Histamine intolerance

Histamine intolerance is a presumed set of adverse reactions to ingested histamine in food. The mainstream theory accepts that there may exist adverse reactions to ingested histamine, but does not recognize histamine intolerance as a separate medical condition that can be diagnosed.
In 2023 blinded provocation study the vast majority of patients with the supposed syndrome reported symptoms to placebo. There is a common suspicion that ingested histamine in persons with deficiencies in the enzymes that metabolize histamine may be responsible for various non-specific health complaints, which some individuals categorize as histamine intolerance; still, histamine intolerance is not included as an explicit condition in the International Classification of Diseases Edition 11. The scientific proof that supports the idea that eating food containing histamine can cause health problems is currently limited and not consistent. Some studies have attempted to elucidate a direct, causal link between histamine ingestion and clinical symptoms associated with histamine intolerance, but the results have been mixed, complicating the interpretation of the data.
Histamine intolerance affects a variable portion of the population, with estimates on about 1%, though exact prevalence is unclear due to diagnostic challenges. Current research focuses on better understanding the condition's etiology, improving diagnostic methods, and developing effective treatments, but no such treatment has been found so far. Research is primarily focused on dietary adjustments and lifestyle modifications which are currently the most promising options. Societally, histamine intolerance has led to increased awareness and dietary adjustments, but it remains a controversial and under-recognized condition in the medical community.

Signs and symptoms

The manifestations of histamine intolerance are usually systemic, affecting the entire body; still, these symptoms are often sporadic and non-specific. The onset of symptoms is usually shortly after specific food or drink consumption, and subsequent remission usually happens in 4-8 weeks of dieting, that is excluding food that causes the onset of symptoms.
Symptoms attributed to histamine intolerance are wide-ranging and may affect various physiological systems, including the skin, gastrointestinal, cardiovascular, respiratory, and nervous systems. These symptoms are not specific to histamine intolerance and may overlap with other conditions or disorders.

Causes

Histamine, a biogenic amine found in various food products, is frequently implicated as a potential instigator of a range of health issues. These issues are often collectively referred to under the umbrella term "histamine intolerance", formulated drawing parallels to "lactose intolerance", a condition resulting from lactase enzyme deficiency. Nevertheless, there are no prospective, controlled studies that would have conclusively established an enzyme or a lack thereof as the root cause of adverse reactions following histamine ingestion.
Some scholars suspect that histamine intolerance is a condition characterized by an imbalance between histamine intake through the diet and the body's ability to metabolize ingested histamine so that this imbalance leads to increased blood histamine concentration, which can cause adverse effects. Histamine intolerance is considered by these scholars a non-immunological disorder that results from reduced activity or levels of the enzymes that metabolize histamine: diamine oxidase and histamine N-methyltransferase. Still, the exact prevalence of histamine intolerance is unknown due to limited data and a lack of validated diagnostic methods.
File:Maquereaux etal.jpg|thumb|right|Atlantic mackerel, a species of fish belonging to Scombridae family, a family of species which if stored improperly, can spoil and upon consumption can cause scombroid fish seafood poisoning, a medical conditionDespite this common attribution of various symptoms as adverse reactions to ingested histamine, the scientific substantiation for a direct link between the ingestion of histamine and the manifestation of clear reproducible symptoms remains inconsistent. A small number of studies have attempted to elucidate this relationship through the rigorous methodology of double-blind, placebo-controlled oral food challenges involving histamine. However, the results yielded from these investigations have been notably mixed and heterogeneous, further complicating the interpretation of the data and comparison of results of these studies. Despite the lack of robust, consistent evidence, the consumption of histamine continues to be suspected as the etiological agent behind a variety of nonspecific health complaints.
The scientific support for such a clinical picture—the combination of symptoms, signs, and other medical information, associated with histamine ingestion—remains limited and presents contradictory findings: for example, histamine present in dietary sources such as Emmental cheese is tolerated better compared to histamine derived from spoiled fish, particularly those belonging to the Scombridae family, which includes species like tuna and mackerel. The adverse physiological responses associated with the consumption of such spoiled fish are typically a result of histamine toxicity rather than intolerance to histamine per se. This response caused by spoiled fish suggests that the intake of abnormally high concentrations of histamine would elicit a reaction in any individual, irrespective of their sensitivity to histamine. It is not clear whether the symptoms observed in cases of fish poisoning can be attributed solely to the histamine content of the spoiled fish, or if other factors may also be involved.
Histamine can bind to four types of receptors and trigger various physiological responses. The physiological responses that histamine can trigger depend on which type of receptor it binds to. For example, H₁ receptors are involved in allergic reactions, inflammation, and sensory perception: they can cause smooth muscle contraction, increased vascular permeability, and stimulation of sensory nerve endings. Histamine levels in the blood and inside the cells are normally regulated by two enzymes: diamine oxidase and histamine N-methyltransferase.
In some cases, circulating histamine levels can rise and cause adverse effects. According to some authors, such cases can be caused by two main reasons: histamine intoxication and histamine intolerance.
Histamine intoxication is a condition that occurs when healthy individuals consume foods that contain high amounts of histamine, such as spoiled fish. In histamine intoxication, the ingested histamine can overwhelm the capacity of the histamine-degrading enzymes and lead to symptoms such as flushing, headache, nausea, diarrhea, hypotension, and arrhythmia. The diagnosis of histamine intoxication is based on the clinical presentation and the history of food intake. The treatment consists of antihistamines, fluids, and supportive measures.
Histamine intolerance, in contrast to histamine intoxication, is a presumed disorder that affects individuals who are supposed to have a reduced or impaired activity of the histamine-degrading enzymes, either due to genetic factors, medications, or gastrointestinal diseases. In healthy individuals, the consumption of small amounts of histamine typically does not have any adverse health effects. However, in supposedly affected individuals, ingesting histamine through food at levels well below those associated with scombroid poisoning can lead to symptoms related to histamine intolerance. In the ICD-11, there is a condition "XM74Y6 Scombroid fish seafood poison", but not "histamine intolerance". In the supposed histamine intolerance, these affected individuals supposedly have a lower threshold for histamine and can develop symptoms even after consuming foods with normal or moderate amounts of histamine, such as tomatoes, eggplants, spinach, strawberriesplants which naturally contain histamineor wine. The symptoms of alleged histamine intolerance are similar to those of histamine intoxication, but they can also include chronic conditions such as urticaria, asthma, rhinitis, or migraine. Some scholars believe that the diagnosis of histamine intolerance is challenging and requires the exclusion of other causes of histamine-related symptoms, as well as a positive response to a low-histamine diet, and the treatment of histamine intolerance, involves avoiding histamine-rich foods. Still, there are currently no measurable indicators that can confirm the occurrence of adverse reactions due to the ingestion of histamine.
The exact causes of histamine intolerance are not fully understood, but they can be multifactorial. One of the factors believed to cause histamine intolerance is an imbalance between uptake of histamine through the diet and a diminished capacity to metabolize ingested histamine, leading to an increased blood concentration of the amines which may potentially cause adverse effects.
The primary cause of histamine intolerance is considered by several authors to be insufficient activity or reduced levels of the enzyme diamine oxidase, which normally metabolizes histamine in the intestine. Dietary histamine enters the body through the intestinal epithelium. While histamine N-methyltransferase, another enzyme that metabolize histamine, is also present in the gastrointestinal tract, DAO is more abundantly expressed in the tract and primarily protects against exogenous histamine from food or gut microbiota. Therefore, the role of HNMT is of lesser significance for breaking ingested histamine. Animal studies using DAO inhibitors have shown its protective role against ingested histamine with food. Other probable factors that may contribute to histamine intolerance include endogenous overproduction of histamine due to allergies or mastocytosis, genetic inheritance resulting in reduced DAO activity or effectiveness, pathological factors such as intestinal diseases affecting DAO production or function, pharmacological factors like medications inhibiting DAO activity, and alterations in gut microbiota leading to increased levels of bacteria secreting biogenic amines, including histamine. It has been established that certain bacteria within the gut microbiota, notably lactobacilli, have the ability to produce substantial amounts of histamine—the recognition of histamine as a significant metabolite of these intestinal bacteria raises doubts about the reliability of diagnostic stool analysis.