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Calciphylaxis - 2/20/2013

posted Feb 20, 2013, 10:32 AM by Rohit Das   [ updated Feb 20, 2013, 11:04 AM by Purnema Madahar ]

Calciphylaxis – when I first heard that term, I thought, hmm…allergic reaction to calcium? What? That can’t be good. Then I read about it, and subsequently realized two things. First, it’s definitely NOT good, and in fact an incredibly bad prognostic sign. Second, I knew NOTHING about calciphylaxis, and now know a decent amount. Hooray! So:

·         Where did the term “calciphylaxis” come from, and does it relate to how the disease is characterized in humans? What’s the pathogenesis?

·         Which patients are at risk? How does it manifest clinically, and how is it diagnosed?

·         How is it treated, and what’s the prognosis?

Where did the term “calciphylaxis” come from, and does it relate to how the disease is characterized in humans? What’s the pathogenesis?

·         The term “calciphylaxis” was first termed in 1962 by Selye and friends, within the context of experimentally causing soft tissue calcification in rats. Selye exposed rats to various agents (vitamin D, excess phosphate, PTH) in a process he termed “sensitization.” The subsequent day, rats were injected with things that chelate calcium (egg albumin, polymyxin, iron salts), a process termed “challenging.” Equating this process of sensitizing and challenging as an anaphylactic reaction, he thus coined the term “calciphylaxis.” Awesome.

·         For our purposes, since we’re not in the business of harming rats but rather helping humans, the term “calciphylaxis” is a misnomer. The modern view of this disease is characterized by intravascular calcification (not soft tissue), endovascular proliferation, microthrombosis and subsequent tissue ischemia and necrosis. Many authors have abandoned the term calciphylaxis, naming the disease things like “vascular cutaneous calcification” or “calcemic uremic arteriolopathy…” Ok, so the bottom line? Think of calciphylaxis NOT as an anaphylactic reaction, but rather a terminal consequence of calcium deposition within small vessels, leading basically to a severe small-vessel ischemia and tissue necrosis.

·         The pathogenesis is similar to the disease – poorly understood. One of the key factors is dysregulation of calcium and phosphate metabolism which often, but not always, is accompanied by advanced chronic kidney disease and associated secondary/tertiary hyperparathyroidism. The concept of an “elevated Ca x P product” is also something commonly associated with calciphylaxis, though a number of case reports have been published where the Ca/P product did not differ significantly from controls.

·         So how does calciphylaxis, or whatever you want to call it, develop in people without significant hyperparathyroidism or an elevated Ca/P product? Well, there seem to be several other factors at play. The literature is filled with several proposed associated mechanisms, including increased NFkB activity, chronic inflammation and cytokine induced vascular calcification, decreased production of calcium-binding proteins…etc., etc., etc.


What patients are at risk? How does it manifest clinically, and how is it diagnosed?

·         Classically, calciphylaxis occurs in patients with ESRD, on dialysis, with dysfunctional calcium/phosphate metabolism, as alluded to above. The best literature is around this population, and the estimated incidence in this group is around 4% annually. The median age is around 50 years old, with females being 5-fold more affected than men, which is thought to be due to estrogen-related contributions to vascular calcifications. Though, important to take these numbers with a grain of salt, as the studies they're based on were small and only provide a snapshot for what is, overall, an underdiagnosed and underappreciated disease.

·         BUT, as mentioned, calciphylaxis also occurs in people without the above, traditional risk factors. Obesity, diabetes (with microvascular complications) and atherosclerosis are commonly found in such patients. Interestingly, warfarin has been highly associated as a risk factor for developing calciphylaxis. It’s thought this association is due to warfarin’s interaction with Matrix GIa protein, an inhibitor of intravascular calcification whose activity is dependent on vitamin-K mediated carboxylation. In addition, a host of other chronic, inflammatory diseases are associated with calciphylaxis - Box 1 of the attached review provides a summary.  

·         Ok – on to what everyone should care about the most – how does it present? Calciphylaxis is a devastating dermatologic disease, representative of local ischemic cutaneous ischemia and eventual necrosis. It most commonly presents as an area of erythematous, tender (usually exquisite), mottled skin that resembles livido reticularis. In more advanced stages, lesions become plaque-like/nodular, with violaceous discoloration surrounded by purpura.  End-stage progression leads to necrosis, ulceration and eschar formation. The most commonly affected areas of the body are those with the greatest adiposity – medial thighs, buttocks and lower part of the abdomen. Lesions tend to be symmetric, bilateral and pretty well-demarcated. Acral involvement (fingers, toes, genitals) is less common and has a better prognosis. Please refer to the review article for some good pictures of both typical skin findings and the associated histology.

·         Ideally, the diagnosis should be made on clinical grounds – typical skin findings in the context of the right epidemiology. However, because of competing differentials in this patient population (cyroglobulinemia, vasculitis, cholesterol emboli…etc.), biopsy is often needed. This however can be troublesome, as biopsy in a patient with calciphylaxis can lead to ulcer progression and ultimately to what these patients die from – skin pathogen sepsis.

·         In trying to make this diagnosis though, do want to make a key point – vascular calcifications and calciphylaxis ARE NOT the same thing – the former is very common, the latter is not. In fact, 10% of all patients undergoing HD, and up to 75% of patients with tertiary hyperparathyroidism, will have evidence of vascular calcifications on imaging – only a small minority of such patients develop the skin manifestations needed to make the diagnosis of calciphylaxis.


How is it treated, and what’s the prognosis?

·         As usual, not a lot of good treatments, and not a lot of good randomized data to support them. In those with an elevated Ca/P product, the goal is to decrease the product to <55. From a phosphate standpoint, this can be done via a low phosphate diet and non-calcium phosphate binders (Sevalemer), with the aim to decrease phosphate levels to 3.5-5.5 mg/dL.

·         PTH levels should be treated to a goal 150-300 pg/mL via Cinacalcet (a calcimimetic that sensitizes the calcium-sensing receptors of the parathyroid gland). Though there are no head to head randomized trials, the general practice is to avoid Vitamin D analogues for the treatment of secondary/tertiary hyperparathyroidism in patients with calciphylaxis.

·         Sodium thiosulfate (NaTh) has emerged as a novel, interesting therapy for calciphylaxis. Case series have documented improvement of pain within two weeks, and complete resolution in some cases within six months of therapy. The proposed mechanism has to do with NaTh’s antioxidant effects and calcium-chelating ability. Interesting…

·         So, what’s the prognosis? BAD. Most deaths result from sepsis from skin infections, which reinforces how imperative adequate wound care is for these patients. Estimated 1-year mortality rates have varied, but estimated to be around 40-80%. Patients presenting with truncal, advanced skin disease have the worst prognosis. Truly a terminal illness for the ESRD population…

 

So who was our patient? If I wrote her name we’d all probably know her, but in summary, she is a 35 year old obese woman with advanced DM (s/p bilateral BKAs, ESRD, gastroparesis…every complication in the book) who presented with bilateral abdominal flank/thigh erythema and tenderness. Her Phosphorus was high (around 6 mg/dL), but overall Ca/P product was only 48. PTH was around 200, so not substantially high, but is evidence of secondary hyperparathyroidism. She ultimately had a biopsy to prove the diagnosis, and is currently being treated with Na Thiosulfate, phosphate binders and Cinacalcet...

 

Attached are review articles on the topic, as well a summary paper on Sodium Thiosulfate’s therapeutic role. Thanks to Dr. Lief for the references!


Calciphylaxis
Daduen et. al., Dermatol Clin 2008, Volume 26: 557-68

Weenig, J Am Acad Derm 2008, Volume 58: 458-71

Hayden et. al., Seminars in Dialysis 2010, Volume 34 (3): 258-262
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