Significantly elevated histamine and/or tryptase levels in a person with symptoms of anaphylaxis are strong evidence for that diagnosis.

Histamine may be elevated with any condition that activates mast cells, and the release of histamine may be triggered by a wide variety of substances.

An allergic reaction to a food is thought to be the most common cause of anaphylaxis.

In some people, histamine-related symptoms, such as flushing, headache, diarrhea, itching, etc., may develop after eating histamine-rich foods. Histamine can be found in a variety of foods, especially those that are "aged" such as cheese, wine, and sauerkraut. Symptoms may also be caused by ingesting alcohol, or by drugs that either stimulate the release of histamine or block its metabolism.

Rarely, histamine poisoning can occur by eating fish that has spoiled (ex. tuna, mackerel) and has high quantities of bacteria-produced histamine. Called scombroid fish poisoning, this condition can cause flushing, sweating, vomiting, headache, and diarrhea.

Some carcinoid tumors located within the digestive tract produce excess histamine.

In addition to allergic reactions, histamine plays a role in inflammatory processes, stimulates gastric acid secretion, acts as a neurotransmitter (chemical substance that transmits messages between nerve cells), dilates blood vessels, increases vascular permeability (allows fluids to move through blood vessel walls), affects smooth muscle contraction in the intestines and lungs, and affects heart rate and contraction. Medications have been developed to block some of the actions of histamine, including antihistamines and drugs that reduce stomach acid secretion.

Note: Plasma histamine levels can be elevated 5–10 minutes after the onset of symptoms. However, such levels are evanescent, usually returning to normal within 60 minutes after the onset of the event. For this reason, plasma histamine levels are of little help if the patient is seen as long as an hour after the event. In this case, however, a 24-hour urinary collection for histamine metabolites may be useful. Such metabolites can be elevated for as long as a day. 

The activation of mast cells:

The activation of many mast cells is associated with a severe form of acute allergic reaction termed anaphylaxis, which can cause hives (blisters on the skin), reddening of the skin (flushing), low blood pressure, severe narrowing of the air passages, and even death. With anaphylaxis, histamine concentrations in the blood increase rapidly, rising within 10 minutes of the start of symptoms and returning to normal within about 30 to 60 minutes. This increased production is also reflected a short time later in the urine as histamine and its primary metabolite, N-methylhistamine, are excreted.

Histamine and tryptase levels may be persistently increased in people with mastocytosis. This rare condition is associated with abnormal proliferation of mast cells and their infiltration and accumulation in the skin (cutaneous mastocytosis) and/or in organs throughout the body (systemic mastocytosis).