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Homocysteine is an amino acid that is produced in the blood during the metabolism of another amino acid called methionine. Normally, it gets further metabolized with the help of some enzymes and vitamins B6, B12 and folic acid.
Hyperhomocysteinema, or elevated levels of homocysteine in the blood, is caused by a number of conditions from vitamin deficiencies, enzyme defects and cancers to liver disorders, kidney failure and consumption of various drugs.
Scientists have noted that hyperhomocysteinemia is harmful as it damages arteries and veins, probably through production of harmful chemicals called free radicals. The injuries initiate a disease process in arteries called atherosclerosis, and also promote clot formation within blood vessels. This leads to heart attacks and strokes. It might also affect veins in the legs causing a painful and life-threatening condition called deep vein thrombosis.
Dr. Kilmer S. McCully, chief of pathology and laboratory medicine services at the U.S. Department of Veterans Affairs Medical Center in Boston, was the first to discover the connection between heart disease and elevated homocysteine levels, in 1969. On performing autopsies on three young children who had hyperhomocysteinemia due to enzyme deficiencies, he found there was widespread atherosclerosis in their arteries. He attributed it to raised homocysteine values, as this was the only metabolic abnormality they shared.
He further asserted his theory when he injected homocysteine into rabbits and pigs, which developed atherosclerosis. It was then that he proposed that all individuals in the general population who have high levels of homocysteine in their blood, due to whatever reasons, are susceptible to damage to the blood vessels and hence heart disease.
A study conducted by O. Nygard and colleagues from the Department of Public Health and Primary Health Care at the University of Bergen's Haukeland University Hospital in Norway, found a strong correlation between homocysteine levels and mortality in patients with coronary artery disease. Several other studies also detected high blood levels of homocysteine in patients with heart disease.
Deficiencies of vitamins B6, B12 and folic acid play an important role in elevating homocysteine levels. So studies were conducted to establish a connection between blood levels of these vitamins and homocysteine. Populations with a high chance of dietary vitamin deficiencies were studied in various situations.
Dr. Marcela Gonzalez-Gross and colleagues from the Faculty of Medicine at the University of Granada in Spain published a study in January this year, conducted on 218 elderly people living in an elderly home. They found a high prevalence of vitamin B and folate deficiency and hyperhomocysteinemia in the studied group.
A group of neurologists led by Jayantee Kalitaa from the Department of Neurology at Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India, published a study in October this year, involving 200 normal volunteers, that compared the levels of homocysteine with their dietary habits. It turned out that homocysteine levels were higher in the vegetarians, probably because their diet is deficient in vitamin B12, which comes from non-vegetarian food. Similar findings were noted in the October 2006 study of 441 men by Dr. C. Yajnik and his team from the Diabetes Unit at KEM Hospital in Pune, India.
Given this connection with vitamins, physicians have attempted to reduce elevated levels of homocysteine with vitamin supplements and thereby bring down the risk of heart disease and associated mortality.
The U.S. Food and Drug Administration have mandated the fortification of grains with folic acid, to prevent fetal abnormalities in the population, since 1998. According to the Framingham Heart Study, an ongoing heart disease study started in 1948 in Framingham, United States, and the U.S. Centers for Disease Control, there has been a decrease in the homocysteine levels and also in deaths due to coronary heart disease and strokes since the fortification.
However, results published in October this year from a large clinical trial suggest otherwise. In the Western Norway B-Vitamin Intervention Trial, 3,090 patients of established heart disease were given vitamin B to decrease homocysteine. The trial, which lasted for three years, found that lowering homocysteine did not lower the risk of heart disease nor the mortality.
Professor Dr. Salim Yusuf, Director of Cardiology at McMaster University in Ontario, Canada, who is studying the risk factors for heart diseases among thousands of people in various ethnic groups, says, "There is no reason now to lower homocysteine levels, but it is still too early to write off the hypothesis completely."
Two trials conducted in the past, Heart Outcomes Prevention Evaluation ( HOPE-2) and the Norwegian Vitamin Trial ( NORVIT), both published in March 2006, including a total of 9,271 patients with known heart conditions, also failed to demonstrate any advantage of vitamin B and folic acid supplements.
Dr. Marta Ebbing of Haukeland University Hospital in Norway, who was the coordinator of the WENBIT trial, said, "There is no justification for including vitamin B and folic acid in the treatment of known cardiac patients, for preventing further episodes. However, homocysteine is a definite risk marker in heart disease though it may not be a causal factor."
These results have created many question marks in the minds of physicians. They await more data with statistical significance from ongoing trials, to decide on the benefit of homocysteine-lowering treatments.
Studies in special populations like the Indians and other Asian populations are warranted, as these are known to have high homocysteine values.
Until then, a balanced diet appears to be the best strategy for dealing with this novel risk factor. Physicians should to be vigilant of the upcoming views on this topic and revise the line of treatment if needed.
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(Dr. Pradnya Kulkarni is a clinical pathologist from India. She worked as a consultant pathologist in a private laboratory in Pune before moving to Hong Kong with her husband and young daughter. She is also a freelance writer, focusing on medical issues of public concern. ©Copyright Pradnya Kulkarni.)
