eMedicine Specialties > Dermatology > Internal Medicine

Calciphylaxis

Author: Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center
Contributor Information and Disclosures

Updated: Jan 28, 2009

Introduction

Background

Calciphylaxis is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia in 1898. However, the significance of this relationship became uncertain when vascular calcification was subsequently shown to be prevalent in uremia, yet the syndrome of vascular calcification with cutaneous necrosis remained rare.

In 1962, Selye1 constructed an experimental model and was able to precipitate systemic calcification, somewhat analogous to this syndrome, in nephrectomized rats. He was the first to coin the term calciphylaxis to characterize this enigma. Over the years, many other names have been suggested to characterize the pathogenic process, which has remained elusive. Interestingly, the clinical importance of this syndrome was not recognized until a 1976 report by Gipstein et al.2 Since then, a multitude of case reports of calciphylaxis have documented data outlining its morbidity and therapeutic dilemmas, as well as a quest to better understand its etiology and pathogenesis. Unfortunately, it remains a conundrum.

Pathophysiology

The pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic renal failure, obesity, diabetes mellitus, hypercalcemia, hyperphosphatemia, an elevated calcium-phosphate product, and secondary hyperparathyroidism. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare.

Using a rat model, Selye1 demonstrated that a series of events might be necessary for the formation of calciphylaxis. He defined calciphylaxis as a condition of hypersensitivity induced by a set of "sensitizing" agents, in which calcinosis occurred only in those subsequently subjected to a group of "challengers" and only after a critical lag time. Experimental sensitizing events and agents included nephrectomy and exposure to parathyroid hormone (PTH) and vitamin D. Substances used as challengers included egg albumin and metallic salts. Calciphylaxis was the end result.3

Although extrapolation of animal data to humans is conjectural, it seems to be true that serial events, most consistently involving renal failure–induced abnormalities in calcium homeostasis, are required to occur over time for calciphylaxis to develop. The cause of calciphylaxis has been elusive, most likely because it is the common endpoint of a heterogeneous group of disorders.

Molecular and cytochemical factors have been identified as crucial in bone metabolism. The receptor activator of nuclear factor-kB (RANK), RANK ligand, and osteoprotegerin appear to regulate skeletal and extraskeletal mineralization. Uremia-induced defects in this system may predispose to calciphylaxis. Corticosteroids, aluminum, hyperparathyroidism, liver disease, and a variety of inflammatory processes all can alter this balance and promote vascular calcification. Chronic inflammatory conditions may predispose to calciphylaxis by reducing serum levels of fetuin-A, an important inhibitor of calcification produced in the liver.

Frequency

International

Calciphylaxis is an uncommon condition that affects 1-4% of the population with ESRD. A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran. No good data are available regarding the incidence of calciphylaxis in the general population without ESRD, but it is probably exceedingly rare.

Mortality/Morbidity

The mortality rate of calciphylaxis is reported to be as high as 60-80%. The leading cause of death is sepsis from infected, necrotic skin lesions, although death due to internal organ failure has been reported. The mortality rate is higher in patients with proximal disease than in those with only distal or acral disease. A 2-fold increase in mortality is seen in those with ulcerative disease. The overall 1- and 5-year survival rates have recently been reported to be 45% and 35%, respectively.

Race

Although the disease may affect persons of any race, it appears to be more prevalent in whites.

Sex

Females are affected more often than males, with a female-to-male ratio of approximately 3:1.  Females also appear to be more commonly affected with nonuremic calciphylaxis.

Age

Calciphylaxis has been reported in individuals ranging in age from 6 months to 83 years. From a large series of patients, a mean patient age of 48 years (±16 y) has been calculated. Individuals seemingly more predisposed are younger patients who have had a longer duration of renal replacement therapy.

Clinical

History

  • Most patients with calciphylaxis have a long-standing history of chronic renal failure and renal replacement therapy.
  • On rare occasions, calciphylaxis may occur in a patient with chronic renal failure prior to the initiation of replacement therapy. Very rarely, it may occur in an individual without a history of chronic renal failure.
  • Many persons who develop calciphylaxis have undergone renal allograft transplantation. The allograft may still be functional when calciphylaxis develops.
  • Frequently, patients have been noncompliant with dietary, medical, and/or dialysis prescriptions prior to the onset of calciphylaxis.
  • Lesions of calciphylaxis typically develop suddenly and progress rapidly. Lesions may be singular or numerous, and they generally occur on the lower extremities (see Media File 1); however, lesions also may develop on the hands and torso.
  • Intense pain is a constant finding.
  • The patient's history may reveal an event that is a suspected trigger or risk factor for the development of calciphylaxis. These triggers include the following: 
    • Long-term obesity
    • Recent and sudden weight loss
    • Malnutrition
    • Infusion of medications such as iron dextran
    • Remote and/or recent use of immunosuppressive agents, especially corticosteroids
    • Liver disease
    • Diabetes mellitus and insulin injections
    • Use of vitamin D and calcium-based phosphate binders
    • Concurrent use of warfarin anticoagulation: Current data suggest that warfarin therapy may lower protein C concentrations, leading to a procoagulant condition in the calcified vessel.  Warfarin may also inhibit carboxylation of matrix Gla protein, an important inhibitor of calcification, thus promoting calcification
  • Review of the patient's medical record usually reveals a history of hyperphosphatemia with hyperparathyroidism and hypoalbuminemia.
  • Patients with nonuremic calciphylaxis frequently have a history of primary hyperparathyroidism, malignancy, alcoholic liver disease, or underlying connective-tissue disease.4

Physical

  • Early lesions of calciphylaxis manifest as nonspecific violaceous mottling; as livedo reticularis; or as erythematous papules, plaques, or nodules.
  • More developed lesions have a stellate purpuric configuration with central cutaneous necrosis (see Media File 2).
  • Multiple lesions of variable age may be present, following the path of the vasculature.
  • Less commonly, lesions may manifest as either bullae (see Media File 3) or distinct subcutaneous, erythematous nodules suggestive of erythema nodosum.
  • Lesions are excruciatingly tender and extremely firm.
  • The distribution of the lesions may be characterized as proximal or distal.
    • Ninety percent of lesions of calciphylaxis occur on the lower extremities.
    • Distal lesions are those that occur below the knee; proximal lesions occur on the thighs or the trunk.
    • Proximally distributed lesions occur in 44-68% of patients, with lesions developing predominantly on the thighs, the buttocks, and the lower part of the abdomen.
    • Distal and visceral involvement are not uncommon.
  • An intact peripheral pulse helps to distinguish acral calciphylaxis from atherosclerotic peripheral vascular disease.
  • Ulceration is considered a late finding and is associated with a higher mortality rate.

Causes

  • Disorders associated with the development of calciphylaxis include the following:
    • Common associations include chronic renal failure, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, and vascular calcification.
    • Speculative associations include aluminum toxicity, coagulation abnormalities, and iron dextran infusion.
    • Associations suggested from clinical observations include renal transplantation, immunosuppressive agents, corticosteroid use, and obesity.
  • The cause of calciphylaxis remains obscure. Most cases occur in the setting of chronic renal failure, abnormal calcium-phosphate homeostasis, and hyperparathyroidism. Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.
  • Case reports exist of calciphylaxis occurring in primary hyperparathyroidism, cirrhosis, and rheumatoid arthritis, without renal disease. The pathogenesis of calciphylaxis in these cases is uncertain. The exact role of PTH is uncertain because calciphylaxis may occur after total parathyroidectomy, in the absence of measurable PTH levels.
  • Patients at an increased risk appear to be those who are obese and those who have been exposed to immunosuppressive agents, including glucocorticoids. Calciphylaxis occurs more frequently in areas where body fat is most abundant, such as the thighs, the buttocks, and the lower part of the abdomen. Fatty areas may be at higher risk for thrombosis, owing to lower blood flow or the increased potential for vascular kinking.
  • Persons with diabetes mellitus may also be at an increased risk; insulin injections may be an independent risk due to trauma to the subcutis. 
  • The clinical appearance of the lesions of calciphylaxis (livedo reticularis and stellate purpura) suggests that the common endpoint of the process is small vessel occlusion. Indeed, microthrombi are found in most cases.
    • Hypercoagulable conditions, including protein C and protein S deficiencies, and the presence of a circulating anticoagulant have been described in a number of patients. However, conditions of hypercoagulability are not found uniformly. If they do exist, they could possibly precipitate or exacerbate calciphylaxis in a predisposed patient.  
    • Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, various pathologic roles may be attributed to this vascular calcification. First, calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability. Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion. Finally, recent data suggest that the uremic milieu may promote calcification through inhibition of various endogenous inhibitors of calcification such as alpha2-Heremans-Schmid glycoprotein/fetuin A (AHSG), osteopontin, and matrix Gla protein. These theories remain speculative.

More on Calciphylaxis

Overview: Calciphylaxis
Differential Diagnoses & Workup: Calciphylaxis
Treatment & Medication: Calciphylaxis
Follow-up: Calciphylaxis
Multimedia: Calciphylaxis
References
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References

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Further Reading

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Keywords

calciphylaxis, necrotizing livedo reticularis, uremic gangrene syndrome, uremic necrosis, uremic small-artery disease with medial calcification and intimal hyperplasia, ischemic tissue necrosis, progressive ischemic gangrene, calcific uremic arteriolopathy, obliterative calcific-thrombotic arteriolopathy, calcifying panniculitis

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Contributor Information and Disclosures

Author

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center
Julia R Nunley, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Nephrology, International Society of Nephrology, Medical Dermatology Society, Medical Society of Virginia, National Kidney Foundation, Phi Beta Kappa, and Women's Dermatologic Society
Disclosure: Johnson and Johnson stock holder dividends; Amgen stock holder dividends; Forest Lab, Inc stock holder dividends; Galaxo Smith Klein stock holder dividends; Covidien stock holder dividends; Novartis Grant/research funds Consulting; Biolex  sub-investigator

Medical Editor

Smeena Khan, MD, Private Practice, Adult and Pediatric Dermatology Associates
Smeena Khan, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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