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      Impact of intercurrent illness on calcium homeostasis in children with hypoparathyroidism: a case series


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          Hypoparathyroidism is characterised by hypocalcaemia, and standard management is with an active vitamin D analogue and adequate oral calcium intake (dietary and/or supplements). Little is described in the literature about the impact of intercurrent illnesses on calcium homeostasis in children with hypoparathyroidism.


          We describe three children with hypoparathyroidism in whom intercurrent illnesses led to hypocalcaemia and escalation of treatment with alfacalcidol (1-hydroxycholecalciferol) and calcium supplements.


          Three infants managed with standard treatment for hypoparathyroidism (two with homozygous mutations in GCMB2 gene and one with Sanjad-Sakati syndrome) developed symptomatic hypocalcaemia (two infants developed seizures) following respiratory or gastrointestinal illnesses. Substantial increases in alfacalcidol doses (up to three times their pre-illness doses) and calcium supplementation were required to achieve acceptable serum calcium concentrations. However, following resolution of illness, these children developed an increase in serum calcium and hypercalciuria, necessitating rapid reduction to pre-illness dosages of alfacalcidol and oral calcium supplementation.


          Intercurrent illness may precipitate symptomatic hypocalcaemia in children with hypoparathyroidism, necessitating increase in dosages of alfacalcidol and calcium supplements. Close monitoring is required on resolution of the intercurrent illness, with timely reduction of dosages of active analogues of vitamin D and calcium supplements to prevent hypercalcaemia, hypercalciuria and nephrocalcinosis.

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          Calcium-sensing receptor, proinflammatory cytokines and calcium homeostasis.

          The calcium-sensing receptor (CaSR) expressed in the parathyroid gland and the kidney tubule acts as the calciostat and orchestrates blood calcium homeostasis by modulating production and release of parathyroid hormone (PTH) and active vitamin D that influence Ca(2+) fluxes across the bone, kidney and intestine. Here we consider the role of the CaSR as a responder to proinflammatory cytokines released as part of the innate immune response to tissue injury and inflammation with resetting of the calciostat on the one hand and as a promoter and mediator of the initial inflammatory response on the other. The importance of the CaSR in systemic calcium homeostasis is exemplified by the fact that inactivating and activating mutations in the gene result in hypercalcemia and hypocalcemia, respectively. Proinflammatory cytokines interleukin-1β and interleukin-6 upregulate CaSR expression in parathyroid and kidney and do this through defined response elements in the CASR gene promoters. This results in decreased serum PTH and 1,25-dihydroxyvitamin D and calcium levels. This is likely to underlie the hypocalcemia that commonly occurs in critically ill patients, those with burn injury and sepsis, for example. The level of calcium in extracellular fluid bathing necrotic cells is often elevated and acts as a chemokine to attract monocytes/macrophages that express the CaSR to sites of tissue injury. Elevated levels of calcium acting via the CaSR can function as a danger signal that stimulates assembly of myeloid cell cytosolic multiprotein inflammasomes resulting in maturation of the proinflammatory cytokine IL-1β by caspase-1. Thus the CaSR is both promoter of and responder to the inflammation.
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            Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium.

            Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. This is the first randomized controlled study in children comparing treatment with synthetic human PTH 1-34 and calcitriol. The primary objective was to assess the efficacy and safety of long-term PTH 1-34 vs. calcitriol treatment in the maintenance of normal serum calcium values and renal calcium excretion in children with hypoparathyroidism. The study was conducted at a clinical research center. Subjects included 12 children aged 5-14 yr with chronic hypoparathyroidism and without severe renal or hepatic insufficiency. The study was a 3-yr randomized parallel trial comparing twice-daily calcitriol (plus calcium and cholecalciferol in four daily doses) vs. s.c. PTH 1-34 treatment, with weekly or biweekly monitoring of serum and urine calcium. Mean predose serum calcium levels were maintained at, or just below, the normal range, and urine calcium levels remained in the normal range throughout the 3-yr study, with no significant differences between treatment groups. Creatinine clearance, corrected for body surface area, did not differ between groups and remained normal throughout the study. Markers of bone turnover were mildly elevated during PTH 1-34 therapy and remained within the normal range during calcitriol therapy. Mean bone mineral density Z-scores at the anterior-posterior lumbar spine, femoral neck, distal radius, and whole body remained within the normal range and did not differ between groups throughout the study. Similarly, height and weight percentiles did not differ between treatment groups and remained normal throughout the 3-yr follow-up. We conclude that PTH 1-34 therapy is safe and effective in maintaining stable calcium homeostasis in children with hypoparathyroidism. Additionally, PTH 1-34 treatment allowed normal skeletal development because there were no differences in bone mineral accrual, linear growth, or weight gain between the two treatment arms over the 3-yr study period.
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              Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism.

              Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. Long-term conventional therapy with vitamin D and analogs may lead to nephrocalcinosis and renal insufficiency.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                November 2017
                06 September 2017
                : 6
                : 8
                : 589-594
                [1 ]Royal Manchester Children’s Hospital Manchester, UK
                [2 ]King Abdullah Specialized Children’s Hospital Riyadh, Saudi Arabia
                [3 ]Royal Preston Hospital Preston, UK
                Author notes
                Correspondence should be addressed to R Padidela; Email: Raja.Padidela@ 123456cmft.nhs.uk
                © 2017 The authors

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

                : 4 September 2017
                : 6 September 2017

                hypoparathyroidism,hypocalcaemia,intercurrent illness,alfacalcidol


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