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      Refractory hypercalcaemia associated with disseminated Cryptococcus neoformans infection

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          Abstract

          Summary

          Hypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described. There are have only been two reported cases in the literature of hypercalcaemia associated with Cryptococcus infection. Although the mechanism of hypercalcaemia in these infections is not clear, it has been suggested that it could be driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas. We describe the case of a 55-year-old woman with a 1,25-OH D-mediated refractory hypercalcaemia in the context of a Cryptococcus neoformans infection. She required treatment with antifungals, pamidronate, calcitonin, denosumab and high-dose glucocorticoids. A disseminated fungal infection should be suspected in immunosuppressed individuals presenting with hypercalcaemia.

          Learning point
          • In immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered as the differential diagnoses;

          • Glucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia; however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection;

          • Fluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.

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          Most cited references6

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          Hypercalcemia in granulomatous disorders: a clinical review.

          Hypercalcemia occurs in most granulomatous disorders. High serum calcium levels are seen in about 10% of patients with sarcoidosis; hypercalciuria is about three times more frequent. Tuberculosis, fungal granulomas, berylliosis, and lymphomas are other conditions that are associated with disorders of calcium metabolism. These abnormalities of calcium metabolism are due to dysregulated production of 1,25-(OH2)D3 (calcitriol) by activated macrophages trapped in pulmonary alveoli and granulomatous inflammation. Undetected hypercalcemia and hypercalciuria can cause nephrocalcinosis, renal stones, and renal failure. Corticosteroids cause prompt reversal of the metabolic defect. Chloroquine, hydroxychloroquine, and ketoconazole are the drugs that should be used if the patient fails to respond or develops dangerous side effects to corticosteroid therapy.
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            Granuloma and cryptococcosis.

            This review describes the general histopathological features of cryptococcosis in immunocompetent individuals, as well as in patients with acquired immunodeficiency syndrome (AIDS). Details of the histological examination of cryptococcal lesions are described, with the consideration of morphological modifications induced by treatment with highly active antiretroviral therapy (HAART). The essential histological features of cryptococcosis in individuals with impaired T-cell functioning are yeast-cell proliferation with a histiocytic response, but only minor lymphocytic and neutrophilic components. Several histological patterns of pulmonary cryptococcal lesions are introduced in this article, some of which could be graded with respect to the degree and type of inflammatory reaction. One pattern was a mild lesion consisting of scattered small foci of intraalveolar cryptococcal proliferation with a histiocytic response. Another pattern involved massive cryptococcal infection, which may have been simply more extensive than that in the mild lesion. Capillary involvement of alveolar septa should be understood as an important common finding in patients with AIDS who had not been treated with HAART. In those patients, the absence of T cells and a decreasing function of antigen-presenting activity in histiocytes were confirmed by immunohistological examination. These findings suggest that the lungs of AIDS patients without HAART offer little resistance to bloodstream dissemination by cryptococci. The unique histological feature demonstrated in patients treated with HAART is characterized by the presence of CD4+ cells, greater response of histiocytes and multinucleated giant-cell formation, and lack of massive capillary involvement.
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              Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole

              Mutations in CYP24A1, encoding the vitamin D 24-hydroxlase enzyme, are known to cause a range of clinical phenotypes and presentations including idiopathic infantile hypercalcaemia and adult-onset nephrocalcinosis and nephrolithiasis. In the context of raised or borderline high serum calcium levels, suppressed PTH and persistently elevated 1,25 dihydroxy vitamin D levels, this rare condition should be considered. We present a case where this biochemical pattern was seen and mutations in CYP24A1 were confirmed. We were able to successfully control serum calcium levels and reduce urinary calcium excretion by treatment with low-dose fluconazole, which inhibits vitamin D-synthesizing enzymes (including 25-hydroxylases and 1-α-hydroxylase) thereby reducing levels of 1,25–dihydroxy vitamin D.

                Author and article information

                Journal
                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                EDM
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                2052-0573
                10 May 2021
                2021
                : 2021
                : 20-0186
                Affiliations
                [1 ]Department of Endocrinology , Austin Health, Victoria, Australia
                [2 ]Department of Infectious Diseases , Austin Health, Victoria, Australia
                [3 ]Liver Transplant Unit , Austin Health, Victoria, Australia
                [4 ]Department of Medicine (Austin Health) , The University of Melbourne, Victoria, Australia
                Author notes
                Correspondence should be addressed to J J Zhu; Email: jasminejzhu@ 123456gmail.com
                Article
                EDM200186
                10.1530/EDM-20-0186
                8240701
                34110303
                1457b7e7-bd24-4754-bfa6-d14b1750f687
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                History
                : 10 November 2020
                : 10 May 2021
                Categories
                Adult
                Female
                Asian - Other
                Australia
                Bone
                Mineral
                Insight into Disease Pathogenesis or Mechanism of Therapy
                Insight into Disease Pathogenesis or Mechanism of Therapy

                adult,female,asian - other,australia,bone,mineral,insight into disease pathogenesis or mechanism of therapy,june,2021

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