Increased Plasma Calcitonin Levels in Systemic Mast Cell Disease

Case Report Increased Plasma Calcitonin Levels in Systemic Mast Cell Disease MICHAEL W. YOCUM, M.D.,

JOSEPH H. BUTTERFIELD, M.D.,

Aspirin therapy for patients with systemic mast cell disease (SMCD) decreases the production of prostaglandin D2, which is thought to be a major mediator of flushing. Paradoxically, in 5 to 10% of patients with SMCD, administration of aspirin causes massive mediator release and an anaphylactoid reaction. We attempted aspirin desensitization in a 34-year-old man with SMCD (confirmed by bone marrow biopsy) who was incapacitated by severe flushing episodes and hypotension. His baseline mediator levels of plasma calcitonin, urinary histamine, and urinary JV-methylimidazoleacetic acid were abnormal. Pentagastrin stimulation increased the plasma level of calcitonin from 47 pg/mL to 130 pg/mL (normal, less than or equal to 110) at 5 minutes. Oral aspirin desensitization was begun; however, after a cumulative dose of 620 mg, an anaphylactoid reaction ensued in conjunction with hypotension, abdominal cramping, and

Because of mast cell proliferation, systemic mast cell disease (SMCD) causes symptoms of bone pain, lymphadenopathy, and nepatosplenomegaly. Symptoms such as flushing, presyncope, abdominal cramps, emesis, diarrhea, and headache are caused by inasticeli mediator release.1 The main cyclooxygenase product of the mast cell, prostaglandin D2 (PGD2), is thought to cause flushing and hypotension.2 The synthesis of PGD2 and the urinary excretion of PGD2 metabolites are suppressed by long-term administration of aspirin but not by antihistamine therapy.3 Approximately 5 to 10% of patients with SMCD react adversely to aspirin; thus, tiny amounts (40 to 80 mg) cause massive mediator release.4 The pathophysiologic mechanism of mediator release in aspirin-sensitive patients with SMCD is unknown. Herein we describe an aspirin-sensitive patient with SMCD who had no urticaria pigmentosa but was incapacitated because of flushing and hypotensive episodes resistant to maximal doses of H, and H2 antihistamines. While atFrom the Division of Allergic Diseases and Internal Medicine (M.W.Y., J.H.B.) and Division of Endocrinology/Metabolism and Internal Medicine (H.G.), Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. M. W. Yocum, Division of Allergic Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1994; 69:987-990

AND HOSSEIN GHARIB,

M.D.

flushing. Coincidentally, 1 hour after the episode, the plasma calcitonin level increased from 37 pg/mL to 540 pg/mL, and the serum tryptase level increased from 1 ng/niL to 3.9 ng/mL. Six hours after the episode, the urine level of histamine increased from 90 μg/g creatinine to 337 μg/g creatinine, and the urinary A/-methylimidazoleacetic acid increased from 32 mg/ 24 h to 81 mg/24 h. Hence, the patient had increased basal levels of plasma calcitonin that increased substantially during aspirin desensitization and increased to above the upper limit of normal during pentagastrin stimulation. Human mast cells may be capable of producing calcitonin or causing secretion of calcitonin in response to skeletal changes. (Mayo Clin Proc 1994; 69:987-990) MI A A = iV-methylimidazoleacetic acid; PGD2 = prostaglandin D2; RIA = radioimmunoassay; SMCD = systemic mast cell disease

tempting to desensitize our patient to aspirin, we detected increased plasma levels of calcitonin. To our knowledge, only one report of increased calcitonin levels in a patient with SMCD has been published; however, that patient had only urticaria pigmentosa lesions and no evidence of mast cell proliferation in the bone marrow.5 REPORT OF CASE A 34-year-old man came to our institution because of a 2year history of "spells" that consisted of nausea, abdominal bloating, and cramps, flushing of the head, upper chest, and trunk, generalized pruritus, headache, dyspnea, and presyncope. He had no atopy. Individual episodes occurred about every 8 weeks and lasted approximately 90 minutes. He had experienced a total of 10 episodes. One spell was precipitated by ingestion of naproxen and another by consumption of aspirin. He had had four duodenal ulcers, which had been active 3 years previously. Computed tomography of the abdomen revealed no abnormal masses or retroperitoneal adenopathy but showed increased bone density and fibrotic marrow in the pelvis and sacrum. A radioactive bone scan disclosed diffusely increased uptake in the axial skeleton. Findings on bone marrow aspirate demonstrated an increased number of

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© 1994 Mayo Foundation for Medical Education and Research

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PLASMA CALCITONIN LEVELS

atypical mast cells, which constituted 30% of the total cell population. A bone marrow biopsy specimen showed myelofibrosis and aggregates of spindle-shaped mast cells that constituted 15% of the total marrow cell population. Results of the tryptase stain of these mast cells were positive. Informed consent was obtained from the patient. He was told that a severe, possibly fatal spell might be triggered with aspirin densensitization conducted in the hospital. Aspirin was administered orally at a dose of 20 mg, and the doses were doubled every 45 minutes. Forty minutes after the 320mg dose of aspirin had been administered (3 hours and 40 minutes after the first dose), the patient experienced symptoms of mast cell mediator release. This anaphylactoid episode was similar to his usual spells but included more severe hypotension; the systolic pressure was approximately 60 mm Hg. The patient's response to subcutaneous administration of epinephrine, intravenous administration of diphenhydramine hydrochloride and fluids, and hydrocortisone was prompt. He was admitted to the intensive-care unit and observed during the next 15 hours; no additional aspirin was given. In the intensive-care unit, another episode of symptoms of mediator release occurred approximately 5 hours after the first episode. This reaction was less severe than the first reaction, and he responded again to subcutaneous administration of epinephrine and continued infusion of hydrocortisone and fluids. By the next day, he had recovered from the anaphylactoid reaction, except for residual fatigue that his family had noted to persist 48 to 72 hours after the spells. MATERIAL AND METHODS The urine concentration of histamine was determined with a competitive radioimmunoassay (RIA) (Amac, Inc., Westbrook, Maine) on the basis of the instructions of the manufacturer. The urine concentration of /V-methylimidazoleacetic acid (MIAA) was determined at Mayo Medical Laboratories. MIAA is isolated on an ion-exchange resin and fractionated by high-performance liquid chromatography. Column effluent is monitored with a diode array spectrometer, and MIAA is quantified at 215 nm. The serum level of tryptase was measured at the Medical College of Virginia with use of a previously published method.6 The plasma level of calcitonin was determined by using an extraction RIA, as previously reported. 7 Pentagastrin (0.5 μg/kg of body weight) was injected intravenously as a bolus (less than 5 seconds), and blood samples for measuring calcitonin levels were obtained at 0,1.5, and 5 minutes. Serum vasoactive intestinal polypeptide and gastrin levels were determined by using competitive binding RIAs at Mayo Medical Laboratories.

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RESULTS Baseline levels of mediators in the urine and blood of our patient and the normal values are listed in Table 1. Urine levels of MIAA and histamine were increased, as was the plasma level of calcitonin. Pentagastrin stimulation further increased the patient's baseline calcitonin value by a factor of 2.77. Mediator levels after aspirin desensitization are listed in Table 2. Serum levels of tryptase and urine levels of histamine were increased after the mediator-release reaction by a factor of 3.9 and 3.7, respectively. The serum tryptase concentration did not exceed the normal range value of less than 5 ng/mL. Urine levels of MIAA increased only 2.5 times, but plasma calcitonin levels increased 14.6 times. For determination of plasma calcitonin levels, random blood samples were obtained from four additional patients with SMCD, none of whom had symptoms of mediator release when the blood sample was withdrawn. The plasma calcitonin levels in these four asymptomatic patients with SMCD were 19, 28, 35, and 124 pg/mL, respectively. DISCUSSION Investigators have reported that PGD2 is the predominant cyclooxygenase product generated by mast cells and that PGD2 overproduction by 150-fold in patients with SMCD may cause flushing and systemic hypotension.2·3 Treatment with aspirin, up to 3.9 g/day, decreases production of PGD2 by as much as 90% and controls flushing and hypotensive episodes in such patients.8 Nonetheless, 5 to 10% of patients Table 1.—Baseline Mediator Levels in 34-Year-Old Aspirin-Sensitive Man With SMCD* Test Urine MIAA (mg/24 h) Histamine (\igfg creatinine) Metanephrine (mg/24 h) 5-HIAA (mg/24 h) Plasma Calcitonin (pg/mL) Serum Vasoactive intestinal polypeptide (pg/mL) Tryptase (ng/mL) Gastrin (pg/mL)

Patient

Values Normal

34 92 1.1 3.8

<5 <45 <1.3 <6

40

<19

17 1.3 53

<75 <5 <200

Pentagastrin test

Baseline

5 min

Plasma Calcitonin (pg/mL)t

47

130

*5-HIAA = 5-hydroxyindoleacetic acid; MIAA = N-methyiimidazoleacetic acid; SMCD = systemic mast cell disease. tNormal, <110.

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Table 2.—Mast Cell Mediator Levels in 34-Year-Old Man With SMCD Before and After Reaction From Aspirin Desensitization*

Levels Test

Before reaction

After reaction

Plasma calcitonin (pg/mL) Serum tryptase (ng/mL) Urinary histamine (\ig/g creatinine) Urinary MIAA (mg/24 h)

37 1 90 32

540t 3.9t 337φ 81*

*MIAA = /V-methylimidazoleacetic acid; SMCD = systemic mast cell disease. 11 hour after reaction. φ6 hours after reaction.

with SMCD are sensitive to aspirin, as was our patient, and few of these patients have been successfully desensitized to aspirin.9 On the basis of this information, we attempted to desensitize our patient. Although he had avoided nonsteroidal anti-inflammatory drugs, he was incapacitated by frequent, spontaneous hypotensive flushing episodes that necessitated repeated hospitalizations. In addition, maximal Hl and H2 receptor blockade had not controlled massive mast cell mediator-release symptoms, which may be fatal in patients with SMCD.10 Although we followed a previously published method of aspirin desensitization, our patient had a severe reaction.9 Thus, we elected not to continue aspirin desensitization. Plasma calcitonin is an excellent and highly sensitive biochemical marker for the diagnosis of medullary thyroid carcinoma. Pentagastrin stimulation produces an increase in plasma levels of calcitonin in patients with this carcinoma.7 Calcitonin levels may be abnormally increased in patients with nonthyroidal conditions including pregnancy, chronic renal failure, pancreatitis, small-cell carcinoma of the lung, carcinoid syndrome, and pheochromocytoma, all of which were excluded in our patient. The plasma calcitonin levels in these nonthyroidal illnesses are mildly increased, however, and do not further increase with pentagastrin stimulation. Consequently, a pentagastrin-stimulated increase in calcitonin is considered a specific and sensitive marker for medullary thyroid carcinoma." Therefore, the fact that pentagastrin stimulation increased the calcitonin level in our patient is interesting. Initially, the plasma calcitonin level was measured to determine whether it was increased and was a possible cause of our patient's flushing, nausea, abdominal cramps, and diarrhea during mediator-release reactions. Pronounced increases in calcitonin levels in patients with medullary thyroid carcinoma may cause nausea, abdominal cramps, and diarrhea." In our patient, the plasma level of calcitonin was noted to be increased in two random blood

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samples, and it increased to an extremely high level when the mediator-release reaction occurred during aspirin desensitization. Our patient received epinephrine, and even though adrenergic stimulation has been reported to increase calcitonin levels modestly (13 to 18 pg/mL), it would not explain the pronounced increase in our patient.12 Only one previous report has described increased plasma levels of calcitonin in a patient with SMCD. That patient had recurrent abdominal pain, diarrhea, fatigue, and extensive confluent urticaria pigmentosa lesions but no skeletal abnormalities; findings on a bone marrow biopsy were normal.5 CONCLUSION Our patient had severe abdominal cramps, emesis, diarrhea, flushing, hypotension, and bone marrow involvement by mast cells but no urticaria pigmentosa lesions. The substantial increase in plasma calcitonin from a value of 37 pg/mL to 540 pg/mL 1 hour after the mediator-release reaction (14.6fold) was more impressive than the increase in the serum level of tryptase, from 1 ng/mL to 3.9 ng/mL, which has been reported to be a sensitive and specific marker of mast cell activation in systemic anaphylaxis and mastocytosis.13 Thus, an increased plasma calcitonin level may be an additional marker of mediator release in patients with SMCD. Monitoring plasma calcitonin levels and determining pentagastrin response in a larger series of patients with SMCD may be helpful. The cause of increased plasma calcitonin levels is currently speculative. Perhaps the mast cells themselves are capable of producing calcitonin and calcitonin messenger RNA, or anti-calcitonin antibodies might be present in either bone marrow biopsy or tissue specimens of mastocytomas in patients with SMCD. Another explanation for an increased calcitonin level in patients with SMCD is that the predominant skeletal change is severe osteoporosis. Thus, the medullary C cells in a patient's thyroid gland may be hypertrophied and vigorously responding to a high rate of bone loss. ACKNOWLEDGMENT We thank Dr. John W. Yunginger for critical comments and review of our report and Lori A. Farlinger for excellent secretarial assistance. REFERENCES 1. Travis WD, Li C-Y, Bergstralh EJ, Yam LT, S wee RG. Systemic mast cell disease: analysis of 58 cases and literature review. Medicine 1988;67:345-368 2. Lewis RA, Roberts LJII, Holgate ST, Oates JA, Austen KF. Prostaglandin D2 production by rat and human mast cells activated by reversed anaphylaxis [abstract]. FedProc 1980; 39:905 3. Roberts LJ II, Sweetman BJ, Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. NEnglJMed 1980;303:1400-1404 4. Roberts LJ Π, Oates JA. Disorders of vasodilator hormones: the carcinoid syndrome and mastocytosis. In: Wilson JD, Foster DW,

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5. 6. 7.

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editors. Williams Textbook of Endocrinology. 8th ed. Philadelphia: Saunders, 1992: 1619-1634 Lundin A, Oberg K. Hypercalcitoninaemia in a patient with urticaria pigmentosa: a possible cause of diarrhoea. ActaMedScand 1984; 215:281-285 Wenzel S, Irani AM, Sanders JM, Bradford TR, Schwartz LB. Immunoassay of tryptase from human mast cells. J Immunol Methods 1986; 86:139-142 Gharib H, Kao PC, Heath H ΙΠ. Determination of silica-purified plasma calcitonin for the detection and management of medullary thyroid carcinoma: comparison of two provocative tests. Mayo Clin Proc 1987;62:373-378 Roberts LJ II, Fields JP, Oates JA. Mastocytosis without urticaria pigmentosa: a frequently unrecognized cause of recurrent syncope. Trans Assoc Am Physicians 1982;95:36-41

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9. 10. 11. 12. 13.

Crawhall JC, Wilkinson RD. Systemic mastocytosis: management of an unusual case with histamine (HI and H2) antagonists and cyclooxygenase inhibition. Clin Invest Med 1987; 10:1-4 Dodd NJ, Bond MG. Fatal anaphylaxis in systemic mastocytosis. J ClinPathol 1979;32:31-34 Robbins J, Merino MJ, Boice JD Jr, Ron E, Ain KB, Alexander HR, et al. Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med 1991;115:133-147 Metz SA, Deftos LJ, Baylink DJ, Robertson RP. Neuroendocrine modulation of calcitonin and parathyroid hormone in man. J Clin Endocrinol Metab 1978;47:151-159 Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. NEnglJMed 1987;316:1622-1626

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