Every week I meet a patient who has already done everything “right.” They’ve had the annual physical, the lipid panel, and the metabolic panel. They’re still sick: tired, foggy, inflamed, and sometimes carrying a fatty liver that nobody can explain. And nobody has checked their homocysteine or asked whether their methylation genetics might be part of the story.
I’ve come to believe that this gap is one of the more fixable blind spots in everyday medicine. Methylation testing has become critical in my practice because it is how I identify homocysteine and phosphatidylethanolamine N-methyltransferase (PEMT) genetic problems. In my experience, finding and treating these problems can change the lives of many patients who are suffering. My argument to fellow clinicians is simple: We should be ordering these tests more often, and acting on what they show.
Homocysteine: a modest predictor we have learned to ignore
Most of us were taught that homocysteine was a promising cardiovascular marker that fizzled. That isn’t quite the whole story. The Homocysteine Studies Collaboration meta-analysis found that, in prospective studies, a 25 percent lower homocysteine level was associated with an 11 percent lower risk of ischemic heart disease and a 19 percent lower risk of stroke. The authors called homocysteine “at most a modest independent predictor” in healthy populations, and that caution is fair.
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But “modest” in a population is not “irrelevant” in an individual. I’ve now treated more than 10,000 patients for homocysteine problems and reviewed more than 40,000 intracellular nutrient tests. I also spent 10 years in cardiology research with a U.S. assistant surgeon general. In that time, I’ve seen how often an elevated homocysteine travels with a cluster of other problems: inflammation, fatigue, poor detoxification, and a family history of early heart attacks or strokes. Those are things we can measure, track, and address.
PEMT: the liver gene almost no one checks
If homocysteine is underused, PEMT is close to invisible. PEMT helps the liver make phosphatidylcholine, which the liver needs to package and export fat. In 2005, a study in the FASEB Journal reported that a loss-of-function PEMT variant (V175M) was significantly more common in patients with non-alcoholic fatty liver disease (NAFLD) than in controls. A 2015 meta-analysis found the rs7946 variant associated with higher NAFLD risk overall, with the effect strongest in East Asian populations. Not every study agrees; the Dallas Heart Study found no association with hepatic triglyceride content. The evidence is real but still maturing.
What I can share is what I see. In my practice, roughly 40 percent of patients carry significant PEMT variants. I’ve observed about 14 patients a year come off liver transplant waiting lists after we identified and treated PEMT-related issues. That is a clinical observation from one practice, not a controlled trial, and I offer it in that spirit. But it is the reason I no longer accept “idiopathic” fatty liver as a stopping point.
The economics are not close
We often hesitate to order tests that feel “extra.” But consider the other side of the ledger. In 2022, Medicare fee-for-service spending averaged about $99,000 per person per year for patients on in-center hemodialysis. A liver transplant carried estimated average billed charges of about $878,000 in 2020, covering the month before the transplant through six months after.
Those figures don’t capture the human cost: the lost work, the strain on families, and the patients who die waiting for an organ. Compared with a preventable myocardial infarction, chronic kidney disease progressing to dialysis, a stroke, or fatty liver disease advancing to non-alcoholic steatohepatitis (NASH) and liver failure, a homocysteine level and a genetic panel cost very little. When an inexpensive test can redirect someone away from those outcomes, ordering it is ordinary prevention, not an extravagance.
Start with the patient, not the genome
None of this means we should hand out genetic panels like flyers. My rule is that genetics should start from the patient’s symptoms. A variant is not a diagnosis, and plenty of carriers are perfectly healthy. I take a history first, then use genetics to explain why.
A practical example is what I call methyl sensitivity. Some patients feel worse (wired, anxious, unable to sleep) when given methylation-support nutrients. Before escalating, I look at COMT, HNMT, and CBS alongside the symptoms. The genes don’t tell the story alone; the patient does.
A few other lessons from my practice:
- Use CLIA-certified laboratories. Consumer raw-data reports are not a substitute for clinical-grade testing.
- Be careful with synthetic folic acid. In my view, it is usually not advisable unless there are known folate absorption difficulties (FOLR1 or SLC19A1).
- Interpretation is the intervention. A report without a clinician who can connect it to the history, the labs, and the exam can create anxiety or false reassurance.
- Re-measure. Homocysteine is a number we can follow over time, which makes it useful for monitoring, not just screening.
What I’m asking of colleagues
I’m not asking anyone to abandon guidelines or to treat a gene as destiny. I’m asking us to stop treating homocysteine and PEMT as curiosities. When a patient has unexplained fatigue and inflammation, a family history of early cardiovascular disease, unexplained kidney decline, or a fatty liver with no obvious cause, these tests deserve a place on the order sheet. When the results come back abnormal, they deserve a plan.
The diseases at the end of this road (heart attack, kidney failure, stroke, liver failure) are among the most expensive and devastating we treat. The tests at the beginning of it are among the cheapest. That imbalance is worth our attention.
Dan Purser provides genetic and nutritional counseling through Purser Wellness in Pleasant Grove, Utah, meeting with clients nationwide via Zoom. His work focuses on homocysteine, methylation genetics (including the MTHFR and PEMT genes), and chronic inflammation.
He has worked with more than ten thousand clients on homocysteine issues, reviewed more than forty thousand intracellular nutrient tests, and spent ten years in cardiology research with a U.S. assistant surgeon general. He has written twenty-three manuscripts and more than thirty books, including Homocysteine: The 2026 Comprehensive Diagnosis & Treatment Protocol, and his clients have left more than 1,400 five-star reviews. His approach starts with each client’s symptoms and then uses genetics and lab testing to find the cause.
