November 06, 2012

History of the Relationship Between Homocysteine and Arteriosclerosis

Homocystinuria and Arteriosclerosis:

In 1965 a nine-year-old mentally retarded girl with dislocated lenses was found to have homocystine in her urine and blood.  The girl’s uncle (an eight year old boy) had similar symptoms, and had died in 1933.  Despite his young age, post mortem at the time had revealed the cause of his death to be carotid artery thrombosis with cerebral infarct and stroke.  The pathologist commented at the time that the thickening of his carotid artery had the appearance of arteriosclerosis in the elderly.

Studies of other children with homocystine in urine (homocystinuria) had shown that the enzyme CBS was abnormal in these cases.  Many early reports emphasized the clotting tendency in these patients, and the vascular lesions were generally attributed to the effects of thrombosis.  There was little evidence of deposition of cholesterol in the arterial lesions.

Another Case, But a Different Cause:

In 1968 a second case of homocystinuria with unusual features occurred in a two-month-old infant with homocystine and cystathionine in urine and blood, clearly showing a different cause for the homocystinuria.  This boy had an abnormality of methionine synthase (now known as cobalamin C disease) causing the metabolic disturbance (McCully KS: The Homocysteine Revolution, Keats Publishing,Inc,1997)

In reviewing the 1968 case of cobalamin C disease the pathologist Kilmer McCully again discovered arteriosclerotic plaques widely distributed in the infants arteries.  This showed that, at least in these very rare cases of inherited disease, raised blood homocysteine, common to both disease processes, was associated with arterial lesions regardless of the enzyme abnormality leading to raised blood levels of homocysteine.

And Another..!:

Identical arteriosclerotic plaques in yet another child with a third type of homocystinuria (caused by methylene tetrahydrofolate reductase deficiency) confirmed this conclusion about the role of homocysteine in causing arteriosclerosis in these rare disorders.

This suggested that homocysteine might also be atherogenic in the general population.  Further studies revealed that injection of homocysteine, or feeding of homocysteine in an experimental diet, causes arteriosclerotic plaques in rabbits, and vascular injury, plaques and thrombosis in baboons.

Many subsequent case-control studies have suggested that raised homocysteine is associated with an increased risk of cardiovascular disease.  However, a direct causal role has yet to be established.

In our next update we will start to look more closely at the relationship between B vitamins and cognition. In due course, we will get back to the story of homocysteine, and see why scientists decided to look more closely at the relationship between homocysteine and dementia in the 1990s

Older article Blog index Newer article