Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
N-methylhistamine (NMH) is the major metabolite of histamine, which is produced by mast cells. Increased histamine production is seen in conditions associated with increased mast-cell activity, such as allergic reactions, but also in mast-cell proliferation disorders, in particular mastocytosis.
Mastocytosis is a rare disease. Its most common form, urticaria pigmentosa (UP), affects the skin and is characterized by multiple persistent small reddish-brown lesions that result from infiltration of the skin by mast cells. Systemic mastocytosis is caused by the accumulation of mast cells in other tissues and can affect organs such as the liver, spleen, bone marrow, and small intestine. The mast-cell proliferation in systemic mastocytosis can be either benign or malignant. In children, benign systemic mastocytosis tends to resolve over time, while in most, but not all adults, the disease is progressive. Systemic mastocytosis may or may not be accompanied by UP.(1,3) Patients with UP or systemic mastocytosis can have symptoms ranging from itching, gastrointestinal distress, bone pain, and headaches; to flushing and anaphylactic shock.
Diagnosis of mastocytosis is made by bone marrow biopsy; however, patients with systemic mastocytosis usually exhibit elevated levels of NMH.(1-5) Other biochemical markers include 11-beta prostaglandin F(2) alpha, a metabolite of prostaglandin D2 (BPG2/81425 11 Beta-Prostaglandin F(2) Alpha, Urine), and tryptase, alpha or beta (TRYPT/81608 Tryptase, Serum).
Screening for and monitoring of mastocytosis and disorders of systemic mast-cell activation, such as anaphylaxis and other forms of severe systemic allergic reactions
Monitoring therapeutic progress in conditions that are associated with secondary, localized, low-grade persistent, mast-cell proliferation and activation such as interstitial cystitis
Increased concentrations of urinary N-methylhistamine (NMH) are consistent with UP, systemic mastocytosis, or mast-cell activation. Because of its longer half-life, urinary NMH measurements have superior sensitivity and specificity than histamine, the parent compound. However, not all patients with systemic mastocytosis or anaphylaxis will exhibit concentrations outside the reference range and healthy individuals may occasionally exhibit values just above the upper limit of normal.
The extent of the observed increase in urinary NMH excretion is correlated with the magnitude of mast-cell proliferation and activation, UP patients, or patients with other localized mast-cell proliferation and activation, show usually only mild elevations, while systemic mastocytosis and anaphylaxis tend to be associated with more significant rises in NMH excretion (2-fold or more). There is, however, significant overlap in values between UP and systemic mastocytosis, and urinary NMH measurements should not be relied upon alone in distinguishing localized from systemic disease.
Up to 25% variability in spot-urine excreted levels may be observed, making 24-hour urine collections preferable for cases with borderline results.
Children have higher NMH levels than adults. By the age of 16 adult levels have been reached.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Individuals who are taking monoamine oxidase inhibitors (MAOIs) or aminoguanidine will have increased levels of N-methylhistamine (NMH); results from patients on MAOIs are uninterpretable.
While an average North American diet has no effect on urinary NMH levels, mild elevations (around 30%) may be observed on very histamine-rich diets. This problem is more pronounced if spot urine specimens rather than 24-hour urine specimens are used and the spot urine specimen is collected following a histamine-rich meal.
NMH may be lowered in individuals who are receiving drugs that inhibit diamine oxidase.
NMH levels may be depressed in individuals who have a polymorphism in the histamine-N-methyl transferase gene, which encodes the enzyme that catalyzes NMH formation. This polymorphism results in an amino acid change that decreases the rate of NMH synthesis.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
0-5 years: 120-510 mcg/g creatinine
6-16 years: 70-330 mcg/g creatinine
>16 years: 30-200 mcg/g creatinine
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Roberts LJ II, Oates JA: Disorders of vasodilator hormones: the carcinoid syndrome and mastocytosis. In Williams Textbook of Endocrinology. Eighth edition. Edited by JD Wilson, DW Foster. Philadelphia, WB Saunders Company, 1992, pp 1625-1634
2. Akin C, Metcalfe DD: Mastocytosis. In Allergic Skin Disease: A Multidisciplinary Approach. Edited by DYM Leung, MW Greaves. New York. Marcel Dekker, Inc., 2000, pp 337-352
3. Keyzer JJ, de Monchy JG, van Doormaal JJ, van Voorst Vader PC: Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites. N Engl J Med 1983;309(26):1603-1605
4. Heide R, Riezebos P, van Toorenbergen AW, et al: Predictive value of urinary N-methylhistamine for bone marrow involvement in mastocytosis. J Invest Dermatol 2000;115(3):587
5. Van Gysel D, Oranje AP, Vermeiden I, et al: Value of urinary N-methylhistamine measurements in childhood mastocytosis. J Am Acad Derm 1996;35(4):556-558