Calciphylaxis: a rare association with alcoholic cirrhosis. Are deficiencies in protein C and S the cause?

Abstract: Calciphylaxis is a rare condition of induced systemic hypersensitivity in which tissues respond to appropriate challenging agents with a sudden local calcification. It is characterized by acute calcium deposition in the medial layer of small and intermediate dermal vasculature that can lead to epidermal ischemia, ulceration, and necrosis. Calciphylaxis typically occurs in patients with end-stage renal disease who are undergoing dialysis and who have secondary hyperparathyroidism. Even in this population the incidence is less than 1%. The cause of calciphylaxis is unknown. However, it has been suggested that deficiencies of protein C and protein S may play a role in the pathophysiology of this disorder. Our patient is the fourth with cirrhosis to be reported to have developed calciphylaxis and adds further evidence that low levels of these anticoagulant factors may be an important etiologic factor for development of calciphylaxis. This report should alert the clinician that calciphylaxis occurs in patients with cirrhosis and should stimulate further research concerning the possible role of protein C and protein S deficiency in calciphylaxis.

Key Words: calciphylaxis, cirrhosis, protein C, protein S

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Calciphylaxis is a rare condition with approximately 160 cases reported in the world's medical literature. (1) The majority of these cases of calciphylaxis have occurred in patients with end stage renal disease who are on long-term dialysis or who have undergone renal transplantation. Secondary hyperparathyroidism appears to be an important contributing factor to the development of calciphylaxis in these situations. (2) Nevertheless, calciphylaxis occurs in less than 1% of patients with these medical disorders. (3,4)

Calciphylaxis is characterized by an acute calcium deposition in the medial layer of small and intermediate-sized arteries and arterioles in multiple organ systems. The skin is the most common tissue affected. Cutaneous lesions characteristically begin as tender, violaceous, livedoid discolorations typically on the medial thighs, the abdominal wall, or on the buttocks. The lesions subsequently become indurated plaques and nodules that progress to necrotic deep ulcerations with eschar formation. (5,6) Less frequently the kidneys, skeletal muscle, lungs, heart and gastrointestinal system are involved.

The cause of calciphylaxis is unknown. However, some investigators believe that deficiencies of protein C and S may play an etiologic role in the development of this disorder. We report a rare case of calciphylaxis occurring in a patient with alcoholic cirrhosis who had low levels of both protein C and protein S. Our case adds further evidence that these anticoagulants may indeed be a factor in the pathophysiology of calciphylaxis.

Case Report

A 45-year-old white woman with a history of alcoholic cirrhosis was admitted in hepatic encephalopathy. She had become progressively more lethargic and somnolent over seven days. Family members had noted black erosive plaques on the inner aspects of the patient's thighs for one week. There was no history of recent trauma, fever, or chills but the patient had been scratching herself and complaining of itching. The patient was a nonsmoker, had no history of hypertension, polycythemia, or renal impairment, and was not diabetic. Her medications included lactulose, rofecoxib, furosemide, and ranitidine. She had no known allergies to medications. The patient had not used topical or oral corticosteroids. In addition, she had not used or taken any over-the-counter medication, herbal remedies, or vitamins.

Her blood pressure was 104/72 mm Hg, heart rate 106 beats per minute, and respiratory rate 20 breaths per minute. Her temperature was 97.2[degrees]F. She weighed 275 pounds, giving her a body mass index of 43.8. The patient was obese and somnolent. Scleral icterus was present. Her respiratory and cardiovascular examinations were unremarkable. Her abdomen was distended with bilateral flank dullness. Caput medusa was not present. An eschar measuring 11 X 6 cm was noted on the left inner thigh and another eschar measuring 10 X 5 cm was seen on the right inner thigh (Fig. 1). All pulses were normal. There were no enlarged lymph nodes present.

Her hematocrit was 18.7% and her white blood cell count was 6.3 [10.sup.3]/mcL with 68% segmented neutrophils. Admission laboratory included a blood urea nitrogen of 66 mg/dL, creatinine 2.1 mg/dL, serum calcium 8.2 mg/dL, serum phosphate 4.3 mg/dL, albumin 1.6 g/dL, magnesium 1.1 mg/dL, total bilirubin 3.5 mg/dL, alkaline phosphatase 80 U/L, and an ammonium level 75 U/L. Her corrected calcium and calcium-phosphorus product were calculated as normal at 10.12 mg/dL and 46.1, respectively. Her calculated creatinine clearance was 47 mL/min at admission as compared with her usual baseline of 98 mL/min. Her protein C was 34% (normal: 70-149%) and protein S 30% (normal: 80-120%). Her protime and partial thromboplastin time were normal. Her serum tested negative for D-dimer and fibrin split products. Fibrinogen, antithrombin III, cryoglobulin, and cryofibrinogen levels were normal. Parathyroid hormone level was also normal.

[FIGURE 1 OMITTED]

Plain x-rays of the thighs demonstrated calcification of vessels (Fig. 2). Biopsy of skin lesions revealed calcification of soft tissue and small and medium-sized blood vessels, consistent with calciphylaxis (Fig. 3).

The patient was treated with empiric IV antibiotics, hydrated with IV fluids, and received local wound care and debridement. She survived for two weeks but died as a result of sepsis.

Discussion

The term calciphylaxis was coined to describe widespread cutaneous and systemic calcification. This disease process has been labeled with various names including calcification-cutaneous necrosis syndrome, calcific azotemic arteropathy, uremic small-artery disease with medial calcification and intimal hyperplasia, uremic gangrene syndrome, and calcific uremic arteriolopathy. While calciphylaxis was reported to occur in chronic renal failure patients as early as 1898, (7) it was not until 1976 that the true clinical importance of this syndrome was recognized. (8) Interestingly there is a 3:1 female preponderance.

Calciphylaxis, as indicated by the above names, occurs primarily in patients with chronic renal failure who are on long-term dialysis and who have secondary hyperparathyroidism and hypercalcemia. However, calciphylaxis can occur in primary hyperthyroidism, vitamin D intoxication, milk-alkali syndrome, idiopathic neonatal hypercalcemia, and various hematologic and solid organ malignancies. (2)

The pathogenesis of calciphylaxis is poorly understood. (4) It has been suggested that the mechanism through which this disorder arises consists of a three-part process: sensitization, lag time, and challenge. The sensitizer, such as renal failure, a high parathyroid hormone level, or an elevated calciumphosphate product (greater than 70), predisposes the vascular tissue to develop calciphylaxis. (9) After an ill-defined but critical time period, exposure to a challenging agent induces acute calcium deposition with the associated inflammatory necrosis. (3,10-12) Since most patients with renal failure and an elevated calcium-phosphate product do not experience calciphylaxis other possible etiologic factors have been proposed.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Due to similarities between purpura fulminans associated with congenital protein C and S deficiencies, warfarin-induced skin necrosis, and calciphylaxis, a possible role for deficiencies in these anticoagulants in the development of calciphylaxis has been proposed. A recent literature review of calciphylaxis cases in which protein C levels were reported demonstrated that 36% of patients had subnormal levels of this anticoagulant. Similarly, protein S was decreased in 50% of cases. (13)

There are three patients reported in the medical literature to have calciphylaxis as a complication of alcoholic cirrhosis. (13-15) Including our patient, the average age of these patients was 48.3 years, with three females and one male. Two of the patients had normal renal function. The third patient had hepatopulmonary syndrome and had undergone transjugular intrahepatic portosystemic shunting. Our patient had mild renal impairment but this was acute in nature and she had not undergone dialysis. Two of the patients had received IV albumin infusion therapy, a proposed challenging agent for precipitating calciphylaxis. Protein C and S levels were not reported in two patients. As with our patient, the levels of protein C and S were decreased in the third patient. This finding suggests that calciphylaxis in patients with alcoholic cirrhosis may have been precipitated by deficiencies in these anticoagulants.

Protein C and S are vitamin K-dependent natural anticoagulants. Protein C is activated at the surface of endothelial cells by a complex of thrombin and thrombomodulin. With protein S serving as a cofactor, activated protein C inhibits coagulation. Congenital homozygous deficiency of protein C and S results in purpura fulminans with hemorrhagic necrosis of the skin and frequently individuals with deficiencies in these factors die due to widespread vascular thrombosis. Patients with heterozygous deficiencies of these proteins result in a reduction of protein C and protein S levels of 50% of normal and are associated with a high risk of venous thromboembolic disease. (16,17)

Warfarin administration results in an early reduction of functional levels of protein C, protein S, and antithrombin III compared with the procoagulant activities of factors II, VII, IX, and X. This phemonena may contribute to the development of warfarin-induced skin necrosis that has many similarities to calciphylaxis. (18)

In addition, there are medical disorders that may induce an environment that predisposes the vascular bed to react to the challenging agent with calciphylaxis. Factors that have been identified to increase the risk for the development of calciphylaxis include diabetes mellitus, peripheral vascular disease, hypertension, hypomagnesemia, obesity, hypoalbuminemia, IV iron dextran and albumin infusion, corticosteroids, trauma, and polycythemia. (6,13,19) Our patient was morbidly obese and had the additional predisposing factor of hypomagnesemia and hypoalbuminemia for the development of calciphylaxis. It may be that one or more of these factors interacted with her deficiencies in protein S and C to induce her calciphylaxis.

Incisional biopsy will often establish the diagnosis of calciphylaxis. Histologically there is vascular calcification with ischemic epidemolysis and calcifying panniculitis may be present. The main differential diagnosis is Monckeberg medial calcific stenosis. In Monckeberg medial calcific stenosis the calcification is located in the media of the vessel wall, as in calciphylaxis. However there is no accompanying luminal narrowing, inflammation, fibroplasias or thrombosis. In addition, unlike atherosclerotic peripheral vascular disease, calciphylaxis lacks smooth muscular proliferation, macrophage or connective tissue extracellular lipid deposits.

Early diagnosis may be important in improving the poor outcome in patients with calciphylaxis. Local wound care, systemic antibiotic prophylaxis, and necrotic tissue debridement are the mainstays of therapy. Despite these interventions, our patient died. Phosphate restriction to lower the calcium-phosphate product may be beneficial. Hyperbaric oxygen has been reported to be beneficial in the treatment of calciphylaxis. (20) In addition, the effect of subcutaneous fractionated heparin in combination with hyperbaric oxygen therapy is under investigation. (19) When hyperparathyroidism is present, parathyroidectomy is recommended in patients who have survived an episode of calciphylaxis. However, the utility of this procedure in preventing a subsequent occurrence of calciphylaxis is uncertain. (21) There is a recent report of a successful treatment of calciphylaxis with IV sodium thiosulfate in a patient that had failed conventional measures. (22) Confirmation of the utility of this therapy, however, is also needed.

Septicemia is the most common cause of death in calciphylaxis. (3) The mortality rate of patients with this disease is estimated to range from 60 to 80%. High morbidity and prolonged hospitalization define the course of those patients who survive. It has been suggested that patients with calciphylaxis involving the trunk and proximal thigh have a worse prognosis when compared with patients with lesions involving the distal parts of the extremities. This observation may be due to delay in diagnosis since the more proximal lesions are less likely to be identified promptly. (23)

Conclusion

We report a rare case of calciphylaxis as a complication of alcoholic cirrhosis. Although most patients with calciphylaxis have abnormalities of their calcium-phosphate axis and/or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder. Rather, calciphylaxis may be preeipitated by low levels of protein C and protein S. Further investigation is needed to define the role that these factors may play in the pathogenesis of calciphylaxis.

References

1. Gilson RT, Milum E. Calciphylaxis: case report and treatment review. Cutis 1999;63:149-153.

2. Adrogue HJ, Frazier MR, Zeluff B, Suki WN. Systemic calciphylaxis revisited. Am J Nephrol 1981;1:177-183.

3. Kent RB, III, Lyerly RT. Systemic calciphylaxis. South Med J 1994;87:278-281.

4. Budisavijevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal failure. J Am Soc Nephrol 1996;7:978-982.

5. Selye H. Calciphylaxis. Chicago; University of Chicago Press, 1962.

6. Khafif RA, Delima C, Silverberg A, Frankel R. Calciphylaxis and systemic calcinosis: collective review. Arch Intern Med 1990;150:956-959.

7. Bryant JH, White WH. A case of calcification of arteries and obliterative endarteritis, associated with hydronephrosis, in a child aged six months. Guys Hosp Rep 1898;55:17-20.

8. Gipstein RM, Coburn JW, Adams DA, Lee DBN, PArsa KP, Sellers A, Suki W, Massry SG. Calciphylaxis in man: a syndrome of tissue necrosis and vascular calcification in II patients with chronic renal failure. Arch Intern Med 1976; 136:1273-1280.

9. Lungo-Somolinos A, Sanchez JL, Mendez-Coll J, et al. Calcifying panniculitis associated with polcystic kidney disease and chronic renal failure. J Am Acad Dermatol 1990;22:743-747.

10. Richardson JA, Herron G, Reitz R, et al. Ischemic ulceration of skin and necrosis of muscle in azotemic hyperparathyroidism. Ann Intern Med 1969;71:129-133.

11. Fox R, Banowsky L, Cruz AB. Postrenal transplant calciphylaxis: successful treatment with parathyroidectomy. J Urol 1983;129:362-363.

12. Rees JKH. Calciphylaxis in man. Br Med J 1969;2:670-672.

13. Chavel SM, Taraszka KS, Schaffer JV, et al. Calciphylaxis associated with acute, reversible renal failure in the setting of alcoholic cirrhosis. J Am Acad Dermatol 2004; 50:S125-128.

14. Fader J, Kang S. Calciphylaxis without renal failure. Arch Dermatol 1996;132:837-838.

15. Lim SP, Batta K, Tan BB. Calciphylaxis in a patient with alcoholic liver disease in the absence of renal failure. Clin Exp Dermatol 2003;28:34-36.

16. Manco-Johnson MJ, Knapp-Clevenger R. Activated protein C concentrates reverses purpura fulminans in severe genetic protein C deficiency. J Pediatr Hematol Oncol 2004;26:25-27.

17. Mahasandana C, Suvatte V, Chuansumrit A, et al. Homozygous protein S deficiency in an infant with purpura fulminans. J Pediatr 1990;117:750-753.

18. Chan YC, Valenti D, Mansfield AO, et al. Warfarin induced skin necrosis. Br J Surg 2000;87:266-272.

19. Mathur RV, Shortland JR, El Nahas AM. Calciphylaxis. Postgrad Med J 2001;77:557-561.

20. Dean SM, Werman H. Calciphylaxis: a favorable outcome with hyperbaric oxygen. Vasc Med 1998;3:115-120.

21. Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia: a complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954-962.

22. Cicone JS, Petronis JB, Embert CD, et al. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kid Dis 2004;43:110401108.

23. Chan YL, Mahony JF, Turner JJ, Poen S. The vascular lesions associated with skin necrosis in renal disease. Br J Dermatol 1983;10:985-995.

How vain it is to sit down to write when you have not stood up to live.
--Henry David Thoreau

Anil K. Goli, MD, Sujatha A. Goli, MD, Lata S. Shah, MD, Ryland P. Byrd, Jr., MD, and Thomas M. Roy, MD

Veterans Affairs Medical Center, Mountain Home, TN, and the Division of Pulmonary Diseases and Critical Care Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN

Correspondence: Dr. Ryland P. Byrd, Jr., Veterans Affairs Medical Center 111-B, Division of Pulmonary Medicine and Critical Care, PO Box 4000, Mountain Home, Tennessee 37684-4000. Email: [e-mail]

Accepted November 4, 2004.

RELATED ARTICLE: Key Points

* Calciphylaxis is a rare disorder.

* People with calciphylaxis typically have end-stage renal disease.

* Calciphylaxis is, however, associated with other disease processes including alcoholic cirrhosis.

* Protein C and S deficiencies may be involved in the pathogenesis of calciphylaxis.