Diagnostic Dilemma: Calciphylaxis

Department Editor: Tania Phillips, MD, FRCPC Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Discuss the presentation of calciphylaxis 2. Diagnose calciphylaxis 3. Describe the pathogenesis of calciphylaxis 4. Discuss the management of calciphylaxis. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC, are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Lin, Goldberg, and Phillips disclose no financial conflicts. Accreditation: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC, is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications, LLC, designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists. Method of Participation: Read the article, take, submit, and pass post-test by June 1, 2003. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: June 1, 2002 Expiration date: June 1, 2003 Presentation A 53-year-old African-American man presented with a year-long history of multiple, nonhealing ulcers on both of his legs. His history included venous insufficiency, peripheral vascular disease, hypertension, hypercoagulable state secondary to antithrombin III deficiency (history of deep venous thrombosis and pulmonary embolus), lupus anticoagulant, hyperhomocystinemia, coronary artery disease, myocardial infarction, end-stage dilated cardiomyopathy, osteodystrophy, and end-stage renal disease on hemodialysis. His medications included warfarin, levofloxacin, dicloxacillin, vancomycin, fentanyl patch, oxycodone/acetaminophen, ranitidine, digoxin, nystatin, carvedilol, lisinopril, quinine sulfate, lactulose, and folic acid. Physical Examination Physical examination revealed a cachetic man. His head, neck, oral mucosa, chest, abdomen, back, upper extremities, and genitalia were normal. His legs revealed extensive necrotic ulcers involving the thighs, calves, and shins, covered with black hemorrhagic crust (eschar) characteristic of calciphylaxis lesions (Figures 1 and 2). Investigations Parathyroid hormone was elevated at 451 (normal: 10–65pg/mL). Calcium at time of admission was normal at 9.5 (normal: 8.4–10.2mg/dL). Phosphorus at time of admission was low normal at 2.9 (normal: 2.7–4.5mg/dL). Highest calcium phosphate product prior to parathyroidectomy was 46.55. BUN at time of admission was 29, but during his admission, it went up as high as 45 (normal: 6–22mg/dL). Creatinine ranged from 5.1 to 6.1 (normal: 0.8–1.3mg/dL) during his admission. Parathyroid scan revealed increased uptake, and parathyroid biopsy was consistent with hyperparathyroidism. The patient underwent a subtotal parathyroidectomy during his admission. X-ray of the patient’s left leg one year prior to his admission showed extensive vascular calcification. Skin biopsy of the necrotic lesions unexpectedly showed no calcification of dermal and subcutaneous blood vessels, possibly due to sampling error. Diagnosis The patient was diagnosed with calciphylaxis on the basis of clinical history, physical exam, and laboratory findings. Discussion Calciphylaxis is the rare condition of systemic calcification of small- and medium-sized vessels associated with cutaneous necrosis. It is characterized by exquisitely tender purpuric lesions, most often located on the medial thighs or buttocks.1 Lesions develop eschar, central necrosis, and ulceration. Acral gangrene of the toes and fingers can also occur.2 Death from sepsis secondary to bacterial invasion through the break in skin integrity often occurs. Calciphylaxis should be differentiated from other causes of metastatic calcification. Both conditions affect the same type of patients; however, in calciphylaxis the parathyroid hormone level is usually markedly higher and so is the calcium x phosphate ion product level (exceeding 6.5–12.0 mmol2/L2).3 Epidemiology. Calciphylaxis most often affects patients with end-stage renal disease (ESRD) undergoing hemodialysis or peritoneal dialysis and those patients who are status post-renal transplantation.1 Renal failure may be secondary to a variety of causes and includes polycystic kidney disease, hepatorenal syndrome, noninsulin-dependent diabetes mellitus, cyclosporine toxicity, systemic lupus erythematosus, and advanced HIV disease.1,4 While the disease occurs almost always in the setting of renal failure, cases of normal renal function have been reported.5 It was previously thought that men and women are affected equally;3 however, Oh, et al.,4 report that women outnumber men by a ratio of 3:1. The range of ages is 6 months to 83 years, with a mean age of 48 ± 16 years.3,4 History. The condition was first described by Selye, et al.,8 in 1962 as a hypersensitivity condition that occurs after exposure to a sensitizing agent and then a challenger after a “critical period” of time, typically ranging from one to several days.4 In the animal (rat) model used in this study, sensitizing agents, including vitamin D compounds, parathyroid hormone, and elevated calcium and phosphate product, followed by challengers, such as egg white, egg yolk, metallic salts, albumin infusion,7 and trauma, caused “acute local calcinosis followed by inflammation and sclerosis.”1,8 The animals experienced subsequent inflammation, calcinosis, and sclerosis in most organs, including the skin.4 Other challenging agents include glucocorticoids, intramuscular tobramycin, iron dextran complex, vitamin D, and immunosuppressive agents. Pathogenesis. The actual pathogenesis of calciphylaxis in humans is unknown. Parathyroid hormone is thought to be a potential tissue sensitizer, thus parathyroidectomy (to reduce parathyroid hormone levels) is one option for therapy of this condition.9 The theory proposed by Selye, et al.,8 explains a mechanism of calciphylaxis; however, the histopathologic finding of intravascular thrombosis may be better explained by Mehta, et al.,10 who noted that skin lesions of calciphylaxis are similar to those of warfarin necrosis. Measurements of antigenic and functional levels of protein C in patients with ESRD and calciphylaxis and undergoing hemodialysis and patients undergoing dialysis without calciphylaxis were compared to those of normal volunteers. Functional levels of protein C were found to be significantly lower in patients with calciphylaxis, which might predispose calciphylaxis patients to a prothrombotic state. Antigenic levels of protein C were normal in all patients. Histopathology. Intravascular thrombi of superficial dermal vessels and vascular calcification with associated ischemic necrosis are seen. Rarely, a perivascular lymphocytic infiltrate is seen in association with subcutaneous vessels. In some cases, calcification of vessels is not seen; however, calcification of subcutaneous adipose tissue occurs.11 The calcification occurs in the intima or media of small- and medium-sized dermal and subcutaneous vessels with intimal proliferation.3,12 Clinical features. Review of the literature reveals that lesions, consisting of tender, necrotic ulcers with surrounding ecchymosis and petechiae, are often proximal and occur on the back, hips, buttocks, and proximal thighs.1,4,13 Pre-infarctive or pre-ischemic lesions may appear as mottling or livedo reticularis. Early cutaneous lesions may range from erythematous to light purple nodules, similar to erythema nodosum, to ill-defined, erythematous, indurated plaques with prominence of follicles and violaceous depressed plaques with telangiectasias and mottled hyperpigmentation. Central necrosis with tightly adherent black eschar or leathery slough often occurs.4 Lesions often enlarge over weeks to months. Ulcers may be deep, extending to fascia. Secondary infection through the breach of skin integrity may occur. Infection may remain superficial or progress to cellulitis, and sepsis may ensue. Laboratory investigations. In addition to laboratory values consistent with renal failure (increased creatinine and blood urea nitrogen), patients often have secondary hyperparathyroidism and an elevated calcium and phosphate product. However, normal levels of parathyroid hormone, calcium, and phosphate may be present.1 There is no single diagnostic test.3 Skin biopsy should be performed extending to the subcutaneous fat. Roentgenograms may reveal arterial calcification.14 Cultures should be done to rule out infection. Treatment. Treatment is largely supportive and aimed at control of the calcium phosphate product.4 It includes surgical removal or conservative debridement of necrotic sites,3 and constant monitoring of infection must also be done.4 Antibiotic therapy and nutritional support may be indicated.3 Patients with high leukocyte count from infection have poorer prognoses.9 Results of parathyroidectomy are controversial.1,9,15 One study reports significantly improved survival rates after parathyroidectomy.15 Another study reports successful outcome to be about 60 percent.1,5 Two-thirds of patients survive surgery, although retrospective analysis is limited due to selection bias and does not differentiate those patients having hyperparathyroidism from those that do not.3,4,12 Lesions secondary to calciphylaxis that have been reported to improve after parathyroidectomy do not show regression of vessel calcification as demonstrated by roentgeno-grams performed after recovery from necrosis.3,15 More controlled trials are needed to study the benefits of anticoagulation, i.e., replacement of protein C with fresh frozen plasma and factor IX concentrate, in the therapy of calciphylaxis patients, as suggested by Mehta, et al.10 Hyperbaric oxygen therapy9 and prednisone/ cimetidine15 therapy have anecdotally been reported to be helpful. Patient Management Despite the absence of subcutaneous calcifications on biopsy, the practitioners believed the patient had calciphylaxis based on other clinical findings, and clinical improvement resulted after subtotal parathyroidectomy was performed. The highest calcium phosphate product prior to parathyroidectomy was 46.55 and the lowest product was 27.55. After parathyroidectomy, the calcium phosphate product ranged from 7.92 to 38.4. Parathyroid hormone levels ranged from 5 to 15 after the procedure. This patient had aggressive wound care, including surgical debridement, followed by local wound care as follows: Some lesions were treated with topical mupirocin ointment and covered by gauze and a waterproof film dressing (Tegaderm™, 3M Company, St. Paul, Minnesota), which were changed every four to five days to promote autolytic debridement, as hydrogel dressings were not available at the time for this patient. Lesions with black eschar were covered with hydrocolloid gel dressings (DuoDERM,® ConvaTec, Skillman, New Jersey) and changed every two to three days to loosen the eschar. Orders for frequent turning of the patient and a special bed were made in order to decrease focal areas of pressure to avoid pressure ulcers. Unfortunately, despite continual improvement of his lower-extremity ulcers, control of infection could not be maintained. His leukocyte count continued to increase despite aggressive antibiotic therapy, wound care, including debridement, and nutritional support. The patient’s last blood culture remained negative; however, he developed severe gastrointestinal symptoms and expired from cardiac arrest. How to obtain educational credits by reading this article Successful completion entails scoring at least 70 percent on the questions, completing the entire evaluation form, submitting it online, or printing it off and mailing or faxing it to the correct address listed below. Certificates will be mailed to those who successfully complete the learning assessment by June 1, 2003. Fax the completed form to: (610) 560-0501 or mail the completed form to: Trish Levy, CME Director HMP Communications, LLC 83 General Warren Blvd. Suite 100 Malvern, PA 19355 Questions 1. Calciphylaxis is associated with which of the following clinical features? A) Exquisitely tender purpuric lesions, most often located on the medial thighs or buttocks B) Eschar, central necrosis, and ulceration C) Acral gangrene of the toes and fingers D) Death from sepsis E) All of the above 2. The diagnosis of calciphylaxis is most likely to be made in which epidemiologic subset of patients? A) Those with end-stage renal disease (ESRD) B) Those undergoing hemodialysis C) Those undergoing peritoneal dialysis D) Those patients who are status post-renal transplantation E) All of the above 3. The majority of cases of calciphylaxis have occurred in patients with: A) Inflammatory bowel disease B) Hepatitis C) Hypothyroidism D) Chronic renal failure E) Hypoparathyroidism 4. Renal failure may be secondary to: A) Polycystic kidney disease B) Hepatorenal syndrome C) Noninsulin-dependent diabetes mellitus D) Cyclosporine toxicity E) All of the above 5. Histopathologic examination of these lesions is expected to demonstrate: A) Intravascular thrombi of superficial dermal vessels B) Vascular calcification with associated ischemic epidermolysis C) Inflammatory infiltrate consisting of neutrophils D) Accumulation of lipoprotein X E) A and B 6. Treatment of these lesions includes: A) Aggressive wound care with meticulous debridement of necrotic tissue B) Removal of potential sensitizers and challengers, such as systemic corticosteroids and other immunosuppressives C) Control of the calcium phosphate product with phosphorus binding agents, low-calcium dialysis, and diet D) Largely supportive E) All of the above 7. The laboratory finding most useful in establishing the diagnosis of calciphylaxis is: A) An increased serum phosphate level B) An increased serum calcium level C) An increased serum vitamin D level D) An increased parathyroid level E) A decreased creatinine level Calciphylaxis Answer Form and Evaluation Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions below): Click on or circle one letter for each answer: 1. A B C D E 2. A B C D E 3. A B C D E 4. A B C D E 5. A B C D E 6. A B C D E 7. A B C D E Evaluation—Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning objectives: 4 3 2 1 Effectiveness of the teaching/learning methods: 4 3 2 1 This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1. Discuss one presentation of calciphylaxis? YES NO 2. Diagnose calciphylaxis? YES NO 3. Describe pathogenesis of calciphylaxis? YES NO 4. Discuss management of calciphylaxis? YES NO What questions do you still have?________________________________________________________ How will you use what you have learned from this activity? ________________________________________________ All tests must be received by 6/1/03.