Barbra S. Miller, Endocrine Surgery, Division of General and Laparoendoscopic Surgery, University of Texas Health Science Center, San Antonio, TX; Richard E. Burney, Professor of Surgery, Division of Endocrine Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI
Barbra S. Miller, MD
Division of General and
University of Texas
Health Science Center
San Antonio, TX
Richard E. Burney, MD
Professor of Surgery
Division of Endocrine Surgery
Department of Surgery
University of Michigan
Ann Arbor, MI
Calciphylaxis is a rare condition that is most often seen in patients with chronic renal failure and secondary hyperparathyroidism. Calciphylaxis in the absence of renal failure has rarely been reported. The authors report a case of calciphylaxis in a patient with normal renal function who presented with irregular necrotic ulcers on both lower extremities. A biopsy suggested calciphylaxis, and further work-up demonstrated primary hyperparathyroidism. The ulcers healed completely after surgical correction of the patient's primary hyperparathyroidism.
Calciphylaxis is a rare condition causing skin necrosis and ulceration. It is most often seen in patients with chronic renal failure and secondary hyperparathyroidism. In such patients, this condition may portend an overall poor prognosis, with a 5-year mortality rate between 50% and 87%.1,2 Calciphylaxis in the absence of renal failure has rarely been reported.3 When it does occur, parathyroidectomy can correct the condition and lead to healing of its characteristic ulcers.
A 76-year-old slender white woman was referred to our institution because of nonhealing, irregular ulcerations on both legs. The patient's medical history was significant for diabetes, hypertension, ischemic heart disease, and atrial fibrillation. Her medications included insulin, hydrochlorothiazide, and digoxin and warfarin for chronic atrial fibrillation. She also took oral calcium supplements with Vitamin D to prevent osteoporosis.
Six months earlier, the patient developed a cutaneous ulcer on the lateral aspect of her right leg, just above the lateral malleolus. This lesion began as a tender, erythematous plaque that enlarged and developed a central area of ulceration with peripheral necrotic edges. A second, almost symmetrical ulcer subsequently developed on the left leg. The patient described the ulcers as excruciatingly painful. The ulcers were treated over several months with a series of medical modalities, including daily wound dressings, topical and systemic antibiotics, a short course of steroids, and even immunosuppressive agents. Despite these measures, the ulcers gradually increased in size and the pain worsened eventually limiting her mobility and confining her to a wheelchair. A vascular surgeon diagnosed the lesions as warfarin-induced skin necrosis, and her warfarin therapy was discontinued. When the ulcers did not heal despite this measure, they were debrided. The tissue was submitted for pathologic evaluation, leading to the histopathologic diagnosis of possible calciphylaxis and subsequent referral to our institution. Warfarin therapy was resumed when it was realized the patient likely had calciphylaxis.
On physical examination, the patient was alert and cooperative. She had a large, tender, irregular ulcer with necrotic margins on the lower third of her right leg (Figure 1). A smaller but similar ulcer also was present on her left leg. There was no evidence of subcutaneous calcification or calcinosis. Pedal pulses were present bilaterally. Ankle brachial indices were not done due to the exquisite pain associated with the ulcers.
Review of the histopathology revealed inflammation and necrosis in both skin and subcutaneous fat (Figure 2). The media of the small vessels revealed calcification and thrombus nearly occluding the lumen. There was septal fibrosis and lobular panniculitis; hemorrhage and microcalcifications were found within the necrotic areas. There were also calcium deposits within the arteriolar vessel walls, with endovascular fibrosis associated with fat necrosis, calcification, and infiltration by neutrophils and macrophages. Ischemic necrosis with central adipocyte infarction was also present. These findings constitute the classic gross and microscopic pathologic findings of calciphylaxis.4,5 Tissue cultures sent at the time of debridement grew nannobacteria.
Laboratory studies revealed the following: fasting glucose, 150 mg/dL (normal, 73-110 mg/dL); hemoglobin A1C, 7.7% (normal, 4%-7% of total hemoglobin); serum creatinine, 0.7 mg/dL (normal, 0.6-1.0 mg/dL); blood urea nitrogen, 22 mg/dL (normal, 8-20 mg/dL); serum calcium, 11.7 mg/dL (normal, 8.6-10.2 mg/dL); ionized calcium, 1.57 mmol/dL (normal, 1.12-1.30 mmol/dL); phosphorous, 3.2 mg/dL (normal, 2.5-4.9 mg/dL); magnesium, 2.2 mg/dL (normal, 1.5-2.3 mg/dL); total protein, 6.4 g/dL (normal, 6.0-8.3 g/dL); albumin, 3.5 g/dL (normal, 3.5-4.9 g/dL); and intact parathyroid hormone (PTH), 157 pg/mL (normal, 2-75 pg/mL). Liver function, thyroid function, protein C, and protein S levels were normal.
Based on the laboratory and histopathologic findings, the diagnosis of calciphylaxis in association with primary hyperparathyroidism was made. Ultrasonography of the neck and a Sestamibi scan were performed for localization purposes, but these did not show evidence of a hyperfunctioning or enlarged parathyroid gland. The patient underwent bilateral neck exploration, which revealed a single enlarged left superior parathyroid gland. It was removed and weighed 0.330 g (normal parathyroid weight, 0.030-0.050 g). Her intact PTH level was measured in the operating room and decreased to 45 pg/mL. Histology confirmed a hypercellular parathyroid gland.
Postoperatively, the patient's serum calcium fell to 9.5 mg/dL and remained between 8.5 and 9.6 mg/dL without calcium supplements. Her leg ulcers were managed with simple, moist gauze dressings, which were changed three times a day, and an elastic wrap-around bandage to reduce edema. The ulcers healed completely over the next 3 months (Figure 3).
Over the past 40 years, there has been considerable debate regarding the role of parathyroidectomy in patients with calciphylaxis. In 1970, Massry and colleagues were the first to report healing of skin and subcutaneous lesions following parathyroidectomy6 Hafner and associates found a statistically significant long-term survival advantage in patients with calciphylaxis who underwent parathyroidectomy (66.5% with surgery compared with 35.1% without).7 A number of other reports in the surgical literature also have described dramatic resolution of calciphylaxis after parathyroidectomy and have reported increases in median survival after surgery compared with medical treatment.8-12 These studies support an aggressive surgical approach in treating patients with calciphylaxis.
In 1962, Selye coined the term "calciphylaxis" based on his observations in a series of experiments on nephrectomized rats.13-14 He found that when he "sensitized" the rats with vitamin D or PTH and then "challenged" them with iron-dextran or intraperitoneal injections of iron or egg albumin, they developed a profound inflammatory response that resulted in calcification of several different organ systems. He hypothesized that a variety of sensitizers (such as vitamin D, dihydrotachysterol, PTH, sodium acetylsulfathiazole, nephrectomy, ureteral damage, and other nephrotoxic insults) and challengers (such as iron and other inorganic salts, glucocorticoids, albumin, egg white and yolk, polymyxin B sulfate, 5-hydroxytryptamine and other mast-cell-releasing agents, radio-opaque contrast media, and even mild physical trauma such as plucking a hair) in different combinations and at different intervals could lead to calcium deposition in different organ systems. Although Selye's original experiments in rodents did not closely mimic the clinical picture of calciphylaxis observed in humans (characteristic cutaneous lesions and histopathologic features), the term he coined nevertheless has been applied to humans ever since. Reports of calciphylaxis in humans began to be published soon after Selye's papers appeared.6,15,16
The pathologic characteristic of calciphylaxis is deposition of calcium in small and medium-sized arteries, leading to tissue ischemia and eventual necrosis and ulceration of skin and subcutaneous tissues.3-8 The clinical manifestations of this disease process were likely first described in 1898.17 Cutaneous and other manifestations of calciphylaxis are caused by the mural deposition of calcium in small- to medium-diameter blood vessels, especially in the dermis and subcutaneous tissue, which leads to calcific thrombogenic microangiopathy.18
The classic histopathological findings may not be present in all patients with calciphylaxis. Clinicians may have to consider this entity in the differential diagnosis of any patient who presents with painful cutaneous ulcers, regardless of the findings on biopsy9,10 To differentiate this condition from metastatic or other types of vascular or organ calcification, one must integrate the clinical history and physical examination and histopathology findings. If the clinical picture appears classic, some clinicians will forego tissue biopsy and proceed to evaluating the patient for hyperparathyroidism, fearing that disruption of an otherwise intact wound could lead to wound breakdown, accelerate the process of necrosis, and predispose the patient to sepsis.
The cutaneous lesions of calciphylaxis begin as small nodules or plaques with a violaceous color, mottling, or livedo reticularis in a stellate pattern. The differential diagnosis includes protein C and protein S deficiency, warfarin-induced skin necrosis, various vasculitides, connective tissue diseases, atherosclerotic thromboembolic disease, septic embolism, dermatomyositis, antiphospholipid syndrome, cryofibrinogenemia, pyoderma gangrenosum, and forms of calcifying panniculitis.5 The ulcers enlarge, become necrotic, and rarely heal with routine wound care measures. The most consistent feature of these lesions is the exquisite pain they produce. The anatomic locations of the lesions may be important, because patients with lesions on the distal extremities may have a better prognosis than those with more centrally located or truncal lesions.2,11,19
Chronic renal failure and secondary hyperparathyroidism have been the most common clinical setting in which calciphylaxis occurs. Many patients with secondary hyperparathyroidism have markedly elevated levels of PTH; however, several studies have shown that the actual PTH level does not necessarily predict calciphylaxis.9-11 Calciphylaxis also has been reported in patients without biochemical abnormalities suggestive of hyperparathyroidism. Some studies have found an increased risk of calciphylaxis when the calcium-phosphate product is above 70 mg2/dL2, whereas other studies dispute such an association.11
Primary hyperparathyroidism, steroid use, and chemotherapeutic medications also may cause calciphylaxis, but these etiologies are rarely reported in relation to what is an already rarely occurring disease process. The largest study of calciphylaxis in association with primary hyperparathyroidism included eight patients.10 Three underwent parathyroidectomy and recovered whereas those who did not undergo parathyroidectomy died. Obese patients and those with diabetes mellitus may be at higher risk than others of developing calciphylaxis in its most severe form. A higher body mass index is seen in patients with proximal versus acral calciphylaxis. One particular study found that for every 1 kg/m2 increase in body mass index, the odds ratio of developing calciphylaxis increased by 6.3% (95% confidence interval, 3.7%?10.7%).20 The reasons for this have not been elucidated; however, hypotheses exist, including lower perfusion of subcutaneous abdominal adipose tissue and diminished adrenergic-mediated abdominal blood flow in obese patients.
Management of calciphylaxis
Initial medical management strategies for a patient with secondary hyperparathyroidism and suspected calciphylaxis include the following: phosphate binding to reduce phosphate levels and calcium-phosphate product to less than 70 mg2/dL2; appropriate low-calcium dialysis; attentive wound care; adequate hydration, fluid and electrolyte balance; nutritional support; and systemic antimicrobial therapy if there is evidence of infection. If there is any question about the diagnosis, it is important to perform a surgical biopsy to rule out other causes of tissue necrosis. Calciphylaxis has a reported mortality rate between 50% and 87% without treatment.12 High mortality accompanies the development of wet gangrene, secondary infections, and resultant sepsis, particularly in patients with central or truncal distribution of necrosis and ulceration.
Significant improvement in survival has been reported when early diagnosis, parathyroidectomy, and aggressive wound care have been undertaken.8-12 Although surgical correction of hyperparathyroidism has not uniformly halted progression of the disease and prevented death, it is still recommended as the most effective treatment available. Because some patients will not benefit from parathyroidectomy, there is some debate regarding its efficacy.
Our patient was different from most calciphylaxis patients because her renal function was normal and the underlying disorder was primary hyperparathyroidism. In such patients, the role of surgery appears to be clearer. Although her disease was due to a single adenoma rather than four-gland hyperplasia, which is commonly associated with renal failure and secondary hyperparathyroidism, the surgical approach to correcting the underlying hyperparathyroidism remains the same.
Calciphylaxis is a progressive, life-threatening condition with a high mortality rate. Although usually seen in conjunction with chronic renal failure and secondary hyperparathyroidism, it can occur in conjunction with primary hyperparathyroidism or other disease processes and treatments. The differential diagnosis for soft tissue abnormalities may be extensive, but when primary hyperparathyroidism is present, early recognition and prompt surgical treatment may play an important role in curtailing the progression of calciphylaxis, aid in healing its characteristic necrotic ulcerations, and prevent death.
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