Calcifediol Rather Than Cholecalciferol for a Patient Submitted to Malabsortive Bariatric Surgery: A Case Report

Vitamin D deficiency following malabsorptive bariatric surgery can lead to osteomalacia. We report a patient with severe vitamin D deficiency following malabsorptive bariatric surgery successfully treated with calcifediol but not cholecalciferol. A 40-year-old woman, submitted to biliopancreatic diversion 20 years before and chronically treated with 50,000 IU cholecalciferol weekly, was admitted to our Endocrine Unit because of severe lower back pain, muscle weakness, and generalized muscular hypotrophy, associated with hypocalcemia and elevated PTH levels. Initial evaluation revealed low serum albumin, low albumin-corrected serum calcium (7.36 mg/dL), high serum PTH (240 pg/mL), bone-specific alkaline phosphatase (125 μg/L) and 1,25-dihydroxyvitamin D (112 pg/mL) concentrations, undetectable serum 25-hydroxyvitamin D (<7 ng/mL), and evidence of reduced liver function. Bone mineral density was markedly low. Normocalcemia was initially restored with intravenous albumin and calcium gluconate. Treatment with calcitriol (0.5 μg three times daily) and oral calcium carbonate (1000 mg daily) was simultaneously started and cholecalciferol was replaced with calcifediol [125 μg (5000 IU) daily)]. During follow-up the calcifediol dose was progressively tapered to 25 μg (1000 IU) daily and the calcitriol dose was progressively reduced and finally withdrawn. Serum albumin and other biochemical parameters normalized, bone mineral density significantly increased, and the patient's clinical conditions progressively improved, with a substantial recovery of autonomy. Serum vitamin D binding protein at the last observation was in the normal range. Our data suggest that calcifediol might be more efficacious than cholecalciferol for prevention and treatment of vitamin D deficiency in patients treated by malabsorptive bariatric surgery

Normocalcemic primary hyperparathyroidism: a survey in a small village of Southern Italy

We investigated the prevalence of normocalcemic primary hyperparathyroidism (NPHPT) in the adult population living in a village in Southern Italy. All residents in 2010 (n=2045) were invited by calls and 1046 individuals accepted to participate. Medical history, calcium intake, calcium, albumin, creatinine, parathyroid hormone (PTH) and 25OHD were evaluated. NPHPT was defined by normal albumin-adjusted serum calcium, elevated plasma PTH, and exclusion of common causes of secondary hyperparathyroidism (SHPT) (serum 25OHD <30 ng/ml, estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m(2) and thiazide diuretics use), overt gastrointestinal and metabolic bone diseases. Complete data were available for 685 of 1046 subjects. Twenty subjects did not meet the inclusion criteria and 341 could not be evaluated because of thawing of plasma samples. Classical PHPT was diagnosed in four women (0.58%). For diagnosing NPHPT the upper normal limit of PTH was established in the sample of the population (n=100) who had 25OHD ≥30 ng/ml and eGFR ≥60 ml/min per 1.73 m(2) and was set at the mean+3s.d. Three males (0.44%) met the diagnostic criteria of NPHPT. These subjects were younger and with lower BMI than those with classical PHPT. Our data suggest, in line with previous studies, that NPHPT might be a distinct clinical entity, being either an early phenotype of asymptomatic PHPT or a distinct variant of it. However, we cannot exclude that NPHPT might also represent an early phase of non-classical SHPT, since other variables, in addition to those currently taken into account for the diagnosis of NPHPT, might cumulate in a normocalcemic subject to increase PTH secretion

Impact of vitamin D deficiency on the clinical and biochemical phenotype in women with sporadic primary hyperparathyroidism

The purpose of the study was to evaluate the relationship between serum 25(OH)D and the clinical phenotype in 215 consecutive Italian Caucasian women with sporadic primary hyperparathyroidism (PHPT) not taking vitamin D supplements. The study was performed at a single Italian tertiary center. PHPT-related manifestations, serum 25(OH)D, and other parameters of calcium metabolism and bone mineral density (BMD) by DXA were recorded. Serum 25(OH)D was negatively correlated with age (r = −0.18; P = 0.006), BMI (r = −0.20; P = 0.002), PTH (r = −0.21; P = 0.001), bone-specific alkaline phosphatase (BSAP) (r = −0.27; P < 0.001), and eGFR (r = −0.22; P = 0.01), and positively with serum creatinine and 1/3 distal radius BMD (R-BMD; r = 0.17; P = 0.015). In a multivariate regression analysis, serum 25(OH)D remained significantly correlated with age (r = −0.18; P = 0.005), BMI (r = −0.23; P = 0.049), serum PTH (r = −0.01; P = 0.023), BSAP (r = −0.01; P = 0.023) and eGFR (r = −0.09; P = 0.001), but not with R-BMD. Serum 25(OHD) was higher in patients with nephrolithiasis than in those without nephrolithiasis (18.5 ± 8.8 vs. 15.6 ± 8.0 ng/ml; P = 0.029), whereas no difference was found between fractured and unfractured patients (16.8 ± 9.3 vs. 16.0 ± 7.7; P = 0.663). There was a statistically significant inverse correlation between vitamin D status [defined by quartiles of measured values as well as commonly accepted cutoffs of serum 25(OH)D] and severity of the disease, as reflected by higher PTH and BSAP, but not by meeting the latest guidelines for parathyroidectomy. In conclusion, a low vitamin D status is associated with some features reflecting a more severe biochemical and clinical phenotype of PHPT in Italian women not taking vitamin D supplements

Parathyroid tumorigenesis

Primary hyperparathyroidism (PHPT) is a common endocrinopathy, mostly caused by a monoclonal parathyroid adenoma. This review primarily summarizes current knowledge concerning molecular pathogenesis of familial forms of primary hyperparathyroidism and sporadic (non familial) parathyroid tumors. The hereditary syndromes have been recognized as exhibiting Mendelian inheritance patterns and include multiple endocrine neoplasia types 1 (MEN 1) and 2A (MEN 2A), hereditary hyperparathyroidism- jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism (FIHP), familial hypocalciuric hypercalcemia (FHH) and severe neonatal hyperparathyroidism (NSHPT). Inactivating mutations of MEN1 tumor suppressor gene are responsible for MEN 1 in >90% of cases. MEN1 gene has also an established role in the pathogenesis of sporadic parathyroid adenomas. Allelic loss (LOH) of chromosome 11q13 occurs in about 30-40% and somatic mutation of MEN1 gene occur in about 12-20% of sporadic parathyroid adenomas. A mouse model of MEN1 deficiency causes a phenotype that includes the same range of major endocrine tumors as in MEN 1 patients, and exhibits multistage tumor progression with metastatic potential. Hormonal disturbances, such as abnormal PTH and insulin levels, were also observed in these mice. Mutations in a newly identified tumor suppressor gene, HRPT2, have been recently associated with the development of HPT-JT. HRPT2 mutations are also frequent in sporadic parathyroid carcinomas and central to their pathogenesis. MEN1 and HRPT2 genes mutations have also been found in a subset of FIHP families. FHH and NSHPT represent the mildest and severest variants of PHPT, respectively. Both cause hypercalcemia from birth and atypical PHPT that always uniquely persists after subtotal parathyroidectomy. Future identification of additional oncogenes and tumor suppressor genes will clarify the molecular basis of abnormalities of parathyroid proliferation and regulatory function and other specific features unique to the parathyroid tumorigenesis

Increased Risk of Renal Complications in Patients with Chronic Postsurgical Hypoparathyroidism Treated with Conventional Therapy

The conventional treatment of chronic hypoparathyroidism with calcium and active vitamin D metabolites exposes patients to the risk of renal complications, due to the lacking action of PTH at the renal tubule. We evaluated 90 patients (68 females and 22 males; age: 51.8±14.1 yrs) with chronic postsurgical hypoparathyroidism diagnosed since at least 3 years. All patients were treated with calcitriol (0.87 ± 0.40 μg/day), 35 (39%) were also taking calcium supplements (1.08 ± 0.75 g/day) and 2 thiazide diuretics. Total albumin-corrected (Alb-Ca) and ionized serum calcium, phosphorus, creatinine, PTH, 25(OH)vitamin D, and 24-hour urinary calcium were measured; renal ultrasound was also performed. A group of 142 healthy Hospital employers, matched for age and sex, undergoing routine medical evaluation, which included Alb-Ca, creatinine and renal ultrasound, was used as control. Mean levels of Alb-Ca and ionized calcium were in the normal range [1.14±0.07 mmol/L (range 0.91 to 1.29) and 8.9±0.49 mg/dL (7.5-10.1), respectively], but 39 (43.3%) patients had values that did not met the range recommended by the recent guidelines of the European Society of Endocrinology (ESE) (1.05-1.15 mmol/L for ionized calcium and 8.4-9.2 mg/dl). When all available serum calcium measurement performed prior to the present evaluation were taken into account for each patients (n=78 with at least 3 determinations, mean 5), we found that only 9 (11.5%) patients had all values within the recommended ESE range, and a large proportion of patients (32, 41.0%) had values ≥ the upper recommended value. The mean phosphorus levels [3.64±0.68 mg /dL (2.2-5.9)] and serum creatinine [0.9±0.2 mg/dL (0.58 to 2.1)] were in the normal range, but 7 (7.7%) patients had elevated values of phosphorus and 22 (24.4%) of creatinine. The serum calcium-phosphate product was normal in all patients (300/dL mg in men and >250 mg/dL in females) was found in 44 (54%) patients. Kidney stones, mostly asymptomatic, were detected at ultrasound in 27 (30%) patients. Compared to the controls, patients had statistically significant lower mean Alb-Ca (p <0.0001), higher mean serum creatinine (p=0.0008) and greater prevalence of kidney stones [27/90 vs 7/142, p <0.0001, OR: 8.2 (3.4-19.9)]. In conclusion, the results of the present study indicate that the conventional treatment of chronic postsurgical hypoparathyroidism is suboptimal and associated with an increased risk of renal complications and suggest the need for careful monitoring of treatment, as recommended by the ESE guideline

Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the CYP24A1 Gene: A Case Report and Review of the Literature

Introduction. Loss of function mutations of CYP24A1 gene, which is involved in vitamin D catabolism, cause vitamin D-mediated PTH-independent hypercalcemia. The phenotype varies from life-threatening forms in the infancy to milder forms in the adulthood. Case Presentation. We report a case of a 17-year-old woman with a history of nephrolithiasis, mild PTH-independent hypercalcemia (10,5mg/dL), and high serum 1,25(OH)2D concentrations (107pg/mL). Other causes of hypercalcemia associated with the above biochemical signature were excluded. Family history revealed nephrolithiasis in the sister. Blood testing in first-degree relatives showed serum PTH in the low-normal range and 1,25(OH)2D at the upper normal limit or slightly elevated. The CYP24A1 gene analysis revealed a known homozygous loss-of-function pathogenic variant (c.428_430delAAG, rs777676129, p.Glu143del). The panel of vitamin D metabolites evaluated by liquid chromatography showed the typical profile of CYP24A1 mutations, namely, low 24,25(OH)2D3, elevated 25(OH)D3:24,25(OH)2D3 ratio, and undetectable 1,24,25(OH)3D3. The parents and both the siblings harbored the same variant in heterozygosis. We decided for a watchful waiting approach and the patient remained clinically and biochemically stable over a 24-month followup. Conclusion. CYP24A1 gene mutations should be considered in cases of PTH-independent hypercalcemia, once that more common causes (hypercalcemia of malignancy, granulomatous diseases, and vitamin D intoxication) have been ruled out

Effect of neridronate in osteopenic patients after heart, liver or lung transplant: a multicenter, randomized, double-blind, placebo-controlled study

none16Transplantation (Tx) is an effective therapeutic option in patients with end-stage organ failure and osteoporosis and related fractures are a recognized complication in these patients. Aim of this study was to evaluate the efficacy of neridronate in patients with reduced bone mass after Tx of the heart, liver or lung.noneGiannini, Sandro; Poci, Carlo; Fusaro, Maria; Egan, Colin G; Marcocci, Claudio; Vignali, Edda; Cetani, Filomena; Nannipieri, Fabrizio; Loy, Monica; Gambino, Antonio; Adami, Giovanni; Braga, Vania; Rossini, Maurizio; Arcidiacono, Gaetano; Baffa, Valeria; Sella, StefaniaGiannini, Sandro; Poci, Carlo; Fusaro, Maria; Egan, Colin G; Marcocci, Claudio; Vignali, Edda; Cetani, Filomena; Nannipieri, Fabrizio; Loy, Monica; Gambino, Antonio; Adami, Giovanni; Braga, Vania; Rossini, Maurizio; Arcidiacono, Gaetano; Baffa, Valeria; Sella, Stefani

Morphometric Vertebral Fractures in Postmenopausal Women with Primary Hyperparathyroidism

Context: An increased risk of fracture in patients with primary hyperparathyroidism (PHPT) compared to the general population has been reported, but available data are controversial