2-Hydroxyisobutyric Acid


(Utility Muffin Research Kitchen) #1

I did an environment toxin test from the Great Plains Laboratory. It shows a very high value of 2-Hydroxyisobutyric Acid (2HIB). Now this page claims that 2HIB is generated in ketogenesis, but high values can also be the result of a genetic disorder (I’m ruling out heavy exposure to gasoline additives). Since I suffer from ME/CFS and I stopped losing weight on keto about 2 years ago, I wonder if it might be the latter.

So, any experiences with this particular metabolite? Which values can be expected for healthy people on a ketogenic diet?


(Bacon enough and time) #2

PubChem describes 2-hydroxyisobutyric acid as

a 2-hydroxy monocarboxylic acid that is isobutyric acid bearing a hydroxy substituent at position 2. It is a metabolite of methyl tertiary-butyl ether. It has a role as a human xenobiotic metabolite. It derives from an isobutyric acid. It is a conjugate acid of a 2-hydroxyisobutyrate.

Not very clear, perhaps, but the gist is that it is produced by human metabolism, but it is not one of the three ketone bodies produced in the human liver, which are acetoacetate, acetone, and β-hydroxybutyrate. (The latter is not actually a ketone, in chemical terms, but it is produced by the process known as ketogenesis, so the term “ketone body” was developed to include it.) Given the similarity in chemical names, I suspect that whoever wrote that 2-hydroxyisobutyric acid was generated by ketogenesis was actually thinking of β-hydroxybutyrate.

PubChem also states that this is a chemical found in the placenta and in cytoplasm. It is associated with colorectal cancer, lung cancer, and eosinophilic esophagitis, but whether it causes them is not clear. I have no idea how worried you should be, unfortunately. For your encouragement, however, I can say that acetone and formaldehyde are both toxic when ingested in sufficient quantity, but the human body produces them and finds them useful in certain processes. The same may well be true of 2-hydroxyisobutyric acid.

What is your source saying are the risks of having an elevated level of 2-hydroxyisobutyric acid? How strong is the association, and do they have any idea whether the association is causal, or a result of the condition? I mention this, because if the 2-hydroxyisobutyric acid level is merely a marker for a condition, manipulating the marker may fail to address the actual cause of the condition.


(Bob M) #3

Have you done any research into genetics for this? Is it possible to get a test to confirm your hypothesis?

I’m thinking of getting a 23andme test done. Once you have the genomic data, you can give it to others who can analyze it for other markers. Like this:

https://www.promethease.com/

I’m specifically looking for genealogy and whether I’m better off limiting my fat intake, but I think you should be able to get a test for your possible condition, too.


(Utility Muffin Research Kitchen) #4

BHB was tested separately. But yes, maybe you’re right.

I think I can answer that one too. MTBE and ETBE (fuel additives) are metabolized to 2HIB. I figure these would cause cancer, hence the association. As you say, it’s not clear if the 2HIB plays a part in this or not.

Not a lot. They say that MTBE and ETBE are metabolized to 2HIB, and that MTBE and ETBE cause cancer. In this case the suggestion is to reduce exposure to these fuel additives --but there is no exposure that I know of. (I don’t even own a car, and I strictly avoid all solvents because of MCS.)

It says “2-hydroxyisobutyric acid (2HIB) (Marker 1) is most often the result of exposure to methyl tertiary-butyl ether (MTBE) or ethyl tertiary butyl ether (ETBE), which are gasoline additives used as octane enhancers. […] Excretion half-lives in humans range from 10 to 28 hours. Reduce exposure if possible. […] -Hydroxyisobutyric acid is also formed endogenously as a product of
branched-chain amino acid degradation and ketogenesis. High values have been reported in both isovaleric acidemia and multiple acyldehydrogenase deficiency.”

So the last sentence points to the possible cause. I’m in the top 2 percentile of 2HIB. However, I’m also very high in BHB and acetate… So I wonder if these high values could be caused by ketogenesis alone, or point to a metabolic defect.

As with many CFS patients, all my standard bloodwork looks normal. If we go to the less well known parameters then we see a LOT outside the normal range – the problem of course is that we know so little about these parameters that it’s hard to tell what exactly is wrong, and if it can be fixed. I could do dozens of tests (mostly testing genetics) of course, but all are expensive and not covered by insurance… :frowning:

Yes, I have a genomic report from Lifestyle Genomics. But the raw file I got contains over 600.000 SNPs… They supply a report consisting of ~400 genes, but naturally some of them are red (unfavorable allele), some of them are yellow (heterozygotic) and some are green (favorable allele). But the report won’t tell you if you have a specific defect or not – in most cases many genes are involved and we’re not yet sure which genes play which role.

I might give Promethease a try, to see if their report is better than the one from Lifestyle Genomics.


(Bob M) #5

Could you purposely eat high carb for a while, then get retested?


(Bacon enough and time) #6

So it sounds as though, first of all, the problem is not the presence of the metabolite, but rather exposure to the precursor. Since you are avoiding that, you should be fine. Unless someone has demonstrated a deleterious effect of 2-hydroxyisobutyrate itself, I wouldn’t worry.

As for the other issue, I’ve never heard of 2-hydroxyisobutyrate being produced as a result of ketogenesis, and I suspect one of the sources would have mentioned it, if it were. But again, in the absence of evidence that 2-hydroxyisobutyrate itself causes problems, it’s probably not worth worrying about.

A similar example of the problem of knowing too much is a man’s PSA level. Experts used to think it was a sign of prostate cancer, so an elevated PSA automatically led to a prostatectomy, with all the possible after effects that can ensue. But now, it is recognised that the meaning of an elevated PSA level is extremely unclear, so doctors are having to learn not to jump into treating something that is most likely not a problem. Many experts are now, in fact, recommending that men not get their PSA tested at all, so as to avoid tempting their doctor into a reaction that may cause more harm than good.


(Utility Muffin Research Kitchen) #7

Well, sure :slight_smile: The test sets me back about $600, if I do the full panel. I might do it eventually, but not anytime soon.

I’m not worried about the 2HIB as a substance. But having a fairly severe health condition, I need to find out what the root cause is. Standard tests haven’t helped. The 2HIB is high. As I’m not exposed to the precursors (=some external influence that drives it up), for some reason my body produces it in much higher quantities than usual. I can see 3 different scenarios:

  1. It’s outside of normal range because of my keto diet and nothing to worry about. (After all, standard ranges are set by observing people on western diets.)
  2. There is some abnormal metabolic pathway and it’s connected to my illness.
  3. There is some abnormal metabolic pathway and it’s not connected to my illness.

If I knew I could rule out (1), then it’s probably time to investigate further. I think I’ll ask the laboratory if they can give me a reference to 2HIB being a result of ketogenesis.

In any case you guys have already helped me to sort thoughts :slight_smile: Thanks!


(Tiffany Lorraine Grove) #8

Hi there, also did the same test and got a very high rating of 2HIB. I have no idea where my exposure could come from. I drive a gas-powered car, but so does most of the country. I do not live near any industrial sites or farming areas. And I do not live in the city. Just suburban mom. Annoying that I can’t reduce exposure if I can’t determine where the exposure is from.


(Edith) #9

How long have you been keto?


(Tiffany Lorraine Grove) #10

I’m not Keto. I eat fairly low carb, but am unable to go low enough for Keto. But eating low carb for years.


(Bacon enough and time) #11

From healthmatters.io:

2-Hydroxyisobutyric acid is formed endogenously as a product of branched-chain amino acid degradation and ketogenesis. This compound is also the major metabolite of gasoline octane enhancers such as MTBE (methyl tertiary-butyl ether) and ETBE (ethyl tertiary butyl ether).

MTBE and ETBE are gasoline additives used to improve octane ratings. Exposure to these compounds is most likely due to groundwater contamination, inhalation or skin exposure to gasoline or its vapors, and exhaust fumes. MTBE has been demonstrated to cause hepatic, kidney, and central nervous system toxicity, peripheral neurotoxicity, and cancer in animals. Very high values have been reported in genetic disorders. Because the metabolites of these compounds are the same, ETBE may be similarly toxic.

Apparently, the problem is not the 2-hydroxybutyric acid itself, but the possibility that a high level of it might be the result of exposure to MTBE and ETBE.

This suggests two things to check: your water supply, and the exhaust systems of your vehicles and any other combustion engines in regular use around you.

If you have a well, it is entirely possible that it has been contaminated by contaminated ground water. A testing agency could determine whether that is the case. If you are on public water, it’s possible the utility may be having problems it’s not dealing with.

Tracing automobile exhaust leaks is difficult, but a carbon monoxide detector inside the passenger compartment might be able to tell you something. I’m thinking of a case where there’s not enough exhaust to give you symptoms of carbon monoxide poisoning, but still enough to expose you to MBTE and ETBE. Or it might be vapour from a leak in the fuel line.


(Edith) #12

You are awesome!