The information contained in this article is very important, but also quite involved. The most important points are these: Women should supplement folic acid before, during and after pregnancy and for the rest of their lives. Women with a history of recurrent early miscarriage, preeclampsia, placental infarct, abruption, or who have offspring with neural tube defects should supplement folic acid, B12, B6, and possibly choline and selenium. DO NOT have a mother restrict protein, unless you know she has a CBS deficiency.

 

Homocysteine is an amino acid. Hyperhomocysteinemia 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. Methylation is the process whereby one methyl group - or one carbon and three hydrogens (CH3) - is donated from one molecule to another. RNA, DNA, phospholipids, proteins, myelin, and epinepherine are some of the molecules that need to receive a methyl group. Refer to the diagram to help you visualize the cycle.

Simplified Diagram of the Methionine Cycle

The main thing to notice about the methionine cycle is that methionine gets converted to homocysteine 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 the methyl group to homocysteine, so it can turn back into methionine. The hardest thing about the different types of folic acid is that they all have very long names.

Diagram of the Folic Acid Cycle

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 is methylated to become 5,10-methylene THF. After this step an enzyme MTHFR is needed to convert 5, 10-methylene THF to 5-methyl THF.11 This is the form that can be used to donate a methyl group to homocysteine so it can be converted back to methionine.

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 that homocysteine can be broken down besides being changed back into methionine. (Refer to the next diagram.) With adequate vitamin B6, it can be converted to cysteine. 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 CBS is also needed for this metabolic pathway.11

Diagram of Homocystein Metabolism

 

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 of homocysteine were first identified in the urine of some retarded children in the 1960's. These children had an inborn error of amino acid metabolism that caused a deficiency of the enzyme CBS. People with the condition, known as homocysteinuria, have two defective copies of the gene that codes for the enzyme CBS. This causes an overabundance of both homocysteine and methionine, 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 the MTHFR enzyme. 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 methionine. Just the opposite will occur because there is less of the right type of folic acid to convert homocysteine 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 polymorphism. This means that in the DNA for the MTHFR enzyme there is a thymine [T] nucleotide 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 the homozygous individuals, the MTHFR enzymes function only about 35% as actively as in heterozygous people or in people with two 677C genes.11 This defect causes moderate increases in homocysteine in the blood. It does not show up in the urine. People with this defect do not need to shun methionine. In fact they might not have enough to support all the needed methylation reactions in the body.

 

The 1298A?C Polymorphism

A second gene variation in coding for the same MTHFR enzyme is the 1298A?C genotype. It does not seem to have as much of an impact as the 677C?T polymorphism. Some studies show that persons with one 677T gene and one 1298C gene also have reduced activity of their MTHFR enzymes and elevated homocysteine. Other studies do not corroborate this.14

 

Problems with B12 Transport

Remember that vitamin B12 is also needed to convert homocysteine back to methionine. There is a genetic variation in a gene for transcobalamin (TC). TC is a molecule that is important for transporting vitamin B12 to peripheral tissues. The polymorphism 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 hyperhomocysteinemia.14

 

Vitamin Deficiencies

Lack of folic acid, vitamin B12, or B6 in the diet can also cause a rise in homocysteine.15 Folic acid is one of the more difficult vitamins to obtain sufficiently from diet. The lack of intrinsic factor 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.

 

Drug Interactions

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 acid methionine can 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 the homocysteine itself. 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 neural tube defects. 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 homozygous for the 677T gene than parents in a control group.13 Another study showed that 28 children with spina bifida had significantly higher homocysteine 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

 

Miscarriage

Recurrent early pregnancy loss has also been associated with hyperhomocysteinemia. Women with classic homocysteinuria 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 methionine (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?T polymorphism than the general population.13

 

Preeclampsia

There is a hyperhomocysteinemia link 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 homocysteine 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. Hyperhomocysteinemia 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 neural tube defects, 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 atherosclerosis. Some mice were fed a diet high in methionine 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 homocysteine 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 and hyperhomocysteinemia were 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 methionine.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

Betaine has also been used as a supplement for people with classic homocysteinuria who still have high homocysteine even after supplementation with B6. Individuals with this defect are deficient in CBS, 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 with hyperhomocysteinemia in pregnancy.

 

Homocystein Testing

It is not yet routine to test pregnant women for homocysteine. 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 methionine 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
8 - 14 mmol/l male subjects
16-30 mmol/l moderately increased
31-100 mmol/l significantly increased
> 100 mmol/l severely increased34.



Notes:

1. Clark R, et.al., (1991) Hyperhomo-cysteinemia: and independent risk factor for vascular disease. New England Journal of Medicine Sep 26;325(13):966-7.

2. High Homocystein Levels Increases Heart Attack Risk In Young Women. http://www.pslgroup.com/dg/2EF5E.htm

3. Steegers-Theunissen RP, et.al., (1994) Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism. Dec;43(12):1475-80.

4. Anderson, Kenneth N. Mosby’s Medical, Nursing & Allied Health Dictionary, 4th ed. (St. Louis: Mosby, 1994) "homocysteinuria" p. 747.

5. Hoogeveen EK, et.al., (2000) Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study. Circulation. Apr 4;101(13):1506-11.

6. Alan L. Miller and Gregory S. Kelly, N.D. Methionine and Homocysteine Metabolism and the Nutritional Prevention of Certain Birth Defects and Complications of Pregnancy http://www.thorne.com/altmedrev/fulltext/meth1-4.html

7.Wouters MG, et.al., (1993) Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertility & Sterility, Nov;60(5):820-5.

8. Toos A.W. Goddijn-Wessel, et. al., (1996) Hyperhomocysteinemia: a risk factor for placental abruption or infarction European Journal of Obstetrics & Gynecology and Reproductive Biology, Vol 66, Issue 1, May, Pages 23-29.

9. http://www.tidsskriftet.no/pls/lts /pa_lt.visSummary?vp_seks_id=34089

10. www.homocysteine.net/pages/homocysteine/1/abouthcy.html

11. Manuela Fodinger, Walter Horl, and Gere Sunder-Plassmann, (1999) Molecular biology of 5,10-methylenetetrahydofolate reductase Journal of Nephrology JN; Vol 13:00-00

12. www.intervencionismosidi.com/revistas/may03/may03_1.4.html.

13. R. Obwegeser, M. Hohlag-schwandtner, and H. Sinzinger (1999) Homocysteine - a pathophysiological cornerstone in obstetrical and gynaecological disorders? Human Reproduction Update Vol 5, No.1 pp.64-72.

14. Henrik Zetterberg (2004) Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical applications, Reproductive Biology and Endocrinology, 2:7.

15. http://lpi.oregonstate.edu/infocenter/vitamins/fa/printfa.html. Linus Pauling Institute’s Micronutrient Information Center, Folic Acid. Last updated 04/08/2002.

16. Li X, Ran J, and Rao H, (1995) Megaloblastic changes in cervical epithelium associated with oral contraceptives and changes after treatment with folic acid.

17. Thompson SJ, et. al., (2003) Periconcetional multivitamin folic acid use, dietary folate, total folate and risk of neural tube defects in South Carolina. Annals of Epidemiology Jul;13(6):412-8.

18. Rachel Z Stolzenberg-Solomon et.al., (1999) Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population The American Journal of Clinical Nutrition, Vol. 69, No.3, 467-475, March.

19. P. O’Callaghan, et. al., (2002) Smoking and Plasma Homocysteine, European Heart Journal Oct;23(20):1580-6.

20. Ahmet Var, et.al., (2003) Endothelial Dysfunction in Preeclampsia: Increased Homocysteine and Decreased Nitric Oxide Levels Gynecologic and Obstetric Investigation 56:221-224.

21. Botto LD, et.al., (1996) Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics Nov;98(5):911-7.

22. Shaw GM, et.al., (1995) Maternal periconceptional use of multivitamins and reduced risk for conotruncal heat defects and limb deficiencies among offspring. American Journal of Medical Genetics Dec 4;59(4):536-45.

23. Werler MM, Shapiro S, Mitchell AA, (1993) Periconceptional folic acid exposure and risk of occurrent neural tube defects. Journal of the American Medical Association Mar 10;269(10):1257-61.

24. Adolfo Correa, et.al., (2003) Do Multivitamin Supplements Attenuate the Risk for Diabetes-Associated Birth Defects? Pediatrics Vol. 111 No. 5 May pp. 1146-1151.

25. Botto LD, et. al., (2002) Maternal fever, multivitamin use, and selected birth defects: evidence of interaction? Epidemiology Jul;13(4):485-8.

26. Mill JL, et.al., (1989) The absence of a relationship between periconceptional use of vitamins and neural-tube defects. New England Journal of Medicine Aug 17;321(7):430-5.

27. Marion A. Hofmann, et.al., (2001) Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model, Journal of Clinical Investigation 2001 March 15; 107 (6);675-683.

28. González-Ordó ez AJ, et.al., Lowering high levels of fasting total homocysteine with folic acid and vitamins B in thromboembolic patients: relationship between response and the C677T methylenetetrahydofolate reductase (MTHFR) genotype. http://www.hsa.es/org/dmedica/centrales/hematologia/docs/mthfr_eng.html

29. Wilcken DE, et.al., (1983) Homocysteinuria-the effects of betaine in treatment of patients not responsive to pyridoxine. New England Journal of Medicine Aug 25;309(8):448-53.

30. Miguel Á. Medina, José L. Urdiales and María I. Amores-Sánchez, (2001) Roles of homocysteine in cell metabolism. European Journal of Biochemistry 268, 3871-3882.

31. Sonia González et.al., (2004) Serum Selenium Is Associated with Plasma Homocysteine Concentrations in Elderly Humans, Journal of Nutrition 134:1736-1740, July.

32. Kang SS, et.al., (1986) Total homcyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism Oct;35(10):889-91.

33. Christine M. Pfeiffer, et.al., (2000) Analysis of Factors Influencing the Comparison of Homocysteine Values between the Third Health and Nutrition Examination Survey (NHANES) and NHANES 1999+. Journal of Nutrition 130:2850-2854.

34. Damien Gruson Cardiovascular diseases and homocysteine, a short summary of a long story. http://www.ifcc.org/ejifcc/vol14no3/140310200303n.htm