WDDTY Issue 236 Jun./Jul. 2025

Case No. 19471,

Published in the New England Journal of Medicine,

describes an eight-year-old Irish American boy admitted

to Massachusetts General Hospital in 1933.

He had begun vomiting four days earlier, but clearly, he had been ill for some time.

There was so little tissue beneath his sallow skin that he appeared emaciated. The lenses of both of his eyes, which seemed extraordinarily bright blue against his yellow complexion, had detached. His mother thought his poor vision accounted for his slow learning—he had attended kindergarten, but his school had refused him entry to upper grades.

His tongue protruded to the left, and tests suggested he may have suffered a stroke. His breathing was shallow and irregular, his blood pressure sky-high at 150/92. Four days later, he died of a stroke.

Looking at images from the autopsy report, doctors reviewing the puzzling case wondered how a boy of eight could have the completely clogged carotid artery of an elderly man.1

More than 30 years later, in 1965, a nine-year-old Irish American girl was seen at Massachusetts General Hospital for slow mental development. Her eye lens was detached, and she had other symptoms of homocystinuria, a rare genetic disease that had recently been discovered in Belfast, Northern Ireland. It was characterized by high levels of the amino acid homocysteine in the urine and blood plasma. Laboratory tests confirmed soaring levels of homocysteine in her blood. Taking her family history, the doctors learned that her uncle had died in his childhood of a similar condition. He was, in fact, the eight-year-old who had mysteriously died of a stroke three decades earlier.

Rare cases lead to a new theory

About this time, Dr Kilmer McCully, a young pathology instructor at Harvard, became intrigued by these rare homocystinuria autopsy reports, including that of a two-month-old baby boy who had died of heart failure. The child’s arteries looked exactly like what would be found in very elderly patient with advanced vascular disease.

Drawing on other research in animals showing that homocysteine is a toxic intermediary in metabolism, McCully developed a theory for the pathology of arteriosclerosis: What if homocysteine is the primary driver of arterial damage, and what if that damage, which is so obvious and devastating in these rare young cases, is also occurring more subtly in the population at large, among people with high homocysteine levels in their blood?

McCully didn’t dismiss the importance of cholesterol in vascular disease, but he suspected homocysteine was the underlying cause of arteriosclerosis, triggering cholesterol’s oxidation, buildup and artery-ravaging inflammatory effects. In other words, homocysteine metabolism and biochemistry determine the more downstream effects of cholesterol.

What causes high homocysteine The following are common factors causing homocysteine
	B vitamin deficiencies High homocysteine almost always occurs in tandem with low levels of vitamins B2, B6, B9 and B12.^1 Magnesium deficiency Without magnesium, it’s harder for the body to convert homocysteine into glutathione or SAMe. Zinc deficiency Like magnesium, zinc is needed to convert homocysteine to other molecules. Trimethylglycine (betaine) deficiency This molecule is also used to remethylate homocysteine, converting it to SAMe. Vegetarian/vegan diet A plant-only diet risks methionine and vitamin B12 deficiency. Carnivore diet A strict carnivore diet may lead to high methionine intake and low vitamin B9. Low stomach acid or impaired digestion If you are unable to digest your food well to extract nutrients like methionine, or if you can’t absorb B vitamins, your intake may not be absorbed, and the effect is like deficiency. High alcohol consumption Excessive alcohol use may block absorption and can lead to deficiencies in vitamins B1 (thiamine), B6, B9 and B12 as well as zinc. In alcoholics, higher homocysteine is related to alcohol cravings, withdrawal seizures and increased dependency in a deadly feedback loop that spikes other health risks as well.^2 REFERENCES 1 Clin Chem, 2003; 49(2): 295–302; JAMA, 1993; 270(22): 2693–8; Am J Epidemiol, 1996; 143(9): 845–59 2 Clin Nutr, 2018; 37(3): 1061–1065; Biomedicines, 2020; 9(1): 7 3 Clin Chem Lab Med, 2011; 49(3): 479–83		Obesity People who are obese have significantly higher homocysteine levels^2 High coffee consumption Drinking more than 3 cups of coffee a day raises homocysteine, an effect that appears only partially related to its caffeine content.^5 Kidney impairment High homocysteine impairs kidney function, accelerates kidney disease and raises the risk of heart attack and stroke in people who have kidney disease.^6 MTHFR genetic variation MTHFR is the gene that codes for methylenetetrahydrofolate reductase (MTHFR), an enzyme important for metabolizing folate. In Europe and North America, 10–15 percent of the population has a variant that significantly interferes with methylation of B vitamins, and about 40 percent carry a variant but aren’t greatly affected by it. Some prescription drugs Methotrexate, corticosteroids, arthritis drugs, metformin, L-dopa (for Parkinson’s), fibric acid derivatives and cholestyramine (for high cholesterol and cardiovascular disease), theophylline (for asthma and other lung diseases) and phenytoin (for seizures) may raise homocysteine sharply.^7 Nitrous oxide (laughing gas) Used to calm anxious patients, nitrous oxide can “irreversibly oxidize” vitamin B12 and lead to serious problems, especially for those with MTHFR mutations, as in the case of a child who died after receiving nitrous oxide during dental treatment.^8 4 J Evid Based Med, 2021; 14(3): 208–217 5 Curr Pharm Des, 2023; 29(1): 30–36; Am J Clin Nutr, 2002; 76(6): 1244–8 6 Leenus Tafline AE, “Homocysteine and Renal Disease,” May 20, 2024, icliniq.com 7 Drugs, 2002; 62(4); 605-616 8 NEngl J Med, 2003; 349: 45–50

With the importance of B vitamins in homocysteine’s metabolism and its breakdown into harmless building blocks recently elucidated, McCully proposed that deficiencies of vitamins B6 (pyridoxine), B9 (folate) and B12 (cobalamin) allow homocysteine, normally benign, to rise to toxic levels.

At every turn, his research seemed to confirm his theory: When he injected rabbits with homocysteine, they developed arteriosclerotic plaques in their coronary arteries within weeks. The plaques were larger if the animals were also fed a diet deficient in vitamin B6.

But when he gave them these vitamins, the animals’ homocysteine levels plummeted, sometimes within hours. Other researchers reported similar findings in baboons. Then, in 1976, Australian researchers published the discovery that coronary heart disease was linked to elevated blood homocysteine in humans, too.²

McCully’s theory was unwelcome at Harvard and in mainstream medicine, however, which had latched onto the cholesterol-heart hypothesis.

The homocysteine theory also threatened a burgeoning industry around cholesterol-lowering drugs—within a decade, these drugs launched as the biggest blockbusters of all time and today still generate more than $30 billion a year.3 But there was no commercial interest in cheap, readily available and unpatentable B vitamin therapy for potential heart attack and stroke victims.

Under a new chief at Harvard in the 1970s, McCully’s theory was ridiculed, his funding dried up and he was moved to the basement. Eventually he lost his tenure and was told not to return.

At a new position at the Veterans Affairs Medical Center in Rhode Island, he quietly continued his research while other labs around the world continued looking at homocysteine, confirming its critical role in cardiovascular disease.⁴

Vindicated at last

Eventually, almost two decades after McCully’s dismissal, homocysteine made its way back to Harvard. Nearly 15,000 male physicians aged 40–84 years, with no prior heart attack or stroke, gave plasma samples and were followed up for five years.

The Physicians Health Study found that homocysteine was strongly correlated with heart disease. Participants who had levels in the top 5 percent of the normal range were three times more likely to have a heart attack.⁵

It was a turning point for homocysteine research. And the story got bigger, too. In a cohort study in Norway, about 5,000 men and women aged 65–67 was recruited as part of a national cardiovascular screening program that followed them for four years. Those with higher homocysteine didn’t just die of cardiovascular disease more often, they died of all causes more often.

A five-point rise in homocysteine level translated into a 49 percent increase in all-cause mortality, a 50 percent increase in cardiovascular mortality, a 26 percent increase in cancer mortality and a 104 percent increase in death by other causes.

“These results should encourage studies of [homocysteine] in a wider perspective than one confined to cardiovascular disease,” the researchers of the Hordaland Homocysteine Study concluded.⁶

As links to killer cancer and Alzheimer’s were uncovered, homocysteine research exploded. Meanwhile, a few randomized trials, such as the HOPE and NORVIT trials, tested whether lowering homocysteine with supplementary B vitamins would reduce the risk of vascular disease after an event, and the results were disappointing.⁷

It virtually became mainstream medical dogma that B vitamins “don’t work” for vascular disease—or anything else, for that matter. Many researchers noted that studies of previous heart attack and stroke sufferers were biased, however, and that research should be done on those who hadn’t had a vascular event.

The dissenters said the trials were too short and questioned the doses. They also noted that the folic acid supplementation mandated in some countries in the late 1990s obscured the vitamins’ benefits in the trials.

One critique, titled “Homocysteine: Call Off the Funeral,” said the HOPE trial had found supplementation did not prevent heart attacks but buried any mention of its own data showing it did prevent strokes. There were just too many unanswered questions about homocysteine to call it a dead end, its authors reasoned.⁸

Fast-forward another two decades, and many of those questions are still unanswered. During this time, the cholesterol theory has gone virtually unchallenged by mainstream medicine, and the lipid-lowering drug

bonanza has continued.

Many researchers, however, say that if homocysteine is central to even just 10–15 percent of vascular incidents, that’s too many to ignore when there are 4,400 heart attacks and strokes daily in the US alone. Add that to other diseases, and at higher levels perhaps, and the homocysteine carnage looks enormous.

100 diseases

“We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine,” say Dr David Smith and Dr Helga Refsum. Smith is emeritus professor of pharmacology at the University of Oxford, and Refsum is a professor of nutrition at the University of Oslo in Norway and a lead author of the Hordaland Homocysteine Study.

“The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age-related conditions are also associated. Few other disease biomarkers have so many associations.”

The list of diseases and conditions that high homocysteine has been linked to reads like a pathology text: alcohol abuse, Alzheimer’s, anxiety, autism, cardiovascular disease, cancer, cognitive impairment, congenital defects, depression, diabetes, gum disease, low birth weight, Parkinson’s disease, polycystic ovarian syndrome, schizophrenia and more.⁹

Two key pathways

Homocysteine sits at the center of two key biochemical pathways in the body: oxidation-reduction (redox) and methylation. The body constantly produces free radicals as byproducts of normal reactions, and it makes even more when we exercise too much, eat bad oils or burned food, get a sunburn, breathe dirty air or live with an inflammatory disease.

This oxidation process, which is at the heart of aging, is countered by antioxidants. The body’s master anti-aging antioxidant, glutathione, is low when homocysteine is high—something is choking the system that converts homocysteine into glutathione, which is needed for detoxification and oxidation, so homocysteine builds up. Like high homocysteine, low glutathione is linked to death from all causes.

Methylation is another key chemical process that happens billions of times a minute as our body does things like break down nutrients into usable molecules, convert neurotransmitters or hormones, or detox poisons from food or the environment. The donation of a methyl molecule (made of one carbon and three hydrogen atoms), called methylation, happens in all these processes. Methylation is used to repair broken DNA and switch genes on and off, including those in many cancers.

“Homocysteine rises if you’re not doing methylation properly,” says Patrick Holford, author of The Homocysteine Solution with Dr James Braly (Piatkis Books, 2012).

Methionine, which we consume in protein-rich foods like meat and fish, is methylated to become homocysteine. That in turn is either converted into glutathione or remethylated and turned into the body’s most important methyl donor molecule, S-adenosyl-methionine (SAMe) which fuels myriad other major methylation reactions.

This biochemistry all depends on levels of B vitamins as well as nutrients like zinc and magnesium that catalyze the conversions. If those nutrients are in scant supply, homocysteine builds up and begins its wrecking cascade, increasing free radicals, stiffening blood vessels, triggering inflammatory pathways10 and mitochondrial dysfunction,11 and damaging proteins,12 the blood-brain barrier13 and DNA.¹⁴