nmwi

Women’s Functional & Integrative Medicine Professional Training

Histamine Intolerance

M O D U L E 1 3

Julie• 11 year old girl, presents to Thrive with profound fatigue, dizziness,

palpitations• Mom reports Julie has been fatigued since she was 5• Some relief with acupuncture and dietary restrictions (gluten, dairy, egg,

almonds)• With first period, fatigue became profound, also experienced dizziness and

tingling in legs, symptoms lasted x week then resolved• One month later, symptoms returned, and haven’t gone away – pt has

missed school and activities because she can’t function

Julie• Other symptoms:

– +heart palpitations– Becomes nauseous and dizzy if she eats at a restaurant

• Has seen various medical providers to seek solutions• Found to be anemic and with +ANA (+scleroderma antibodies), treated for

anemia and saw rheum but no clear autoimmune diagnosis• Hx of tick bite but recent Lyme testing negative

Julie: Birth and Childhood Hx• Born at term, forceps used during birth• Bottle fed with soy-based formula• Lots of candy as a child• No mercury fillings• Fully vaccinated• About 10 rounds of antibiotics for various illnesses (ear, sinus infx) in

childhood

JulieSocial Hx.• Parents together, 3 siblings whom

she is close with• When 7 years old, childhood friend

passed away from cancer• Traumatic experience with a

teacher in 4th grade (details not shared)

• Symptoms seem to be worse during the school year, better in the summer

Family Hx• Sibling with anxiety• Maternal aunt with autoimmune

condition• MGM with RA• MGM and PGM with anxiety• Mom with food intolerances

Julie: Initial Visit A&P• Histamine intolerance:

– 3 mo: Low histamine diet, no gluten or cross reactives– Supportive supplements (see next slide)– Daily walking and gentle movement

• Labs• Conventional panel w/Lyme and AI labs• iSpotLyme• GI Effects• Organix,

Histamine Intolerance and the Low Histamine Plan

Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;

Histamine 101• Histamine is a biogenic amine that the immune system releases from a variety of cells in

which it is stored, in response to a variety of allergic and toxic exposures, for example, bee stings and certain foods like peanuts in those with peanut allergies.

• When such an exposure happens, histamine-containing cells (mostly mast cells and basophils) dump histamine into the bloodstream leading to a rapid inflammatory reaction that causes the blood vessels to become more permeable, allowing the immune system’s white blood cells to reach the area where the ‘invasion’ has occurred.

• Its also activates nerves that stimulate the respiratory passages to constrict, eyes to water, and nose to run.

• Because cells throughout the body including the digestive system, heart and vascular system, skin, and lungs respond to histamine as part of its protective response, the response occurs widely throughout the body and can be multi-systemic causing all of the symptoms I list in the next section.

• Histamine produced in the brain acts as a neurotransmitter – a chemical involved in signaling in the nervous system; in the stomach, histamine stimulates the production of gastric acid necessary for digestion.

Histamine 102• Histamine also occurs, to various degrees, in many foods.• In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases,

whereas persons with low amine oxidase activity are at risk of histamine toxicity.• Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested

histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator

• release. • Conversely, histamine N-methyltransferase, the other important enzyme

inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells.

• An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction.

Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;

Histamine intolerance is really a misnomer – it’s more a matter of excess histamine exposure or poor clearance leading to symptoms.

Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation.

It is not an IgE mediated allergy – so is neither technically an allergic reaction nor typically life-threatening, but reactions can be severe and serious (i.e., hypotension, hypertension)

nmwi

Symptoms Can Include• Abdominal cramps,

diarrhea

• Alcohol intolerance

• Anxiety

• Chronic urticaria

• Difficulty falling asleep or staying asleep

• Dizziness, vertigo

• Eczema

• Feeling too hot or

frequently chilled for now reason

• Fatigue or weakness

• Low of high blood pressure (can be extreme in either direction)

• Migraines or headaches

• Menstrual cramps or premenstrual headaches

• Nasal congestion, sneezing, itchy eyes, difficulty breathing

• Nausea or vomiting

• Pruritis

• Puffiness, swelling

• Racing heart, especially but not always after eating certain foods

• Skin flushing, especially but not always after eating certain foods

1Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;

nmwi

An Enzyme Problem• Histamine intolerance results from an imbalance between the amount of

histamine that is released from the cells in response to certain triggers, or builds up in the body as a result of foods you eat – and the body’s ability to break it down and clear it out, which it does using two naturally occurring enzymes the body is supposed to produce – Diamine oxidase (DAO) and histamine N-methyltransferase (HNMT).

• However, due to either genetics or acquired reasons, the body might not produce enough of one or the other, or both of these. HNMT is produced inside the cells and is usually more genetically influenced. DAO, however, is produced in the intestine, and is also the enzyme responsible for breakdown of ingested histamine, so if there has been intestinal damage, DAO production might be reduced.

nmwi

Predisposing or Triggering Factors (Root Causes)

• Leaky gut

• Crohn’s disease or ulcerative colitis

• Celiac disease and non-celiac gluten intolerance

• Small intestinal bacterial overgrowth (SIBO)

• Certain medications including: NSAIDS (ibuprofen), Antidepressants (Cymbalta, Effexor, Prozac, Zoloft), Antihistamines (Allegra, Benadryl ,Zyrtec), Histamine (H2) blockers (Pepcid, Zantac0, Immune modulators (Enbrel, Humira, Plaquenil), Antiarrhythmics/Calcium channel blockers (amlodipine, diltiazem, propanolol, metoprolol)

nmwi

Histamine and Diet• DAO-blocking foods including alcohol can also lead to decreased

availability of DAO to break down histamine, resulting in elevated levels.

• Consuming high histamine foods can also cause a problem, especially if the enzyme system is impaired

• HIT is more common in people with Inflammatory Bowel Disease (IBD –Ulcerative colitis and Crohn’s), celiac disease, and SIBO, as well as eczema, all conditions that have been associated with intestinal inflammation and hyperpermeability.

nmwi

Testing• There are currently no tests that are proven to diagnose histamine intolerance, and

though blood and urine levels of histamine can be measured, because histamine levels are so naturally variable depending on time of day and also when you’ve eaten, it’s just not a reliable way to test for this problem.

• Similarly blood levels of DAO can be measured, but these levels don’t really correlate neatly with symptoms.

• Because it’s not a true allergic condition, allergy testing, including food allergy testing, is not useful. However, it is important to r/o true allergy and also mastocytosis.

• The best way to ‘test’ for histamine intolerance is through a low histamine diet. A reduction in symptoms on the diet, and a return of symptoms when higher histamine foods are re-introduced, suggests that there is histamine intolerance.

nmwi

Histamine and the HPA Axis

• Dysregulation in the stress response system – whether adrenal overdrive with high cortisol, or inhibited adrenal function with low cortisol – can also impair the immune system leading to increased reactivity to foods, and stress seems to worsen HIT in many individuals.

nmwi

Histamine and Women• Histamine is produced by mast cells, endothelial cells, and epithelial cells in the uterus

and ovaries.

• Histamine has been shown to stimulate, in a dose dependent manner, the synthesis of estradiol and it also has contractile activity.

• Histamine may augment dysmenorrhea by increasing estrogen concentrations and as a result increasing PgF2.

• A significant increase in migraines, as well weal and flare size in hives in response to histamine has also been observed to correspond to ovulation and peak estrogen concentrations

• In pregnancy DAO production is increased 500x due placental production possibly explaining reductions in allergic-type sx in many pregnant women In pregnancy, DAO is produced at very high

nmwi

Therapeutic Strategies

There are 3 steps to treating histamine intolerance:

• Reduce exposure to histamine (i.e., low histamine diet)

• Reduce intestinal hyperpermeability, HPA axis dysruption, or both

• Supplement

nmwi

High Histamine Foods to Eliminate

• Aged and fermented foods, leftover meats, poultry and fish, and wine are often the biggest triggers

• Alcohol: Champagne, red wine, beer, white wine

• Aged cheeses: Parmesan, Gouda, Swiss, and cheddar

• Grains: Wheat

• Legumes: Chickpeas,

soybeans

• Fermented or smoked Meats/Fish: Sardine, mackerel, herring, tuna, salami

• Fermented and pickles vegetables: Pickles, sauerkraut, kimchi, relish, soy sauce/tamari

• Fermented milk products: Yogurt, kefir, and buttermilk

• Fruit: Dried fruit, citrus, strawberries

• Vegetables: Tomatoes and tomato products, spinach, avocado, and eggplant

• Also: Cinnamon, chocolate

Also AvoidHistamine Liberators• Citrus, bananas, papaya,

pineapple, strawberries• Dairy products• Chocolate, nuts• Food additives, artificial dyes and

preservatives• Shellfish

DAO Inhibitors• Alcohol• Black and green tea• Mate

21

Well-Tolerated, Low HA Foods• Freshly cooked meat and poultry (fresh or frozen – no leftovers!)• Freshly caught or flash frozen fish• Eggs• Gluten-free grains: rice, quinoa• Peanut butter• These fruits: mango, pear, watermelon, apple, kiwi, cantaloupe, grapes• Most vegetables except those listed earlier• Dairy alternatives: coconut milk, rice milk, hemp milk, almond milk• Oils: olive oil, coconut oil• Many of the non-caffeinated herbal teas

Supplements (Study-Based)• Vitamin B6: 50 to 100 mg a day (do not exceed 100 mg/day)• Buffered Ascorbic Acid: 500 mg 2 to 4 times daily

PLUS:• Zinc carnosine• L-glutamin• Gut healing infusion (minus the licorice!)

Supplements: Mechanism-based• Freeze Dried Stinging Nettles: For allergies, the studied dosage is 300 mg

twice a day of freeze-dried nettle leaf.• Isoquercitin: Dose: A combination product that provides 250 mg quercetin

or isoquercetin three times daily; quercetin should not be used in pregnancy or if you have kidney disease.

• Probiotics and Prebiotics: A daily combination of both a probiotic and a prebiotic helps to repair the intestinal wall, however, be avoid probiotics with Lactobacillus casei, a strain that may increase histamine.

DAO Supplementation• Direct DAO supplementation is often recommended, however, I’ve not

found nearly as effective as the above combination, and therefore rarely recommend it anymore.

Julie’s Labs

Conventional Labs

Celiac

iSpot Lyme

GI Effects

GI Effects (con’t)

Organic Acids

24h Salivary Cortisol

Food Intolerance Labs – Notice Anything?

Julie: First Follow Up (2 mo. Later)– Has made a lot of dietary changes but still struggling with diet; craving sugar, ate a lot

of sweets over the holidays– Got period last week, profound fatigue hit hard– About 40% better in terms of energy but still not able to do much but lay on the couch,

occasionally helps with cooking, does some coloring– New onset of tension headaches– Working with a therapist and an in-home physical therapist– Constipated since starting supplements and changing diet

Julie: First Follow Up• A&P:

– Supplement changes:• Add Licorice for chronic hypotension/POTS • Add magnesium glycinate and citrate (max combined dose 1200, titrate citrate up until daily

BM, then add glycinate to reach 1200mg/day)• Stop Meriva

Second Follow Up: 3 mo. after initial

Second Follow Up: Plan• Continue low histamine diet• Be sure to include high quality protein, 1 Tbsp good quality fat at each meal• Increase veggies – two servings of a brightly colored veggie or some berries

each meal• Continue PT• Continue current supplements, and add:

– Vit D3 2000iu/day– Selenium 200mcg/day

Third Follow Up• Updates:

– Went back to school for a few days, felt better, then started to decline again in terms of energy

– Overall making great progress, but the regressions are frustrating for Julie– Has been strict with low histamine diet– Totally exhausted after expending a lot of energy– Getting pressure from family members to be back in school and back to her “old self”

Third Follow Up: Plan• Continue low histamine diet and supplements• Pace energy expenditure, keep a schedule of Julie’s activities so

that they aren’t clustered and there is time for rest• Mitochondrial support:

Fourth Follow Up: 6 mo after initial• Julie is back in school! • Up this week at 6:30am which she hasn’t done in months• Mom feels that Julie is about 70% better• Julie is wanting to be off the couch, being active• When she does get fatigued, recovers faster• Also recovering faster when she eats something that is “off” of diet

Fourth Follow Up: Plan• Continue current plan for 8 more weeks (end of school year)• Work with nutritionist to start adding in some lower histamine foods in the

next few weeks• Revisit all symptoms this summer before school starts up again

Fifth Follow Up: 10 months after initial• Julie excited to go back to school!• Plans to play recreational soccer• Has added in some low histamine foods and tolerating well, has discovered

some foods that she absolutely cannot tolerate (gluten, dairy)• Periods much more tolerable, aren’t disabling her anymore, has some mild

cramps

Fifth Follow Up: Plan• Pace activities going back to school• Continue to reintroduce foods, slowly, and keep out the problematic foods

long term• Continue supplements:

– B6– vit C– Probiotic– mitochondrial support– Vit D– Mag citrate & glycinate– Licorice Plus– Quercetin & nettles

Case: Melissa• 55 yo woman• Concerns:

– Stubborn weight– Brain fog– Anxiety– Bladder/utethral/vaginal irritation x 1 year – has not responded

to topical estradiol, meds for interstitial cystitis• Intervention: Low histamine diet to target genitourinary

symptoms, with supportive supplements

Melissa• Follow up:

– Stuck with low histamine diet for a month and had 90% resolution in urogenital symptoms

– Traveled to Paris, got off track, symptoms have returned– Has had trouble sticking with supplement plan– New plan: re-start low histamine and supplements with ongoing support

nmwi