Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue. European Journal of Endocrinology 168 R45-R53

Parathyroid carcinoma is associated with mutations in the HRPT2/CDC73 gene and with decreased parafibromin and calcium-sensing receptor (CASR) expression, but in some cases establishing an unequivocal diagnosis remains a challenge. The aim of our study was to evaluate the prognostic value of CASR and parafibromin expression and of HRPT2/CDC73 mutations in patients with an established diagnosis of parathyroid carcinoma. Data on survival and disease-free survival were obtained from hospital records of 23 patients with an established diagnosis of parathyroid carcinoma in whom CASR and parafibromin expression and HRPT2/CDC73 mutation analyses were available from paraffin-embedded pathological specimens. KaplanMeier curves were used for survival analysis. Downregulation of CASR expression, global loss of parafibromin staining and a HRPT2/CDC73 mutation were, respectively, found in 7 (30%), 13 (59%) and 4 (17%) patients, and were associated with, respectively, 16-fold, 4-fold and 7-fold increased risk of developing local or distant metastasis. These findings suggest that although downregulation of CASR expression, global loss of parafibromin staining and mutations in the HRPT2/CDC73 gene are tools of proven value to assist in establishing a diagnosis of parathyroid carcinoma, their absence does not exclude it. Notwithstanding, we demonstrate a significant added value of these markers as strong determinants of increased malignant potential and thus as negative prognostic markers in this malignancy.

Objective: In vitro and in vivo studies in animal models have shown that parathyroid hormone (PTH) inhibits the expression of the SOST gene, which encodes sclerostin, an osteocyte-derived negative regulator of bone formation. We tested the hypothesis that chronic PTH excess decreases circulating sclerostin in humans. Design: We studied 25 patients with elevated serum PTH concentrations due to primary hyperparathyroidism (PHPT) and 49 patients cured from PHPT after successful parathyroidectomy (PTx; euparathyroid controls (EuPTH)). Methods: We measured plasma PTH and serum sclerostin levels and the serum markers of bone turnover alkaline phosphatase, P1NP, and b-CTX. Results: As expected by the design of the study, mean plasma PTH was significantly higher (P!0.001) in PHPT patients (15.3 pmol/l; 95% confidence interval (CI): 11.1-19.5) compared with that of EuPTH controls (4.1 pmol/l; 95% CI: 3.6-4.5). PHPT patients had significantly lower serum sclerostin values compared with those in EuPTH subjects (30.5 pg/ml; 95% CI: 26.0-35.1 vs 45.4 pg/ml; 95% CI: 40.5-50.2; P!0.001) and healthy controls (40.0 pg/ml; 95% CI: 37.1-42.9; PZ0.01). Plasma PTH concentrations were negatively correlated with serum sclerostin values (rZK0.44; P!0.001). Bone turnover markers were significantly correlated with PTH, but not with sclerostin. Conclusion: Patients with PHPT have significantly lower serum sclerostin values compared with PTx controls with normal PTH concentrations. The negative correlation between PTH and sclerostin suggests that SOST is downregulated by PTH in humans.

BackgroundIn primary hyperparathyroidism (PHPT) the predictive value of technetium 99m sestamibi single emission computed tomography (Tc99m-MIBI-SPECT) for localizing pathological parathyroid glands before a first parathyroidectomy (PTx) is 83–100%. Data are scarce in patients undergoing reoperative parathyroidectomy for persistent hyperparathyroidism. The aim of the present study was to determine the value of Tc99m-MIBI-SPECT in localizing residual hyperactive parathyroid tissue in patients with persistent primary hyperparathyroidism (PHPT) after initial excision of one or more pathological glands.MethodWe retrospectively evaluated the localizing accuracy of Tc99m-MIBI-SPECT scans in 19 consecutive patients with persistent PHPT who had a scan before reoperative parathyroidectomy. We used as controls 23 patients with sporadic PHPT who had a scan before initial surgery.ResultsIn patients with persistent PHPT, Tc99m-MIBI-SPECT accurately localized a pathological parathyroid gland in 33% of cases before reoperative parathyroidectomy, compared to 61% before first PTx for sporadic PHPT. The Tc99m-MIBI-SPECT scan accurately localized intra-thyroidal glands in 2 of 7 cases and a mediastinal gland in 1 of 3 cases either before initial or reoperative parathyroidectomy.ConclusionsOur data suggest that the accuracy of Tc99m-MIBI-SPECT in localizing residual hyperactive glands is significantly lower before reoperative parathyroidectomy for persistent PHPT than before initial surgery for sporadic PHPT. These findings should be taken in consideration in the preoperative workup of patients with persistent primary hyperparathyroidism.

Introduction: Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are major players in the bone-parathyroid-kidney axis controlling phosphate homeostasis. In patients with primary hyperparathyroidism (PHPT), data on the relationship between PTH and FGF23 are scarce and not always concordant. Objective: The aim of our study was to evaluate the relationship between PTH and FGF23 in patients with PHPT and in euparathyroid patients cured after successful parathyroidectomy (PTx). Patients and methods: Twenty-one patients with PHPT and 24 patients in long-term cure after successful PTx (EuPTH) were studied. All patients underwent biochemical evaluation of renal function, parathyroid status, vitamin D status, bone turnover markers, and serum intact FGF23 levels. Results: Mean serum FGF23 concentration was significantly higher in PHPT than in EuPTH patients (50.8G6.1 vs 33.1G2.6 pg/ml, PZ0.01). FGF23 levels significantly correlated with PTH levels (rZ 0.361, PZ0.02), also after correction for 1,25(OH) 2 D levels (rZ0.419, PZ0.01). FGF23 levels showed a significant negative correlation with 1,25(OH) 2 D, which was more pronounced in PHPT than in EuPTH patients (rZK0.674, PZ0.001, vs rZK0.509, PZ0.01). Conclusion: Our findings suggest that in PHPT, FGF23 levels are increased independent of 1,25(OH) 2 D levels. The more pronounced negative relationship between FGF23 and 1,25(OH) 2 D in the presence of high circulating PTH levels suggests that the increase in FGF23 levels may be an adaptive mechanism to counteract the PTH-induced increase in 1,25(OH) 2 D levels, although not completely overriding it.

Introduction: Localization studies are mandatory prior to revision surgery in patients with persistent hyperparathyroidism in order to improve surgical outcome and reduce the risk of lengthy explorations. However, in this case, noninvasive localization studies are reported to have a poor sensitivity. The aim of our study is to determine the accuracy of selective venous sampling (SVS) for parathyroid hormone (PTH) in localizing residual hyperactive parathyroid glands in patients with persistent or recurrent hyperparathyroidism. Patients and methods: We retrospectively evaluated the localizing accuracy of 20 PTH SVS performed prior to revision surgery in 18 patients with persistent or recurrent primary hyperparathyroidism (nZ11) or autonomous (tertiary) hyperparathyroidism (nZ7). Tc99m-methoxy-isobutyle-isonitrile (MIBI)-single photon emission computed tomography (SPECT) was also performed in all patients prior to revision surgery. Operative and pathological data were obtained from hospital records. Results: The SVS was able to accurately localize 15 of the 20 pathological glands removed at revision surgery, representing a sensitivity of 75%. This sensitivity is significantly higher than that of Tc99m-MIBI-SPECT, which was only 30% (PZ0.012).Conclusion: Our findings demonstrate that SVS is a valuable localization study in patients with persistent or recurrent hyperparathyroidism, with a sensitivity significantly higher than that of Tc99m-MIBI-SPECT. Our data suggest that SVS represents a useful addition to the preoperative workup of these patients prior to revision surgery.

BackgroundSternocostoclavicular hyperostosis (SCCH; ORPHA178311) is a rare inflammatory disorder of the axial skeleton, the precise pathophysiology of which remains to be established. We addressed the potential association of SCCH with autoimmune processes by evaluating the lifetime prevalence of autoimmune disease in 70 patients with adult-onset SCCH and 518 SCCH-unaffected first-degree relatives (parents, siblings and children). Danish hospital registry data for autoimmune diseases were used as reference data.ResultsThe mean age of interviewed patients was 56.3 years (range 26–80 years) and 86% were female. Interviewed patients belonged to 63 families, with four families having clusters of 2–3 patients. A diagnosis of at least one autoimmune disease was reported in 20 SCCH patients (29%) and in 47 relatives (9.1%), compared to an estimated 3.9% prevalence of autoimmune disease in the Danish reference population. A diversity of autoimmune diseases was reported in SCCH patients and relatives, most frequently psoriasis vulgaris (14%). Palmoplantar pustulosis was reported by 28 patients (40%). In SCCH patients, inclusion of palmoplantar pustulosis as putative autoimmune disease increased the overall prevalence to 54%.ConclusionsThe high prevalence of autoimmune disease in patients with sternocostoclavicular hyperostosis and their first-degree relatives suggests that autoimmunity may play a role in the still elusive pathophysiology of the intriguing osteogenic response to inflammation observed in this rare bone disorder.

A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. A diagnosis of primary hyperparathyroidism was established and the patient was referred for parathyroidectomy. At neck exploration, an enlarged parathyroid gland with invasive growth into the thyroid gland was found and removed, lymph nodes were cleared and hemithyroidectomy was performed. A suspected diagnosis of parathyroid carcinoma was confirmed histologically. Serum calcium and PTH levels normalised post-operatively, but hyperparathyroidism recurred within 3 years of surgery. Over the following 17 years, control of hypercalcaemia represented the most difficult challenge despite variable success achieved with repeated surgical interventions, embolisations, radiofrequency ablation of metastases and treatment with calcimimetics, bisphosphonates and haemodialysis using low-dialysate calcium. In this paper, we report the challenges and pitfalls we encountered in the management of our patient over nearly two decades of follow-up and review recent literature on the topic.