Urinary N-Methylhistamine

The primary application of urinary N-methylhistamine (NMH) testing is in the diagnosis and monitoring of mast-cell disorders, including mastocytosis, anaphylaxis, and other severe systemic allergic reactions. ^{[1, 2, 3, 4, 5, 6, 7]}

The reference range for urinary NMH varies according to subject age, as follows:

• Age 0-5 years - 120-510 µg/g creatinine

• Age 6-16 years - 70-330 µg/g creatinine

• Older than16 years - 30-200 µg/g creatinine

As a rule, NMH levels are elevated in individuals with mast-cell disorders, including mastocytosis (systemic and localized urticaria pigmentosa), anaphylaxis, and other severe systemic allergic reactions; however, they may be normal in some cases. (See Systemic Mastocytosis, Mastocytosis & Urticaria Pigmentosa, and Anaphylaxis.)

NMH levels correlate with the size of the mast-cell population and strength of activation. Adults have lower NMH levels than children do. Adult levels of NMH have been reached by the age of 16 years. Urinary NMH has a longer half-life than histamine, the parent compound; accordingly, NMH testing has better diagnostic accuracy. Because spot-urine excreted levels may vary by as much as 25%, 24-hour urine collection is preferable in cases where the results are ambiguous.

Specifics of specimen collection and handling are as follows:

• Specimen - Urine

• Container/tube - Plastic 6-mL tube

• Specimen volume - 5 mL (minimum, 3 mL)

• Collection instructions - Collect urine for 24 hours; no preservative; although 24-hour collection is preferred, random specimens are also acceptable

• Stability - Refrigerated (preferred), 8 days; ambient temperature, 24 hours; frozen, 14 days

Urine preservative collection options include refrigeration (preferred), freezing, ambient temperature, 6N hydrochloric acid, 50% acetic acid, sodium carbonate, toluene, 6N nitric acid, boric acid, and thymol.

Description

NMH is a major metabolite of histamine, which is released from storage in mast cells and basophils when these cells degranulate in response to stimulation (both immunologic and nonimmunologic). Large quantities of histamine can also be produced by dendritic cells and T cells, though these cells do not store histamine. Lipopolysaccharide (LPS) stimulation, infection, inflammation, and graft rejection have all been shown to induce histamine production in vivo.

Histamine is metabolized almost entirely via 2 major pathways. In the first, histamine N-methyltransferase metabolizes most of the histamine to NMH, and monoamine oxidase (MAO) then metabolizes NMH to M-methyl imidazole acetic acid. In the second, diamine oxidase metabolizes 15%-30% of the histamine to imidazole acetic acid.

Indications/Applications

The main application of urinary NMH measurement is in the diagnosis and monitoring of mast-cell disorders, such as mastocytosis (systemic and localized urticaria pigmentosa), anaphylaxis, and other severe systemic allergic reactions.

Mastocytosis is a rare disorder characterized by functional secretion or abnormal proliferation of tissue mast cells. The localized form usually occurs in the skin as urticaria pigmentosa. The systemic form often infiltrates bone marrow and other organs (eg, skin, liver, spleen, lymph nodes, and gastrointestinal [GI] tract; 10%-30% of cases).

In most instances, diagnosis is based on biopsy of tumor sites. Whereas marrow biopsy is quite accurate, yielding positive results in about 90% of cases, marrow smears are less useful. The diagnosis is confirmed by means of immunohistochemical (IHC) staining with monoclonal antibodies against mast-cell markers (CD117 and tryptase). Serum tryptase is a highly specific marker for mastocytosis, being increased in more than 83% of cases.

Histamine levels are increased in urine, blood, and tissues; however, because histamine is released intermittently and has a short half-life, it is sometimes missed in the blood. Greater diagnostic specificity and sensitivity can be achieved by measuring levels of histamine metabolites in random and 24-hour urine specimens than by determining levels of histamine itself.

Histamine is also elevated in anaphylaxis, and the extent to which the levels are increased is correlated with the clinical severity of the anaphylactic state. It has been suggested that constitutive hyperhistaminemia may contribute to recurrent anaphylaxis.

Considerations

Some individuals with myeloproliferative disorders, carcinoid syndrome, insulinoma, medullary thyroid carcinoma, pheochromocytoma, VIPoma, or glucagonoma have increased urinary NMH levels. In some cases, basophil degranulation during phlebotomy or conversion of histidine to histamine by bacteria in urine may give rise to false increases in NMH levels. Finally, NMH levels are increased in individuals who are taking MAO inhibitors (MAOIs) or aminoguanidine; consequently, results from patients on MAOIs are uninterpretable.

Depressed NMH levels may result when there is a polymorphism in the histamine-N-methyl transferase gene (the gene encoding the enzyme responsible for catalyzing NMH formation), which gives rise to an amino acid change that slows NMH synthesis.

The effect of histamine-rich foods (eg, certain fish, aged cheeses, chocolate, red wine, tomatoes, spinach, and eggplant) should be considered, though it is not clear whether there is a definite relation between the presence of histamine in foods and the appearance of histamine or its metabolites in blood or urine, partly because the factors that govern absorption of ingested histamine have not been fully elucidated.

Scombroidosis, an illness that results from the ingestion of improperly stored fish that has accumulated high histamine levels, can give rise to elevated urinary and plasma histamine or histamine metabolite levels, though tryptase levels are typically normal. This illness is characterized by flushing, headache, and widened pulse pressure; however, unlike systemic anaphylaxis, it is not associated with pruritic urticaria and hypotension. Not uncommonly, it affects multiple people who have partaken of the same fish.

Elevated histamine levels are not found in other forms of food poisoning.

A retrospective study by Giannetti et al indicated that while patients with indolent systemic mastocytosis have elevated levels of urinary mast-cell mediator metabolites, including N-methylhistamine, the same is not true for individuals with the mast-cell disorder symptomatic hereditary alpha tryptasemia, even though both disorders can present with symptoms of mast-cell activation, a condition associated with elevation of those metabolites. According to the investigators, this may suggest that the symptoms of hereditary alpha tryptasemia are not driven by granule- and membrane-derived mast-cell mediators. ^[8]