(See also Overview of Lipid Metabolism.)
Hypolipidemia is defined as a total cholesterol (TC) < 120 mg/dL (< 3.1 mmol/L) or low-density lipoprotein cholesterol (LDL-C) < 50 mg/dL (< 1.3 mmol/L).
Causes may be primary (genetic) or secondary. Secondary causes are far more common than primary causes and include all of the following:
Chronic infections (including hepatitis C infection) and other inflammatory states
Hematologic and other cancers
Undernutrition (including that accompanying chronic alcohol use)
The unexpected finding of low cholesterol or low LDL-C in a patient not taking a lipid-lowering drug should prompt a diagnostic evaluation, including measurements of AST (aspartate aminotransferase), ALT (alanine aminotransferase), and thyroid-stimulating hormone; a negative evaluation suggests a possible primary cause.
There are 3 primary disorders in which single or multiple genetic mutations result in underproduction or increased clearance of LDL:
Abetalipoproteinemia
Chylomicron retention disease
Hypobetalipoproteinemia
Loss-of-function mutations of PCSK9 (proprotein convertase subtilisin-like/kexin type 9) are another cause of low LDL levels. There are no adverse consequences and no treatment.
Abetalipoproteinemia (Bassen-Kornzweig syndrome)
This autosomal recessive condition is caused by mutations in the gene for microsomal triglyceride (TG) transfer protein, a protein critical to chylomicron and very-low-density lipoprotein (VLDL) formation. Dietary fat cannot be absorbed, and lipoproteins in both metabolic pathways are virtually absent from serum; total cholesterol is typically < 45 mg/dL (< 1.16 mmol/L), TGs are < 20 mg/dL (< 0.23 mmol/L), and LDL is undetectable.
The condition is often first noticed in infants with fat malabsorption, steatorrhea, and failure to thrive. Intellectual disability may result. Because vitamin E is distributed to peripheral tissues via VLDL and LDL, most affected people eventually develop severe . Symptoms and signs include visual changes due to slow retinal degeneration, sensory neuropathy, posterior column signs of ataxia and paresthesias, and cerebellar signs of dysmetria, ataxia, and spasticity, which can eventually lead to death.
Diagnosis is made by the absence of apoprotein B (apo B) in plasma. Intestinal biopsy specimens show lack of microsomal transfer protein. Red blood cell acanthocytosis is a distinguishing feature on blood smear. Genetic testing can confirm the diagnosis.
Treatment of vitamin E
Chylomicron retention disease (Anderson disease)
Chylomicron retention disease is a very rare autosomal recessive condition caused by deficient apo B secretion from enterocytes. Mutations in a gene encoding a protein important in transport of chylomicrons through enterocytes have been linked to this disorder.
Affected infants have fat malabsorption, steatorrhea, and failure to thrive and may develop neurologic disorders similar to those in abetalipoproteinemia.
Diagnosis is by intestinal biopsy of patients with low cholesterol levels and absence of postprandial chylomicrons.
Hypobetalipoproteinemia
Hypobetalipoproteinemia is an autosomal dominant or codominant condition caused by mutations in the gene coding for apo B.
Heterozygous patients have truncated apo B, leading to rapid LDL-C clearance. Heterozygous patients manifest no symptoms or signs except for TC < 120 mg/dL (< 3.1 mmol/L) and LDL-C < 80 mg/dL (< 2.1 mmol/L). Triglycerides are normal. Some patients may have hepatic steatosis.
Homozygous patients have either shorter truncations, leading to lower lipid levels (TC < 80 mg/dL [< 2.1 mmol/L], LDL-C < 20 mg/dL [< 0.52 mmol/L]), or absent apo B synthesis, leading to symptoms and signs of abetalipoproteinemia.
Diagnosis is by finding low levels of LDL-C and apo B on a serum lipid profile. Hypobetalipoproteinemia and abetalipoproteinemia are distinguished from one another by family history.
