJM. 356(16):1620
12. Kastelein JJ, Akdim F, Stroes ES, et al. 2008. NEJM. 358(14):1431