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Subtotal parathyroidectomy: a possible treatment for calciphylaxis. (Original Article).

Abstract

Calciphylaxis is a rare disorder in patients with chronic renal failure that is characterized by ischemic necrotic skin lesions. The prognosis is grave and mortality is high (80%). The precise mechanism of calciphylaxis is still unknown, but in addition to chronic renal failure, elevated parathyroid hormone levels appear to play a role. The role of parathyroidectomy in treating affected patients is questionable. In this article, we describe the case of a patient with chronic renal failure who developed rapidly progressive subcutaneous calcifications and ulcerations in the lower extremities. These lesions regressed following subtotal parathyroidectomy. We also review the literature on calciphylaxis, with a focus on treatment options.

Introduction

Calciphylaxis is a rare disorder that appears almost exclusively in patients who have chronic renal failure. More than 100 cases have been reported (1) since Bryant and White (2) first described a case of hypercalcinosis in a 6-month-old child with hydronephrosis in 1898. This entity has been variously termed uremic small-vessel disease, uremic small-artery disease, uremic gangrene syndrome, medial calcification, and intimal hyperplasia. (1,3,4) Very few cases of calciphylaxis have been reported in patients with normal renal function. (5) Reports have noted a 4.1% incidence among patients in the hemodialysis population. (6) Calciphylaxis can also occur in predialysis patients and in otherwise healthy kidney transplant recipients. (7,8) The highest risk of calciphylaxis is seen in long-term hemodialysis patients who have high levels of panthyroid hormone (PTH) (>1,000 pg/mi). (6) Females are affected more than males (ratio: 3 to 1). (8-10) Although the mean age of affected patients is 48 years, the reported ag e spectrum is wide, ranging from 6 months to 83 years. (1)

The clinical features of calciphylaxis are primarily cutaneous. In the early phase of the disorder, dermatologic features can include purpuric patches and plaques in a reticulate pattern with focal central necrosis. Late skin manifestations include dusky plaques with woody induration, which can evolve into irregular ulcers covered by thick, dark eschars that are exquisitely tender and lead to necrosis of the subcutaneous fat. Extracutaneous manifestations are rarely reported. Lesions primarily involve the proximal part of the lower extremities and trunk (44 to 68% of cases); the abdomen and penis have been reported to be involved, as well. (11,12) Digital gangrene sometimes occurs. (13,14)

Histopathologic examination reveals the presence of calcium deposits in the wall of the small-to-medium blood vessels of the dermis and subcutaneous fat; the development of these deposits is followed by fibroblast proliferation and giant-cell formation. (15) As a result, fibrosis, intimal hyperplasia, and occasionally thrombosis of the vessels occur, followed by ischemic necrosis of the skin. (6)

The differential diagnosis of calciphylaxis includes antiphospholipid-antibody syndrome, warfarin-induced skin necrosis, purpura fulminans, microembolization, pyoderma gangrenosum, and necrotizing fasciitis. (13)

The mechanism responsible for the hypercalcinosis involves the metabolism of calcium, phosphorus, vitamin D, and PTH in the presence of long-standing end-stage renal failure. The kidney dysfunction leads to decreased hydroxylation of 1,25-dihydroxyvitamin [D.sub.3], inadequate synthesis of biologically active vitamin D, hypocalcemia caused by diminished calcium absorption from the intestine, and secondary hyperparathyroidism. In advanced stages, autonomous parathyroid gland secretion might develop and cause tertiary hyperparathyroidism. The end points of the process are elevated calcium and phosphorus levels. (12-14)

The pathogenesis of calciphylaxis was first described in detail by Selye in 1962. (17,18) He found that iron, inorganic salt, or glucocorticoid challenge in vitamin D- or PTH-sensitized rats led to the development of varying degrees of inflammation, calcinosis, and sclerosis in the skin and in virtually all organs examined. Selye concluded that unlike the case with simple metastatic calcifications, this response occurred only with the use of a sensitizer and a challenger. (17) In humans, the high serum PTH levels act as the sensitizer, but the identity of the challenger remains unknown. Trauma, albumin, warfarin, and steroids have all been suggested. (5,15) The pathogenesis is still not entirely clear because not every case of hyperparathyroidism involves calciphylaxis.

Because no feature is pathognomonic for calciphylaxis, the diagnosis must be based on a combination of the clinical history, physical examination, and histopathologic findings on skin biopsy along with the typical finding of "pipestem" vessels on radiologic studies. (6)

Mortality is high (80%), and death is usually attributable to infection of the skin lesions in immunocompromised patients. (1) The location of disease manifestations is an important prognostic factor; when the disease is confined to the distal extremities, the prognosis is better. (1) Chan et al reported that patients whose disease involves the toes distal to the midcalf have a more favorable prognosis than do patients whose disease involves the trunk, shoulder, buttocks, and thighs. (19) In their review of the literature, Hafner et al found that 40 of 53 patients (75.5%) with distal localization necrosis survived their skin complications (all skin lesions had healed); the remaining patients died of their disease 6 weeks to 21 months following the onset of uremic small-artery disease, most as a result of complications. (1) In that study, only 11 of 42 patients (26.2%) who exhibited a proximal pattern survived. Leukocytosis exceeding 20,000 cells/m1 predicts a worse outcome. (12) Age, dialysis, and kidney tra nsplantation do not have any prognostic value.

In view of the grave prognosis of patients with calciphylaxis, a wide variety of treatment modalities has been tried, all with limited success. In this article, we describe the case of a patient with calciphylaxis in whom subtotal parathyroidectomy effectively alleviated all signs and symptoms. We also review the literature and discuss other therapies, as well.

Case report

A 56-year-old man with a 6-year history of dialysis-dependent chronic renal failure secondary to streptococcal glomerulonephritis was admitted to our center with a 4-month history of induration of both thighs that had become painful 1 week earlier. His medical history was significant for chronic obstructive pulmonary disease, blindness of unknown cause, paroxysmal atrial fibrillation, ischemic heart disease, congestive heart failure, and hepatitis B virus infection. He also had a history of repeated hospitalizations for pneumonia as well as the atrial fibrillation. The patient was taking vitamin D, a calcium supplement, and a beta blocker.

On physical examination, the patient. was pale and exhibited edema of both legs. An erythematous livedo reticularis rash was noted on both thighs. Palpation of the thighs revealed the presence of hard and painful subcutaneous nodules covered with puerperal erythema and two ulcerative areas with round, sharp edges (figure 1). Ultrasonography detected splenomegaly and calcifications of the large vessels around the subcutaneous calcifications. No other significant finding was recorded.

Laboratory studies revealed that the patient's serum PTH level ranged between 325 and 1,540 pg/dl. His erythrocyte sedimentation rate was 40 mm/hr, and his white blood cell count was 12,300/[mm.sup.3]. Serum values were as follows: calcium, 9.3 mg/dl; phosphorus, 6.0 mg/ dl; albumin, 3 g/dl; urea, 105 mg/dl; creatinine, 6.57 mg/ dl; and fasting total proteins, 7.9 g/dl. His liver enzyme and proteins C and S values were within normal limits. Cultures of his skin lesions were positive for coagulase-positive, methicillin-resistant, fucidic-acid-sensitive staphylococcus.

Microscopic analysis of the cutaneous lesion sections revealed the presence of widespread ulceration and necrosis in both the skin and subcutaneous fat. The media of medium-sized blood vessels contained heavy deposits of calcium (figure 2). In addition, some of these vessels were occluded by organizing thrombi. Microcalcifications were also present freely within the necrotic tissues, and they were accompanied by a foreign-body reaction. The histologic findings were consistent with both metastatic and dystrophic calcifications, and overall they were typical of calciphylaxis.

The patient was treated with antibiotics and vitamin D, but he showed no improvement. Ultrasonography of the parathyroids and sestamibi scanning detected no evidence of parathyroid enlargement. Because of the rapid progression of the cutaneous lesions and associated aseptic necrosis, exploration of the neck via subtotal parathyroidectomy was performed. Three-and-one-half glands were removed, leaving only one-half of the left inferior parathyroid gland. All of the glands were larger and heavier than average; their size ranged from 0.6 to 1.5 cm and their weight from 0.24 to 0.29 g.

The parathyroid tissue submitted for examination was markedly hypercellular and did not contain a rim of residual normal parathyroid tissue (figure 3). The hypercellular gland was predominantly made up of chief cells and a small number of clear and oncocytic cells. These features were consistent with secondary parathyroid hyperplasia--a diagnosis that was supported by the patient's clinical history of chronic renal failure.

After surgery, the patient's serum PTH level dropped to 188 pg/dl. His serum calcium level was maintained at 7.8 to 7.9 mg/dl with calcium and vitamin D supplements. His phosphorus level ranged from 4.1 to 6.6 mg/dl and his albumin level from 2.8 to 3.1 g/dl. The improvement in his skin lesions was dramatic. The skin incisions healed rapidly, and the necrotic lesions regressed. The patient later underwent skin transplantation, and the repair was almost complete. He was discharged after 5 weeks.

Discussion

Because the pathogenesis of calciphylaxis and its relationship to high levels of PTH are not completely understood, the need for parathyroidectomy in affected patients is still controversial. (1,3,12) Nonsurgical treatment with wet dressings, a low-calcium and low-phosphorus diet, phosphate-binding agents, antibiotics, and dialysis have all been tried with various degrees of success. (20) Hyperbaric oxygen therapies have also been reported to be beneficial. (21,22)

Parathyroidectomy would appear to be an important treatment because it removes the presumed sensitizing agent (PTH) as well as the stimulus for hypercalcemia, which is believed to play an important etiologic role. (6) The first successful use of subtotal parathyroidectomy in a patient with vascular calcification and skin necrosis was described in 1970 by Massry et al. (23) In 1976, Gipstein et al suggested that total or subtotal parathyroidectomy be considered for the treatment of ischemic skin lesions in uremic patients and in renal transplant recipients. (24) Autotransplantation or cryopreservation of removed parathyroid tissue is routine when total parathyroidectomy is chosen as the mode of treatment. After our patient underwent subtotal parathyroidectomy, his calcium level returned to normal.

The two main complications of parathyroidectomy in patients with calciphylaxis are infections of the incision (12) and recurrent hyperparathyroidism with nonregressive cutaneous lesions. (3) Neither of these complications occurred in our patient. In terms of survival, Hafner et al demonstrated the advantage of parathyroidectomy in 104 cases of calciphylaxis. (1) In their study, two-thirds of the 58 patients who underwent surgery survived, compared with only one-third of those who did not undergo surgery. In contrast, Chan et al reviewed 47 cases of calciphylaxis and concluded that parathyroidectomy was not associated with any statistically significant survival advantage. (19) Likewise, Roe et al also failed to note any dramatic advantage to surgery, as only two of their seven patients experienced any benefit from it. (22)

The role of parathyroidectomy for calciphylaxis is particularly questionable in patients whose serum calcium and PTH levels are normal. Kane et al claimed that parathyroidectomy should not be performed in the absence of documented hyperparathyroidism because it would result in low-turnover bone disease, which would eventually elevate calcium and phosphorus levels and promote further calciphylaxis. (3)

Because removal of the parathyroid glands does not always result in a resolution of the clinical condition, several authors have concluded that the primary factors associated with surgical success are (1) the amount of time that has elapsed between diagnosis and surgical intervention, (2) the patient's general health status, and (3) the location, number, and severity of the skin lesions. (1,3,12,13)

On the basis of our experience and that of others who have reported a rapid regression of calciphylactic skin lesions following parathyroidectomy, we suggest that this procedure is a potentially important modality for the treatment of this life-threatening condition, and we recommend that it be considered for every calciphylaxis patient. Further studies are needed to elucidate the pathogenesis of the disorder and the optimal treatment modality.

References

(1.) Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954-62.

(2.) Bryant JH, White WH. A case of calcification of the arteries and obliterative endarteritis associated with hydronephrosis in a child aged six months. Guy's Hospital Rep 1898;55:17.

(3.) Kane WJ, Petty PM, Sterioff S, et al. The uremic gangrene syndrome: Improved healing in spontaneously forming wounds following subtotal parathyroidectomy. Plast Reconstr Surg 1996;98:671-8.

(4.) Coates T, Kirkland GS, Dymock RB, et al. Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 1998;32:384-91.

(5.) Fader DJ, Kang S. Calciphylaxis without renal failure. Arch Dermatol 1996;132:837-8.

(6.) Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients on hemodialysis: A prevalence study. Surgery 1997;122:1083-9; discussion 1089-90.

(7.) Fine A, Fleming S, Leslie W. Calciphylaxis presenting with calf pain and plaques in four continuous ambulatory peritoneal dialysis patients and in one predialysis patient. Am J Kidney Dis 1995;25:498-502.

(8.) Budisavljevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal failure. J Am Soc Nephrol 1996;7:978-82.

(9.) Bleyer AJ, Choi M, Igwemezie B, et al. A case control study of proximal calciphylaxis. Am J Kidney Dis 1998;32:376-83.

(10.) Ross CN, Cassidy MJ, Thompson M, et al. Proximal cutaneous necrosis associated with small vessel calcification in renal failure. Q J Med 1991;79(289):443-50.

(11.) Ivker RA, Woosley J, Briggaman RA. Calciphylaxis in three patients with end-stage renal disease. Arch Dermatol 1995;131:63-8.

(12.) Kriskovich MD, Holman JM, Hailer JR. Calciphylaxis: Is there a role for parathyroidectomy? Laryngoscope 2000;110:603-7.

(13.) Oh DH, Eulau D, Tokugawa DA, et al. Five cases of calciphylaxis and a review of the literature. J Am Acad Dermatol 1999;40 (Pt 1):979-87.

(14.) Dub QY, Lim RC, Clark OH. Calciphylaxis in secondary hyper. parathyroidism: Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213-8; discussion 1218.9.

(15.) Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: Study of three cases with literature review. Hum Pathol 1995;26:1055-64.

(16.) Melikoglu M, Apaydin S, Hamuryudan V, et al. Calciphylaxis: A condition mimicking necrotizing vasculitis. Clin Rheumatol 1996;15:498-500.

(17.) Selye H. Calciphylaxis. Chicago: University of Chicago Press, 1962.

(18.) Selye H. The dermatologic implications of stress and calciphylaxis. J Invest Dermatol 1962;39:259-75.

(19.) Chan YL, Mahony JF, Turner JJ, Posen S. The vascular lesions associated with skin necrosis in renal disease. Br J Dermatol 1983;109:85-95.

(20.) Lipsker D, Chosidow O, Martinez F, et al. Low-calcium dialysis in calciphylaxis. Arch Dermatol 1997;133:798-9.

(21.) Vassa N, Twardowski ZJ, Campbell J. Hyperbaric oxygen therapy in calciphylaxis-induced skin necrosis in a peritoneal dialysis patient. Am J Kidney Dis 1994;23:878-81.

(22.) Roe SM, Graham LD, Brock WB, Barker DE. Calciphylaxis: Early recognition and management. Am Surg 1994;60:81-6.

(23.) Massry SG, Gordon A, Coburn JW, et al. Vascular calcification and peripheral necrosis in a renal transplant recipient. Reversal of lesions following subtotal parathyroidectomy. Am J Med 1970;49:416-22.

(24.) Gipstein RM, Coburn JW, Adams DA, et al. Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 1976;136:1273-80.

From the Department of Otorhinolaryngology (Dr. Bahar, Dr. Popovzer, and Dr. R. Feinmesser), the Department of Dermatology (Dr. Mimouni and Dr. David), and the Department of Pathology (Dr. M. Feinmesser), Rabin Medical Center, Beilinson Campus, Petab Tiqva, Israel, and the Sackler Faculty of Medicine, Tel Aviv University.

Reprint requests: Raphael Feinmesser, MD, Department of Otorhinolaryngology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. Phone: 972-3-937-6459; fax: 972-3-527-7024 or 972-3-937-6467; e-mail: raphae15@barak.net.il
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Author:Feinmesser, Raphael
Publication:Ear, Nose and Throat Journal
Geographic Code:7ISRA
Date:May 1, 2003
Words:2654
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