Calciphylaxis: A Case Study with Differential Diagnosis
Calciphylaxis is a relatively rare, but horribly disfiguring, skin condition that is most often associated with end-stage renal disease and long-term dialysis. Unfortunately, calciphylaxis-related morbidity and mortality are significant. The case study presented demonstrates many of the findings associated with the “typical” calciphylaxis patient; end-stage renal disease and an extensive, painful ulcer. The complexity of the patient’s history and medical/surgical interventions, especially medication therapy with coumadin and heparin, complicated initial diagnostic processes. Close scrutiny of multiple physical assessment findings, historical factors, and test results was required for correct diagnosis. Crucial components of differential diagnosis of calciphylaxis versus coumadin-induced skin necrosis or heparin-induced thrombocytopenia necrosis include: patient history and characteristics, clinical presentation, and diagnostic test results.
Calciphylaxis is a relatively rare, debilitating, potentially life-threatening, and exquisitely painful disease in which calcification of the skin, subcutaneous tissue layer, or internal organs leads to skin necrosis, skin discoloration, and/or other systemic changes. Affected patients typically have end-stage renal disease (ESRD) and associated hyperparathyroidism. Nurses and other healthcare clinicians who practice in chronic care settings such as subacute facilities, dialysis centers, and home care may be more likely to encounter people with this disorder. The major focus of this article is a case study of a calciphylaxis patient, followed by a discussion of the syndrome. The patient's complex medical/surgical history provided a learning experience for differentiating among several causes of extensive skin necrosis, including coumadin-induced skin necrosis (CISN) and heparin-induced thrombocytopenia (HIT) necrosis.
A 51-year-old Hispanic male was admitted to a subacute care facility after transfer from a tertiary care hospital. A Wound Ostomy Continence (WOC) Clinical Nurse Specialist was consulted to assess a "large" wound on the patients" left leg. A record review revealed significant medical and surgical history. His admitting diagnosis was ESRD, change in mental status, and a large painful lower left leg ulcer. His medical history included coronary artery disease, hypertension, peripheral vascular disease (PVD), myocardial infarction, status post percutaneous transluminal coronary angioplasty (PTCA), brachytherapy of the left circumflex artery, and possible calciphylaxis. The patient had been on renal dialysis since 1989.
The patient's surgical history was extensive. He had a kidney transplant in 1986; the kidney failed by 1989 and was removed. In the same year, he had an aortic valve replacement with a St. Jude prosthetic valve. He had a right total hip replacement in 1991 and a coronary artery bypass (times two) in 1993. In July 2001 (1 month before subacute admission), he had a femoral popliteal bypass of the right leg. During this perioperative experience, he received heparin and coumadin therapy.
The patient's pharmacotherapy included aspirin 80 mg once daily, clopidogrel bisulfate (Plavix, Sanofi-Synthelabo Inc., New York, NY) 75 mg daily; metoprolol tartrate and hydrochlorothiazide (Lopressor, Novartis Pharmaceuticals, East Hanover, NJ) 100 mg BID; warfarin sodium (Coumadin, Bristol-Myers Squibb, Princeton, NJ) 1 mg daily; Nephrocap (Fleming and Company, Fenton, Mo.), one capsule daily, and a fentanyl patch, 25 mcg every hour with an every 72-hour change protocol. He received dialysis on a Monday, Wednesday, and Friday pattern.
Before the tertiary care hospital admission, the patient had been living at home, receiving care from a nephew. He was divorced from his wife and had not interacted with his ex-spouse and children in many years. The hospital admission was triggered by the development of an extensive, painful, full-thickness ulcer on his lower left leg. He also exhibited periodic disorientation alternating with lucidity.
Diagnosis of the leg ulcer's etiology was complicated by the fact that the patient had recently received heparin and coumadin in addition to long-term dialysis. A biopsy of the ulcer supported calciphylaxis rather than coumadin-induced skin necrosis because of calcium deposits. Clinical presentation and progression also were consistent with calciphylaxis.
The WOC Clinical Nurse Specialist recommended daily application of a hydrogel dressing for the pink granulation tissue and immediate sharp debridement because of the extensive nature of the necrosis (see Figures 1 and 2). If surgical debridement was not possible immediately, papain-urea (Accuzyme, Healthpoint, San Antonio, Tex.), applied twice daily, was recommended for eschar debridement as a slower, backup therapy. A consult to vascular surgery and plastic surgery was ordered. The WOC Specialist advised consultation to the pain management team.
Despite attempts to control deterioration (eg, debridement, pain control, prevention of further trauma), the leg wound worsened over the next 2 weeks and an above-knee amputation was performed at the acute care facility of the healthcare system. Two weeks following surgery, the patient developed severe respiratory distress, abdominal pain, and subsequently required transfer to the ICU. Diagnostic testing suggested possible calciphylaxis of internal organs such as the lungs. The patient developed overwhelming cardiopulmonary failure and sepsis and subsequently died.
Calciphylaxis: A Challenging Clinical Care Situation
Calciphylaxis is an abnormal skin calcification process found mostly in ESRD patients who have secondary hyperparathyroidism. The cardinal features of calciphylaxis include irregular cutaneous purplish lesions (plaques and patches) that progress to necrosis. The integumentary deterioration is related to calcification of soft tissues and blood vessel walls, causing cessation of blood supply. The ulcers are most often exquisitely tender.1
The term calciphylaxis was originally coined by Hans Selye in 1962.2 He proposed his calciphylaxis theory of 'sensitizers and challengers." He described a three-part process of sensitization, lag time, and challengers. The hyperparathyroidism of renal failure acts as a tissue sensitizer. At a later period in time, "challenging" agents such as blood transfusions, albumin administration, corticosteroid administration, immunosuppression, subcutaneous injections, intravenous calcitriol, and iron dextran injections trigger the calcification process.3 The exact nature and order of the triggering process is unknown because diagnostic interventions begin after the condition commences. Calcification and sclerosis are outcomes of the process. Although patients with calciphylaxis usually have high calcium and phosphorus levels (called calcium-phosphate product, Ca x PO4), most ESRD patients do not develop calciphylaxis. Why this selective sparing occurs is unknown.4 Retrospective analyses suggest that certain factors predispose some renal failure patients to calciphylaxis, including diabetes mellitus, atherosclerosis, hypertension, and obesity.4 Calciphylaxis develops in approximately 1% of patients with ESRD yearly, with a potential total prevalence up to 4% of all ESRD patients.5,6 Calciphylaxis occurrence or severity is not predicted on the type or duration of chronic renal failure, the severity of hyperparathyroidism, or the degree of parathyroid hormone elevation.7
In addition to the vascular calcification-cutaneous necrosis syndrome, other possible systemic manifestations of calciphylaxis include calcification of the lungs, stomach, kidneys, and adrenal glands. It is noteworthy that calciphylaxis has been reported for years. The first published article appeared in 1898.8 Increasing incidence may be related to better recognition of the syndrome and increased numbers of people with ESRD and long-term dialysis.7
A number of diseases can simulate calciphylaxis lesions, including polyarteritis nodosa, Sjogren's Syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, and septic embolism. Coumadin necrosis and heparin-induced thrombocytopenia necrosis also can cause similar extensive tissue destruction (see Figures 3 and 4). Differential diagnosis of the two disorders from calciphylaxis can be discerned based on differences in patient history, patient characteristics (age, gender), physical findings, and diagnostic test results5,9 (see Table 1). Prompt and correct diagnosis is crucial because early treatment significantly increases the likelihood of a positive outcome, and treatment for the three conditions differs markedly.
Biopsy is a helpful tool in understanding the pathophysiology of the disorder. Histologically, a constant in all cases of calciphylaxis is the presence of intravascular calcium deposits, chiefly within small- and medium-sized venules and arterioles. They also may be found in extravascular soft tissues such as the skin (calcinosis cutis), subcutaneous tissue (calcifying panniculitis), and viscera.5
Calciphylaxis has a clinical presentation and progression that is relatively common among patients. It occurs more often in women and obese patients. Skin lesions and necrotic ulcers occur more frequently in the lower extremities and abdominal area than on the trunk or upper extremities.10 The clinical presentation starts with the development of lesions that are painful, often pruritic, violaceous in color, and bizarrely shaped (Livedo Reticularis) plaques or nodules. They evolve into well-demarcated nonhealing ulcers that are necrotic and gangrenous.3 Generally, involvement of the internal organs is uncommon, and the head is usually unaffected.7,11 The ischemic process due to calcification may extend down to the muscle layer. In contrast to other forms of peripheral vascular disease, blood flow is usually demonstrably distal or deep to the necrosis - ie, distal pulses are present.11
Diagnosis and treatment. Following scrutiny of patient history and physical findings, diagnosis ultimately depends on clinical testing that especially includes tissue biopsies and levels of selected blood parameters. Tissue biopsy usually shows multiple discrete foci of calcification within the adipose lobules, in subcutaneous septa, and in the tunica media layer of small- to medium-sized blood vessels.12 Small arteries can have calcification of the intima.13 Laboratory values of calcium, phosphorus, calcium-phosphorus product, and parathyroid hormone levels are likely to be significantly elevated. If infection exists, leukocytosis will be present.
Treatment of calciphylaxis involves both surgical and medical approaches to the underlying disease process and local wound therapy. The surgical treatment of calciphylaxis is only variably successful.11 Total parathyroidectomy or parathyroidectomy with autotransplantation is recommended for patients with hyperparathyroidism.7,14 Severe necrosis of extremities often involves amputation.
Some authors suggest that the limitation of alleged "challengers" is helpful. However, the need to use iron, glucocorticoids, and blood products is absolutely critical in ESRD patients at times.13 Consequently, the need for limitation remains speculative.
Medical management of the altered calcium and phosphorus metabolism involves several approaches. Normalization of altered calcium and phosphorus levels is the first logical step to prevent or treat the disease. Laboratory values have to be monitored so the calcium-phosphorus product (normal < 70mg/dL), parathyroid hormone level (normal 10 to 65 picograms/mL), total protein (normal 5.5 to 8 g/dL), and pre-albumin level (normal 20 to 43 mg/dL) stay within normal limits.15 Food high in calcium (milk, milk products, cheese, cream soups, pudding, and the like) and phosphorus (cola drinks, beans, nuts, seeds, and the like) must be limited. Medications can be used to control the hyperphosphatemia, including magnesium carbonate.12 Calcium carbonate is not used as phosphate binder because it increases the link of hypercalcemia.16
The nature of local wound care is highly dependent on the severity of the necrosis. Interventions may include vigorous sharp debridement, enzymatic debridement, wound irrigation or whirlpool, and antibiotic therapy. Necrotic tissue must be debrided as much as possible. Adjunctive wound therapies are used as appropriate. Despite quality wound care, sepsis and necrosis are the leading causes of death.14,17
Unfortunately, notwithstanding multiple treatment modalities, patients with advanced symptoms of calciphylaxis (eg, ulceration, infection) rarely improve. Patients with beginning skin changes (ie, indurations) are more likely to experience healing and survival after parathyroidectomy. The best form of "treatment" is early recognition of the disease process, accompanied by early operative intervention before the development of advanced local or systemic symptoms.16
The pathomechanisms of calciphylaxis are poorly understood. This unusual pathological and clinical entity is likely the result of multiple factors aggravating the tissues and blood vessels already altered by the effects of renal failure and chronic dialysis. The case study represented a severe manifestation of the syndrome and permitted a brief discussion of differential diagnosis, contrasting calciphylaxis to two similarly presenting conditions, coumadin-induced skin necrosis and heparin-induced thrombocytopenia necrosis.
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Dr. Beitz is Associate Professor, Director of Certificate and Distributive Learning Programs, and WOCNEP Co-Director, at the School of Nursing, La Salle University, Philadelphia, Pa. Please address correspondence to: Janice M. Beitz, PhD, RN, CS, CNOR, CWOCN, Associate Professor, Director of Certificate and Distributive Learning Programs, WOCNEP Co-Director, School of Nursing, La Salle University, 1900 West Olney Avenue, Philadelphia, PA 19141; email: email@example.com.