|Hyperhomocysteinemia: Obstetric Arch-Villain or Genetic Diversity?|
|Thursday, 28 January 2010 04:23|
is an amino acid. is a condition where there is too much homocysteine in the blood. This condition has been associated with several types of vascular disease1, heart attack in young women2, spina bifida3, osteoporosis4, vascular disease among diabetics5, pre-menstrual syndrome6, and kidney failure6. We also see it with the pregnancy complications of miscarriage7, placental abruption8, and severe pre-eclampsia.9
Before we begin talking about the studies that demonstrate the relationship between homocysteine and disease, we should explore some metabolic cycles.
The Methionine Cycle
Methionine is an essential amino acid in our diets. It is often the limiting amino acid in many body proteins. This means the only thing limiting sufficient numbers of certain proteins being made is running out of methionine. Methionine is used for many reactions that are known as methylation reactions.is the process whereby one - or one carbon and three hydrogens (CH3) - is donated from one molecule to another. RNA, DNA, , proteins, , and are some of the molecules that need to receive a methyl group. Refer to the diagram to help you visualize the cycle.
The main thing to notice about the methionine cycle is thatgets converted to and then, if everything is working well, it gets converted back to methionine. It gets converted to homocysteine in the process of giving up a methyl group. Homocysteine gets converted back to methionine by receiving a methyl group from folic acid. The body can also get rid of excess homocysteine by modifying it and eliminating it from the body by way of the "trans-sulphuration pathway".10
The Folate Cycle
The next cycle to understand is the folic acid cycle. There are many forms of folic acid, but only one form can be used to donate theto , so it can turn back into . The hardest thing about the different types of folic acid is that they all have very long names.
Shortly after folic acid is absorbed into the body it is changed to THF (tetrahydrofolate). This is a biologically active form of folate. The THF isto become 5,10-methylene THF. After this step an enzyme is needed to convert 5, 10-methylene THF to 5-methyl THF.11 This is the form that can be used to donate a to so it can be converted back to .
Vitamin B12 is also needed. In reality, the folic acid passes the methyl group off to B12, which gives it to homocysteine.
After the 5 methyl THF gives up its methyl group it returns to being just ordinary THF and resumes its cycle.
The Trans-Sulphuration Pathway
There is another way thatcan be broken down besides being changed back into . (Refer to the next diagram.) With adequate vitamin B6, it can be converted to . Cysteine is a precursor to glutathione, an important antioxidant. Cysteine can also be broken down into carbon dioxide and sulfate which can be eliminated through the urine. The Enzyme is also needed for this metabolic pathway.11
What Can Go Wrong with Metabolism to Cause a Buildup of Homocystein?
If you were able to get through the discussion and diagrams to this point, you might be able to get a clearer picture of what can go wrong.
High levels ofwere first identified in the urine of some retarded children in the 1960's. These children had an that caused a deficiency of the enzyme . People with the condition, known as , have two defective copies of the gene that codes for the enzyme CBS. This causes an overabundance of both homocysteine and , because the homocysteine cannot be broken down and eliminated via the trans-sulphuration pathway. It only keeps getting recycled to methionine. About 25% of people with homocysteinuria die by the age of 30 from cardiovascular disease.10 They also suffer from osteoporosis, psychiatric disturbances, and eye abnormalities.12 With this specific defect it is important to avoid foods with methionine, because these individuals accumulate too much of it and can’t get rid of what they have.
Carriers for CBS deficiency who only have one defective gene, also demonstrate higher than normal levels of homocysteine in the blood.13
Variations of the MTHFR Enzyme
It is much more common for there to be alterations to the gene that codes for theenzyme. As you can see from the diagrams, this enzyme is needed to change folate from 5, 10- methylene THR to 5-methyl THR. This will not cause a buildup of . Just the opposite will occur because there is less of the right type of folic acid to convert back into methionine. But we still often see increased levels of homocysteine in the blood. There are two variations of the gene for MTHFR being researched.
The 677C→T Polymorphism
The variation that seems to cause the most concern is called the 677C→T. This means that in the DNA for the enzyme there is a thymine [T] nucleotide where usually a cytosine [C] would be located. In the MTHFR enzyme itself this causes a valine amino acid to show up where normally the amino acid alanine would be. This amino acid substitution occurs near the binding site for folic acid on the MTHFR enzyme.
About 12% of the population have the two of these 677T genes. Among French Canadians 51% of the population have one gene6. In theindividuals, the MTHFR enzymes function only about 35% as actively as in people or in people with two 677C genes.11 This defect causes moderate increases in in the blood. It does not show up in the urine. People with this defect do not need to shun . In fact they might not have enough to support all the needed reactions in the body.
The 1298A→C Polymorphism
A second gene variation in coding for the sameenzyme is the 1298A→C genotype. It does not seem to have as much of an impact as the 677C→T . Some studies show that persons with one 677T gene and one 1298C gene also have reduced activity of their MTHFR enzymes and elevated . Other studies do not corroborate this.14
Problems with B12 Transport
Remember that vitamin B12 is also needed to convertback to . There is a genetic variation in a gene for . TC is a molecule that is important for transporting vitamin B12 to peripheral tissues. The is known as the 776C→G. Having the more common 776C genes promotes higher levels of TC in the blood plasma and may be important for enabling B12 to reach the embryo in pregnant women. Having one 776G gene is associated with .14
Lack of folic acid, vitamin B12, or B6 in the diet can also cause a rise in.15 Folic acid is one of the more difficult vitamins to obtain sufficiently from diet. The lack of needed for absorption of B12 is not uncommon as people age. And in all of the elderly, less food consumption and poor absorption can lead to deficiencies. And as we have seen from the 776C→G polymorphism, some people lack efficiency in getting vitamin B12 into their tissues.
Several drugs inhibit absorption of folic acid. The list includes large doses of ibuprofen; the anticonvulsants phenytoin, phenobarbital, and primidone; and the cholesterol-lowering drugs cholestyramine and colestipol. Methotrexate is a folic acid antagonist and can lead to side effects similar to folic acid deficiency. Other drugs that have anti-folate activity include the antibiotic trimethoprim, the antimalarial pyrimethanine, the blood pressure medication triamterene, and a ulcerative colitis drug sulfasalazine. Birth control pills also undermine body folate status.15, 16
As we can see there are many ways that the metabolism of the essential amino acidcan be disrupted. Current research is demonstrating that this disruption may be at the heart of several birth defects and other problems associated with pregnancy.
Research is still trying to discover what aspects of the disrupted metabolism actually cause the problems. It may be theitself. For some birth defects it may be the lack of needed methionine. Or some researchers have suspected other compounds such as SAH (see the third, large diagram) of interfering with the methylation reactions.14 What is known is that high blood homocysteine is at least a marker for many disease processes.
Neural Tube Defects
For a long time we have known that folic acid may prevent. In 1995 a study was done that showed parents of children born with a neural tube defect were about three times more likely to be for the 677T gene than parents in a control group.13 Another study showed that 28 children with spina bifida had significantly higher levels than controls. And 16 of the 28 children had one or two of the 677T genes.13 The good news is that folic acid supplementation before and after conception can reduce the risk of having a second baby with a neural tube defect.6
In 1998 the US began adding folic acid to enriched grain products. Since that time, blood homocysteine levels in the population have declined.15 Some researchers are now finding it more difficult to link folic acid supplementation to lower incidences of neural tube defects.17 This could be that the defects that would have been caused by folic acid deficiency have been taken care of by the food fortification. Or it could be that newer studies are more careful to control for such factors as cigarette smoking and coffee drinking, both of which are associated with high homocysteine levels.18, 19
Recurrent early pregnancy loss has also been associated with. Women with classic experience miscarriage 50% of the time.13 But classic homocysteinuria is not the only cause. A study was done using only women with normal CBS activity, who therefore did not carry any genes for homocysteinuria. Still, between a quarter and a third of the women who had recurrent pregnancy loss either had high blood homocysteine, or demonstrated an abnormal methionine cycle when given a large dose of (called a methionine loading test).13
In a 1997 study women who had unexplained recurrent early miscarriages were three times more likely to have the 677C→Tthan the general population.13
There is alink with preeclampsia. In 2003 a study was done using 19 women with mild or moderate preeclampsia and 15 normally pregnant women for a control group. They were matched by gestational age. The plasma averaged 13.23 ± 6.76 [ìmol/l] for the preeclamptic women and 4.86 ± 0.77 [ìmol/l] for the controls.20
Placental Abruption or Infarction
A study was done in 1995 with women who had experienced placental abruption or infarction. 84 women with a history of abruption or placental infarct (the study group) were compared to 46 controls who had experienced normal pregnancy.was diagnosed in 31% of the women in the study group and only 9% of the controls.8
Vitamin levels were also assessed in these subjects. The women of the study group had significantly lower levels of serum folate, serum B12, and an active form of B6 in whole blood. Both groups did have comparable levels of folate in their red blood cells, however.8
Can Supplementation Help?
Many studies have been done that link folic acid or multivitamin supplementation before and during early pregnancy with improved outcomes for, some heart defects and some limb deformities21-25 although other studies have failed to find a connection.17, 26
At least in mice some conditions can improve with supplementation. Researchers took some special mice that were bred to have a defect which causes them to spontaneously develop high blood cholesterol and. Some mice were fed a diet high in and low in vitamins B6, B12, and folate. Others were fed a diet high in methionine, but with extra vitamins B6, B12, and folate. The level of in the supplemented group was less than half that of the low vitamin group. The supplemented mice developed 30% less area of atherosclerotic lesions. The lesions themselves were also less severe.27
Supplementation has been shown to reduce homocysteine levels in humans as well. Patients diagnosed with thromboembolism andwere given 1 mg folic acid, 0.2 mg B12, and 100 mg B6 daily for six weeks. Their average reduction of homocysteine was 42.1%28
What Supplements May Help?
It seems that supplementation beginning before pregnancy occurs, should be recommended seeing that we do not know which women may have a genetic predisposition to abnormal metabolism. The specific vitamins recommended are folic acid and B12 to help with recycling homocysteine to.15 B6 can help eliminate excess homocysteine through the trans-sulphuration pathway. In this pathway a powerful antioxidant, namely glutathione, can be formed as well.29
has also been used as a supplement for people with classic who still have high even after supplementation with B6. Individuals with this defect are deficient in , an enzyme needed for the trans-sulphuration pathway. In these cases betaine has been shown to cause a decrease in homocysteine and a modest increase in the amino acid serine. Serine is also needed for the trans-sulphuration pathway.29 Choline can be used as a source of betaine.30
Another study has shown that low selenium levels in the body are associated with high homocysteine levels in elderly humans.31
Dr. Tom Brewer long felt that plenty of quality protein in a pregnant woman’s diet would prevent preeclampsia, yet he felt it unethical to do a study where some pregnant women ate adequate protein and others did not. The quality protein that he recommended is an excellent source of methionine, the lack of which may be contributing to some of the problems associated within pregnancy.
It is not yet routine to test pregnant women for. During the second and third trimesters of pregnancy the levels of homocysteine are generally half that of non-pregnant adult women.32 Two tests commonly done are the fasting total homocysteine and the loading test. Many times a person will have a normal fasting level, but will demonstrate abnormalities when given large amounts of methionine to process. Normal values for homocysteine vary from one laboratory to another33 but the following are approximations:
6 - 12 mmol/l female subjects
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