Histamine – NET or NOT?

Histamine is mentioned a lot in both patient groups and in literature as somehow connected with NETs, particularly with so called carcinoid syndrome (CS). In fact, various putative mediators, including serotonin, catecholamines, brady- and tachykinins, kallikrein, histamine, motilin, and prostaglandins, have been suggested as potential causative factors for the symptoms and complications associated with CS. It is generally believed that most of these tumour-derived secretory products are inactivated by hepatocytes and, therefore, only cause symptoms when they either bypass or are secreted outside of the portal vein drainage system. I wanted to focus on Histamine in this article. But what is the scientific evidence of causation other than random mentions in articles over the years? Serotonin has plenty of evidence and is already covered in The NET Effect Series.

Please do not interpret anything I say as histamine being the cause of your symptoms. Nor I am saying that your histamine issues are unrelated to NET. I’ll let your doctors speculate on that.

What is histamine?

Histamine is a signalling chemical your immune system releases to send messages between different cells. Histamine has several functions, but it’s mainly known for its role in causing allergic and anaphylactic symptoms. Allergies are your body’s reaction to a foreign protein. Usually, these proteins (allergens) are harmless. However, if you have an allergy to a particular protein, your immune system overreacts to its presence in your body. A cascade of reactions leads to a release of histamine, which causes allergy symptoms. These symptoms are usually confined to one area of your body. If the immune reaction is severe, it causes anaphylaxis, which affects most of your body. Anaphylactic shock can be life-threatening. (2)

Your body mainly stores histamine in mast cells in tissues and basophils in blood. Mast cells are a type of white blood cell that’s present in connective tissues throughout your body, Histamine regulates countless bodily functions and plays a key role in your body’s inflammatory response. The effect histamine has depends on which histamine receptors it binds to. Researchers have identified four types of histamine receptors. (2)

H1 receptors

You have H1 receptors throughout your body, including in neurons (brain cells), smooth muscle cells of your airways and blood vessels. Activation of the H1 receptors causes the well-known allergy and anaphylaxis symptoms, e.g. itchy skin (pruritus), expanding of blood vessels (vasodilation), low blood pressure (hypotension), increased heart rate (tachycardia), flushing, narrowing of your airways (bronchoconstriction), pain, movement of fluids through blood vessel walls (vascular permeability). Some of these bodily changes result in sneezing, nasal congestion and runny nose (rhinorrhoea). (2)

H2 receptors

You have H2 receptors mainly in the cells in your stomach that release acid, smooth muscle cells and heart cells. Activation of the H2 receptors leads to: stomach acid secretion, which helps with digestion, stimulation of mucous glands in your airways, vascular permeability, hypotension, flushing, headache, tachycardia, bronchoconstriction. (2)

H3 receptors

H3 receptors are mainly involved in blood-brain barrier function. They’re found in neurons in your central nervous system. H3 receptors regulate the release of histamine and neurotransmitters like dopamine, norepinephrine and acetylcholine. (2)

Researchers are currently studying H3 receptor antagonist medications for potential use in the treatment of neurodegenerative diseases. (2)

H4 receptors

H4 receptors are present in your bone marrow and hematopoietic cells (immature cells that can develop into all types of blood cells). They play a role in the formation of certain blood cells.

They also play important roles in inflammatory disorders and autoimmune diseases. (2)

Histamine intolerance (HIT)

A condition where the body can’t break down excess histamine from food, alcohol, or internal production, leading to allergy-like symptoms (headaches, hives, nasal issues, gut problems, heart palpitations) because of histamine build-up, often due to a lack of the enzyme DAO, genetics, or gut issues, managed by low-histamine diets, supplements, and avoiding triggers. It’s not a true allergy but mimics one, making diagnosis tricky, though dietary changes and DAO enzyme support are key management strategies. Histamine intolerance isn’t a true allergy — it’s more like a mismatch between how much histamine you take in and how well your body can break it down.

Is Histamine part of carcinoid syndrome?

The description of Histamine above is generally accepted as a standard overview of Histamine and you can see something similar on many of the top medical sites in the world. It’s also worth saying that histamine issues unrelated to NET affect a large proportion of the general population including (but not limited to); histamine intolerance, mast cell disorders, food allergies (histamine can be found in certain foods), flushing unrelated to NETs, and many more. It follows that many NET patients will have histamine issues unrelated to their NET.

NET hormonal syndromes are known to be caused by the over secretion of excess NET related hormones from tumour cells.

Histamine – is there a specific NET connection?

There would appear to be mainly connections with foregut NETs e.g. gastric/duodenum/pancreas/lungs. These group of tumours almost always have a low content of serotonin (5-HT), and often secrete the serotonin precursor 5-HTP rather than serotonin itself, histamine (evidence is weak), and a multitude of polypeptide hormones. Foregut NETs are said to be associated with an atypical CS.

Gastric NETs. These are usually classified according to the background gastric pathology into three major categories: (i) type I when chronic atrophic gastritis (CAG) is present resulting in hypergastrinemia (the most common type, accounting for 75%–80% of all gNENs); (ii) type II when the tumour occurs due to hypergastrinemia in the context of Zollinger–Ellison syndrome (ZES) and multiple endocrine neoplasia type I (MEN-I) syndrome (5% of gNENs); type III, which are sporadic lesions not associated with hypergastrinemia (15%–25% of gNENs). (3)

Types I and II Gastric NETs are known to be associated with hypergastrinemia, i.e. they are gastrin-dependent tumours. Normally, food stimulates the vagus nerve to initiate the cephalic phase of gastric acid secretion that includes the release of gastrin from antral G cells Secreted gastrin binds to the cholecystokinin B receptor (CCKBR), which is normally expressed on ECL cells. Ligand-receptor binding triggers histamine release from ECL cells that subsequently binds to histamine H2 receptors on parietal cells to stimulate acid. Some texts describe this as Gastrin-induced histamine release. The inference is that it is not a tumour release of histamine, it’s more of an indirect effect. This may be why some NET documents describe this as an atypical syndromic effect. Type III Gastric NETs are not normally associated with hypergastrinemia. Type II Gastric NETs are associated with the presence of a Gastrinoma (see below).

Duodenal NETs and Pancreatic NETs

Gastrin is also related to a functional syndrome known as Gastrinoma predominately found in the duodenum or pancreas. In this scenario, the combination of high levels of gastrin normally along with the combination of high levels of gastrin, too much acid and stomach or small bowel ulcers is called Zollinger Ellison Syndrome (ZES). As a gastrin dependant tumour, it may be causing Gastrin-induced histamine release as described above in Gastric NETs. .

Depending on where you look, around 70% start in the duodenum where they are usually small (often less than 1 cm across). They are called duodenal gastrinomas. About 25 out of every 100 gastrinomas (25%) start in the pancreas (pancreatic gastrinomas) where they usually start in the widest part of the pancreas (the head). Around 5% are in much less common primary sites (4)

Lung NETs

Up to half of the patients (13–51%) with lung NETs have no symptoms and are incidentally diagnosed on routine chest X-rays or computerized tomography (CT) scans. Common presenting symptoms include classic pulmonary symptoms such as dry cough, wheezing sound, haemoptysis, dyspnea, recurrent pneumonia, persisting lung infiltrates, and chest pain. Although lung NETs may secrete various hormones, endocrine symptoms are rare. Carcinoid syndrome (CS) due to elevated 5-hydroxy indoleacetic acid (5-HIAA) with flushes, diarrhea, asthma, and right-sided valvular heart disease, is normally seen only when liver metastases are present and is seen in 2–12% of patients with lung NETs. The low frequency of CS can be explained by the high concentration level of monoamine oxidase in the pulmonary system, which metabolizes serotonin, and the rare occurrence of distant metastases in patients with lung NETs. An atypical CS with generalised flushing, edema, lacrimation, bronchoconstriction, and diarrhea caused by histamine secretion may be seen occasionally. (5)

What’s the new evidence?

Despite several fairly recent papers from well known NET specialists stating that histamine is involved with CS, a more recent paper from the long established ENETS Centre of Excellence in Rotterdam now claims there is insufficient evidence to include histamine (and others) as a mediator of CS. An extract from that study follows.

A potential link of histamine with CS was first described by Oates and colleagues in 1962, who described an “atypical” CS associated with metastasized gastric NEN (type and grade not defined). These patients would present with elevated urinary concentrations of histamine and 5-hydroxytryptophan (5-HTP), the precursor of serotonin, combined with clinical features of red, patchy flushes, markedly different from the regular carcinoid flush. Surprisingly, aside from case reports, only 1 study could be identified that mentioned such patients. This study of 27 CS patients only measured histamine concentrations in the 4 patients who had elevated circulating 5-HTP levels. In these CS patients (1 pancreas, 1 gastric, and 2 of unknown primary origin), 24-hour urinary histamine concentrations were increased in 2 patients and symptoms that resembled those described by Oates and colleagues were only described for the patient with the gastric NEN (type and grade not defined). The only other study that measured 5-HTP in CS patients did not find elevated 24-hour urinary 5-HTP concentrations in 6 NEN patients with symptoms of flushing and diarrhea (3 ileum tumors, 3 tumors of unknown primary origin), 3 of whom reported episodes of wheezing. In these studies, concentrations of 5-HTP and histamine were compared with reference values obtained in healthy controls.

Three other studies measured histamine concentrations in CS patients, reporting contradictory results. While urinary histamine concentrations were elevated in 1/6 CS patients in 2 studies (controls not defined), plasma histamine concentrations were elevated in 8/8 patients compared to “control patients” in the third study (threshold upper limit of normal defined as 3 pmol/L). The only study that analyzed the effect of histamine pathway blockers in more than 1 patient did not find an effect of pharmacological doses of the histamine-1 receptor blockers mepyramine (50-100 mg/6-8 hours IV, IM, and PO) and promethazine (50 mg IM) on flushing in 3 investigated patients. Provocation of 3 CS patients with an intravenous injection of 25 mg histamine acid phosphate induced a flush accompanied by a fall in blood pressure, in contrast to a rise in blood pressure, which occurred in spontaneous and adrenaline-induced flushes. The prospective study by Condron and colleagues was unable to associate plasma histamine concentrations with the occurrence of carcinoid crisis. While some authors have reported elevated intratumoral histamine concentrations in NEN tissue, no studies were found in which intratumoral histamine concentrations were measured in the tumor tissue of more than 1 CS patient. Moreover, no studies could be identified that correlated histamine concentrations to the wheezing associated with CS. Available evidence is summarized in the sixth row of Tables 1 and 2 of Reference 1 and the authors of that reference concluded as follows:

“Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, motilin, and other putative mediators to CS, even though medications that can regulate these mediators are still either recommended or generally used to treat patients with CS.”

What Is Carcinoid Syndrome? A Critical Appraisal of Its Proposed Mediators Merijn C F Mulders, Wouter W de Herder, Johannes Hofland Endocrine Reviews, bnad035, https://doi.org/10.1210/endrev/bnad035 Published: 01 December 2023

References:

P.S.

Based on my prescription based use of anti-histamines since 2023, I may have had a histamine related issue with several breakouts of hives (urticaria). However, I know with 99.99999% certainty that it is unrelated to NETs after analysing events leading up to these breakouts (I keep a diary). Read more about these issues by clicking here spoiler alert, think cortisol.

hives Ronny Allan — Click picture to read more

P.P.S.

Causation, correlation, coincidence and confounding factors (the 4 Cs) are important principles to understand in these complex issues with NET. Read more about the 4 Cs by clicking here or on the graphic below.

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