‍

I frequently meet patients who seem to have a multitude of complaints that have not been solved despite numerous doctor visits, diagnostic testing, medication and/or supplements. They may experience headaches, pain, itching, digestive distress, respiratory disfunction, bladder pain or lymphedema. Most of the time patients experience a combination of these symptoms that may plague them for years.

‍

‍The Role of Histamine in Neurogenic Inflammation 1

Although seemingly unrelated, they are all caused by histamine, which drives allergic symptoms, food reactions, and mold reactions, as well as contributing to brain fog, increased pain, and a whole host of other mischief.

The factors above are connected through the mechanism of histamine release and neurogenic inflammation. When mast cells encounter a trigger, they release histamine, evoking the release of 3 neuropeptides from the neighboring sensory nerves, a process known as neurogenic inflammation. (NI) These neuropeptides are:

  1. Substance P (SP) that causes inflammation and pain
  2.  Calcitonin Gene Related Peptide (CGRP) is a well-known driver of both migraine and clusters of symptoms including leg swelling (lymphedema) when in a histamine-mediated flare
  3. Vasoactive Intestinal Polypeptide (VIP) is a neuropeptide that functions as a neuromodulator and neurotransmitter. It is a potent vasodilator, regulating smooth muscle activity, epithelial cell secretion, and blood flow in the gastrointestinal tract. Beyond just the GI tract, VIP drives the activity of innate lymphoid cells type 2 (ILC2), a cell of the T-helper lymphocyte type 2 response system (Th2). These Th2system cells release mediator cytokines IL-5 (driving mast cell activation) andIL-13 (causing mucus production)

Furthermore, these neuropeptides stimulate the adjacent mast cells maintaining a continuous release of histamine from these cells. This becomes a bidirectional loop between histamine and neuropeptides, causing an ongoing neurogenic inflammation

Some patients make too much histamine in response to environmental and/or dietary triggers. Some patients can’t clear it out of their systems efficiently. Some patients have both overproduction and slow clearance leading to excessive CGRP, SP and/or VIP release.

These self-perpetuating loops suggest that patients with any combination of mast cell disorders, histamine intolerance, Th2 dominance, interstitial cystitis, migraine, lymphedema, itching, dysbiosis, respiratory issues, and related disorders should be assessed with an understanding of neurogenic inflammation in mind.

Furthermore, many patients with allergies or other promoters of excess histamine often tend to also be sensitive to perfumes and other sources of aldehydes like building materials, new carpets, etc. Histamine and aldehyde metabolism both require aldehyde dehydrogenase (ALDH). The abundance of histamine means the ALDH enzyme system capacity is being used up getting rid of histamine, so there’s not enough capacity to deal with the excess histamine or to deal with aldehydes when exposures occur.

The goal is to inhibit the neurogenic loop, by:

  1. Identifying and minimizing exposure to respiratory triggers. Use Mast Cell Assist to reduce the release of histamine, ease the symptoms, and facilitate histamine metabolism and clearance
  2. Reducing total histamine burden, rather than absolute avoidance since most people do well if they do not exceed their threshold ability to clear histamine. It is beneficial to know which foods are high in histamine but should not be taken as a list of foods that must be completely avoided, but rather as a list to help identify ways to decrease your total load
  3. Easing the symptoms caused by high histamine intake and/or released in the GI tract and facilitates is an important step and may be accomplished with  Histagest-DAO enzyme
  4. Enhancing aldehyde dehydrogenase (ALDH) function, which is the ultimate histamine neutralizing and clearing enzyme. Besides histamine, ALDH is responsible with the clearance of aldehydes found in perfumes or are released from new carpets, building materials, and molds. Patients who are sensitive to these triggers are often the same patients who have trouble with histamine. Therefore, it is necessary to test the cofactors for ALDH (i.e., molybdenum, B2, B3, andiron) and supplementing if necessary
  5. Rebalancing the Th1 and Th2 systems:
    • Identifying and addressing the sources of Th2 system dominance: dysbiosis or other GI issues, molds, pesticide residues, air pollution, advancing age, sleep disruption, stress chemistry, some pathogens. Th2dominance may be presented as food reactions, asthma, allergies, atopy, mast cell issues, histamine issues, frequent colds, persistent or repeat infections (UTI’s, URI’s, sinus infections, persistent dysbiosis, high background viral burdens) and others.
    • Ensuring adequate Th1 response and vitamin D control of Th2 system, promoting autophagy, and lowering inflammation. Identifying and addressing all sources of inflammation: hyperglycemia, elevated uric acid, low potassium below 4.0, hypercholesterolemia, sources of free radicals, pathogens, etc. Th1response often diminishes as we age. Therefore, direct support for Th1 and NK cell activity should be considered especially in patients over 70 years old.

By implementing these practical steps, you’ll be giving your body the support it needs to function at its best. However, if you're dealing with intense, lingering symptoms or have an ongoing diagnosis, I strongly encourage you to seek out the guidance of an experienced Integrative and Functional Medicine Doctor, who can test and interpret your results, as well help create a personalized protocol tailored to your specific needs – ensuring that you get the best outcomes.

‍Reference

  1. The role of histamine in neurogenic inflammation, Rosa AC, Fantozzi R., Br J Pharmacol. 2013 Sep;170(1):38-45.
  2. Neuro-immune interactions in allergic diseases: novel targets for therapeutics, Voisin T, Bouvier A, Chiu IM., Int Immunol.2017 Jun 1;29(6):247-261.
  3. CGRP and its receptors provide new insights into migraine pathophysiology, Ho, T. W. et al., Nat. Rev. Neurol. 6, 573–582(2010).
  4. The small intestine plays an important role in upregulating CGRP during sepsis, Zhou M, Arthur AJ, Ba ZF, Chaudry IH, Wang P., Am J Physiol Regulatory Integrative Comp Physiol 280: R382–R388, 2001.
  5. Enhancement of CGRP sensory afferent innervation in the gut during the development of food allergy in an experimentalmurine model, Lee J, Yamamoto T, Hayashi S, Kuramoto H, Kadowaki M., Biochem Biophys Res Commun. 2013 Jan 18;430(3):895-900.
  6. Endogenous Calcitonin Gene-Related PeptideDeficiency Exacerbates Postoperative Lymphedema by Suppressing LymphaticCapillary Formation and M2 Macrophage Accumulation, Matsui S, Tanaka M,Kamiyoshi A, et al., Am J Pathol. 2019, Dec; 189(12): 2487-2502.