Misleading localization by 18F-fluorocholine PET/CT in familial hypocalciuric hypercalcemia type-3: a case report.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. CASE PRESENTATION: A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. CONCLUSIONS: In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinopathies. We report a unique case of hypophysitis, thyroiditis, severe hypercalcaemia and pancreatitis following combined ICI therapy. CASE PRESENTATION: A 46-year old Caucasian female with a background history of malignant melanoma and lung metastases presented to the emergency department with lethargy, nausea, palpitations and tremors. She had been started on a combination of nivolumab and ipilimumab 24 weeks earlier. Initial investigations revealed thyrotoxicosis with a thyroid stimulating hormone (TSH) of < 0.01 (0.38-5.33) mIU/L, free T4 of 66.9 (7-16) pmol/.L. TSH receptor and thyroperoxidase antibodies were negative. She was diagnosed with thyroiditis and treated with a beta blocker. Six weeks later she represented with polyuria and polydipsia. A corrected calcium of 3.54 (2.2-2.5) mmol/l and parathyroid hormone (PTH) of 9 (10-65) pg/ml confirmed a diagnosis of non-PTH mediated hypercalcaemia. PTH-related peptide and 1, 25-dihydroxycholecalciferol levels were within the normal range. Cross-sectional imaging and a bone scan out ruled bone metastases but did reveal an incidental finding of acute pancreatitis - both glucose and amylase levels were normal. The patient was treated with intravenous hydration and zoledronic acid. Assessment of the hypothalamic-pituitary-adrenal (HPA) axis uncovered adrenocorticotrophic hormone (ACTH) deficiency with a morning cortisol of 17 nmol/L. A pituitary Magnetic Resonance Image (MRI) was unremarkable. Given her excellent response to ICI therapy she remained on ipilimumab and nivolumab. On follow-up this patient's thyrotoxicosis had resolved without anti-thyroid mediations - consistent with a diagnosis of thyroiditis secondary to nivolumab use. Calcium levels normalised rapidly and remained normal. ACTH deficiency persisted, and she is maintained on oral prednisolone. CONCLUSION: This is a remarkable case in which ACTH deficiency due to hypophysitis; thyroiditis; hypercalcaemia and pancreatitis developed in the same patient on ipilimumab and nivolumab combination therapy. We postulate that hypercalcaemia in this case was secondary to a combination of hyperthyroidism and secondary adrenal insufficiency.

Paradoxical scintigraphy bone scan findings with malignancy-associated extreme hypercalcemia.

We report the first case of extreme hypercalcemia (Ca 2+ >6.0 mmol/L) as the initial presentation of de novo metastatic breast cancer. Following treatment and stabilization of the patient, imaging revealed a large breast mass and widespread osseous metastases. Whole body bone scintigraphy demonstrated significant extra osseous uptake of radiotracer in the lungs, liver, and kidneys-a rare phenomenon secondary to profound hypercalcemia. Biopsy revealed estrogen receptor (ER) positive breast carcinoma, for which the patient was treated.

PETC/CT with 18F-Choline localizes hyperfunctioning parathyroid adenomas equally well in normocalcemic hyperparathyroidism as in overt hyperparathyroidism.

PURPOSE: Identification of pathologic parathyroid glands in primary hyperparathyroidism, traditionally based on neck ultrasound (US) and/or 99mTc-Sestamibi scintigraphy, can be challenging. PET/CT with 18F-Fluorocholine (18F-FCH) might improve the detection of pathologic parathyroid glands. We aimed at comparing the diagnostic performance of 18F-FCH-PET/CT with that of dual-phase dual-isotope parathyroid scintigraphy and neck US. METHODS: Thirty-four consecutive patients with primary hyperparathyroidism were prospectively enrolled, 7 had normocalcemic hyperparathyroidism, and 27 had classic hypercalcemic hyperparathyroidism. All patients underwent high-resolution neck US, dual-phase dual-isotope 99mTc-Pertechnetate/99mTc-Sestamibi scintigraphy, and 18F-FCH-PET/CT. RESULTS: In the whole patients' group, the detection rates of the abnormal parathyroid gland were 68% for neck US, 71% for 18F-FCH-PET/CT, and only 15% for 99mTc-Sestamibi scintigraphy. The corresponding figures in normocalcemic and hypercalcemic hyperparathyroidism were 57 and 70% for neck US, 70 and 71% for 18F-FCH-PET/CT, and 0 and 18% for 99mTc-Sestamibi scintigraphy, respectively. In the 17 patients in whom the abnormal parathyroid gland was identified, either at surgery or at fine needle aspiration cytology/biochemistry, the correct detection rate was 82% for neck US, 89% for 18F-FCH-PET/CT, and only 17% for 99mTc-Sestamibi scintigraphy. CONCLUSIONS: 18F-FCH-PET/CT can be considered a first-line imaging technique for the identification of pathologic parathyroid glands in patients with normocalcemic and hypercalcemic hyperparathyroidism, even when the parathyroid volume is small.

Refractory hypercalcemia due to an ectopic mediastinal parathyroid gland in a hemodialysis patient: a case report.

BACKGROUND: Hypercalcemia crisis is a complex disorder rarely induced by tertiary hyperparathyroidism, which clinically presents as nonsuppressible parathyroid hyperplasia with persistent increased PTH levels and hypercalcemia. It is one of the major risk factors of morbidity and mortality in end-stage renal disease. Parathyroidectomy should be in consideration in dialysis patients with severe hyperparathyroidism who are refractory to medical therapy. The implications and consequences of it, however, are not fully understood. CASE PRESENTATION: We present a case of a 70 year-old man disturbed by gastrointestinal manifestations due to hypercalcaemic crisis. The patient had longstanding hypercalcaemia and hyperparathyrodism refractory to calcimimetics, calcitonin, hormone and haemodialysis. A ectopic parathyroid gland in anterior mediastinum was found and elucidated by Tc-99 m scan. Futhermore, a video-assisted thoracoscopic parathyroidectomy was performed. Histologically, the tumour consisted of densely arranged chief cells immunohistochemically positive for PTH antigens. Consequently, calcium and parathormone were declining stably without any complications. CONCLUSIONS: On account of refractory hypercalcemia and hyperparathyroidism, radionuclide scanning is useful in the diagnosis of ectopic parathyroid gland. it is of great significance for multidisciplinary therapy combing anesthesia, surgical, endocrinology and nephrology staff.

Ultrasonographic size of the canine parathyroid gland may not correlate with histopathology.

Accurate ultrasonographic differentiation of normal versus abnormal parathyroid glands is important for clinical workup and presurgical screening in dogs with hypercalcemia. In previous published studies, size has been the only ultrasonographic criterion correlated with histologic diagnoses of abnormal parathyroid glands. In this retrospective, cross-sectional study, the medical records of dogs with ultrasonographic examinations of the parathyroid glands and histologic diagnoses of parathyroid gland hyperplasia, adenoma, and adenocarcinoma were evaluated. Ultrasonographic characteristics were recorded for each gland and compared among histologic diagnosis groups. A total of 49 dogs and 59 parathyroid glands were sampled and assigned to the following groups for analyses: adenoma (n = 24), hyperplastic (n = 20), and adenocarcinoma (n = 15). There were no associations with dog age, sex, weight, breed; or gland laterality, location, ultrasonographic shape, or echogenicity among histologic diagnosis groups (P > .05). Parathyroid gland adenocarcinomas were found to be less likely to have a homogeneous echotexture on ultrasonographic evaluation, with hyperplastic glands being smaller (P = .022) and adenocarcinomas being larger (P = .042). While 3 mm was the optimum cutoff for differentiating hyperplastic and neoplastic parathyroid glands in this sample of dogs, values varied widely within groups and there were overlapping values between groups. Therefore, authors caution against using ultrasonographic size as a sole criterion for differentiating hyperplasia from neoplasia and normal versus abnormal parathyroid glands.

Hypercalcemic crisis in third trimenon: evaluating the optimal treatment strategy.

Hypercalcemia due to primary hyperparathyroidism during pregnancy is a rare condition and associated with increased morbidity and mortality for the mother and the unborn child. Whereas parathyroidectomy is favored during the second trimester, no clear recommendations exist for its management during the third trimenon. We here report the case of a 26-year-old woman in the 29th week of her first pregnancy, who was admitted to our clinic with hypertension, intra-uterine growth retardation and polyhydramnios. Severe hypercalcemia due to primary hyperparathyroidism was diagnosed (total calcium 3.34 mmol/l; PTH 216 pg/ml), but no enlarged parathyroid gland could be localized by ultrasound. Treatment with calcitonin and cinacalcet could not control hypercalcemia. Therefore explorative surgery was performed and a single parathyroid adenoma was resected, resulting in normalization of serum calcium levels. The surgical procedure was tolerated well by the mother and fetus. Hypercalcemia-induced hypertension and polyhydramnios ameliorated before C-section was performed two weeks later and unrelated to the intervention. This case report underlines the importance of early diagnosis and treatment of primary hyperparathyroidism during pregnancy. If diagnosed in the third trimenon, an interdisciplinary approach is crucial. If medical treatment fails to sufficiently control hypercalcemia, surgical parathyroid exploration should be considered even in cases of unsuccessful localization of adenomatous parathyroid glands.

Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

Urolithiasis is prevalent and associated with reduced bone mineral density in ß-thalassaemia major.

Asymptomatic urolithiasis is common and of mixed composition in patients with ß-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores.

Prevalence of incidental thyroid nodules in ultrasound studies of dogs with hypercalcemia (2008-2013).

Ultrasound is commonly used to evaluate the cervical region in dogs with hypercalcemia due to suspected hyperparathyroidism. Incidental thyroid nodules may be detected during these studies, however little information has been published to guide clinical decision-making when this occurs. The purpose of this cross-sectional study was to determine the prevalence of incidental thyroid nodules in hypercalcemic dogs undergoing cervical ultrasound at our hospital during the period of 2008-2013. Dogs with a palpable neck mass were excluded. Cervical ultrasound images for each dog were retrieved and reviewed by a board certified veterinary radiologist who was unaware of patient outcome. Presence, number, and dimensions of thyroid nodules were recorded. Results of thyroid nodule aspirate, biopsy or necropsy were recorded from medical records when available. Ninety-one dogs met inclusion criteria. Of these, 14/91 (15%) dogs had at least one thyroid nodule. Mean (± standard deviation) thyroid gland nodule length, width, and height were 1.51 ± 0.74, 0.96 ± 0.73, and 0.75 ± 0.36 cm, respectively. A histologic diagnosis was available for the incidental thyroid lesions in eight dogs, including one dog with two nodules. Confirmed diagnoses for these nodules were thyroid cyst (3/9, 33%), thyroid adenoma (3/9, 33%), thyroid adenocarcinoma (2/9, 22%) and nodular hyperplasia (1/9, 11%). Findings indicated that incidental thyroid nodules may be present in hypercalcemic dogs with no palpable neck mass and no clinical signs of thyroid disease. Some of these nodules may be malignant and therefore a recommendation for cytology or biopsy may be justified.

Increased trabecular volumetric bone mass density in Familial Hypocalciuric Hypercalcemia (FHH) type 1: a cross-sectional study.

Familial Hypocalciuric Hypercalcaemia (FHH) Type 1 is caused by an inactivating mutation in the calcium-sensing receptor (CASR) gene resulting in elevated plasma calcium levels. We investigated whether FHH is associated with change in bone density and structure. We compared 50 FHH patients with age- and gender-matched population-based controls (mean age 56 years, 69 % females). We assessed areal BMD (aBMD) by DXA-scans and total, cortical, and trabecular volumetric BMD (vBMD) as well as bone geometry by quantitative computed tomography (QCT) and High-Resolution peripheral-QCT (HR-pQCT). Compared with controls, FHH females had a higher total and trabecular hip vBMD and a lower cortical vBMD and hip bone volume. Areal BMD and HRpQCT indices did not differ except an increased trabecular thickness and an increased vBMD at the transition zone between cancellous and cortical bone in of the tibia in FHH. Finite element analyses showed no differences in bone strength. Multiple regression analyses revealed correlations between vBMD and P-Ca(2+) levels but not with P-PTH. Overall, bone health does not seem to be impaired in patients with FHH. In FHH females, bone volume is decreased, with a lower trabecular volume but a higher vBMD, whereas cortical vBMD is decreased in the hip. This may be due to either an impaired endosteal resorption or corticalization of trabecular bone. The smaller total bone volume suggests an impaired periosteal accrual, but bone strength is not impaired. The findings of more pronounced changes in females may suggest an interaction between sex hormones and the activity of the CaSR on bone.

Reoperations for primary hyperparathyroidism--improvement of outcome over two decades.

PURPOSE: Reoperations (R-PTX) for primary hyperparathyroidism (pHPT) are challenging, since they are associated with increased failure and morbidity rates. The aim was to evaluate the results of reoperations over two decades, the latter considering the implementation of Tc(99m)sestamibi-SPECT (Mibi/SPECT), intraoperative parathormone (IOPTH) measurement, and intraoperative neuromonitoring (IONM). PATIENTS AND METHODS: Data of 1,363 patients who underwent surgery for pHPT were retrospectively analyzed regarding reoperations. Causes of persistent (p) pHPT or recurrent (r) pHPT, preoperative imaging studies, surgical findings, and outcome were analyzed. Data of patients who underwent surgery between 1987 and 1997 (group 1; G1) and between 1998 and 2008 (group 2; G2) with the use of Mibi/SPECT, IOPTH, and IONM were evaluated. RESULTS: One hundred twenty-five patients with benign ppHPT (n = 108) or rpHPT (n = 17) underwent reoperations (R-PTX). Group 1 included 54, group 2 71 patients. Main cause of ppHPT (G1 = 65 % vs. G2 = 53 %) and rpHPT (G1 = 80 % vs. G2 = 60 %) was the failed detection of a solitary adenoma (p = 0.2). Group 1 patients had significantly less unilateral/focused neck re-explorations (G1 = 23 % vs. G2 = 57 %, p = 0.0001), and more sternotomies (G1 = 35 vs. G2 = 14 %, p = 0.01). After a median follow-up of 4 (range 0.9-23.4) years, reversal of hypercalcemia was achieved in 91 % (G1) and in 98.6 % in group 2 (p = 0.08, OR 7.14 [0.809-63.1]). The rates of permanent recurrent laryngeal nerve palsy (G1 = G2 = 9 %, p = 1) and of postoperative permanent hypoparathyroidism (G1 = 9 % vs. G2 = 6 %, p = 0.5) were not significantly different. Other complications such as wound infection, postoperative bleeding, and pneumonia were significantly lower in group 2 (p < 0.001). CONCLUSION: Nowadays, cure rates of R-PTX are nearly the same as in primary operations for pHPT. These results can be achieved in high-volume centers by routine use of well-established preoperative Mibi/SPECT and US in combination with IOPTH. However, morbidity is still considerably high.

Forearm bone mineral density in familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a comparative study.

Studies have shown that cancellous bone is relatively preserved in primary hyperparathyroidism (PHPT), whereas bone loss is seen in cortical bone. Familial hypocalciuric hypercalcemia (FHH) patients seem to preserve bone mineral in spite of hypercalcemia and often elevated plasma parathyroid hormone (PTH). The objective of this study was to compare total and regional forearm bone mineral density (BMD) in patients with PHPT and FHH and to examine if differences can be used to separate the two disorders. We included 63 FHH, and 121 PHPT patients in a cross-sectional study. We performed dual-energy X-ray absorptiometry scans of the forearm, hip and lumbar spine and measured a number of biochemical variables. PTH patients had significantly lower Z-scores in all parts of the forearm compared to FHH. This was also the case after adjustment for body mass index. When stratifying for age, gender and PTH, T-scores were still significantly lower in PHPT patients than in FHH patients at the total, the mid and the ultradistal forearm, but not at the proximal 1/3 forearm. In a multiple regression analysis BMD Z-score was lower in PHPT compared to FHH at the total forearm, the mid forearm and the ultradistal forearm but not the proximal forearm when adjusting for biochemical variables including PTH, 1,25(OH)(2)D and Ca(2+). These observations support that inactivating mutations in the CASR gene in bone cells in FHH may protect against forearm bone loss. Differences between the two groups in total or regional forearm BMD were inferior to the calcium/creatinine clearance ratio as a diagnostic tool to separate FHH from PHPT.

Establishment of a new murine model of hypercalcemia with anorexia by overexpression of soluble receptor activator of NF-κB ligand using an adenovirus vector.

Hypercalcemia is a significant complication of certain human malignancies that is primarily caused by the release of calcium from bone due to marked bone resorption by osteoclast activation. Osteoclast differentiation and activation is mediated by receptor activator of NF-κB ligand (RANKL). Transgenic mice overexpressing murine soluble RANKL (sRANKL) that we generated previously exhibited severe osteoporosis accompanied with enhanced osteoclastogenesis, but never exhibited hypercalcemia. To analyze the relationship between serum concentration of sRANKL and hypercalcemia and generate a simple and quick hypercalcemia model, an adenovirus vector harboring murine sRANKL cDNA (Ad-sRANKL) was injected i.p. into male C57BL/6 mice. Sera were collected to measure the levels of sRANKL, calcium and biochemical markers of bone turnover. Food intake and body weight were measured every 3 or 4 days. All the mice were killed 2 weeks after the injection, and femurs were collected to measure bone structure and bone mineral density (BMD). Serum sRANKL and calcium increased, peaking on day 7. Food intake and body weight significantly declined on day 7. These results indicated that the mice had anorexia as a symptom of hypercalcemia. Increases in bone resorption and formation markers with a marked decrease in BMD were observed on day 14. These results reflect accelerated bone formation following activation of osteoclasts, indicating coupling between bone formation and resorption. In conclusion, a new murine model of hypercalcemia with anorexia was established by overexpressing sRANKL. This model would be useful for studies of hypercalcemia and coupling between bone formation and resorption.

Imaging features of hypercalcemia: A primer for emergency radiologists.

Hypercalcemia is a marker for a wide variety of underlying etiologies, and its presentation in the emergency setting may be asymptomatic, incidental, or a primary complaint with associated symptoms and physical exam findings. While the workup is initially driven through serum laboratory testing, imaging plays an important role in diagnosis and post-treatment follow up. This review covers multiple common and uncommon etiologies of hypercalcemia, details their underlying mechanisms, and identifies the most important associated imaging findings. It is important for radiologists to be familiar with these etiologies and imaging findings, particularly in the emergency setting since hypercalcemia may represent the only significant laboratory abnormality associated with the presenting condition. Furthermore, the radiologist's interpretation of a study may be directly influenced by knowing about a patient's hypercalcemia.