Indolent systemic mastocytosis as the cause of a long history of unexplained hypotensive episodes.

Abstract: Assessment of patients with unexplained hypotensive episodes in outpatient practice is often challenging, with an extensive differential diagnosis. The prevalence of systemic mast cell disease (MCD) is unknown, and the diagnosis is often elusive because serum and urine markers may become positive only after one of the self-limited, recurrent hypotensive episodes. Nevertheless, MCD is increasingly recognized as a cause of unexplained hypotension, secondary osteoporosis, and anaphylactic reactions to Hymenoptera stings. We describe a 38-year-old man who had a 15-year history of undiagnosed, recurrent hypotensive episodes with stereotypic symptoms. Extensive evaluation during these years was unrevealing. On physical examination, he appeared to be a healthy man with a prominent macular rash. Results of skin biopsy showed tryptase-positive mast cells. He had markedly elevated serum tryptase levels, and results of bone marrow biopsy revealed 10% mast cells; all these findings were consistent with indolent systemic mastocytosis. Key features in his history and physical examination prompted the conclusive testing. The most telling features were hypotension, tachycardia, and the rash (urticaria pigmentosa).

Key Words: hypotension, mast cell disease, mastocytosis, urticaria pigmentosa

**********

Stereotypic, self-limited, recurrent symptoms in patients presenting with hypotension are a frequent complaint that can present a diagnostic challenge. The extensive differential diagnosis for unexplained hypotension includes rare disorders that can be difficult to diagnose. (1) Systemic mastocytosis is a classic example of this diagnostic challenge. Mastocytosis is a rare disease of uncertain prevalence, but it is a treatable cause of recurrent hypotension. We report a case of recurrent symptoms associated with hypotension caused by previously undiagnosed indolent systemic mastocytosis. We briefly review the literature on mast cell biology, the classification of mast cell disease (MCD), diagnostic and treatment strategies, and prognostic factors, and we suggest a population in which an evaluation for MCD should be considered.

Case Report

A 38-year-old man presented to a tertiary referral institution for evaluation of a 15-year history of stereotypic, self-limited, recurrent symptoms characterized by a sudden onset of intense "pounding" of his heart, followed by head, arms, and legs. Shortly thereafter, he had incapacitating weakness, vomiting, and diarrhea. These episodes were so severe that he called 911 for assistance. He denied ever losing consciousness. Hypotension was documented by the paramedics on several occasions. The symptoms lasted approximately 80 minutes, occurred infrequently (about 1 episode per year) and were unpredictable. He could think of no specific triggers but reported that the unexplained hypotensive episodes had occurred twice after binge drinking, once after using marijuana, and once after eating seafood. However, he had consumed beer and fish and smoked marijuana without having an episode.

On review of systems, the patient reported a "freckle-like" rash on his thorax and extremities. He was uncertain when it first began, but it had clearly gotten worse over the previous 5 years. In addition, he noted that sometimes the spots became palpable. The remainder of his review of systems was negative. During the past 15 years he had the following investigations with negative findings: multiple biochemical evaluations; several cardiac evaluations, including electrocardiography, Holter monitor recording, and static and stress echocardiography; seizure evaluations, including 2 magnetic resonance imaging studies of the head; and allergy testing.

The patient had no other remarkable medical history. He specifically denied having pathologic fractures or peptic ulcer disease. He was not taking prescription or nonprescription medication; he had no known allergies to medication or food. He was employed as a logger and had an active lifestyle. He smoked 1 pack of cigarettes daily, used marijuana weekly, and drank a few beers several times per week, with occasional binges. His family history was unremarkable.

Physical examination revealed a healthy-appearing man with hundreds of reddish-brown macules on his arms, legs, and chest. The macules extended onto the non-sun-exposed areas of his inner forearms (Fig. 1) and urticated when stroked (positive Darier sign). The remainder of his physical examination was normal.

The following values were increased: serum tryptase, 43.3 ng/mL (reference range, <11.5 ng/mL); serum histamine, 1.2 ng/mL (reference range, <1.0 ng/mL); and 24-hour urinary histamine, 38.7 [micro]g/g creatinine (reference range, <35 [micro]g/g creatinine). Results from a skin biopsy of his macular rash were relatively unremarkable on routine hematoxylin and eosin-stained sections and showed only a slight superficial dermal cellular infiltrate (Fig. 2A). However, immunoperoxidase stains for tryptase highlighted a markedly increased number of mast cells in the papillary dermis (Fig. 2B), consistent with cutaneous mastocytosis in the form of urticaria pigmentosa. Bone marrow biopsy findings showed hypocellular marrow with 10% mast cells that stained positive for tryptase. Cytogenetic studies showed a normal male karyotype. A skeletal survey demonstrated mild generalized osteopenia with slight anterior wedging of several mid and lower vertebral bodies.

The patient was treated with histamine [H.sub.1] and [H.sub.2] blockers and was instructed to carry self-injectable epinephrine at all times and wear a Medic Alert tag. He was advised to avoid the typical triggers for mast cell degranulation (which caused the hypotensive episodes and associated symptoms), including alcohol, heat, cold, exertion, emotional upset, narcotics, radiocontrast agents, nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, seafood, Hymenoptera stings, anticholinergic agents, polymyxin B, surgery, and mechanical irritation of his urticaria pigmentosa rash (eg, massage). (1-3) The patient has been well for the subsequent year.

Discussion

Although MCD as a cause of stereotypic, hypotensive episodes was originally described in 1949, (4) the prevalence remains unknown. In Reggio Emilia, Italy, the incidence of systemic MCD was estimated at 0.3 new cases per 100,000 people per year, (5) but it was underestimated owing to the number of cases that were asymptomatic or not diagnosed since mast cell markers often normalize between episodes. Interestingly, elevated serum tryptase levels were found in 10% of patients allergic to Hymenoptera stings, (6) and, recently, cutaneous mastocytosis was documented in 1% of patients allergic to Hymenoptera stings. (2) A retrospective analysis found that the incidence of mastocytosis was 1.25% among 12,689 patients with osteoporosis. (7) Furthermore, the incidence of mastocytosis was 2.25% in the patients younger than 45 years, thereby revealing MCD as an important cause of secondary osteoporosis. (7)

Mast cells are derived from hematopoietic stem cells and function in immune defense. Mast cells contain numerous inflammatory mediators, including histamine and tryptase. (3) The characteristic features of mastocytosis occur secondary to inappropriate mast cell degranulation. Numerous triggers of degranulation are recognized. However, the response to these triggers differs in each patient and specific triggers do not consistently cause degranulation in an individual, as demonstrated by the variable response to marijuana, beer, and seafood in our patient.

The World Health Organization classification of MCD recognizes 7 clinical syndromes. (8) Cutaneous mastocytosis is the most common form of all MCD, (9) and the most common subcategory of cutaneous mastocytosis is urticaria pigmentosa. Our patient had indolent systemic mastocytosis, which is the most common form of systemic MCD; it involves the skin in 90% of cases. (10) The other forms of systemic MCD are rare and generally more aggressive.

[FIGURE 1 OMITTED]

A diagnostic strategy and a treatment algorithm for MCD are described in detail in reviews by Valent et al. (11) and Tefferi and Pardanani, (12) respectively. Briefly, in patients with lesions suggestive of urticaria pigmentosa, a serum tryptase level and skin biopsy are indicated. Of note, a high degree of clinical suspicion is necessary to alert the pathologist to look for mast cells. As with our patient, the findings on routine histologic examination can be subtle and easily missed (Fig. 2 A). If the serum tryptase or skin biopsy results are positive, a bone marrow biopsy is recommended. If the patient has no skin lesions, but the episodes are characteristic of mast cell degranulation, the serum tryptase level should be measured, and, if positive, a bone marrow biopsy should be done. The test for tryptase, an enzyme specific to mast cells, is the most sensitive and specific blood test available and is a minor criterion for diagnosis of systemic MCD. (10) Results from 24-hour urine collections for histamine may be positive only if collected during an episode of unexplained hypotension; tests done when patients are asymptomatic may be negative, hence adding to the diagnostic challenge.

[FIGURE 2 OMITTED]

Treatment of indolent systemic mastocytosis is generally symptomatic. A combination of histamine antagonists and cromolyn sodium may block symptoms from mast cell degranulation. Anaphylaxis is treated with IM epinephrine. Also, patients should carry self-injectable epinephrine and wear a Medic Alert tag. (12) Patients with indolent systemic mastocytosis generally have a normal life expectancy. In both indolent and aggressive systemic mastocytosis, poor prognostic indicators include elevated serum alkaline phosphatase, high bone marrow mast cell burden, bone marrow eosinophilia, anemia, and hepatosplenomegaly. (13) Serum tryptase level does not correlate with disease severity. (13)

Conclusion

Our patient had indolent systemic mastocytosis and vasomotor, anaphylactic episodes for 15 years before diagnosis. Indolent systemic mastocytosis is often asymptomatic, but it can cause significant clinical problems, as in our patient. Altogether, systemic mastocytosis may occur more frequently than previously recognized, and it is an important consideration when evaluating a patient with stereotypic, recurrent, self-limited symptoms, particularly if associated with hypotension. Although the incidence of mastocytosis is unknown, we suggest that the diagnosis be considered in all patients with unexplained hypotension, secondary osteoporosis, or anaphylaxis-like symptoms.

References

1. Young WF Jr., Maddox DE. Spells: in search of a cause. Mayo Clin Proc 1995;70:757-765.

2. Haeberli G, Bronnimann M, Hunziker T, et al. Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy. Clin Exp Allergy 2003;33:1216-1220.

3. Tefferi A, Pardanani A. Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol 2004;11:58-64.

4. Sagher F, Even-Paz Z. Mastocytosis and the Mast Cell. Chicago: Year Book, 1967.

5. D'Inca M, Ghirarduzzi A, Albertini G, et al. Systemic mastocytosis: a review of the literature and of the cases in Reggio Emilia from 1986 to 1994 [Italian]. Ann Ital Med Int 1996; 11:52-58.

6. Ludolph-Hauser D, Rueff F, Fries C, et al. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001;357:361-362.

7. Delling G, Ritzel H, Werner M. Histological characteristics and prevalence of secondary osteoporosis in systemic mastocytosis: a retrospective analysis of 158 cases [German]. Pathologe 2001;22:132-140.

8. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603-625.

9. Middelkamp Hup MA, Heide R, Tank B, et al. Comparison of mastocytosis with onset in children and adults. J Eur Acad Dermatol Venereol 2002;16:115-120.

10. Valent P, Horny H-P, Li CY, et al. Mastocytosis (mast cell disease). In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphatic Tissues. Lyon: IARC Press, 2001. pp. 291-302.

11. Valent P, Sperr WR, Schwartz LB, et al. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004;114:3-11.

12. Tefferi A, Pardanani A. Systemic mastocytosis: current concepts and treatment advances. Curr Hematol Rep 2004;3:197-202.

13. Pardanani A, Baek JY, Li CY, et al. Systemic mast cell disease without associated hematologic disorder: a combined retrospective and prospective study. Mayo Clin Proc 2002;77:1169-1175.

To dare is to lose one's footing momentarily. To not dare is to lose
oneself.
--Soren Kierkegaard

Elizabeth H. Nora, MD, PHD, Kirsten L. Hamacher, MD, Clive S. Zent, MD, and Amit K. Ghosh, MD

From the Division of General Internal Medicine, the Department of Dermatology, and the Division of Hematology, Mayo Clinic, Rochester, MN.

Reprint requests to Amit K. Ghosh, MD, Division of General Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Accepted January 19, 2006.

RELATED ARTICLE: Key Points

* Systemic mastocytosis is a cause of unexplained hypotension with stereotypic, self-limited, recurrent symptoms; it may have unpredictable triggers and is difficult to diagnose.

* To diagnose mastocytosis, the clinician must remain alert for characteristic features during the history and physical examination and inform the pathologist if mast cell disease (MCD) is suspected.

* Measurement of serum tryptase levels is a more useful diagnostic test than the formerly used 24-hour urine collection for histamine.

* Mast cell disease should be considered in patients with stereotypic, self-limited, recurrent symptoms, anaphylactic-like episodes, and secondary osteoporosis.

* Symptomatic treatment is available, and patients with untreated MCD may have significant morbidity.