It can be difficult to distinguish the symptoms of histamine intolerance and sulfur intolerance. Both can present with hives, itchiness, asthma, headaches, nausea, fatigue, flushing, and brain fog—and sometimes a problem with one can lead to a problem with the other.

The Methylation Connection

What connects these two problems is methylation, one of the liver’s six main pathways of detoxification. This connects back to the now-famous gene, MTHFR.

Long story short, if your methylation pathway is backed up, you may be more predisposed to both sulfur intolerance, and to histamine intolerance… but other predisposing factors may affect whether you have one or both.

Your methylation pathway may be backed up because you have one or more homozygous (two bad copies) genetic mutations of MTHFR, because you’re deficient in the vitamins that act as methyl donors (primarily folate and Vitamin B12), or it may be backed up because it’s just overwhelmed. Think of this like a bottleneck: too many substances trying to get through too small a door. This is what Ben Lynch calls a “dirty” MTHFR. Those who have a genetic mutation will be prone to more easily overwhelmed enzymes than those without, but the overwhelm can happen to anyone; the difference is really the threshold.

Since histamine has three main pathways for degradation, and one of them involves methylation, a backup in this pathway can lead to increased levels of histamine.

Since homocysteine, the breakdown product of the methylation pathway, is a sulfur-containing compound, it’s easy to see how an inefficient methylation cycle leading to increased levels of homocysteine may also trickle down into higher levels of sulfites. As long as the body can convert sulfites to sulfates (the usable form for the detoxification pathways which require sulfur), this won’t lead to a sulfur problem—but if this pathway is also compromised for whatever reason, then sulfur sensitivity and histamine intolerance might coexist.

Sulfur Sensitivity: A Recap

As I wrote here, and as you can perhaps see from the flow chart, there are other possible causes for sulfur intolerance than methylation backup. In fact, often low homocysteine corresponds to sulfur intolerance, because it’s all been funneled into sulfites and cannot convert to sulfates from there. Just like on a freeway, an accident at any point in your route can cause the same end result: you’re delayed in getting to your destination. Other possible causes for sulfur intolerance include a CBS mutation, a SUOX mutation, a molybdenum deficiency, a magnesium deficiency, or a vitamin B6 or B3 deficiency. The enzymes, even if not mutated, could also be overwhelmed in cases of significant environmental toxicity, since sulfur is required for three of the liver’s six main pathways for detoxification.

In almost every case I’ve seen of sulfur sensitivity, Hydrogen Sulfide SIBO also coexists as a compensatory mechanism. So treatment of the sensitivity should also include testing for and treatment of SIBO.

Histamine Intolerance: A Recap

As I wrote here, histamine intolerance very often corresponds to inflammation in the gut, leading to compromise of the DAO enzyme. As you can see from the flow chart, though, other possible causes include homozygous mutations of DAO, NAT, or MAO, or  deficiencies of any of the cofactors involved (Vitamins B5, B6, C, magnesium, and copper).

The Upshot

For those who have struggled with both sulfur sensitivity and histamine intolerance, there’s very likely a toxic cause that needs to be identified and removed—but genetic analysis can be very enlightening, or at least homocysteine testing. There’s likely more than just methylation backup going on, but it’s probably a contributing factor.