Familial HDL deficiency is a condition characterized by low levels of high-density lipoprotein (HDL) in the blood. HDL is a molecule that transports cholesterol and certain fats called phospholipids through the bloodstream from the body's tissues to the liver. Once in the liver, cholesterol and phospholipids are redistributed to other tissues or removed from the body. HDL is often referred to as "good cholesterol" because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. People with familial HDL deficiency may develop cardiovascular disease at a relatively young age, often before age 50.
Severely reduced levels of HDL in the blood is a characteristic feature of a related disorder called Tangier disease. People with Tangier disease have additional signs and symptoms, such as disturbances in nerve function; enlarged, orange-colored tonsils; and clouding of the clear covering of the eye (corneal clouding). However, people with familial HDL deficiency do not have these additional features.
Some patients remain asymptomatic until advanced adulthood.
Others may present from adolescence with a combination of the following symptoms:
- blurred vision due to corneal opacities or cataract
- tubero-eruptive, tendinous, palmar and/or planar xanthomas
- premature coronary heart disease (CHD) (e.g. myocardial infarction, carotid atherosclerosis)
Less often Apo A-I deficiency may manifest with neurosensory signs:
- cerebellar ataxia
- neurosensory hearing loss
- proliferative retinopathy
or other multi-organ manifestations of systemic amyloidosis:
-> all potentially progressing into end-stage organ failure (liver, renal or cardiac failure).
Mutations in the ABCA1 gene or the APOA1 gene cause familial HDL deficiency. The proteins produced from these genes work together to remove cholesterol and phospholipids from cells.
The ABCA1 gene provides instructions for making a protein that removes cholesterol and phospholipids from cells by moving them across the cell membrane. The movement of these substances across the membrane is enhanced by another protein called apolipoprotein A-I (apoA-I), which is produced by the APOA1 gene. Once outside the cell, the cholesterol and phospholipids combine with apoA-I to form HDL. ApoA-I also triggers a reaction that converts cholesterol to a form that can be fully integrated into HDL and transported through the bloodstream.
Diagnosis is based on biochemical analysis of plasma Apo A-I and HDL cholesterol levels showing extremely low HDL cholesterol levels and very low to undetectable Apo A-I (inferior to 5 mg/dL). Low HDL cholesterol levels are associated with normal VLDL and LDL cholesterol levels, and normal or decreased triglyceride levels. Histological examination of skin lesions reveals numerous foam cells. Diagnosis is confirmed by genetic testing.
The differential diagnosis includes Tangier disease, LCAT deficiency (see these terms) and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, paradoxical response to fibrates) and malignancies.
Prognosis depends on the occurrence of premature CHD and end-stage organ failure in cases with signs of amyloidosis.
To date, there is no curative therapy. In case of carotid atherosclerosis or cardiovascular complications, a low-fat diet balanced in anti-oxidants (e.g. Mediterranean type) may be combined with statins (HMGCoA reductase inhibitors) that lower LDL cholesterol levels below 70 mg/dL. Oral anti-oxidants, or infused synthetic HDL-mimetics or reconstituted HDL, are being investigated as potential anti-atherosclerotic therapies. Regular cardiovascular monitoring should be offered to Apo AI deficient patients with extremely low HDL cholesterol (<20 mg/dL) because of the increased risk (Odds Ratio x2-3) of coronary artery disease. In cases exhibiting signs of amyloidosis, long-term follow-up of target organ function should be proposed.