A case of non‐uremic calciphylaxis in a patient with secondary hyperparathyroidism and panhypopituitarism

Calciphylaxis is a rare and frequently fatal condition characterized by arteriolar calcification, resulting in thrombosis and ischemic necrosis.1-3 While commonly associated with end-stage renal disease (ESRD), calciphylaxis also arises in various non-uremic conditions.1, 3 To date, no association between panhypopituitarism and calciphylaxis has been reported. Herein, we present a case of calciphylaxis in a 58-year-old Japanese woman without ESRD but with secondary hyperparathyroidism (SHPT) and panhypopituitarism. The patient visited our clinic due to painful lesions on her thighs that had developed over 2 weeks. She also complained of year-long general malaise. She underwent a liver transplant 7 years prior. She had stage 3 chronic kidney disease (CKD) secondary to hepatorenal syndrome. She was not taking warfarin. Examination revealed atrophic lesions with black eschar on the thighs (Figure 1a,b). Biopsy revealed skin necrosis, fibrin thrombi, and calcium deposition in subcutaneous vessels (Figure 1c–f). Laboratory tests showed decreased 25-hydroxy vitamin D, elevated creatinine, phosphorus, and parathyroid hormone (PTH) (Figure 1g). Modified calcium and protein C and S levels were normal. Based on the calcification and thrombosis in subcutaneous small vessels, she was diagnosed with calciphylaxis because the combination of these is reported to be specific for calciphylaxis.2 Sodium thiosulfate was not administered, considering the risk of fluid overload and acidosis. The history of CKD, decreased 25-hydroxy vitamin D, and elevated PTH led to the diagnosis of SHPT, and treatment with infusion and lanthanum carbonate was initiated. After 1 month, serum phosphorus decreased (Figure 1g). Moreover, endocrinological evaluation revealed panhypopituitarism, namely, general loss of adenohypophysial hormones. Notably, the growth hormone (GH)-releasing peptide-2 test showed a decreased peak level of GH (7.5 ng/mL), meeting the criteria for severe adult GH deficiency (GHD) (<9 ng/mL).4 Following rehydration and the replacement of thyroid hormone and cortisol, her general malaise gradually improved. After 4 months, the lesions had neither spread nor increased in number. Although the etiology of calciphylaxis is intricate, the key mechanism driving vascular calcification seems to be the activation of nuclear factor kappa B (NFκB).3 NFκB upregulates the expression of calcification promotors, namely bone morphogenetic proteins 2 and 4.3 The imbalance of calcification promotors and calcification inhibitors, such as matrix gamma-carboxyglutamic acid protein, leads to vascular calcification.1, 3 The combination of arteriolar calcification, endothelial damage, and thrombosis results in ischemic skin necrosis.1-3 Although our patient had recognized risk factors for calciphylaxis, including CKD, SHPT, and hepatic dysfunction,1, 3 she also had panhypopituitarism, a condition that reportedly causes atherosclerosis primarily through GHD.5 GHD impairs endothelial function by reducing endothelial nitric oxide production,5 increases serum inflammatory cytokines including tumor necrosis factor-α, and decreases serum glutathione, the main antioxidant in oxidative balance.5 Chronic inflammation and elevated oxidative stress upregulate NFκB expression,3, 5 possibly exacerbating calciphylaxis. In conclusion, we experienced a case of non-uremic calciphylaxis with SHPT and panhypopituitarism. Our case highlights the potential contribution of panhypopituitarism, especially GHD, to the pathogenesis of calciphylaxis through the NFκB pathway. Endocrinological evaluation should be considered in patients with non-uremic calciphylaxis. None. No funding or support was received from any pharmaceutical industry. The authors declare no conflict of interests for this article. Approval of the research protocol by an Institutional Reviewer Board: N/A. Informed Consent: The patient provided informed consent for the publication of this case, including all relevant clinical information and accompanying images. All efforts were made to ensure patient privacy and confidentiality. Registry and the Registration No. of the study/trial.: N/A. Animal Studies: N/A.