Section 19.2  


Move over cholesterol, there’s a new molecule in town. It’s homocysteine, a by–product created in the digestion of protein, and it’s making health headlines. High levels of homocysteine have been linked to cardiovascular disease. As a result, the American Heart Association (AHA) has recently named homocysteine as a risk factor for heart attack and stroke. Now, new research is suggesting that homocysteine plays a part in such diverse health concerns as osteoporosis, depression, Alzheimer’s disease and pregnancy. To understand how one molecule can do so much, we need to take a closer look at this compound. Homocysteine is an amino acid, although not one of the twenty "standard" amino acids that serve as the building blocks of protein in our bodies.

Homocysteine is not found in our diet, and thus the answer to why it represents such a problem lies in examining how it is produced in our bodies. The story of homocysteine involves several more familiar nutritional players, the vitamins B6, B12, and B8 (more commonly known as folic acid).

Homocysteine's place in metabolism

When proteins are metabolized, they are broken down into individual amino acids, including the sulfur-containing amino acid methionine. Methionine is in turn broken down further in several steps to produce homocysteine, which, once formed, can be removed from the body in only two ways. One, it can be remade into methionine through a process called remethylation. This requires both folic acid and vitamin B12, where B12 functions as an essential "cofactor" in the reaction. Secondly, homocysteine can be made into the amino acid cysteine through a process called transulfuration, a process that requires two enzymes to work in concert with vitamin B6. Thus, if a person ingests lots of protein, and there is not enough folic acid, B6 and B12 available to help digest it, homocysteine levels can build up in the blood stream. As might be expected, the opposite is also true. Increased levels of these vitamins in the blood stream result in a reduction of homocysteine levels. Indeed, studies have shown that oral folic acid supplements are effective in bringing homocysteine levels down. In a seesaw effect, as folic acid levels rise in the blood stream, levels of homocysteine drop.

The inverse relationship between homcysteine and folic acid

The importance of homocysteine to human health first came to light in the 1960s when a doctor named Kilmer McCully became interested in homocystinuria, a rare disease that results in high homocysteine levels in the blood. It turned out that people with this condition often suffered from heart disease and strokes, even at a very young age. He wrote a paper describing several children with homocystinuria who had died of heart attacks. Despite their youth and lack of fat deposits, Dr. McCully noticed that they had blood vessels damaged by atheroschlerotic plaques. He suggested that maybe the homocysteine had something to do with how these cholesterol deposits were formed inside the arteries. Although these findings were published in a good journal, they didn’t capture the imagination of medical researchers, and Dr. McCully’s results were ignored for many years.

Homocysteine joins cholesterol in the ranks of risks of heart disease

In the meantime, cholesterol was getting all the press as the cause of cardiovascular disease. Warnings went out to avoid it in our diets to lower our risk of heart attacks and strokes. "Good" and "bad" cholesterol became household words and it became widely believed by the general public that if you could just lower that cholesterol, you wouldn’t need to worry about a heart attack. However, while high cholesterol clearly increases the risk of having a heart attack, it has always been the case that many heart attack victims actually have normal cholesterol levels. And thus there must be more to the story, and the search for answers has led back to those early observations by Dr. McCully. Recent research has confirmed his hunch that homocysteine was playing a part in heart disease, and lately much has been made in the popular press about homocysteine as the "new cholesterol," or the "cholesterol of the 90s."

Homocysteine, perhaps working in tandem with cholesterol, may indeed be behind the development of arterial plaques, which deposit where the wall of an artery has been damaged. But although cholesterol is part of the sticky plaque material, it is has never been clear whether cholesterol itself is the culprit that breaks down the arterial wall in the first place. Now studies have shown that homocysteine damages the smooth vascular wall tissue, creating a scratch in the inside of the vessel where plaque can build up. Although more research needs to be done, it looks like homocysteine causes toxic superoxide radicals to form in the blood, which in turn kill cells in the blood vessel walls. Once damaged, the affected area swells and forms a "rough spot" where sticky cholesterol, (along with platelets and white blood cells that arrive to fix the damage) start to collect into a plaque. The problem is further exacerbated because homocysteine travels around the blood stream linked to low density lipoproteins (also known as LDLs, or "bad cholesterol"), the kind of cholesterol that builds up into plaques. And as if that were not enough, homocysteine can also thiolate (add sulfur groups) to LDLs, which causes them to be even more sticky and also attracts more white blood cells. All these reasons add up to point the finger at homocysteine as a potent new "bad guy" in the world of heart disease. This evidence, and studies linking high homocysteine to both heart attack and clogging of the arteries (atheroschlerosis), finally prompted the AHA to add homocysteine to the more well known risk factors for heart disease (such as smoking, high blood pressure, high cholesterol levels, obesity and lack of exercise).

But the bad work of homocysteine does not stop with damaging the circulatory system. Besides being suspected as a causative agent of atheroschlerosis, there are some early clues that homocysteine plays a role in proper brain function. When researchers looked at how nutrition could affect depression, they found that low levels of folic acid increased the symptoms of depression and prevented anti-depressant medications from working well. Of course because of the see-saw effect, patients with low folic acid levels have high levels of homocysteine, and these high homocysteine levels may themselves contribute to the problem. Homocysteine appears to inappropriately stimulate some nerve cell receptors, which can hinder normal brain function. High homocysteine levels also lead to high levels of S-adenosylmethionine (SAM, which is needed to make neurotransmitter molecules) and S-adenosyl homocysteine (which inhibits the proper methylation of some brain chemicals). Thus, elevated homocysteine levels may adversely affect a whole range of brain processes, and cause or worsen psychological abnormalities. Of course because high homocysteine and low folic acid levels go hand in hand, it is hard to know which of these molecules is more important in combating depression. It will likely turn out to be a combination of both.

High levels of homocysteine have now also been linked to diseases that cause dementia such as Alzheimer’s Disease. Deficiencies in vitamin B12 and folic acid have already been linked to neuropsychiatric disorders, although the biochemical reasons for these relationships remain to be worked out. Now, although the research is still in its early stages, it seems that certain thinking skills, such as making sense of visual input and understanding spatial relationships, are decreased by high homocysteine levels. Such links of folic acid, vitamins B6, B12 and homocysteine to cognitive function suggest that good nutrition may help prevent, or at least delay, the onset of diseases such as Alzheimer’s, good news in an age where more and more people are living longer, healthier lives.

Homocysteine is critically important during pregnancy

But keeping homocysteine levels in check is not just important as we age. Homocysteine has been identified as playing an important part in healthy fetal development. High maternal homocysteine levels in the bloodstream increase the chance of miscarriage, and of serious pregnancy complications such as pre-eclampsia and placental abruption. Such conditions can result in premature birth of the baby, low birth weight and, sadly, even the death of the baby or mother. Clearly, preventing high homocysteine levels during pregnancy is important for the health of both mother and child. Luckily, because folic acid has gotten so much attention as a vital nutrient for preventing serious neural tube birth defects such as Spina Bifida, pregnant women and women planning to get pregnant are already routinely advised to take folic acid supplements, which has the added benefit of keeping homocysteine levels down as well. The results from these studies that link high homocysteine levels with poor pregnancy outcomes now make taking those folic acid supplements during pregnancy doubly important.

As if all these studies pointing to the importance of homocysteine in human health are not enough, high homocysteine levels have even been proposed as causative agents for osteoporosis, a condition where bones become progressively weaker in postmenopausal women, and presbyopia, far sightedness due to aging. Connections to yet other health disorders are sure to follow. Yet despite the mounting evidence that high homocysteine levels correlate to increased risk of heart attack, stroke, birth defects, mental health problems, and perhaps other ailments, studies still need to be done to determine if lowering homocysteine levels in the general population, perhaps by supplementing the food supply, could increase our health as a nation.

The importance of homocysteine in health and well-being

Because folic acid supplements do significantly lower homocysteine levels in the blood stream, such proposals to add folic acid to foods have been made. Proponents note that the addition of vitamin B6 to the food supply has resulted in a gradual drop in death from cardiovascular causes since the 1960s. However, such plans are controversial, for one because folic acid supplements can mask the symptoms of pernicious anemia, a vitamin B12 deficiency that hampers the bone marrow’s ability to make blood, which can cause irreversible nerve damage. Thankfully, in the absence of metabolic defects that keep homocysteine levels abnormally high, all the risks associated with high homocysteine levels seem to be avoidable with good nutrition. Leafy green vegetables, orange juice and beans are good sources of folic acid. Vitamin B6 is found in starchy foods such as whole grains, potatoes, bananas, as well as turkey and tuna, and vitamin B12 is found in meat, seafood and dairy products. A well balanced diet can provide ample amounts of these important nutrients.

Much work on this simple yet powerful molecule still needs to be done. While high homocysteine levels are found in tandem with many ailments, proving a real biochemical connection between homocysteine and disease is important before serious recommendations can be made about diet and vitamin supplementation. Scientists will need to unearth more clues as to the harmful effects of homocysteine, and then hopefully come up with practical ideas to apply this knowledge for the health of everyone.

Copyright 2002, John Wiley & Sons Publishers, Inc.