AskScience AMA Series: I am Prof. Beverley Hunt, OBE, and I am a hematologist in London, England. I am also chair of the World Thrombosis Day Steering Committee. I am here to talk about why MTHFR testing is unnecessary and can cause misinterpretation. AMA!

Submitted by AskScienceModerator t3_y0bsu7 in askscience

I am Prof. Beverley Hunt, OBE, and I am a Professor of Thrombosis and Haemostasis at King's College, England. Research shows that MTHFR polymorphisms do not meet the criteria to be called an inherited thrombophilia. As such, the World Thrombosis Day campaign recommends it should be removed from thrombophilia testing panels. I look forward to answering your questions about thrombophilia testing, the MTHFR gene polymorphism, and why I believe MTHFR should be removed from standard testing. I will be on at 12 p.m. US ET (16 UT), AMA!

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Trustybob t1_irqyuef wrote

What is MTHFR testing and what is it for?

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WorldThrombosisDay t1_irry7fp wrote

>MTHF

MTHFR is short for methylenetetrahydrofolate reductase, which is an enzyme that is involved in getting and removing homocysteine from the blood. Homocysteine is a toxin that the body likes to break down. In 1988, it was found that some people had a gene change in their MTHFR gene. This was a gene change at position 677. This change meant that if an individual had this change, when they were short of a vitamin called folic acid, they were not so good at metabolizing homocysteine. Sorry this is so complicated!

After it was discovered, there were studies that suggested just maybe this change was associated with increased risk of having blood clots (VTE). This led to the MTHFR test being added to thrombophilia testing. But in actual fact, it wasn't properly validated. In the last five years, we know from beautiful, large, randomized, controlled trials that MTHFR has nothing to do with a higher rate of blood clots.

Indeed, we have learned more than that. We have learned that if we give people with this defect folic acid, it makes no difference to their VTE risk. So I hope you can see that MTHFR testing is therefore not a thrombophilia test. The problem is that lots of labs aren't up to date and they have not removed it from their testing.

The other problem is that the MTHFR change is present in a single dose in 46% of the population, and a double dose of the change is present in 12% of the population. That means over half of the population have got this change! So, we really shouldn't be testing for something that is expensive to test for and is present in normal people.

Here are a few new resources talking about this: https://www.worldthrombosisday.org/news/post/wtd-publishes-new-resources-recommending-mthfr-should-be-removed-thrombophilia-testing-panels/

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RougeGarbageMouth t1_irredyi wrote

Hi Professor Hunt! My question is not specifically about the MTHFR mutation, but is a little more general about to the increased risk of thrombosis with hormonal birth control. Are you aware of research being done on ways that this can be minimized or new classes of birth control that don’t carry the same risk? For many women who are taking BC for medical reasons (other than to prevent pregnancy), there are not many good alternatives if clotting proves to be an issue. Long term non hormonal birth control methods (specifically copper IUDs) carry their own issues with extremely heavy periods, made even worse if a patient is on anticoagulants - and of course, they don’t treat the hormonal issues that estrogen BC would. As a woman who falls into this category, it is hard not to feel left behind.

Edit: Typo

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WorldThrombosisDay t1_irs03kd wrote

Sorry you are having problems. The options to estrogens for birth control for people who have had previous clots or have had a thrombophilia are: progestogen only pill, progesterone implants, coils (I find the coils such as the Mirena coils particularly good), and mechanical methods. The only method you can't uses is the combined oral contraceptive pill.

Many thrombosis experts would offer the combined oral contraceptive pill if the woman had no other option and they were taking long-term anticoagulation because they had already had a clot.

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PHealthy t1_irrd0r8 wrote

Why do you think that the alternative medicine industry has really latched on to MTHFR testing?

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Vonspacker t1_irre39r wrote

Do you think we should be doing more to address the inaccessibility of information contained within reports of scientific research. I study within the area and am constantly frustrated by the lack of clarity within figures and written sections where it seems easily possible to make yourself more clear at the expense of sounding marginally less academic and abbreviated.

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WorldThrombosisDay t1_irs2mju wrote

I agree with you! In England, we have something called the "plain English campaign," and they will help you write leaflets to keep the language very simple. In academic medicine, many journals now ask for a laymen's abstract, which means that you have to simplify your findings for a lay person. However, having simplification of the figures and tables seems difficult.

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Ah_Go_On t1_irr13zy wrote

Do you know much about, or have much faith in, the capacity of regulatory authorities such as the EU or the FDA to limit or restrict the sale of genetic tests to the public for profit? I was hoping the pandemic would really kick-start the regulatory restriction of medical disinformation but am not aware of any major upcoming changes. Would love to hear your thoughs on this matter in general.

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WorldThrombosisDay t1_irs1jn4 wrote

The EU and FDA regulatory authorities don't appear to have any capacity the uptake of genetic testing. If they didn't, we wouldn't be here today having this AMA because they would have asked everybody to remove MTHFR from thrombophilia testing.

I think it would be a great idea if they did have more control about who did what tests for what individual. Thanks for the great question!

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audreydeez t1_irr4n69 wrote

What do you think about the proposed link between MTHFR and schizophrenia?

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WorldThrombosisDay t1_irs10ho wrote

It's an interesting question. I've had a quick look at the literature and as far as I can see, there is no clear link between MTHFR and schizophrenia. I think you'll have to go and ask a psychiatrist what the latest opinion is.

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thunder-bug- t1_irri0ny wrote

Can you explain that in a laymans terms? I don’t know what several of those things are 😅

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freedcreativity t1_irt1ocn wrote

While I understand the issues with alternative medicine quackery, MTHFR is an interesting biomarker in mental health and the use of methylfolate in inadequate responders to SSRI medication is evidence based. https://pubmed.ncbi.nlm.nih.gov/34794190/

Are you only suggesting that commercially available genetic testing remove MTHFR C677T and A1298C? Or are you suggesting that it be removed from pharmacogenomics panels as well?

A second, more philosophical question would be, why stop people from having the data? Methyltransferases are ubiquitous, and it is an interesting entry point into folate-mediated one carbon metabolism. FOCM has a number of uses, like controlling epigenetics (DNMT), creating DNA (via Pyrimidine), phosphatidylcholine (via PEMT), and creating neurotransmitters (via BH4 and COMT). Knowing the issues with the biochemical system is interesting, and MTHFR is a very old and well studied set of polymorphisms. Dr. Nijhout & Reed at Duke even have a full computational enzyme kinematic model of FOCM. You'll have quacks regardless of what actual data you provide. Why does removing the MTHFR polymorphism from 23andMe provide any benefit? Save for preventing unnecessary blood draws for hyperhomocystinuria testing and preventing people from asking doctors about their lack of up-to-date biochemical or genomic knowledge.

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DanielDooberstein t1_irs6520 wrote

It's unnecessary in regards to thrombosis but it has been a miracle for many of my health issues to discover I have this gene on both sides. Adding a special kind of Folate and a special kind of B12 gave me my life back and more.

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Unique_Height_6863 t1_irr3roh wrote

Do you also consider homocystein testing unnecessary?

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WorldThrombosisDay t1_irrzjq8 wrote

>Do you also consider homocystein testing unnecessary?

I consider it unnecessary in "thrombophilia testing." It has its place in other diseases.

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Houki01 t1_irr3yb2 wrote

What is thrombophilia? I get that thrombosis is a medical condition involving the arteries around the heart, but doesn't the -philia suffix denote an affection for something?

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WorldThrombosisDay t1_irrx21t wrote

>What is thrombophilia? I get that thrombosis is a medical condition involving the arteries around the heart, but doesn't the -philia suffix denote an affection for something?

Great question! "Thrombo" is short for thrombosis (or blood clot) and "philia" means "loving." So thrombophilia is loving clots.

What we mean by thrombophilia these days is looking for inherited or acquired things that predispose to having venous thromboembolism (VTE).

Venous thromboembolism is when you have a deep vein thrombosis (DVT - a clot in the deep vein of the leg) which can break off and cause a pulmonary embolism (PE - when the clot moves to the lungs).

These days, laboratories across the world agree on the essential factors we need to test for, but there has been disagreement about some of the factors, and therefore some laboratories are doing many more tests than others.

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AbsentEmpire t1_irrfydd wrote

Under what conditions would someone be prescribed this test?

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WorldThrombosisDay t1_irryd7u wrote

If they had a problem with homocysteine metabolism. Ha! But not for thrombophilia.

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AlbayCorc t1_irs0led wrote

Hello Mr Hunt, I am curious what you think of this real condition: 35 years old male, has thrombosis in left popliteal artery, with total occlusion, extending down for 11cm. Smoked for 9 yrs, alcohol used, condition worsened after heavy depression and pandemic period but started long before (at least a year before pandemic). Was failed to diagnose in Europe, finally diagnosed at 4th of August 2022 in turkey. Never had covid during this time.

He has MTHFR hetorozygot and 4G/5G allelles from thrombophilia genetic tests. Do you think it may be buergers? The hematology docent thinks the mutations could be contributing at least, He also has mild hyperhomocysteinemia. I repeat another user's question here, is homocysteine testing also unnecessary? Could it be harmful to try to lower homocysteine with b vitamins and folic acid?

Sorry that's too many questions in one comment, it's not often to find a hematology professor with time to answer! All my questions are out of curiosity rather than trying to prove otherwise. Thank you for your time! Have a nice day!

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WorldThrombosisDay t1_irs2dja wrote

I can't talk about a specific patient because I don't have enough information and they have to be my own specific patient, otherwise I could lose my ability to practice! However, I can say that if I saw a young man with a popliteal artery thrombosis, I would not think it was Buergers because Buergers affects the small tiny arteries first. And therefore it wouldn't present usually just in one leg - it would affect the fingers and toes first.

Secondly, the thrombophilia I would be looking for would be antiphospholipid syndrome, which is notorious for affecting young people. Lastly, raised homocysteine levels do not cause thrombosis in blood vessels such as the popliteal artery, neither do the 4G/5G polymorphism.

If you have mildly raised homocysteine levels, it's also because you're not eating enough folic acid. Folic acid is a vitamin in present in green foods, so I always encourage patients to follow the old wives tale of "eat your greens."

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GSPMom21 t1_irrmxl3 wrote

One more question if you don't mind: Specifically what is MTHFR and why shouldn't we be tested for this if we've had a clot?

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WorldThrombosisDay t1_irryilh wrote

It's a gene change in the molecule MTHFR and it shouldn't be tested for in those who have had a clot because it's got nothing to do with clots. It doesn't increase the risk of thrombosis.

Removing MTHFR from standard thrombophilia testing will reduce the confusion, emotional upset, and misinformation that it currently causes in the patient group.

https://www.worldthrombosisday.org/news/post/wtd-publishes-new-resources-recommending-mthfr-should-be-removed-thrombophilia-testing-panels/

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sorzach928 t1_irrxpfx wrote

What will the removal of MTHFR polymorphisms from thrombophilia testing panels do to support patient care and cost of care?

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WorldThrombosisDay t1_irs0j12 wrote

Removing MTHFR from thrombophilia testing will reduce the cost of thrombophilia testing and will prevent misinformation being passed on to patients.

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hvd521 t1_irrxr0v wrote

Thanks for your AMA, Dr. Hunt - what are your thoughts on the purported link between MTHFR polymorphisms and infertility, specifically the polymorphisms that are implicated in the failure of embryos to implant? Some women have reported getting the test and switching to a different form of folate or receiving infusions of intralipid and other supplements to support implantation in the presence of mutations - is this scientifically founded?

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Sgt_PuttBlug t1_irs1jj9 wrote

If you didnt play the trombone, what other instrument do you think you would have played?

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Federal-Relation-754 t1_irs3gfm wrote

Clearly MTHFR testing should not be performed, but hat are your general thoughts on thrombophilia testing (protein C, protein S, FVL, etc.) in recurrent pregnancy loss?

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Rj924 t1_irtthe5 wrote

I am a lab tech, and have been for over ten years. When I started we saw a lot of orders for MTHFR testing. I can't remember the last time I sent one out. So in my experience the use of it has declined. And yes, we call it what you think we call it.

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CuriousLRB t1_irroa6q wrote

Thank you for your work on this. How do go about ensuring the global community recognizes that MTHFR testing is not necessary? Is there some sort of recommendation that can be adopted by an international group or medical journal?

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ExpendedMagnox t1_irrrxqs wrote

Where do you stand on the potential for UK Junior Doctors to strike; do you agree with their plight and is it likely to be successful?

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Cultural-Twist7546 t1_irrxkgg wrote

Does a person with a genetic MTHFR variant have an increased risk of thrombosis? What is the criteria to be called inherited thrombophilia?

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WorldThrombosisDay t1_irrz60w wrote

The MTHFR variant is not related to increased risk of venous thromboembolism (VTE). There are six tests that are definitely associated with increased risk of venous thromboembolism and should be on any inherited thrombophilia testing.

They are: measuring functional antithrombin levels, protein C levels, protein S levels, looking for Prothrombin 22 10, measuring fibrinogen levels, and lastly doing a test for Factor V Leiden.

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Business_Panda9728 t1_irry62s wrote

What is World Thrombosis Day and how can I get involved?

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WorldThrombosisDay t1_irw8zdl wrote

World Thrombosis Day is on Thursday, October 13! Next year is the 10th anniversary of the campaign, which focuses attention on the often overlooked and misunderstood condition of thrombosis (blood clots). The campaign has thousands of educational events in countries around the world. There are lots of ways you can get involved in and support World Thrombosis Day this week. Here are a few ideas: https://www.worldthrombosisday.org/news/post/your-guide-week-world-thrombosis-day/

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plaerzen t1_irrz9ri wrote

Is pan haematin a good treatment for porphyria?

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Spidersandbeavers t1_irrzuei wrote

What would be a legitimate reason to test for mthfr?

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WorldThrombosisDay t1_irs0djq wrote

If someone had a high homocysteine. Homocysteine levels are indicated in patients with other types of diseases, not venous thromboembolism.

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Styphonthal2 t1_irs70fj wrote

I am in NY and Our local/nation lab has removed MTHFR from our thrombotic panels, although we still test for homocysteine. We also have a "recurrent miscarriage panel" which is basically the same.

I know we had MTHFR testing previously, specifically for miscarriages, but I am unsure when it was removed.

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TheoCupier t1_irt8yrq wrote

What are your views on links between Ehlers Danlos syndrome and thrombophlia?

Do you think there is sufficient awareness of the potential risks of EDS in cardiovascular medicine and treatment?

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WorldThrombosisDay t1_is0oluq wrote

I am not aware of any association of Ehlers Danlos with thrombophilia, but Ehlers Danlos is associated with easy bruising and increased bleeding risk.

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[deleted] t1_irtnosi wrote

[deleted]

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WorldThrombosisDay t1_is0oqct wrote

Interesting one. Folic acid supplementation should not be required in those following a healthy diet. But considering their general health, if someone has an unhealthy diet they may have multiple deficiencies so maybe they should take a multivitamin pill, which includes folic acid?

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sumguysr t1_irto1hp wrote

What is your view on MTHFR testing or methylfolate supplementation in populations with psychiatric diagnoses like ADHD, autism and depression?

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WorldThrombosisDay t1_is0ouji wrote

As the evidence base for MTHFR being associated with any psychiatric diagnosis shows that we are not clear there is any relationship at all, I would not be supplementing patients with folic acid.

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abbiefirefly t1_irumcai wrote

Interesting stuff. I have one daughter who is FVII deficient and another who has two mutations on the MTHFR. We were part of a study with Dr. Diane Nugent and she took all data to the World Hemophilia Gathering a couple years ago. Neither of my girls show any symptoms and don’t receive any treatments or medication. Although, no doctor has ever attempted to discuss if I should give the one with MTHFR mutation folic acid or folate. I live in South Texas and don’t always have the most faith in our health care. Is there something else I should be doing to ensure adequate care for my girls or treat if symptoms arise only?

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WorldThrombosisDay t1_is0osjs wrote

A healthy diet is full of folic acid, so no supplementation should be required. As you are a concerned mother, I am sure you are feeding your girls well, and don’t need to worry about this.

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BubblyPurple1173 t1_iruw95b wrote

What is the link between anticardiolipin antibodies and thrombosis? Is testing for these a standard part of a thrombosis panel of tests?

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WorldThrombosisDay t1_is0ooom wrote

Anticoardiolipin antibodies are one of three tests that are done to see if an individual has “antiphospholipid antibodies.” Antiphospholipid antibodies carry an increased risk of thrombosis and in women can cause problems in pregnancy. Yes, they should be part of thrombophilia testing.

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UsedChocolate1990 t1_ishbzxo wrote

Hi I understand that this thread is speaking about the MTHFR testing and it's past association with thrombosis but I just have to say I completely disagree with the medical advice you are giving people on this thread that are asking you about supplementation for MTHFR mutations. Getting on a specially methylated formula (with intrinsic factor) has been such a huge relief to my system. Some that show this mutation do not make the enzyme "intrinsic factor" in their gut which allows for proper metabolization of B vitamins . People with this mutation are ALLERGIC to synthetic folate (aka folic acid) which is what you are referring people to take. I am so unnerved by the medical establishment sometimes. Stick to what you know and stop giving people advise on something you clearly have an outside opinion on! My methylation panel was FREE through my genetic raw data and shows many markers for this autoimmune disease. Furthermore, because of the MTHFR genes association with narrowed veins it's totally possible to be a precursor to thrombosis! Why not test for it?

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CrigglestheFirst t1_irsb91d wrote

>Research shows that MTHFR polymorphisms do not meet the criteria to be called an inherited thrombophilia.

I would love to hear Samuel L Jackson tell some scientists, that their "motherfucking MTHFR (pronounced motherfucker) polymorphisms do not meet the motherfucking criteria to be called a motherfucking inherited thrombophilia, motherfuckers."

I understand none of this. Please dont hate me

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