There are three biochemical pathways used by the body to reduce homocysteine. In one pathway TMG donates a methyl group which detoxifies homocysteine. In this reaction, TMG is reduced to DMG (dimethylglycine), that familiar-product sold as a supplement for its energizing effects. In the other routes, folic acid, B12 and B6 convert homocysteine into nontoxic substances. Some people can't utilize one or another of these pathways. That is why a combination of all these nutrients is most effective for lowering homocysteine. In some people vitamin B may not be efficiently converted to its active co-enzyme form, pyridoxyl-5-phosphate. In that case supplementing with pyridoxyl-5-phosphate would be necessary. There we go again..good health depends on nutrition and yet many medical types insist nutrition has nothing to do with overall health!

 

 Trimethylglycine

Trimethylglycine (aka TMG) is the biochemical term for betaine.  TMG is able to donate methyl groups (a methyl group is one carbon molecule and three hydrogens..very, very important to our chemistries) to biochemical events and in the case of  homocysteine this leads to the increased production of S-adenosyl-methionine (SAM or sometimes it is written SAMe) which is the bioactive form of the amino acid methionine…also a methyl donor.  SAM has been used successfully to treat problems such as cirrhosis of the liver, depression, osteoarthritis and Fibromyalgia. 

Methyl groups are thought to protect cellular DNA from mutation, a process which is also helped by good antioxidants. As people age, they often do not have enough available methyl groups to safeguard DNA. Abnormal methylation patterns are found in many people with cancer. Eating foods that contain methyl groups such as beets, green leafy vegetables and legumes is helpful, but these must be eaten in relatively large quantities several times a week. Therefore, dietary supplements such as TMG may often be necessary to provide the body with sufficient protective methyl groups.

Betaine comes from beet sugar and is extracted through a very complex process.  Don’t think the betaine HCL you see in digestive supports is the same thing..it isn’t.  It has not been shown that betaine HCL is a methyl donator..although it may be..it is very acidic and for long term use, would not be a good plan.

There are essentially two ways to lower homocysteine levels.  One, the most common, would be to add methyl groups to it to convert it to methionine or SAMe.

This is accomplished, as mentioned, through TMG (which as its name suggests, has three methyl groups on each glycine molecule – glycine is another amino acid.  They are transferred to homocysteine, but need the help of folic acid, vitamin B12, and zinc.

Another methyl donor of importance is choline and this remethylation of homocysteine does NOT need co-factors.  One hitch, though, is that this process is only active in the liver and kidneys..so to protect the whole body, in particular the brain one should be sure to take a complex with all factors present.

The second pathway to lower homocysteine involves converting it into cysteine (an very important amino acid), which then through a cascade of chemistry becomes glutathione.  This pathway is dependent on vitamin B6 and the exact amount needed to lower homocysteine from person to person can vary greatly.  It is only the amino acid methionine which can create homocysteine and the amount of that in someone’s diet, really depends on the individual’s diet.  One higher in red meat and chicken would be higher in methionine and so this person would need more B6 (and the other co-factors for that matter) to ensure the clearing of homocysteine.

Elevated homocysteine can also be caused by a genetic defect that blocks the trans-sulfuration pathway (the path which ultimately changes it to glutathione) by inducing a deficiency of the vitamin B6-dependent enzyme cystathionine-B-synthase. In this case, high doses of vitamin B6 are required to suppress excessive homocysteine accumulation. Since one would not want to take excessive doses of vitamin B6 (greater than 300 to 500 mg a day for a long time period), a homocysteine blood test can help determine whether you are taking enough vitamin B6 to keep homocysteine levels in a safe range. There are some people who lack an enzyme to convert vitamin B6 into its biologically active form, pyridoxal-5-phosphate. In this case, if low-cost vitamin B6 supplements do not sufficiently lower homocysteine levels, then a high-cost pyridoxal-5-phosphate supplement may be required. I generally suggest to my patients to take the bio-active form without thinking about the cheaper brands. 

For many people, the daily intake of 500 mg of TMG, 800 mcg of folic acid, 1000 mcg of vitamin B12, 250 mg of choline, 250 mg of inositol, 30 mg of zinc, and 100 mg of vitamin B6 will keep homocysteine levels in a safe range. But the only way to really know is to have your blood tested to make sure your homocysteine levels are under 7. If homocysteine levels are too high, then up to 6 grams of TMG may be needed along with higher amounts of other remethylation cofactors. Some people with cystathione-B synthase deficiencies will require 500 mg a day or more of vitamin B6 to reduce homocysteine to a safe level. For the prevention of cardiovascular disease, you would want your homocysteine blood level to be under 7. For the prevention of aging, some people have suggested that an even lower level is desirable, but more research needs to be done before any scientific conclusions can be reached.

A Life Extension article (July, 1997), sites these cases of people with problems in these pathways. “People with these disorders frequently die of cardiovascular disease before reaching adulthood. In one case history report, a 16-year-old Japanese girl was unable to walk with or without support, and had severe peripheral neuropathy, muscle weakness and convulsions. Her vascular system was on the verge of collapse. B6 or B12 didn't help. Folic acid lowered homocysteine, but didn't improve her symptoms. Two months after adding TMG to the regimen, her homocysteine level dropped and she was able to walk with support. Seventeen months later, she was free from convulsions and able to walk normally again.

This case history demonstrates the seesaw relationship between homocysteine and SAM. The girls SAM levels went from undetectable to near normal after the first two months of treatment while her homocysteine levels fell dramatically. If these nutrients can overcome a genetic disorder, consider how powerful they can be in reducing the risks associated with elevated homocysteine in the general population. Some people who have been taking this homocysteine lowering nutrient combination for more than a decade reported many benefits including fewer colds, more energy, increased endurance and lower blood sugar levels.”

Homocysteine is Not a New Story

Also from the Life Extension article – “The homocysteine theory of cardiovascular risk was first tested and published by Dr. Kilmer McCully in 1969, but, with everyone focusing on cholesterol at that time, his findings were ignored. Finally, almost 30 years later, the word is out on homocysteine. In addition to NBC Nightly News with Tom Brokaw, articles have been published in Newsweek, The Wall Street Journal, The Los Angeles Times, Prevention magazine and more.”

Homocysteine levels rise as people age. Therefore, any anti-aging program must take homocysteine level control into consideration. Lowering homocysteine has benefits beyond heart protection. When the blood supply to the heart is blocked, a heart attack results. When blood to the brain is blocked, a stroke results. If the penile artery is occluded, impotence results. Blockages in the extremeties results in intermittent claudication or pain in the affected extremity. 

Homocysteines relationship to heart disease may explain some things that cholesterol never could. These B vitamins and homocysteine are so interrelated that homocysteine levels could be used to assess vitamin status. This could explain the increase in heart disease which has occurred in women over the past two decades which coincides with the use of birth control pills. Birth control pills deplete vitamin B6 and raise homocysteine levels. Smoking, a known risk factor for heart disease, also depletes vitamin B6 and smokers generally have low levels of folio acid and vitamin B12...all needed for homocysteine metabolism. Its not surprising that the statistics linking smoking to heart disease are similar to those linking high homocysteine levels to heart disease.(l)

The homocysteine story may explain some of the increases in heart disease that the cholesterol scare never could.  We also know now that things like taking birth control bills and smoking deprive the body of vitamin B6 (and also B12 and folic acid in smoking).  These both add to the risk of heart attack and it may be because of the effect on the homocysteine nutrients that they pose risk.

In general I recommend about 500 mg of TMG per day, 800 mcg of folic acid, (preferrably in the active MTHF form) 500 mcg of B12, 25 mg of B6 and 5 mg of zinc.  This should of course be taken in divided doses over the day.  Clinically, I use Vessel Care from Metagenics. 

Methylation/Homocysteine and Other Disease

I cannot speak enough of the importance of the process of methylation to our health and functions. For one, it is essential to DNA repair, which if not repaired will result in breaks and mutation.  This in turn leads to accelerated aging because of larger amounts of “half-baked” or even dangerous proteins being produced. In fact, in a journal  Medical Hypothesis (1998, 51[3]:179-221), it was suggested that aging, period, could be a result of cellular demethylation, or in other words, a slowing of “re-methylation” needed to maintain and repair DNA.   Methylation is a key process in the liver with respect to its ability to detoxify our bodies.  It is needed for the growth of new cells, nerve sheath production (myelination) and a whole host of other critical processes.  

 Homocysteine is a “biggy” for interfering with the whole methylation pathway. High homocysteine speaks to us of poor methylation in a patient.  Homocysteine may also be causing damage through oxidative stress (free radical formation).  This is the reason I use a good antioxidant with most protocols such as Metagenic’s Oxygenics or Naturpharm’s Super A/O. 

PART TWO – BOTANICAL AND OTHER SUPPLEMENT SUPPORT

Guggul:

Guggul is the name given to the yellowish resin produced by the stem of the mukul myrrh (Commiphora mukul) tree found throughout India.  It has been used in Ayurvedic medicine for centuries in the treatment of arthritis, obesity, and one of its prime uses was for “medoroga”.  Medoroga is basically an ancient diagnosis for what we know as atherosclerosis.  It was effective for this problem because of its ability to lower serum cholesterol and triglycerides.

Guggul extract isolates contain safe plant steroid compounds known as guggulsterones, which have been shown to lower lipid levels in your blood.  They actually lower serum triglycerides and cholesterol, as well as LDL VLDL cholesterols (the “bad” ones) and as a bonus..raises HDL cholesterol (the “good” guys).  Guggulsterones also act as antioxidants in that they keep LDL cholesterol from oxidizing, protecting you further from atherosclerosis.  Guggul has also decreased the “stickiness” of platelets, which of course also lowers the risk of coronary artery disease and stroke.  There was a study which actually found guggul extract similar and even slightly better than clobfibrate for lowering cholesterol levels.

I recommend 75 mg. of guggulsterones, twice per day.  Most formulations contain 250-375 mg. of guggul at a 10% content of guggulsterones which is inadequate. That is why I choose Lipotain from Metagenics for its superior amount and quality.   I would keep this up for 2-3 months and then have cholesterol checked.  When it comes down, reduce the guggul to once per day.

There are no real side effects associated with guggul.  In earlier times, when the crude oleoresin was used, side effects such as diarrhea, anorexia, abdominal pain and skin rash were reported.  The modern extracts are much more purified and this is no longer the case.  Clinically I use Lipotain from Metagenics which also contains niacin in the safer Inositol Hexanicotinate form.

Niacin:

For some time, some practitioners have been using high amounts of niacin (Vitamin B3) (also called nicotinic acid) to lower cholesterol.  The problem with this is that at the doses needed, about 3 grams per day, divided dosing, patients experience side effects of flushing, headache, stomach pains and even chronic liver damage, diabetic responses, gastritis or stomach inflammation, eye damage and even gout.  The other common form of B3 – niacinamide (also called nicotinamide) – does NOT help cholesterol levels.

An acceptable variation on niacin called inositol hexaniacinate has more recently been prescribed by European doctors for cholesterol treatment without the unwanted effects of niacin.  It is used at the 500 to 1,000 mg. taken three times per day.  It is newer and fewer studies have been done, so if one takes it, make sure you have your cholesterol monitored to evaluate its effectiveness and have liver enzymes, uric acid and glucose levels checked just to be sure you are not one of the people prone to problems with B3 therapy. This is the form of B3 found in Lipotain from Metagenics.

 

Beta-Sitosterol:

Guggul is a phytosterol or plant steroid.  Not, like the harmful steroids of pharmaceutical fame, though.  Another, Beta-sitosterol alone and with other plant sterols, lowers blood levels of cholesterol.  This probably happens becaust beta-sitosterol blocks the absorption of cholesterol.  Beta-sitosterol (and others such as campesterol, stigmasterol, etc.) are found in high levels in rice bran, wheat germ corn oils and soybeans.

My recommedation is to take 200 – 250 mg. three times per day, preferably before meals to block the cholesterol. My recommendation of choice is Meta-Sitosterol by Metagenics.

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MORE HEALTHY LIFESTYLE FEATURES:

Supplementing with E-Complex 1:1 Vitamin E (800 IU per day), Ultra Potent Vitamin C (3 grams per day), and Super Garlic 6000 garlic supplements (600 – 900 mg per day) all have shown to be very helpful in lowering cholesterol and triglycerides levels.

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Adverse Side Effects From Long Term Use of Statin Drugs..Statin Side Effects Studies

WHAT DO STATINS DO?

Statins (formally called HMG-CoA reductase inhibitors..because of this enzyme which they inhibit from being produced) work by cutting off a pathway in your body which ultimately results in the production of cholesterol. But..as with most chemicals, it knows no boundaries...and with the blocking of this enzyme..there are a cascade of problems in that a whole family of intermediary substances ..many if not all have very important jobs to do in your body...are also blocked.

There have been cases of people born with an inherent defect to make melvonate (this is the first step to our body's making cholesterol). These children are mentally handicapped, anemic, have frequent fevers, etc. This would represent the extreme in low cholesterol levels...you do not want to be there.

 

Very recent research suggests that statins...in the short term..may help decrease actual heart diesease..but this probably because it acts as an antioxidant..NOT because it blocks cholesterol production.

From Dr. Mary Enig and Sally Fallon in their Statin report...Dr. Enig has summarized some of the more popular and "telling" studies:

Honolulu Heart Program (2001)	This report, part of an ongoing study, looked at cholesterol lowering in the elderly. Researchers compared changes in cholesterol concentrations over 20 years with all-cause mortality.(1) To quote: “Our data accords with previous findings of increased mortality in elderly people with low serum cholesterol, and show that long-term persistence of low cholesterol concentration actually increases risk of death. Thus, the earlier that patients start to have lower cholesterol concentrations, the greater the risk of death. . . The most striking findings were related to changes in cholesterol between examination three (1971-74) and examination four (1991-93). There are few studies that have cholesterol concentrations from the same patients at both middle age and old age. Although our results lend support to previous findings that low serum cholesterol imparts a poor outlook when compared with higher concentrations of cholesterol in elderly people, our data also suggest that those individuals with a low serum cholesterol maintained over a 20-year period will have the worst outlook for all-cause mortality [emphasis ours].”
ALLHAT (2002)	ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), the largest North American cholesterol-lowering trial ever and the largest trial in the world using Lipitor, showed mortality of the treatment group and controls after 3 or 6 years was identical.(2) Researchers used data from more than 10,000 participants and followed them over a period of four years, comparing the use of a statin drug to “usual care,” namely maintaining proper body weight, no smoking, regular exercise, etc., in treating subjects with moderately high levels of LDL cholesterol. Of the 5170 subjects in the group that received statin drugs, 28 percent lowered their LDL cholesterol significantly. And of the 5185 usual-care subjects, about 11 percent had a similar drop in LDL. But both groups showed the same rates of death, heart attack and heart disease.
Heart Protection Study (2002)	Carried out at Oxford University,(3) this study received widespread press coverage; researchers claimed “massive benefits” from cholesterol-lowering,(4) leading one commentator to predict that statin drugs were “the new aspirin.”(5) But as Dr. Ravnskov points out,(6) the benefits were far from massive. Those who took simvastatin had an 87.1 percent survival rate after five years compared to an 85.4 percent survival rate for the controls and these results were independent of the amount of cholesterol lowering. The authors of the Heart Protection Study never published cumulative mortality data, even though they received many requests to do so and even though they received funding and carried out a study to look at cumulative data. According to the authors, providing year-by-year mortality data would be an “inappropriate” way of publishing their study results.
PROSPER (2001)	PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) studied the effect of pravastatin compared to placebo in two older populations of patients of which 56 percent were primary prevention cases (no past or symptomatic cardiovascular disease) and 44 percent were secondary prevention cases (past or symptomatic cardiovascular disease).(7) Pravastatin did not reduce total myocardial infarction or total stroke in the primary prevention population but did so in the secondary. However, measures of overall health impact in the combined populations, total mortality and total serious adverse events were unchanged by pravastatin as compared to the placebo and those in the treatment group had increased cancer. In other words: not one life saved.
Statins and Plaque (2003)	A study published in the American Journal of Cardiology casts serious doubts on the commonly held belief that lowering your LDL-cholesterol, the so-called bad cholesterol, is the most effective way to reduced arterial plaque.(8) Researchers at Beth Israel Medical Center in New York City examined the coronary plaque buildup in 182 subjects who took statin drugs to lower cholesterol levels. One group of subjects used the drug aggressively (more than 80 mg per day) while the balance of the subjects took less than 80 mg per day. Using electron beam tomography, the researchers measured plaque in all of the subjects before and after a study period of more than one year. The subjects were generally successful in lowering their cholesterol, but in the end there was no statistical difference in the two groups in the progression of arterial calcified plaque. On average, subjects in both groups showed a 9.2 percent increase in plaque buildup.
ASCOT-LLA (2003)	ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm) was designed to assess the benefits of atorvastatin (Lipitor) versus a placebo in patients who had high blood pressure with average or lower-than-average cholesterol concentrations and at least three other cardiovascular risk factors.(9) The trial was originally planned for five years but was stopped after a median follow-up of 3.3 years because of a significant reduction in cardiac events. Lipitor did reduce total myocardial infarction and total stroke; however, total mortality was not significantly reduced. In fact, women were worse off with treatment. The trial report stated that total serious adverse events “did not differ between patients assigned atorvastatin or placebo,” but did not supply the actual numbers of serious events.
Statins and Women (2003)	No study has shown a significant reduction in mortality in women treated with statins. The University of British Columbia Therapeutics Initiative came to the same conclusion, with the finding that statins offer no benefit to women for prevention of heart disease.(10) Yet in February of 2004, Circulation published an article in which more than 20 organizations endorsed cardiovascular disease prevention guidelines for women with several mentions of “preferably a statin.”(11)

References:

(1) Schatz IJ and others. Lancet 2001 Aug 4;358:351-355

(2) The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007

(3) Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.

(4). Medical Research Council/British Heart Foundation Heart Protection Study.Press release. Life-saver: World’s largest cholesterol-lowering trial reveals massive benefits for high-risk patients. Available at www.ctsu.ox.ac.uk/~hps/pr.shtml.

(5). Kmietowicz A. BMJ 2001;323:1145

(6). Ravnskov U. BMJ 2002;324:789

(7) Shepherd J and others. Lancet 2002;360:1623-1630.

(8) Hecht HS and others. Am J Cardiol 2003;92:334-336

(9) Sever PS and others. Lancet 2003;361:1149-1158.

(10) Jenkins AJ. BMJ 2003 Oct 18;327(7420):933.

(11) Circulation, 2004 Feb 17;109(6):714-21.

Here are some books I HIGHLY recommend. Today..the public needs to educate itself about the adverse side effects from long term use of statin drugs.

 

 

If you have any questions, do not hesitate to write me Dr. Deb's E-Mail and I will be glad to help you!