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

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, gastro-

intestinal 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 (#81425 "11 Beta-Prostaglandin F(2) Alpha, Urine"), and

tryptase, alpha or beta (#81608 "Tryptase, Serum").

0-5 years: 120-510 ug/g creatinine

6-16 years: 70-330 ug/g creatinine

>16 years: 30-200 ug/g creatinine

Increased concentrations of urinary 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.

Individuals who are taking monoamine oxidase inhibitors (MAOIs)

or aminoguanidine will have increased levels of 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 poly-

morphism in the histamine-N-methyl transferase gene, which

encodes the enzyme that catalyzes NMH formation. This poly-

morphism results in an amino acid change that decreases the

rate of NMH synthesis.

1.  Roberts LJ II, Oates JA:   Disorders of vasodilator hormones:

      the carcinoid syndrome and mastocytosis.  In Williams

      Textbook of Endocrinology. 8th 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