Treatment without prevention is simply unsustainable.
– Bill Gates
Histamine Intolerance (HIT)
Mast cells are immune cells that are manufactured in bone marrow and are distributed in all tissues of the body, especially at environmental interfaces. Mast cells react to potential threats to the body such as infection and mediate inflammatory responses such as hypersensitivity and allergic reactions.
Mast Cell Activation Disease (MCAD) is a condition associated with abnormal mast cells that feature dysregulated activation in response to threats or even inappropriate activation when there is no threat at all. When activated, mast cells release their contents, called mediators, which both promote and regulate activity in other cells related to immunological as well as non-immunological processes.
See:
Mast Cell Activation Disease (MCAD)
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Histamine Intolerance (HIT)
Histamine Intolerance (HIT) is a condition associated with nonspecific gastrointestinal (GI) symptoms and extra-intestinal symptoms. In HIT, there is a disproportionate amount of histamine in the body which is thought to result from eating food with high histamine content along with having a reduced ability to digest histamine. The digestion of histamine is mainly accomplished by the enzyme diamine oxidase (DAO) and the diagnosis of HI is usually based on significantly reduced blood levels of DAO (<10U/ml).
Symptoms
Symptoms associatecd with HIT includes gastrointestinal symptoms such as bloating, the most common symptom (92%), along with other abdominal symptoms such as postprandial fullness (73%), diarrhea (71%), abdominal pain (68%), constipation (65%), intestinal cramping (53%), belching (52%), nausea (48%), painful menstruation (29%) vomiting (15%).
Skin symptoms of HIT include itching (48%), flush (34%), rash/eczema (27%), swollen, reddened eyelids (27%).
Cardiovascular system symptoms of HIT include dizziness (66%), headache (65%), palpitation (47%), loss of muscle tone (32%), collapse (8%).
Respiratory system symptoms of HIT include runny nose (48%), nasal congestion (48%), sneezing (48%), shortness of breath (26%).
Cause of HIT
The cause of HIT is believed to result from abnormal histamine metabolism. It is unclear whether patients with histamine intolerance react inappropriately to small quantities of histamine or whether they may suffer from an increased level of endogenous or exogenous histamine. In fact, some patients with histamine intolerance turn out to have MCAD when evaluated further by laboratory testing.
Treatent of Histamine Intolerance
(1) Antihistamines
Antihistamines are most commonly used to treat allergic symptoms such as hives and itching. Antihistamines block the effects of histamine, one of the major mediators released by activated mast cells, responsible for the wheal and flare of hives. There are 4 types of histamine receptors, H1-4.
Histamine receptors are transmembrane receptors on cells which mediate cellular responses to histamine, a mediator of an inflammatory response generated by mast cells. Currently, four histamine receptors have been identified, although medications have generally been directed only at H1 and H2 receptors. Histamine receptors are widely distributed in the body in nerve, smooth muscle (vascular, gastric and bronchial), blood, heart, immune system and the endocrine system.
Historically, histamine receptor antagonist medications are functionally targeted based on their properties: as anti-inflammatory (H1 receptors), anti-ulcer (H2 receptors) and sleep-inducing (H1 receptors). In some cases, “dual-histamine receptor blockade,” using both H1 and H2 antagonists in combination has been employed for treating conditions such as recurrent urticaria (hives). Unfortunately. there are currenttly no FDA-approved H1-H2 receptor combination drugs available.
H1 Antihistamines:
In the lung, the H1 receptors mediates the contraction of airway smooth muscle and is implicated in heightened airway hyperresponsiveness in COVID-19 (see above). Other effects of the H1 receptor include urticaria and increased vascular permeability. H1 antihistamines medications are histamine receptor antagonists that block activation of H1 receptors on mast cells and antagonize H1-mediated symptoms:
(a) Benadryl (diphenhydramine) or;
(b) Zyrtec® (cetirizine) or Xyzal(levocetirizine) or;
(c) Atarax/Vistaril (hydroxyzine)
H2 Antihistamines:
Similarly, these medications are histamine receptor antagonists that block activation of H2 receptors on mast cells and antagonize H2-mediated symptoms:
(a) Pepcid® (famitodine)
(b) Axid (Nizatidine)
(c) Tagamet (cimetidine)
Dual-histamine Receptor Blockade
The combined use of both H1 and H2 antihistamines, or “dual-histamine receptor blockade,” is recommended as baseline management of MCAD.
When the combination of cetirizine (10 mg twice a day) and famitodine (20 mg twice a day) was studied and reported in a June 2020 publication, it was found this c0mbination exhibited beneficial reductions in inpatient mortality and symptom progression. While this was a small “proof-of-concept” study that needs further research to confirm their findings, the authors concluded this dual combination is safe and effective in management of COVID-19.
Additionally, another COVID-19 study evaluaing famotidine alone in doses ranging from 10 to 40 mg found a reduced risk of death and intubation. In comparison, use of proton pump inhibitors (that reduce gastric acid independent of a histamine mechanism) were not associated with reduced risk of death or intubation, reinforcing the conclusion that the famotidine benefit is histamine-mediated.
Long term side effects with antihistamines
There is growing recognition of the detrimental effects on thinking (mental clouding and other cognitive impairments) caused by long term use of antihistamines. Patients at increased risk of this are patients >65 years and patients taking 50 mg of benadryl (diphenhydramine)/day for >3 years or doxepin (25 mg for 6 years). Also, high doses of sedating antihistamines such as diphenhydramine can cause increased seizure activity, seen mostly in children. A tolerance to or a dependence upon diphenhydramine may result in a need for even higher doses. Caution and restraint must be used when taking antihistamines long term and titrate to the lowest dose necessary to control symptoms.
Other Antihistamines
In addition to H1 and H2 antihistamines, it has also been proposed that antihistaminew with anti-eosinophilic action (ketotifen, rupatadine)
and antihistamines with anti-serotonin action (cyproheptadine)
be considered for trial. Tricyclic antidepressants with combined antihistamine action (doxepin) have also been suggested.
(3) Cromolyn sodium
Cromolyn is a mast cell stabilizers used to prevent asthma and symptoms of seasonal or chronic allergic rhinitis. It works by blocking a calcium channel that is essential for mast cell degranulation (the release of chemical mediator-containing secretory granules which occurs after exposure to a specific antigen). It has been successfully used in the management of inflammatory bowel diseases (ulceratice colitis, Crohn’s) and interstitial cystitis, conditions sometimes associated with dysregulated mast cell activity.
(4) Vitamin C
Vitamin C increases degradation of histamine and inhibits mast cell degranulation. Dosing limited to not more than 750 mg/day. Additionally, studies suggest that the combination of quercetin with Vitamin C offers a synergistic benefit.
Treatment of Anaphylaxis and Severe Allergic Reactions due to MCAS
In cases of life-threatening symptoms of MCAS such as anaphylaxis, the use of epinephrine (EpiPen, AnaPen) is indicated. Any patient with this history should always have a prescription of injectable epinephrine on hand.
Complementary and Alternative Medical (CAM) Therapy
Because conventional medical care for MCAD offers only imperfect relief for many afflicted patients, Complementary and Alternative Medicine (CAM) approaches are suggested to offer additional benefit. CAM treatment in this case includes the use of nutraceuticals. The term “nutraceutical,” derived from “nutrition” and “pharmaceutical,” refers to a product that is isolated from herbs, botanicals or foods that has physiological benefit by supporting the structure or function of the body or providing protection against diseases.
Palmitoylethanolamide (PEA)
Palmitoylethanolamide (PEA) is a naturally occuring, biologically active lipid that acts on the endocannabinoid system and interacts with inflammatory cells in the nervous system. Sometimes referred to as a cannabinomimetic compounds (i.e. an agents able to modulate endocannabinoid function), PEA has been shown to stabilize mast cells. What is particularly exciting about PEA is that it is a naturally occuring agent produced by the body that has no reported serious side effects or drug-drug interactions, making it an extraordinarily safe treatment option
While little research is available at this time on PEA in MCAD, it has preliminary research to suggest potential benefit.
See: Palmitoylethanolamide (PEA)
Flavonoids
Flavoniods with research-supported benefit for stabilizing mast cells include quercetin, luteolin and others.
Quercetin
Quercetin is the most plentiful, most studied representative of polyphenols, flavonoids subgroup, flavonols. Its main food sources include: onions, broccoli, apples, berries, grapes, some herbs, teaa and wine. While generally found at relatively low concentrations of 15–30 mg/kg (fresh weight), several vegetable varieties have much more extensive content such as onions and shallots.
Quercetin stabilizes mast cells and suppresses mast cell activity including the inhibition of histamine release, pro-inflammatory cytokines, leukotrienes creation, and suppression of interleukin IL-4 production.
Quercetin has strong antioxidant and anti-allergic properties and may reduce the inflammation involved with severe infection. It stimulates the immune system, and, has a broad range of antiviral properties which can potentially interfere with COVID-19 infection including virus entry into cells and virus replication.
The benefits of quercetin can be enhanced by the co-administration of vitamin C.
Cannabinoids
It appears that to date there is no high-quality research evaluating cannabinoids to treat patients with MCAS or mastocytosis. One must therefore turn to preclinical studies to judge their potential for benefit.
Early research suggests that cannabinoids stabilize mast cells. There are two primary cell receptors in the human endocannabinoid system, CB1 and CB2. CB1 receptors are abundantly present in the brain and spinal cord. They are found in very high concentration in the hypothalamus and the amygdala, which are responsible for appetite regulation, control of stress and anxiety, reducing nausea and memory and emotion processing. CB1 receptors are also present in nerve endings where they reduce pain sensations. CB2 receptors are mostly located in the immune cells of the peripheral nervous system and play a dominant role in reducing inflammation.
Mast cells contain both CB1 and CB2 receptors, which when activated inhibit mast cell release. Cannabinoids, both endocannabinoids (natural., manufactured in the body) and phytocannabinoids (found in mariuana) have been found to suppress mast cell degranulation, the process of releasing their mediators.
Cannabidiol (CBD) alone without THC may be less effective at treating dysfunctional mast cells because while THC has a strong binding affinity for both CB1 and CB2 receptors, CBD does not bind directly to either receptors but instead act indirectly through other pathways to reduce inflammation. However, anecdotally in the online MCAS community CBD seems to be helpful for some patients, particular those with high pain levels, inflammation, and insomnia.
Low Dose Naltrexone (LDN)
Naltrexone is an opioid antagonist that has been used conventionally for the treatment of alcoholism and opioid addiction. Low-dose naltrexone (LDN) is used off-label for treatment of pain and inflammation in many pain conditions including multiple sclerosis, Crohn’s disease and fibromyalgia. LDN inhibits cellular proliferation of T- and B- cells and block Toll-like receptor 4 (TLR4) and reduces production of multiple cytokines including IL-6, thought to be the mechanisms by which it provides anti-inflammatory benefit and pain relief. It has been proposed as an alternative treatment option to stabilize mast cells.
Resources
References
Mast Cell Activation Disease (MCAD)
Histamine Intolerance – Overviews
- Evaluation of symptoms and symptom combinations in histamine intolerance – 2019
- Comparing histamine intolerance and non-clonal mast cell activation syndrome – 2020
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