Calciphylaxis Clinical Presentation
- Author: Julia R Nunley, MD; Chief Editor: Dirk M Elston, MD more...
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 image below); 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[5, 8, 7, 19, 20, 21, 22, 23, 24] :
Recent and sudden weight loss
Infusion of medications such as iron dextran
Remote and/or recent use of immunosuppressive agents, especially corticosteroids
Diabetes mellitus and insulin injections
Use of vitamin D and calcium-based phosphate binders
Elevated aluminum levels
Concomitant vascular disease
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 or pro-inflammatory condition.[19, 20, 25, 26, 27]
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 the image below).
Multiple lesions of variable age may be present, following the path of the vasculature. Less commonly, lesions may manifest as either bullae (see the image below) 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.
Disorders associated with the development of calciphylaxis include the following[2, 5, 20, 21, 22] :
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.
Systemic inflammation appears to be a predisposing factor. [11, 12]
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, Crohn disease, malignancy, and rheumatoid arthritis, without renal disease. The pathogenesis of calciphylaxis in these cases is uncertain.[19, 20, 25, 26] 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.[21, 22] 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;[20, 21, 22] 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.[28, 29, 30, 31, 32] 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, 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.[7, 10]
Complications of calciphylaxis range from moderate interference with activity to death. Lesions of calciphylaxis frequently result in nonhealing ulcers and cutaneous gangrene. Acral lesions may fail to heal with conservative therapy and lead to amputation. Sepsis may result from the nonhealing wounds.
Patients with internal involvement may develop gastrointestinal hemorrhage, infarction, or organ failure.
Patients treated with calcimimetics, sodium thiosulfate, and parathyroidectomy must be monitored for hypocalcemia.
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