HPF = high-power field; LPF = low-power field.
Calciphylaxis: An important imitator of cutaneous vasculitis
Version of Record online: 29 MAR 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis Care & Research
Volume 57, Issue 3, pages 533–537, 15 April 2007
How to Cite
Jacobs-Kosmin, D. and DeHoratius, R. J. (2007), Calciphylaxis: An important imitator of cutaneous vasculitis. Arthritis & Rheumatism, 57: 533–537. doi: 10.1002/art.22616
- Issue online: 29 MAR 2007
- Version of Record online: 29 MAR 2007
- Manuscript Accepted: 31 AUG 2006
- Manuscript Received: 10 MAY 2006
- South Jersey Lupus Foundation
Although it remains poorly understood, the clinical syndrome calciphylaxis has received increased attention, especially in the nephrology literature. We describe a middle-aged man with extensive lower extremity ulcerations initially ascribed to cutaneous vasculitis who was ultimately diagnosed with calciphylaxis.
A 42-year-old man was transferred to our institution for management of severe ulcerations of the lower extremities thought to be secondary to vasculitis. Three months previously, the patient was hit on the left shin by a soccer ball. The next day, his left pretibial region became erythematous and swollen. He was given cephalexin for presumed cellulitis, and the erythema improved but the swelling did not. Within a few days, the erythema returned and the swelling extended to his calf. Small, tight bullae formed over the affected skin. His right leg also began to swell and blister. The patient developed generalized edema and decreased urine output. He was admitted to an outside hospital.
The patient had hypertension and a baseline creatinine level of 2 mg/dl. Medications included amlodipine, furosemide, and acetaminophen/propoxyphene napsylate. There were no known drug allergies. Social and family histories were noncontributory.
Upon admission, the patient was afebrile and vital signs were normal except for a blood pressure of 150/90 mm Hg. The examination was remarkable for erythema of the lower extremities with 3+ pitting edema and mild flexion contractures of the knees. The skin below the knees was covered with scattered bullae, indurated violaceous patches, and ulcers.
Initial laboratory results are shown in Table 1. A portable chest radiograph showed cardiomegaly with clear lung fields. Renal ultrasound revealed a right renal cyst, increased cortical echogenicity, and diminished renal cortices. Cephalexin was continued, and dialysis was initiated. Results of blood and urine cultures were negative. Cultures of the wounds grew mixed bowel and skin flora. Erythrocyte sedimentation rate was 85 mm/hour. Hepatitis B and C serologies, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cryoglobulins were negative. Serum protein electrophoresis was normal. Intact parathyroid hormone (PTH) was increased at 196.5 pg/ml (normal range 10–55 pg/ml). There was no evidence of venous thromboembolism on duplex ultrasonography of the lower extremities or by a ventilation/perfusion scan. Transthoracic echocardiogram showed no evidence of endocarditis, atrial myxoma, or atheroembolic disease.
|White cells, per mm3||26,800||5,200–12,400|
|Differential count, %|
|Platelets, per mm3||307,000||130,000–400,000|
|Blood urea nitrogen, mg/dl||133||5–26|
|Alkaline phosphatase, units/liter||321||38–126|
|Total bilirubin, mg/dl||0.6||0.2–1.3|
|Alanine aminotransferase, units/liter||17||11–66|
|Aspartate aminotransferase, units/liter||15||15–46|
|International normalized ratio||1.3|
|Adjusted partial-thromboplastin time, seconds||47||23–36|
|White blood cells||Too numerous to count||0–2/HPF|
|Red blood cells||5–10||0–2/HPF|
Despite ciprofloxacin and ceftazidime, whirlpool treatments, and wound debridement, numerous ulcers with black eschar and indurated, erythematous margins developed below the knees. New violaceous and indurated lesions progressed proximally to involve the thighs followed by the lower abdomen. Punch biopsy samples of the left and right thigh were reported as necrotizing vasculitis. Treatment with methylprednisolone 60 mg intravenously every 6 hours was begun. The histopathologic findings, however, also included focal fat necrosis and a patent blood vessel with mural calcification, features suggesting calciphylaxis. A repeat punch biopsy sample of the thigh obtained 1 week later for immunofluorescent studies showed vascular and perivascular fibrin deposits that were suggestive of atrophie blanche from stasis dermatitis or livedo vasculitis. Mycophenolate mofetil was initiated and subsequently discontinued days later, when blood cultures grew Pseudomonas and Enterobacter.
Computed tomography of the chest, abdomen, and pelvis revealed no masses or lymphadenopathy. Rheumatoid factor, anticardiolipin antibodies, lupus anticoagulant, and anti–double-stranded DNA antibody were repeatedly negative. Serum C3 and C4 were normal.
Three months after the initial admission the patient was transferred to our institution for further treatment. He was stable and afebrile but in severe pain. The physical examination revealed extensive skin involvement (Figure 1). A necrotic lesion was present over the left lower abdomen and a small blister surrounded by erythematous, indurated skin was on the right lower abdomen. Eschar covered much of the lower extremities. Small necrotic lesions were noted on the dorsum of each foot.
We reviewed the patient's presentation, rapid clinical course, and negative serologic workup. Although the distribution of lesions did not appear to progress after immunosuppression with corticosteroids, the lesions themselves did not resolve. This prompted a re-reading of the skin biopsy slides by our pathology department. Vasculitis was not seen. Ischemic changes with secondary inflammatory alterations were observed along with extensive focal larger vessel calcification. Subcutaneous microvascular endothelial injury with thrombosis was appreciated, in addition to foci suspicious for microvascular calcification, findings consistent with calciphylaxis (Figure 2).
The calcium-phosphate product was normalized by stopping a calcium-containing phosphate binder and adjusting to a low calcium dialysate. Parathyroidectomy was not performed because the repeat intact PTH was 63 pg/ml, and there was a concern of inducing low-turnover bone disease in the absence of appropriate PTH stimulation. Steroids were discontinued. The patient's pain was refractory to long-acting opiates. His wounds continued to worsen and became foul smelling. He could not tolerate local wound care and was transferred to a burn center. In spite of aggressive care at the burn center, including extensive debridement several times under general anesthesia, the patient died of sepsis.
Calciphylaxis is a form of small-vessel vasculopathy that results in ischemia. It occurs mainly in patients with renal insufficiency, especially those with end-stage renal disease on dialysis. Affected individuals tend to be obese, diabetic, white, and female (1, 2). A high calcium-phosphorous product is common in the majority of patients and hyperparathyroidism is noted in many cases. PTH itself may lead to derangements of calcium and phosphorous, directly injure vessels by stimulating intimal proliferation, or create a vascular steal phenomenon in calcified vessels by vasodilating other vessels (1). However, patients without abnormalities in calcium, phosphorous, renal function, or parathyroid function have been described to develop calciphylaxis. Risk factors unique to these unusual cases include hyperparathyroidism, inflammatory bowel disease, malignancy, and cirrhosis (3–8).
Skin and subcutaneous tissues are the most common sites affected. Initially, calciphylaxis may develop in an acral pattern on distal extremities (i.e., fingers, toes, or ankles) or proximally on the thighs or buttocks (9). Areas with increased vascularity and significant subcutaneous adipose tissue, such as the thighs, abdomen, and breasts, often become involved. Facial involvement has been reported (10). Lesions begin characteristically as a livedo reticularis pattern of mottling with violaceous, superficial, tender nodules (9, 11, 12). As in our case, this presentation can be mistaken for cellulitis (1). With progression, lesions ulcerate and become hemorrhagic with dry necrosis (1, 9, 11, 13). As demonstrated in Figure 1B, bilateral lesions are frequently symmetric and involve medial areas of the extremities that come into contact, called kissing lesions (1). The disorder is intensely painful. Whereas the skin is the predominant organ affected, skeletal and heart muscle, and joint, lung, eye, and intestinal tissue can be involved (1).
Histopathologic features vary depending on the stage of the lesion biopsy sample that is tested. Pathologic specimens show characteristic intravascular calcium deposits within arterioles and venules. In one series, acute and chronic panniculitis was also frequent (14). Later stage lesions have shown intimal proliferation and endovascular fibrosis (13, 14). This intimal change appears to correspond with the development of end-organ damage (1). Microthrombi may be present (1, 14, 15), and a giant cell reaction has been reported in a minority of cases (12, 16). Finally, the most evolved lesions show necrosis with little inflammation (14).
Laboratory evaluation may reveal elevated serum phosphate and calcium phosphorous product along with elevated PTH, although these are not diagnostic of calciphylaxis (13). In addition, imaging techniques are neither sensitive nor specific to the changes of calciphylaxis (13). Transcutaneous oxygen saturation probes may be useful to identify skin ischemia prior to the development of skin necrosis (1). Vascular calcification may be identified by abnormal uptake on bone scan imaging (1).
Vessel calcification in calciphylaxis is hypothesized to result from the dysregulation of vascular calcium deposition. The impairment of endogenous calcification inhibitors, including osteoprotegerin and matrix γ-carboxyglutamic acid protein, has been proposed to play a role (1). Small-vessel calcification is a common finding in patients with chronic renal failure; these lesions do not usually result, however, in ischemia and tissue injury. Therefore, it appears a secondary insult is required for tissue infarction to arise. Low serum albumin is strongly associated with the development of calciphylaxis (17). Local trauma (e.g., from subcutaneous injections) has been described as inciting calciphylaxis (18). Other reported precipitants include systemic hypotension, sepsis, intravenous iron dextran, corticosteroids, albumin, blood products, immunosuppressants, heparin, and warfarin (1, 2). Several lines of evidence suggest that vitamin K deficiency or resulting abnormalities of protein C or protein S are important factors in many cases: the frequent presence of thrombosis, the similarity of calciphylaxis lesions to those of warfarin necrosis, and the reports of the development of calciphylaxis in patients taking warfarin (1). Direct causal evidence for these factors has not been established.
The differential diagnosis for calciphylaxis includes more commonly recognized entities such as severe peripheral vascular disease and atheroemboli, necrotizing vasculitis, marantic endocarditis, myxoma, antiphospholipid antibody syndrome, cryoprecipitate disorders (cryoglobulinemia and cryofibrinogenemia), and, less commonly, oxalate vasculopathy in patients with end-stage renal disease and oxaluria (1, 12). As noted, small-vessel calcification is not specific for calciphylaxis, but this feature, along with panniculitis, intimal proliferation or fibrosis, or microthrombi with a paucity of inflammation can support the diagnosis of calciphylaxis in the right clinical setting.
In retrospect, our patient's story was very typical of calciphylaxis. In the setting of advanced renal failure, this white male patient had an episode of localized trauma that triggered a generalized vasculopathic response characterized by early violaceous plaques followed by rapidly progressive, symmetric, necrotic ulcerations with eschar formation. Although his skin lesions appeared to stop advancing at the lower abdomen after initiation of steroids, this pattern of involvement was consistent with calciphylaxis. Cases of calciphylaxis such as that described here, mimicking vasculitis or connective tissue disease, have been reported previously (19–21). A clinician's awareness of the clinical characteristics of this uncommon disorder, in conjuction with an experienced pathologist, can significantly influence the recognition of calciphylaxis.
Treatment of advanced calciphylaxis is rarely successful and mortality remains common, with most patients dying from infectious complications leading to sepsis (22). In one center in Canada, the development of ulcers at any time was associated with 80% mortality (13). A presentation confined to nonulcerating plaques may portend a better prognosis, and steroids may be beneficial in this subset of patients (13). Normalization of the calcium-phosphorous product through dietary changes, non–calcium-containing phosphate binders, and low calcium dialysate is recommended (9). Local injections to areas with significant adipose tissue should be avoided (9). Parathyroidectomy has been emphasized, but it remains unsuccessful in many cases, especially in patients with normal or mildly elevated PTH, and survival benefit has not been routinely demonstrated (1, 9, 22–24). Surgical debridement, and possible amputation, may be indicated (9). Even with debridement, the underlying vasculopathy may prevent the formation of granulation tissue and impede wound healing (25), often resulting in a poor outcome (1). Some researchers advocate the use of systemic antibiotics (9). Intravenous sodium thiosulfate, an extremely soluble, inorganic salt long used as the antidote for cyanide poisoning, has been administered in a few cases of calciphylaxis with good outcomes (26–28). Hyperbaric oxygen has also been reported to lead to resolution of ulcers in some cases (29, 30). Limited availability and cost, however, may be obstacles to such therapy. A recent report of dramatic improvement with the bisphosphonate pamidronate indicates another possible treatment (31).
An improved awareness of calciphylaxis is necessary for accurate diagnosis. Calciphylaxis should be suspected in patients with cutaneous necrosis and chronic renal failure. Given the high rate of infections in these patients, timely identification should minimize the exposure to potentially toxic immunosuppressive treatments intended to remedy a diagnosis such as vasculitis. Early diagnosis is also the first step to evaluating potential therapies for this frequently devastating disorder.
Dr. Jacobs-Kosmin had full access to all of the data in the study and takes responsibility for the integrity of the data.
Study design. Jacobs-Kosmin, DeHoratius.
Acquisition of data. Jacobs-Kosmin.
Analysis and interpretation of data. Jacobs-Kosmin, DeHoratius.
Manuscript preparation. Jacobs-Kosmin, DeHoratius.