Histamine and Nutrigenomics
Histamine has many important biological functions including digestion (gastric acid secretion), sleep-wake regulation, blood clotting and, of course, immunity. However, as with many ‘good’ things it is possible to have too much.
Symptoms of excess histamine include eczema, hives, asthma, headaches, swelling, flushing, itching, watering eyes, runny nose, GI distress, heart palpitations, anxiety, low blood pressure, light-headedness and insomnia.
‘Histamine intolerance’ (HIT) is usually described a ‘food allergy’ (NHS website) and increased tendency to intolerance reactions after oral ingesting histamine due to reduced degradation capacity. The genetic component of HIT is assumed to be due to genetic variance on DAO (Diamine Oxidase) genes only. ‘Histaminosis’ refers to a status of excess histamine without specifying the cause, this broader term enables consideration of the multiple genetic and environmental (nutrigenomic) factors involved in histamine metabolism.
A Day in the Life of Histamine
Histamine is synthesised from histidine (an essential amino acid). It is released in response to allergens, cytokines, stress hormones, alcohol and hormones, and exerts its effects by binding to histamine receptors on, basophils, enterochromaffin-like cells, platelets and neurons.
There are two major pathways for histamine degradation - 1) oxidative deamination by DAO and 2) methylation by HNMT; and two minor pathways - acetylation (NAT) (which is affected by microbes) and to a lesser extent hydroxylation. DAO is responsible for metabolism of extracellular histamine whereas HNMT breaks down intracellular histamine. Insufficient DAO or HNMT enzymatic activity can result in accumulation of histamine. The products - imidazole acetaldehyde, ammonia and hydrogen peroxide are highly reactive (ROS), and must be detoxified by ALDH2 (aldehyde dehydrogenase), GPX1 (glutathione peroxidase 1), and CAT (catalase).
Histamine Intolerance - the Extended Edition
Classic HIT is triggered by ingestion of foods or drinks that are either i) high in histamine which may be produced as the food begins to spoil or ferment - kefir, sauerkraut, tinned or smoked fish and meats, or ii) are histamine liberators foods - kiwi, citrus, tomatoes and avocado, pollen, dust mites, pollution (petrol fumes), xenoestrogens (in plastics) or chemicals that trigger mast cells to release histamine. Histamine intolerance is often likened to a bucket which is overflowing due to more histamine being poured in than can be removed.
Diamine Oxidase (DAO) is the main enzyme that metabolises ingested histamine. It is secreted by mucosal cells in the gut, where it breaks down histamine before it can be absorbed. DAO is also produced in the kidneys (an alternate name is KAO - Kidney Amine Oxidase) and the placenta.
Two common DAO SNPs have been shown to have significant functional effects on diamine oxidase activity. DAO serum levels of individuals carrying the rs1049793 (His645Asp) risk allele (frequency 30.6%) were reduced by 34% for heterozygotes and 49% for homozygotes compared with none carriers. As well as being associated with lower DAO activity generally, the rs10156191 (Thr16Met) minor allele is specifically associated with crossed-hypersensitivity allergic responses (shortness of breath and asthma) to NSAIDs (non-steroidal inflammatory drugs) including aspirin (salicylate), and with migraine risk in Caucasian women. The effect of the two genotypes (645Asp and 16Met haplotype) is additive.
As a copper dependent enzyme (another alternate name is Amine Oxidase Copper Containing 1 (AOC1)), DAO can be impacted by copper insufficiency. Excess zinc, most likely due to supplementation, can inhibit copper absorption. Medications such as semicarbazones (antiviral, antibacterial and chemotherapy drugs can also inhibit DAO activity due to their copper binding effect. Other DAO ‘blockers’ are alcohol (ethanol) and acetaldehyde - the intermediate metabolite of alcohol and of histamine itself, and nicotine.
DAO also requires the cofactor pyridoxal 5’-phosphate (PLP), an active form of vitamin B6. PLP availability can be impacted by genetics, a SNP (rs4654748) on the ALPL gene is associated with low B6 status (and with pyroluria), and multiple environmental factors. As B6 is a cofactor for synthesising many biogenic amines - excess dopamine, adrenaline or histamine can significantly deplete it.
As DAO is synthesised and released by enterochromaffin-like cells in mucosal membrane, it (DAO) will be impacted by anything that could damage the gut lining. There are multiple genetic factors to be considered: HLA (Human Leukocyte Antigen) genetic variance which can confer risk of coeliac disease, and other autoimmune conditions; SNPs associated with increased levels of inflammatory cytokines, such as IL6 (Interleukin 6) and TNF (Tumour Necrosis Factor); SNPs on FUT2 (Fucosyltransferase 2) which confers Secretor status and H. Pylori risk, and FKBP5 (FK506 Binding Protein 5) SNPs which impact stress resilience, to name a few.
The allopathic approach to HIT is to focus on reducing histamine inputs - low histamine diet, usually without considering gut health, differential diagnosis (such as coeliac disease or IBD), or other genetic factors. The use of DAO enzymes may also be considered. However, as DAO enzymes are typically manufactured from porcine (pig) kidney, they are unsuitable for vegetarians, vegans and some religious groups, as well as being expensive. Polyphenols, such as quercetin, are more universally acceptable, and often as effective. Quercetin, a flavonoid found in onions, apples, green tea and berries, has been shown to exhibit amine oxidase activity including metabolism of histamines.
Hormones & Histamine
It is well established that atopic diseases, including eczema, hay fever and asthma, are more prevalent in women, implying hormonal interaction. Oestrogen interacts with (oestrogen) receptors on mast cells to induce IgE-mediated degranulation. Progesterone may either stimulate and inhibit mast cell secretion of histamine. Via another mechanism, oestrogen inhibits DAO and progesterone induces it. Thus, overall oestrogen is histaminergic, whereas progesterone can act as an antihistamine.
Progesterone plays a key role in induction of DAO in pregnancy, when levels are increased by a magnitude of 500x. DAO acts as barrier to prevent excessive entry of histamine from the placenta into the maternal or foetal circulation. The suppression of the maternal immune response enables relief from allergic symptoms during pregnancy, although they often rebound postpartum.
The interplay between oestrogen and progesterone and DAO can also impact histamine levels outside of pregnancy. Histamine levels are likely at their highest in oestrogen dominance, other words when oestrogen levels are relatively high compared to progesterone. This can be due to excess oestrogen exposure, up-regulated oestrogen synthesis and/ or slow metabolism. It is more prevalent during perimenopause, when oestrogen levels may be more volatile. It can also happen during a regular menstrual cycle towards the end of the luteal phase when progesterone drops and as oestrogen starts to rise at the start of the follicular phase, and may coincide with menstrual migraines, cramps and pain, and allergic symptoms.
Some people are predisposed to oestrogen dominance due to genetics. A SNP on the CYP19A1 gene (rs10046) implies faster synthesis, COMT SNPs (V158M and H62H) slow COMT ability to deactivate oestrogen, and variants on SULT1E1 and UGT1A1 impact phase 2 sulphonation and glucuronidation, respectively. The good news is that all these SNPs, genes and pathways can be supported, and compensated for by nutrition and lifestyle interventions.
HNMT - Interior Methylator
The HNMT gene codes for Histamine N-Methyltransferase which is found in the cytosol (in the cell) and uses S-adenosyl-L-methionine (SAMe) as the methyl donor to metabolise histamine to (inactive) methyl-histamine. HNMT plays the dominant role in histamine biotransformation in bronchial epithelium. A common genetic polymorphism found in about 10% of Europeans Thr105IIe (rs11558538 C/T) conveys significantly lower activity and less effective metabolism of cellular histamine. Several studies have associated the consequent immune-reactivity with increased risk of asthma, although some have found no association.
The T allele has also been shown as a risk factor for attention deficit hyperactivity disorder (ADHD), allergic rhinitis and migraine, the association being stronger if DAO SNPs are also present. However the (105IIe) variant was strongly associated with lower risk of schizophrenia, Parkinson’s disease and essential tremor (due to negative feedback on histamine synthesis). Disrupted HNMT activity in the brain has been linked to more aggressive behaviour and dysregulated sleep-wake cycling.
HNMT activity is dependent on availability of its cofactor SAMe (S-Adenosyl-Methionine). SAMe supply can be impacted by i) Methylation dysfunction or disruption - which is common, and more likely when genetic SNPs are not known about, understood or adequately supported. ii) Increased demand - high levels of oestrogen, dopamine, adrenaline and/ or histamine, and other substrates that require methylation. It is worth noting that methylation status and histamine levels are often inversely correlated.
MAOB - a double edged sword
The methylhistamine produced by HNMT is then oxidatively deaminated to methyl-imidazole acetaldehyde by MAOB (Monoamine Oxidase B) in cells, or DAO extracellularly. A common variant, rs1799836 (T/C), occurs at a frequency of 46% in Caucasians, 80% Africans and 17% in Asians, and is associated with slower MAOB activity.
Although SNPs associated with lower activity are often interpreted as negative, the MAOB product hydrogen peroxide is a highly reactive oxygen species (ROS) and proliferator of oxidative stress. MAOB increases with age, as does predisposition towards Parkinson’s Disease, in part due to the increased oxidative stress.
In the context of histamine metabolism, the methylhistamine substrate of MAOB is already inactive, so slower conversion to ROS, acetaldehyde, ammonia and hydrogen peroxide, is preferable. So in this case, the SNP is considered protective. Quercetin, the flavonoid found in onions, apples, green tea and berries, is known to inhibit MAOB activity, as does curcumin.
ROS - The Consequences
Whether histamine is degraded by HNMT and MAOB or DAO directly, it results in imidazole acetaldehyde, hydrogen peroxide and ammonia. These metabolites are highly reactive and can cause substantial damage, including to DNA, if they aren’t detoxified efficiently.
Imidazole acetaldehyde is metabolised to acetic acid by ALDH2 (Aldehyde Dehydrogenase 2), the same enzyme that breaks down the acetaldehyde product of (phase 1) alcohol (ethanol) detoxification. The ALDH2 SNP rs671 (known as Glu487Lys) results in significantly lower ALDH2 activity risk of acetaldehyde toxicity. Symptoms include facial flushing, urticaria, dermatitis, rhinitis and asthma after consumption of alcohol. As the risk allele (A) is dominant, the heterozygous genotype (*1/*2) is almost as impactful as the homozygous (*2/*2). The 487Lys risk allele is common (up to 30%) in some Asian populations but is rare (almost zero) in Caucasians. However, the ADH1B Arg48His SNP (in 9% of Europeans) confers more rapid metabolism of ethanol to acetaldehyde with similar consequences (as ALDH2).
The ADH1B and ALDH2 oxidation reactions require the cofactor nicotinamide adenine dinucleotide (NAD+), a form of vitamin B3. Increased demand, due to high levels of ethanol and/ or acetaldehyde, can deplete NAD+. Fasting, exercise and consumption of foods rich in tryptophan and vitamin B3 can support NAD+ levels.
Hydrogen peroxide (H2O2) is a major reactive oxygen species and has been proposed as a whole body biomarker of oxidative stress. Glutathione peroxidase 1 (GPX1) uses glutathione to reduce H2O2, limiting its accumulation, and thereby protecting cells against oxidative damage. GPX1 is also a selenoprotein, requiring the mineral selenium. The GPX1 SNP Pro198Leu (rs1050450) has lower activity, and associated (negatively) with ageing and longevity, an association that was strengthened in conjunction with a MnSOD (Superoxide Dismutase) variant (rs4880).
A Functional Approach to a Complex Problem
Histamine intolerance (HIT) is commonly assumed to be due to histamine ingestion exceeding capacity to detoxify it. Whilst exposure to a food that is high in histamine or stimulates histamine release may be the final straw in triggering allergic symptoms, it is unlikely to be the sole root cause.
As a single food is unlikely to be the sole cause, the same applies to genetics. DAO SNPs are impactful and are strongly associated with symptoms, but not everyone with DAO SNPs develops histaminosis, and not everyone with histaminosis has DAO SNPs.
The functional medicine model enables diagnosis of complex, many cause - many symptom conditions, like histaminosis. The power of nutrigenomics comes from recognising the connections between genes, nutrition and lifestyle. We want to avoid “treating SNPs”, but we can support healthy gene expression by personalising nutrition and supplementation based on an individual’s unique genetics.
Histamine Report includes HNMT, MTHFR, DAO, MAOB, NAT2, GPX1 and ALDH2 genes.
Hormones report includes CYP17A1, CYP19A1, CYP1B1, MTHFR, COMT, SUL1A1, SULT1E1, UGT1A, GSTM1 genes and more