Role of histamine in chronic inflammations

Many chronic or recurring problems discussed in this blog have in common the existence of permanent pelvic inflammation sometimes “deaf”, sometimes “acute” from the symptomatic point of view: abacterial cystitis, recurrent cystitis, endometriosis, bladder pain syndrome, interstitial cystitis, vaginitis and vaginal infections, pelvic contracture, vulvovaginal syndrome, etc. This perennial inflammation, whatever its origin, involves histamine, a molecule that is useful to know and try to control to manage or alleviate the discomfort of inflammatory processes.

What is histamine?

Histamine is a cytokine: a protein-signaling molecule of the immune system. The body naturally produces it, in particular mast cells in all tissues of the body such as the skin, the gastric wall and the brain, but also in the pelvic organs such as the bladder urothelium, the vaginal mucosa or the intestinal wall.

It is a “chemical mediator” that plays a fundamental role in one of the main processes of immune response to infections (presence of pathogens such as bacteria, yeast, fungi, parasites or viruses): the inflammatory response.

How is histamine produced?

The cells involved in inflammation (mainly mast cells) are present but dormant in all tissues and have secretory granules (similar to “pockets”) that contain inactive chemical mediators (histamine and other biologically active molecules).

When the cell comes into contact with a substance that it identifies as “enemy” or potential cause of infection (see antigen in the image), mediators are activated and released at the site -> this is the specific inflammatory response (because it will be the same whatever the cause of the activation).

Mast cell

Among the most well-known “triggers” (also known as “triggering factors”) of mast cells, in addition to infections, we can also mention:

excessive heat or “cold blast”

– vibrations and movements (postures, contracture, etc.)

– stress and trauma (physical and emotional)

– food and medicine

What are the consequences of histamine release?

1. Under physiological conditions

Histamine has an important vasodilatory action and increases the permeability of blood vessels, thus favoring the influx of blood to the affected area and increasing mucus production.

Furthermore, the release of histamine (and other mediators) by mast cells acts as a call against more specific immune system cells, such as antibodies, thereby enhancing the immune response against the pathogen.

For these reasons, histamine release and more generally the immune response, is characterized by: redness, warmth, edema and pain that are more or less evident and localized depending on the subject and the reaction site.

1. Anomalies

Other triggers can induce an inappropriate or excessive release of histamine:

– allergy: the body identifies a harmless substance as “enemy” (antigen) which causes a false response by the immune system

– inflammation chronicization: in some cases, mast cell activation continues despite the resolution of initial infection or when the cause of the inflammatory response is not identified and managed correctly. This is the case, for example, of certain forms of BPS, endometriosis, recurrent or chronic urogenital infections, formation of intracellular biofilms (both vaginal and bladder) also incorrectly called “embedded infection“.

Histamine and pelvic and bladder inflammation

The presence of mast cells in high and therefore significant quantities has been demonstrated in the following situations:

1. Bladder Pain Syndrome

Several studies have demonstrated the presence of large numbers of mast cells in bladder tissue biopsies of subjects suffering from interstitial cystitis/bladder pain syndrome (BPS/IC)1.

Furthermore, it has been shown that histamine plays an important role in the neuronal transmission responsible for bladder and pelvic pain associated with BPS/IC.

These studies have shown that BPS/IC patients have a much higher mast cell count than the healthy population in the submucosal layer of the bladder wall (urothelium) and in the smooth muscle layer of the bladder1 2. Therefore, increased histamine release can lead to wall edema and contraction of the bladder muscles, resulting in decreased bladder capacity, decreased bladder stretch (elasticity) capacity and the need to urinate frequently and imperiously.

2. Recurrent bacterial cystitis

An important role for mast cells has also been demonstrated in patients with chronic bacterial cystitis3: mast cell infiltrates have been found in biopsies of bladder tissue from patients suffering from chronic bacterial cystitis*. This finding is completely justified by the main function of mast cells: to guarantee the local immune response to a pathogen attack. In particular, in the presence of E. coli infection, they secrete not only histamine but also TNF-α, a key mediator in the recruitment of neutrophilic granulocytes4.

*it is for this reason that the mast cell infiltrate count is no longer an accepted criteria for the diagnosis of BPS/IC.

Histamine and estrogen

Women are prone to histamine intolerance much more than men and histamine often worsens during ovulation and during the first phase of the menstrual cycle (periods when estrogen levels are higher than progesterone ones).

Estrogens stimulate mast cells to release histamine and cause inhibition of the DAO enzyme that is involved in the decomposition of histamine. At the same time, the histamine produced stimulates the ovaries to produce more estrogen, thus creating a vicious cycle that leads to increased and excessive production of histamine and its accumulation in the tissues (lack of means for elimination).

For this reason, progesterone-based hormone therapy is an often beneficial option for pelvic pain in cases of chronic inflammation. However, we must be careful weighing the benefit/risk balance of this type of approach with a specialist since the other side of the reduction in the level of estrogens (menopause, for example) is a decrease in the trophism of the mucous membranes and the growth of flora, sometimes at the origin of some disorders.

Histamine intolerance

Histamine intolerance corresponds to a situation of imbalance between the production (excessive) and the degradation (insufficient) of histamine in the body.

Typical symptoms of histamine intolerance vary depending on the location of the histamine accumulation (excess production site) and can be:

– gastrointestinal disorders (diarrhea, abdominal cramps)

– asthma, breathing difficulties

– dermatitis, skin rashes

– headache, migraine

– dysmenorrhea

– pain

– contracture

– neuropathies

Reduction in histamine levels

Unlike pathological situations such as allergies where antihistamine therapies are used, there is no specific treatment for histamine intolerance. The management of this problem, as soon as it is detected or assumed, consists of a series of natural measures:

1. follow an adequate diet, limiting the main sources of histamine:

– tomatoes, sauerkraut, spinach

– all kinds of canned foods

– smoked fish (herring, salmon, etc.), seafood and shellfish

– all kinds of cold cuts (sausages, salami, dried meat, smoked ham, bologna, etc.)

– fermented and mature cheeses

– alcohol of all kinds (wine, beer, etc.) and wine vinegar

– yeasts

A low histamine diet is used to control bladder pain syndrome and, thanks to the association with an alkaline diet, many people have seen an improvement in pain and a decrease in bladder5 inflammation.

2. Complement the diet with food supplements capable of reducing or inhibiting the activation of mast cells such as quercetin and chondroitin sulfate like Alaquer and Cistiquer.

Bibliography

1. Kim A1, Han JY2,3, Ryu CM2,3, Yu HY2,3, Lee S3, Kim Y3, Jeong SU4, Cho YM4, Shin DM3, Choo MS2.- Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion.- Histopathology. 2017 Sep;71(3):415-424. doi: 10.1111/his.13235.

2. Malik ST1, Birch BR2, Voegeli D1, Fader M1, Foria V3, Cooper AJ4, Walls AF2, Lwaleed BA1.- Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies?-  J Clin Pathol. 2018 Sep;71(9):840-844. doi: 10.1136/jclinpath-2017-204881. Epub 2018 May 15.

3. Choi HW1, Bowen SE2, Miao Y2, Chan CY3, Miao EA4, Abrink M5, Moeser AJ6, Abraham SN7.- Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules.-  Immunity. 2016 Dec 20;45(6):1258-1269. doi: 10.1016/j.immuni.2016.11.003. Epub 2016 Dec 6.

4. Varadaradjalou S1, Féger F, Thieblemont N, Hamouda NB, Pleau JM, Dy M, Arock M. -Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells.- Eur J Immunol. 2003 Apr;33(4):899-906.

5. Oh-Oka H1.- Clinical Efficacy of 1-Year Intensive Systematic Dietary Manipulation as Complementary and Alternative Medicine Therapies on Female Patients With Interstitial Cystitis/Bladder Pain Syndrome.- Urology. 2017 Aug;106:50-54. doi: 10.1016/j.urology.2017.02.053.

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