Calciphylaxis · What Is It, Signs, Symptoms, Diagnosis, and More

The exact mechanisms and cause of calciphylaxis are not well understood; however, it is thought to be related to changes in calcium and phosphate metabolism. These metabolic changes are common in those with ESRD and undergoing dialysis. The skin lesions in calciphylaxis result from reductions in the arteriolar blood flow caused by vascular calcifications, fibrosis, and thrombus formation.  

Calciphylaxis is also commonly associated with primary hyperparathyroidism, a condition associated with increased levels of parathyroid hormone (PTH), which regulates and increases calcium levels in the blood. Malignancy, protein C and S deficiency, and antiphospholipid syndrome are also associated with calciphylaxis since they typically cause a hypercoagulable state. Individuals with hypoalbuminemia are predisposed to calciphylaxis, since albumin binds to excess calcium and regulates calcium and phosphate balance. Thus, calcium and phosphate may accumulate in blood vessels with lower albumin levels. Individuals with vasculopathy, including atherosclerosis, may also be more susceptible to vascular calcification. Other risk factors for calciphylaxis include chronic inflammatory conditions such as diabetes mellitus; obesity (i.e., body mass index [BMI] >30); and autoimmune disorders (e.g., systemic lupus erythematosus [SLE], polymyositis, Sjögren syndrome, rheumatoid arthritis, sarcoidosis, and Crohn disease).  

Lastly, certain medications such as warfarin, vitamin D, oral glucocorticoids, and iron supplementation may increase the risk of calciphylaxis. 

The exact mechanism and cause of calciphylaxis are not well understood; however, it is thought to be related to changes in calcium and phosphate metabolism. These metabolic changes can be seen in those with ESRD. The skin lesions in calciphylaxis result from reductions in the arteriolar blood flow caused by vascular calcification, fibrosis, and thrombus formation. 

Calciphylaxis is also commonly associated with primary hyperparathyroidism, a condition associated with increased levels of parathyroid hormone (PTH), a regulator of calcium levels in the blood. Malignancy, protein C and S deficiency, and antiphospholipid syndrome are also associated with calciphylaxis since they typically cause a hypercoagulable state. Individuals with hypoalbuminemia are predisposed to calciphylaxis since albumin binds to excess calcium and regulates calcium and phosphate balance. Calcium and phosphate may accumulate in blood vessels with lower albumin levels. Individuals with vasculopathy, including atherosclerosis, may also be more susceptible to vascular calcification. Other risk factors for calciphylaxis include chronic inflammatory conditions such as diabetes mellitus; obesity (i.e., body mass index [BMI] >30); and autoimmune disorders (e.g., systemic lupus erythematosus [SLE], polymyositis, Sjögren syndrome, rheumatoid arthritis, sarcoidosis, and Crohn disease). 

Lastly, certain medications such as warfarin, vitamin D, oral glucocorticoids, and iron supplementation may increase the risk for calciphylaxis.

The signs and symptoms of calciphylaxis include extremely painful, ischemic, and necrotic skin lesions that heal slowly. In some cases of calciphylaxis, pain may precede the development of skin lesions. Early in the disease course, calciphylaxis lesions may appear plaque-like, violaceous, and indurated (i.e., thickened and hardened). As the disease progresses, these areas can become ischemic, necrotic ulcers with eschar (i.e., dead tissue). Areas of eschar are also susceptible to bacteria superinfection, with infection being the most common cause of death. While lesions frequently develop in regions richer in adipose tissue (e.g., lower extremities and trunk), in some cases the upper extremities, buttocks, and genitalia can be affected.  

Other atypical manifestations include papules, erythema resembling cellulitis, and erosions with hemorrhagic crusts. Systemic manifestations of calciphylaxis may include fatigue, weakness, and easy bruising and bleeding.  

Calciphylaxis is frequently diagnosed by conducting a thorough interview and physical examination. Healthcare professionals, specifically dermatologists, evaluate and rule out conditions that mimic calciphylaxis (e.g., cellulitis, deep vein thrombosis, or other forms of vasculitis). Often, the diagnosis is reached by identifying painful ulcerated lesions covered by a black eschar, particularly in individuals with ESRD. If the diagnosis remains uncertain or the presentation is atypical, a dermatologist or a surgeon may perform a skin biopsy- either with a punch or telescoping biopsy technique - to confirm the diagnosis. 

Imaging studies are not routinely ordered to confirm the diagnosis; however, radiography and computed tomography (CT) have been shown to detect tissue calcifications in patients with calciphylaxis. Laboratory tests may be ordered to measure serum calcium, phosphorus, and parathyroid hormone levels. Other markers of kidney failure, such as creatinine and blood urea nitrogen (BUN), may also be assessed. Additionally, a three-phase technetium 99m methylene diphosphonate bone scan (or triple phase bone scan) can identify cutaneous calcifications and support the diagnosis of calciphylaxis.  

The treatment of calciphylaxis primarily involves pain control and wound care. An interdisciplinary team approach is frequently used, involving dermatologists, nephrologists, wound care specialists, and pain and palliative care specialists. Pain control can be achieved with the help of opioid analgesics and consultation with a pain management service to improve quality of life. Wound care is a critical aspect in the management of calciphylaxis and includes proper dressing application and debridement of necrotic tissue. Hyperbaric oxygen therapy may be used to promote wound healing. Repetitive local trauma to the skin (e.g., subcutaneous injections) is usually avoided due to the risk of worsening symptoms. While there is no approved treatment for calciphylaxis, medications such as sodium thiosulfate (STS), bisphosphonates, and calcimimetics are frequently used; however, their efficacy remains unproven.  

Mitigating risk factors and controlling underlying medical conditions are essential for the prevention of calciphylaxis. If necessary, individuals may control serum calcium, phosphorus, and parathyroid hormone levels through diet, medications, and dialysis. A healthy diet is similarly helpful in treating diabetes and obesity. Lastly, surgery may be necessary to remove necrotic tissue and repair damaged blood vessels.