Primary hyperparathyroidism

* We present the case of a 69-year-old woman with calciphylaxis due to primary hyperparathyroidism. A 0.5-g parathyroid adenoma was surgically removed, which resulted in complete recovery of the patient. Review of the literature revealed 7 other cases of calciphylaxis due to primary hyperparathyroidism and showed that prompt surgical removal of the autonomous parathyroid gland lesion results in clinical recovery of calciphylactic skin lesions. (Arch Pathol Lab Med. 2001;125:1351-1353)

Calciphylaxis, also known as calcifying panniculitis1 and vascular calcification-cutaneous necrosis syndrome,2 is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification. It is seen most often in patients with end-stage renal disease who are on dialysis or who have recently received a renal transplant, and it is usually associated with secondary or tertiary hyperparathyroidism.3,4 We report an unusual presentation of calciphylaxis in an elderly woman with primary hyperparathyroidism, mild renal failure, and non-insulin-dependent diabetes mellitus.

REPORT OF A CASE

A 69-year-old, obese white woman presented in February 1996 for renal insufficiency and proteinuria. The patient had a long-- standing history of non-insulin-dependent diabetes mellitus, hypertension, coronary artery disease, and congestive heart failure. Her medical history was also significant for peripheral vascular disease, obesity, gout, hypothyroidism, and status postcholecystectomy. Physical examination was positive for edema in the lower extremities and multiple violaceous cutaneous ulcers surrounded by tender brawny erythema.

Her laboratory workup revealed a serum creatinine level of 160 (mu)mol/L (reference range, 61.8-106.08 wmol/L); potassium, 5.7 mmol/L (3.8-5.0 mmol/L); urine protein, 2.5 g/24 h; creatinine clearance, 0.66 mL/s (1.33-2.16 mL/s); erythrocyte sedimentation rate, 55 mm/h; antinuclear antibodies, negative; anti-hepatitis C antibody, nonreactive; unremarkable serum protein electrophoresis; and normal complement levels. Of note, her ionized calcium level was elevated at 1.37 mmol/L (1.17-1.29 mmol/L); phosphate, 1.8 mmol/L (0.77-1.42 mmol/L); parathyroid hormone, 18.42 pmol/L (1.05-6.0 pmol/L); and she had a decreased 1,25 dihydroxy vitamin D3 concentration, 28 pmol/L (36-144 pmol/L). A diagnosis of hyperparathyroidism was rendered. Renal ultrasound revealed 1 left and 2 right renal cysts. Kidney size was 9.3 cm on the right and 11.4 cm on the left with bilateral cortical thinning, but no hydronephrosis. The workup for her renal insufficiency and non-nephritic-range proteinuria was unremarkable, but the clinical scenario was consistent with diabetic nephropathy. Technetium-99 radionuclide scan showed no evidence of osteomyelitis of the lower extremities. Doppler and duplex scans showed valvular incompetence and varicosities of bilateral lower extremity deep veins with absence of thrombosis. Microbiologic studies performed on swabs obtained from leg ulcers were negative. However, she received local wound care and antibiotics for prophylactic coverage of bilateral lower extremity cellulitis and superficial ulcers, which resulted in no significant improvement. She also received low-dose oral vitamin D therapy (calcitriol, 0.25 [(mu)g x 3/wk).

She continued to complain of severe leg pain, difficulty in walking, and persistent painful cutaneous leg ulcers for which she was admitted in July 1996. Examination of the lower extremities demonstrated induration of the subcutaneous tissues with extreme tenderness and formation of blisters. The subcutaneous tenderness extended to the lower abdomen. A full-thickness biopsy of the skin and subcutaneous tissue was performed. Histologic examination revealed microvascular calcification with ischemic epidermolysis. Widespread calcification within the adipose lobules, in connective tissue septae, and in the adventitia of small and medium-sized vessels with narrowing of their lumina was noted, consistent with calciphylaxis (Figure). At that time, vitamin D therapy was discontinued. A repeat parathyroid hormone evaluation produced a value of 12.63 pmol/L, and her ionized calcium concentration was 1.38 mmol/L.

She underwent a parathyroid exploration that showed a large adenoma in the left inferior gland, measuring 1.0 x 0.7 x 0.3 cm and weighing 0.5 g. Cut section showed grayish-brown homogenous tissue. Microscopically, the tumor was encapsulated and cellular and was composed of a diffuse proliferation of chief cells with a thin rim of compressed nonneoplastic parathyroid tissue. This compressed rim of tissue, as well as the resected right inferior gland, appeared microscopically normal, but with high intracytoplasmic fat by oil red 0 stain. The 2 superior parathyroid glands were explored during surgery. They were noted to be grossly unremarkable and were left intact. These histomorphologic and clinical findings were consistent with the diagnosis of primary hyperparathyroidism.

Following parathyroidectomy, the patient's serum calcium level remained in the low end of the reference range: 1.18 mmol/L and later 1.20 mmol/L (reference range, 1.17-1.29 mmol/L). Therapy with nonsteroidal anti-inflammatory agents was initiated and she was discharged. Her leg pain subsequently disappeared, and she experienced near complete resolution of her skin lesions. However, she died 7 months after her last admission of congestive heart failure.

COMMENT

Calciphylaxis was first described by Selye5 in 1962 as a condition of induced hypersensitivity in which tissues respond to appropriate challenging agents with calcium deposition. The current understanding of the pathogenesis of this process implicates elevated calcium and phosphate levels, which exceed their solubility and subsequently deposit as CaPO4, in vessels.6 Progressive vascular compromise follows, with ischemic necrosis of skin, subcutaneous fat, and less often of muscle. These ischemic changes lead to livedo reticularis, painful violaceous plaquelike subcutaneous nodules, or both. The lower extremities are predominantly involved. Patients with skin involvement of the trunk and proximal extremities have a worse prognosis. The skin changes usually progress to nonhealing, black, leathery, escharlike lesions that often develop superimposed infection. Infected ulcers are a frequent source of sepsis, which is ultimately the cause of death in a majority of patients. The mortality rate approaches 60%.7

Although the presentation and histopathologic changes of calciphylaxis are variable, it is usually associated with secondary and tertiary hyperparathyroidism. In our patient, there were several unusual features. Calciphylaxis developed in the context of mild renal insufficiency (serum creatinine, 160 (mu)mol/L; creatinine clearance, 0.66 mL/s), primary hyperparathyroidism (intact parathyroid hormone, 18.42 pmol/L) with mild hypercalcemia (ionized calcium, 1.37 mmol/L), near normal CaPO, product (phosphate, 4 mmol/L), and low-dose vitamin D therapy. Only 7 other reports of calciphylaxis associated with primary hyperparathyroidism were identified in our search of the literature.1,7-11 The patients ranged from 29 to 71 years of age with a preponderance of females (Table). Most of these cases involved a chief cell adenoma, but 2 patients had carcinoma of the parathyroid gland. Of the 3 cases of hyperparathyroidism reported by Winkelmann and Keating,10 only 2 cases with definitive diagnosis of primary hyperparathyroidism were included in our review. Our patient also had bilateral varicose veins as demonstrated by Doppler and duplex venous scans. The resulting stasis may have contributed to the development of calciphylactic lesions in this patient.

Parathyroidectomy has been advocated as a mode of therapy for calciphylaxis, since it often leads to marked clinical improvement.12 Our patient had complete resolution of her cutaneous lesions after parathyroidectomy. Of note, clinical recovery was also associated with surgical removal of the parathyroid adenoma in cases 5 and 7, indicating that the disease may be self-limiting if the underlying metabolic derangement is corrected. Other therapeutic options include hyperbaric oxygen, antihistamine, and corticosteroid therapy. 12,13 Delay in diagnosis is associated with high mortality. The presence of bilateral, symmetrical, superficial skin lesions and persistence of dorsal pulses are important clinical clues for the diagnosis of calciphylaxis.14

As demonstrated by our report, timely recognition of this disease with appropriate intervention has a favorable impact on patient outcome.

The authors thank Salvador Sena, PhD, for reviewing the manuscript and for offering helpful suggestions.

References

1. Anderson DC, Stewart WK, Piercy DM. Calcifying panniculitis with fat and skin necrosis in a case of uraemia with autonomous hyperparathyroidism. Lancet. 1968;2(7563):323-325.

2. Dahl PR, Winkelmann RK, Connolly SM. The vascular calcification-cutaneous necrosis syndrome. J Am Acad Dermatol. 1995;33:53-58.

3. Adrogue HJ, Frazier MR, Zeluff B, Suki WN. Systemic calciphylaxis revisited. Am J Nephrol. 1981;1:177-183.

4. Fisher AH, Morris DJ. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol. 1995;26:1055-1064.

5. Selye H. Calciphylaxis. Chicago, III: University of Chicago Press; 1962:1100.

6. Khaffif RA, DeLima C, Silverberg A, Frankel R. Calciphylaxis and systemic calcinosis: collective review. Arch Intern Med, 1990;150:956-959.

7. Essary LR, Wick MRW. Cutaneous calciphylaxis: an underrecognized clinicopathologic entity. Am J Clin PathoL 2000;113:280-287.

8. Ellis IT, Barr DP, Metastasizing carcinoma of the parathyroid gland with osteitis fibrosa cystica and extensive calcinosis. Am J PathoL 1951;27:383-397.

9. Bogdonoff MD, Woods AH, White JE, et al. Hyperparathyroidism. Am) Med. 1956;21:583-595.

10. Winkelmann RK, Keating FR. Cutaneous vascular calcification gangrene and hyperparathyroidism. Brj Dermatol. 1970;83:263-268.

11. Khafif RA, DeLima C, Silverberg A, Frankel R, GroopmanJ. Acute hyperparathyroidism with systemic calcinosis: report of a case. Arch Intern Med 1989; 149:681-684.

12. Worth RL. Calciphylaxis: pathogenesis and therapy. I Cutan Med Surg. 1998;2:245-248.

13. Dean SM, Werman H. Calciphylaxis: a favorable outcome with hyperbaric oxygen. Vasc Med. 1998;3:115-120.

14. Fischer AH, Morris Dj. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol. 1995;26:1055-1064.

Imran Mirza, MD, MS; Damanjeet Chaubay, MD; Himanshu Gunderia, MD; Winston Shih, MD; Hani EI-Fanek, MD

Accepted for publication March 15, 2001.

From the Departments of Pathology (Drs Mirza, Gunderia, and ElFanek) and Internal Medicine (Drs Chaubay and Shih), Danbury Hospital, Danbury, Conn.

Reprints: Hani EI-Fanek, MD, Department of Pathology & Laboratory Medicine, Danbury Hospital, 24 Hospital Ave, Danbury, CT 06810 (e-mail: Hani.ElFanek@danhosp.org).

Copyright College of American Pathologists Oct 2001
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