Hyperhomocysteinaemia - Metabolic disorders

Hyperhomocysteinaemia

Definition

Raised levels of homocysteine (an amino acid formed by the conversion of methionine to cysteine) have been associated with premature atherosclerotic disease.

Aetiology

1.     Severe hyperhomocysteinaemia with raised homocysteine levels in the urine is due to a rare autosomal recessive disorder called homocystinuria.

2.     Moderate homocysteinaemia occurs in approximately 5–7% of the population. Causes include the following:

·        Genetic defects in enzymes involved in homocys teine metabolism. The enzyme affected most commonly (approximately 10% of the population) is a variant of methylene tetrahydrofolate reductase, which converts homocysteine into methionine, using folic acid as a cofactor.

·        Vitamin deficiencies (folate, and to a lesser extent vitamin B6 or vitamin B12).

·        Smoking and chronic illnesses, e.g. renal failure.

Pathophysiology

There are several postulated mechanisms by which homocysteine may have its atherogenic and prothrombotic effects, including increased uptake of LDL cholesterol into the arterial intima (to form foam cells), smooth muscle cell proliferation, activation of clotting factors and a proaggregatory effect on platelets. There may also be a proinflammatory effect by upregulating neutrophils through increased expression of cytokines such as IL-8, and oxidative stress caused by free radicals produced during the oxidation of homocysteine.

Clinical features

1.     1 Homocystinuria presents in childhood with developmental delay. Other features include a Marfan’s like syndrome, ocular abnormalities, thromboembolic disease and severe premature atherosclerosis.

2.     Hyperhomocysteinaemia without the other features of homocystinuria has been found to be associated with ischaemic heart disease and stroke, although the effects are less strong than those of, e.g. hypertension, diabetes mellitus and smoking. It is more strongly associated with an increased risk of pulmonary embolism and deep vein thrombosis.

Investigations

Homocysteine levels can be measured (normal being 5–15 µmol/L, moderate 15–30 µmol/L and severe >100 µmol/L). A methionine challenge can be given to induce a rise in homocysteine levels in those with normal fasting levels, but the clinical significance of this is unknown.

Management

Increased folic acid intake reduces homocysteine levels. Vitamin supplementation with folic acid, vitamin B6 and vitamin B12 is advocated by some for those with premature cardiovascular disease and recurrent venous thromboembolism. There is as yet no clear evidence that supplements should be given to all those with ischaemic heart disease, although several trials are in progress.