Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "g... more Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "giant" parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the >3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 5 <36years), serum calcium 11.6 ± 1.1 mg/dl, alkaline phosphatase 799 ± 487 IU/L, PTH 1440 ± 477 pg/ml, 25-hydroxyvitamin D 13.0 ± 8.9 ng/ml, 1,25dihyroxyvitamin D 26.5 ± 13.7 pg/ml, urine calcium 562 ± 274 mg/day, and parathyroid adenoma weight 4.53 ± 2.2 g. Parathyroidectomy led to the resolution of both the biochemical indices and OFC in each patient without recurrence over >10 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC.
Objective: Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular morbidi... more Objective: Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular morbidity and mortality with inconsistent results on the reversibility of cardiovascular changes after parathyroidectomy (PTx). The present study was undertaken to evaluate both structural and functional cardiac changes and their reversal after PTx in patients with PHPT. Material and Methods: Thirty patients of symptomatic PHPT without cardiovascular risk factors were evaluated prospectively by means of 2D echocardiography (ECHO) and Multigated Acquisition (MUGA) study before surgery and six months after curative parahyroidectomy. Results: Nine of 30 patients had hypertension which improved in two after PTx (p 0.20). Two patients had left ventricle hypertrophy on 2D ECHO preoperatively which improved after PTx (p< 0.001). Left ventricular ejection fraction (LVEF) did not show significant change before and after PTx on 2D ECHO. Nine out of 30 patients had hypertension which improved in two after PTx (p 0.20). Two patients with left ventricle hypertrophy on 2D ECHO preoperatively improved after PTx (p< 0.001). Left ventricular ejection fraction (EF) did not depict significant change before and after PTx on 2D ECHO. Whereas, four out of six patients with preoperative EF <50% representing systolic dysfunction on MUGA study showed improvement after PTx. On 2D ECHO, eight patients depicted diastolic dysfunction which improved in six patients after curative surgery (p= 0.07). However, on MUGA study, 13 patients presented with tTPF >180 ms indicating diastolic dysfunction, of which ten showed improvement after PTx (p= 0.007). Conclusion: The present study analyzed preoperative and postoperative cardiac function using both 2D ECHO and MUGA study. MUGA study provided a more objective assessment of the cardiac function by determining left ventricular ejection fraction and diastolic dysfunction.
Objective: Primary hyperparathyroidism (PHPT) is a systemic disease which, along with bone and st... more Objective: Primary hyperparathyroidism (PHPT) is a systemic disease which, along with bone and stone disease, also causes several subjective symptoms which impairs the quality of life (QoL). However, NIH guidelines do not include non-specific physical and neuropsychological symptoms as an indication of parathyroidectomy. SF-36 is one of the most commonly used tools for assessing QoL; it measures both physical health (PH) and mental health (MH). Material and Methods: This is a prospective observational study including 50 patients of symptomatic PHPT. Patients were categorized into normocalcemia (8.5-10.4 mg/dL), mild hypercalcemia (10.5-11.9 mg/dL), moderate hypercalcemia (12-13.9 mg/dL), and severe hypercalcemia (>14 mg/dL). QoL was assessed by using SF36 survey both pre-operative and three months after parathyroidectomy. Results: There was an overall improvement in QoL of individual groups both in PH and MH components (p< 0.001). The improvement was more substantial for bodil...
Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becom... more Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becomes more prevalent after menopause. In this study, we compared the demographic, clinical, and biochemical variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT. Methods: A retrospective analysis (from 2005 to 2019) of enrolled women PHPT patients from an online Indian PHPT registry. Results: Of the women with PHPT, 232 and 122 were pre-M and post-M, respectively. The number of post-M PHPT cases registered had a 3.3-fold increase in 2015-2019 from 2005-2009 compared with only a 2.5-fold increase in pre-M cases in the same duration. The majority were symptomatic (90%), although pre-M had a higher proportion of symptomatic than post-M (92% vs 85%; P ¼ .04). Pre-M women showed more prevalence of osteitis fibrosa cystica than post-M women (28% vs 13%; P ¼ .03), although hypertension and gallstone disease were seen more frequently in post-M PHPT women. Pre-M women had a significantly higher median PTH (403 vs 246 pg/mL; P ¼ .02) and median alkaline phosphatase (202 vs 145 pg/mL; P ¼ .02) than post-M women, and vitamin D deficiency was more common in pre-M women (58% vs 45%; P ¼ .03). Gland localization, tumor weight, and disease cure rates did not differ according to menopausal status. Conclusion: PHPT was more prevalent in pre-M women, although the number of post-M cases had significantly increased in the last 10 years. Pre-M women had generally more severe clinical and biochemical variables than post-M PHPT women.
Summary Osteoporosis is a disease with a high burden of morbidity. For its accurate diagnosis, us... more Summary Osteoporosis is a disease with a high burden of morbidity. For its accurate diagnosis, using indigenous data as reference standards is needed. However, normative data on bone density is lacking in India. Therefore, we aimed to determine the reference range for bone density for the healthy population of north India. Introduction Osteoporosis is a major public health problem around the globe including India, resulting in significant morbidity, mortality, and health care burden. However, the reference values used for its diagnosis are largely based on data from the western population, which may lead to over- or underdiagnosis of osteoporosis in Indians. Our study aimed to determine the reference range for bone mineral density for the healthy population of India. Methods This is a cross-sectional study of 825 subjects (men 380, women 445) (median age: 41 years, IQR 32–55 years), recruited by a house-to-house survey. The population was stratified into decade-wise groups and biochemical measurements including renal and liver function tests, glycated hemoglobin, serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density were performed in all the subjects. The T-scores for men aged > 50 years and post-menopausal women were calculated based on the data generated from this study in young men and women aged 20–40 years. Results According to the BMD manufacturer’s data, which is based on the western population, 70% of the Indian men (> 50 years) and 48% of the post-menopausal Indian women had osteopenia while 18% of the men and 25% of the women had osteoporosis. However, according to the re-calculated T-scores from the current study, only 56% and 7.2% of men and 33% and 5% of women had osteopenia and osteoporosis, respectively. An age-related decline in bone mineral density, as seen in the western population, was also seen in both Indian men and women. Conclusion We have established a reference database for BMD in healthy Indian adult population, which may have clinical implications for the diagnosis and intervention strategies for the management of osteoporosis.
Primary hyperparathyroidism(PHPT)is clinically characterised by Pentad of PHPT.PHPT is also ass... more Primary hyperparathyroidism(PHPT)is clinically characterised by Pentad of PHPT.PHPT is also associated with various gastrointestinal manifestations viz constipation, acid peptic disease, pancreatitis and cholelithiasis, however all of these are sparsely reported with PHPT. Gastrointestinal manifestations are less specific and literature is silent on cause and effect relationship. Recently, we have shown that constipation (38%) is the most common GI manifestation followed by acid peptic disease (30%), cholelithiasis( 28%%) pancreatitis( 22%) and from PHPT reg istry of our department(n =300 ). PHPT pancreatitis often remains undiagnosed for long period due to lack of awareness and low index of suspicion. Pancreatitis in PHPT is multifactorial and curative parathyroidectomy prevents recurrence of pancreatitis. The aim of present review is to increase awareness amongst clinicians and gastroenterologists about gastrointestinal manifestations of PHPT.
The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice gui... more The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India. Purpose In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines, the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country. Methods The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians, researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guidelines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India. Results Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diagnostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice. Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential, which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/ absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy. Conclusions Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India.
Introduction: Focused parathyroidectomy is the gold standard treatment for primary hyperparathyro... more Introduction: Focused parathyroidectomy is the gold standard treatment for primary hyperparathyroidism (PHPT) due to single gland disease with a comparable success rate as that of conventional four gland exploration. It is also associated with fewer surgical complications. Despite these benefits, there is still controversy about the high recurrence following the focused approach. Aim: The aim was to analyse our experience regarding the success rate of focused parathyroidectomy for PHPT. Methods: This was a retrospective analysis of 192 patients of PHPT between January 2017 and August 2020 who underwent focused parathyroidectomy without intraoperative parathormone analysis, and had a minimum follow up of six months. Demographic profile, biochemical (pre and postoperative), radiological, operative and histological detail of all patients were recorded. Parathyroidectomy was considered curative if the patient maintained normal serum calcium and parathormone (PTH) levels six months after...
The Journal of Clinical Endocrinology & Metabolism, 2020
Aim Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorig... more Aim Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorigenesis, but the underlying mechanism remains elusive. Accordingly, we aimed to explore the epigenetic changes (DNA methylation and histone modifications) involved in CaSR regulation in sporadic parathyroid adenomas and correlate epigenetic state with disease indices. Experimental Design Forty sporadic parathyroid adenomas and 10 control parathyroid tissues were studied. Real-time quantitative PCR (qPCR) for mRNA and immunohistochemistry for protein expression of CaSR were performed. The methylation status of the CaSR promoter 2 was determined by bisulphite sequencing analysis of sodium bisulphite-converted DNA. To determine the role of histone modifications in the CaSR regulation, chromatin immunoprecipitation-qPCR assay was performed. Results Real-time qPCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P < 0.0001) in parathyroid adenomas. Immunohistochemistry r...
Background: Focused parathyroidectomy is the adequate treatment for primary hyperparathyroidism f... more Background: Focused parathyroidectomy is the adequate treatment for primary hyperparathyroidism for localised disease. Adequacy of resection is confirmed by the availability of intraoperative parathormone assay (iOPTH). In the absence of availability of iOPTH assay, the radio guided surgery is an option. The aim of this study was to evaluate the feasibility of radioguided parathyroidectomy in tertiary care centre in India and to compare the overall success rate, operative time, hospital stay and postoperative outcome between focused open and radioguided parathyroidectomy.Methods: This was a prospective study which included 30 primary hyperparathyroidism patients with a single gland disease localised on Tc99m Sesta MIBI scan. Patients were randomized into two equal groups, and they underwent focused open or radioguided parathyroidectomy. Patients were followed up for three months.Results: All patients achieved biochemical cure as evident by the normalization of serum calcium and para...
Inorganic phosphate is a vital constituent of cells and cell membranes, body fluids, and hard tis... more Inorganic phosphate is a vital constituent of cells and cell membranes, body fluids, and hard tissues. It is a major intracellular divalent anion, participates in many genetic, energy and intermediary metabolic pathways, and is important for bone health. Although we usually think of phosphate mostly in terms of its level in the serum, it is needed for many biological and structural functions of the body. Availability of adequate calcium and inorganic phosphate in the right proportions at the right place is essential for proper acquisition, biomineralization, and maintenance of mass and strength of the skeleton. The three specialized mineralized tissues, bones, teeth, and ossicles, differ from all other tissues in the human body because of their unique ability to mineralize, and the degree and process of mineralization in these tissues also differ to suit the specific functions: locomotion, chewing, and hearing, respectively. Biomineralization is a dynamic, complex, and lifelong process by which precipitations of inorganic calcium and inorganic phosphate divalent ions form biological hard tissues. Understanding the biomineralization process is important for the management of diseases caused by both defective and abnormal mineralization. Hypophosphatemia results in mineralization defects and osteomalacia, and hyperphosphatemia is implicated in abnormal excess calcification and/or ossification, but the exact mechanisms underlying these processes are not fully understood. In this review, we summarize available evidence on the role of phosphate in biomineralization. Other manuscripts in this issue of the journal deal with other relevant aspects of phosphate homeostasis, phosphate signaling and sensing, and disorders resulting from hypo-and hyperphosphatemic states.
Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2020
Background and aims: The novel coronavirus disease (COVID-19) pandemic and the resulting nationwi... more Background and aims: The novel coronavirus disease (COVID-19) pandemic and the resulting nationwide lockdowns have posed a major challenge to the management of pre-existing and newly diagnosed endocrine disorders. Herein, we have summarized the management approaches of common endocrine disorders amid the ongoing pandemic. Methods: We have performed an extensive literature search for articles in PubMed, EMBASE and Google Scholar databases till 25 May 2020, with the following keywords: "COVID-19", "diabetes mellitus", "thyroid disorders", "primary adrenal insufficiency", "Cushing's syndrome", "pituitary tumors", "vitamin D 00 ", "osteoporosis", "primary hyperparathyroidism", "hypoparathyroidism", "management", "treatment" and "guidelines" with interposition of the Boolean operator "AND". Results: We have summarized the most feasible strategies for the management of diabetes mellitus, thyroid disorders, primary adrenal insufficiency (including congenital adrenal hyperplasia), Cushing's syndrome, pituitary tumors, osteoporosis, primary hyperparathyroidism and hypoparathyroidism amid the constraints laid down by the raging pandemic. In general, medical management should be encouraged and surgical interventions should be deferred whenever possible. Ongoing medications should be continued. Sick-day rules should be sincerely adhered to. Regular contact with physicians can be maintained through teleconsultations and virtual clinics. Conclusions: Considering the burden of endocrine disorders in the general population, their management needs to be prioritized amid the ongoing COVID-19 pandemic.
Hypophosphatasia is an inborn error in metabolism characterized by low serum alkaline phosphatase... more Hypophosphatasia is an inborn error in metabolism characterized by low serum alkaline phosphatase (ALP) activity resulting from deactivating mutations in TNSALP (also known as ALPL), the gene that encodes the 'tissue-specific' isoenzyme of ALP. The disease exhibits significant clinical heterogeneity that spans from death in utero to only dental complications in adult life. Herein, we report a 47-year-old woman presenting with fracture of shaft of left femur. She had been complaining of pain in both of her thighs for the past 3 years. In addition, she gave a history of premature loss of teeth. Review of old radiographs revealed pseudo-fractures involving the lateral cortices of the femora on both sides. Biochemical panel revealed hyperphosphatemia, persistently low total alkaline phosphatase (ALP) and low-normal bone turnover markers. Screening of her siblings revealed low ALP in her younger sister and brother who were otherwise free from any major dento-arthro-osseous complaints. Sanger sequencing showed a novel, heterozygous, missense mutation in exon 5 at position 311 (c.311a > g;p.104 Asn > Ser) of ALPL gene in the three members. The patient underwent open reduction and intramedullary nailing of left femur along with prophylactic nailing on right side. This case report represents the first genetically confirmed kindred of adult hypophosphatasia from the Indian subcontinent.
Objective: Present a case of an atypical parathyroid adenoma in the mediastinum as a part of mult... more Objective: Present a case of an atypical parathyroid adenoma in the mediastinum as a part of multiple endocrine neoplasia type 1 (MEN1). Methods: Clinical, laboratory, imaging, and histolopathogic analyses were performed. Results: A 50-year-old man who was diagnosed with chronic kidney disease secondary to bilateral nephrolithiasis was referred for evaluation of incidentally detected hypercalcemia. He had an acromegaloid facies and lipomas over the forehead. Laboratory evaluation revealed hypercalcemia (3.33 mmol/L), hyperphosphatemia, and elevated intact parathyroid hormone level (215 pmol/L). Serum insulin-like growth factor 1 was elevated and growth hormone was non-suppressible on oral glucose load. Contrast-enhanced magnetic resonance imaging of the sella showed a pituitary microadenoma. A scan using 99mTc-Sestamibi and combined positron emission and computed tomography using fluorocholine F-18 revealed a mediastinal ectopic parathyroid adenoma, thereby attributing hypercalcemia to primary hyperparathyroidism. A clinical diagnosis of MEN1 was made. Genetic analysis revealed an A>T substitution at cDNA 253 in exon 2 of the MEN1 gene. He underwent median sternotomy and a 3 × 3-cm mass was excised, weighing 14 g. Histopathology showed parathyroid tissue with moderate pleomorphism, pushing margins, fibrous trabeculae, atypical mitoses, and low Ki-67 index, suggestive of atypical parathyroid neoplasm. After surgery the patient became normocalcemic. On follow-up, he is asymptomatic without any evidence of recurrence of primary hyperparathyroidism. Conclusion: Parathyroid involvement in MEN1 is almost exclusively in the form of benign hyperplasia. Atypical parathyroid adenomas and parathyroid carcinomas in MEN1 are very rare, limited to only a few anecdotal case reports to which ours contributes a new case. (AACE Clinical Case Rep. 2018;4:e383-e387) Abbreviations: CKD = chronic kidney disease; iPTH = intact parathyroid hormone; MEN1 = multiple endocrine neoplasia type 1
Primary hyperparathyroidism (PHPT) is a rare endocrine disease in the pediatric population. Spora... more Primary hyperparathyroidism (PHPT) is a rare endocrine disease in the pediatric population. Sporadic parathyroid adenomas remain the most common cause of pediatric PHPT. Parathyroid carcinoma (PC) is an extremely rare cause of pediatric PHPT. We report a 16-year-old boy presenting with a nonhealing fragility fracture of the right leg along with florid features of rickets. Examination revealed a neck mass, mimicking a goiter. Biochemical findings were consistent with PHPT. Imaging was suggestive of a right inferior parathyroid mass infiltrating the right lobe of thyroid. The patient underwent en bloc surgical excision of the parathyroid mass along with the right lobe of thyroid. Histopathology was suggestive of a PC. He achieved biochemical remission with normalization of serum calcium and parathyroid hormone levels. At follow-up, there was no biochemical or imaging evidence of recurrence or metastasis. Genetic analysis revealed heterozygous germline deletion of CDC73. An extensive l...
Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and ... more Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and elevated levels of parathyroid hormone. The primary cause for PHPT is a benign overgrowth of parathyroid tissue causing excessive secretion of parathyroid hormone. However, the molecular etiology of PHPT is incompletely defined. Here, we demonstrate that semaphorin3d (Sema3d), a secreted glycoprotein is expressed in the developing parathyroid gland in mice. We also observed that genetic deletion of Sema3d leads to parathyroid hyperplasia, causing PHPT. In vivo and in vitro experiments using histology, immunohistochemistry, biochemical, RT-qPCR, and immunoblotting assays revealed that Sema3d inhibits parathyroid cell proliferation by decreasing the epidermal growth factor receptor (EGFR)/Erb-B2 receptor tyrosine kinase (ERBB) signaling pathway. We further demonstrate that EGFR signaling is elevated in Sema3d-/parathyroid glands and that pharmacological inhibition of EGFR signaling can partially rescue the parathyroid hyperplasia phenotype. We propose that since Sema3d is a secreted protein, it may be possible to use recombinant Sema3d or derived peptides to inhibit parathyroid cell proliferation causing hyperplasia and hyperparathyroidism. Collectively, these findings identify Sema3d as a negative regulator of parathyroid growth.
The Journal of Clinical Endocrinology & Metabolism, 2019
Context: Fibrogenesis imperfecta ossium (FIO) is a rare and progressive skeletal bone disorder of... more Context: Fibrogenesis imperfecta ossium (FIO) is a rare and progressive skeletal bone disorder of undetermined etiology. Given its rareness, the pathogenesis of FIO remains elusive and no effective treatment exists. Based on review of all published cases and our collective experience of FIO, we offer a comprehensive approach for the diagnosis and management of this complex and fatal disorder. Design: A review of electronic and print medical literature comprising case reports and articles retrieved from PubMed database up to March 2018 was conducted using the search term "fibrogenesis imperfecta." In addition, references from retrieved case reports and articles were screened for articles containing information on FIO and differential diagnoses. Results: Twenty-six articles containing information concerning 29 cases were identified. We reviewed the clinical and pathophysiologic features of all published cases. Comprehensive information on FIO is lacking in the literature. Diagnostic approach, in an attempt to gain insight into the disease, differed depending on the advancements in science and tools available at the time of patient identification. The response to various treatments used has been widely variable. Conclusion: The dearth of information on FIO and low index of suspicion may lead to delayed or missed diagnoses and management. The fundamental skeletal defect appears to be an abnormality in organic matrix of bone characterized by defective mineralization of the abnormal collagen. Research focused on the identification of pathogenetic factors is needed. Although long-term outcomes of GH therapy are yet to be ascertained, short-term effectiveness appears promising.
Primary hyperparathyroidism (PHPT) is considered a state of insulin resistance. However, it is un... more Primary hyperparathyroidism (PHPT) is considered a state of insulin resistance. However, it is unclear whether the state of insulin resistance and adverse levels of adipocytokines are reversed in PHPT patients who have undergone curative parathyroidectomy. Ten consecutive patients with PHPT were studied at baseline and three months after curative parathyroid surgery in this prospective interventional study. Fasting blood calcium, intact parathyroid hormone (PTH), glucose, insulin, adiponectin and leptin concentrations were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA- IR) and insulin sensitivity, by the quantitative insulin sensitivity check index (QUICKI). Four out of the ten patients were male. The mean age of the patients was 32.40 +/- 11.42 years, and the mean body mass index was 23.70 +/- 5.19 kg/m2. The HOMA-IR value was found to be higher, while the QUICKI value was significantly lower before surgery in patients ...
Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "g... more Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "giant" parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the >3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 5 <36years), serum calcium 11.6 ± 1.1 mg/dl, alkaline phosphatase 799 ± 487 IU/L, PTH 1440 ± 477 pg/ml, 25-hydroxyvitamin D 13.0 ± 8.9 ng/ml, 1,25dihyroxyvitamin D 26.5 ± 13.7 pg/ml, urine calcium 562 ± 274 mg/day, and parathyroid adenoma weight 4.53 ± 2.2 g. Parathyroidectomy led to the resolution of both the biochemical indices and OFC in each patient without recurrence over >10 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC.
Objective: Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular morbidi... more Objective: Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular morbidity and mortality with inconsistent results on the reversibility of cardiovascular changes after parathyroidectomy (PTx). The present study was undertaken to evaluate both structural and functional cardiac changes and their reversal after PTx in patients with PHPT. Material and Methods: Thirty patients of symptomatic PHPT without cardiovascular risk factors were evaluated prospectively by means of 2D echocardiography (ECHO) and Multigated Acquisition (MUGA) study before surgery and six months after curative parahyroidectomy. Results: Nine of 30 patients had hypertension which improved in two after PTx (p 0.20). Two patients had left ventricle hypertrophy on 2D ECHO preoperatively which improved after PTx (p< 0.001). Left ventricular ejection fraction (LVEF) did not show significant change before and after PTx on 2D ECHO. Nine out of 30 patients had hypertension which improved in two after PTx (p 0.20). Two patients with left ventricle hypertrophy on 2D ECHO preoperatively improved after PTx (p< 0.001). Left ventricular ejection fraction (EF) did not depict significant change before and after PTx on 2D ECHO. Whereas, four out of six patients with preoperative EF <50% representing systolic dysfunction on MUGA study showed improvement after PTx. On 2D ECHO, eight patients depicted diastolic dysfunction which improved in six patients after curative surgery (p= 0.07). However, on MUGA study, 13 patients presented with tTPF >180 ms indicating diastolic dysfunction, of which ten showed improvement after PTx (p= 0.007). Conclusion: The present study analyzed preoperative and postoperative cardiac function using both 2D ECHO and MUGA study. MUGA study provided a more objective assessment of the cardiac function by determining left ventricular ejection fraction and diastolic dysfunction.
Objective: Primary hyperparathyroidism (PHPT) is a systemic disease which, along with bone and st... more Objective: Primary hyperparathyroidism (PHPT) is a systemic disease which, along with bone and stone disease, also causes several subjective symptoms which impairs the quality of life (QoL). However, NIH guidelines do not include non-specific physical and neuropsychological symptoms as an indication of parathyroidectomy. SF-36 is one of the most commonly used tools for assessing QoL; it measures both physical health (PH) and mental health (MH). Material and Methods: This is a prospective observational study including 50 patients of symptomatic PHPT. Patients were categorized into normocalcemia (8.5-10.4 mg/dL), mild hypercalcemia (10.5-11.9 mg/dL), moderate hypercalcemia (12-13.9 mg/dL), and severe hypercalcemia (>14 mg/dL). QoL was assessed by using SF36 survey both pre-operative and three months after parathyroidectomy. Results: There was an overall improvement in QoL of individual groups both in PH and MH components (p< 0.001). The improvement was more substantial for bodil...
Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becom... more Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becomes more prevalent after menopause. In this study, we compared the demographic, clinical, and biochemical variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT. Methods: A retrospective analysis (from 2005 to 2019) of enrolled women PHPT patients from an online Indian PHPT registry. Results: Of the women with PHPT, 232 and 122 were pre-M and post-M, respectively. The number of post-M PHPT cases registered had a 3.3-fold increase in 2015-2019 from 2005-2009 compared with only a 2.5-fold increase in pre-M cases in the same duration. The majority were symptomatic (90%), although pre-M had a higher proportion of symptomatic than post-M (92% vs 85%; P ¼ .04). Pre-M women showed more prevalence of osteitis fibrosa cystica than post-M women (28% vs 13%; P ¼ .03), although hypertension and gallstone disease were seen more frequently in post-M PHPT women. Pre-M women had a significantly higher median PTH (403 vs 246 pg/mL; P ¼ .02) and median alkaline phosphatase (202 vs 145 pg/mL; P ¼ .02) than post-M women, and vitamin D deficiency was more common in pre-M women (58% vs 45%; P ¼ .03). Gland localization, tumor weight, and disease cure rates did not differ according to menopausal status. Conclusion: PHPT was more prevalent in pre-M women, although the number of post-M cases had significantly increased in the last 10 years. Pre-M women had generally more severe clinical and biochemical variables than post-M PHPT women.
Summary Osteoporosis is a disease with a high burden of morbidity. For its accurate diagnosis, us... more Summary Osteoporosis is a disease with a high burden of morbidity. For its accurate diagnosis, using indigenous data as reference standards is needed. However, normative data on bone density is lacking in India. Therefore, we aimed to determine the reference range for bone density for the healthy population of north India. Introduction Osteoporosis is a major public health problem around the globe including India, resulting in significant morbidity, mortality, and health care burden. However, the reference values used for its diagnosis are largely based on data from the western population, which may lead to over- or underdiagnosis of osteoporosis in Indians. Our study aimed to determine the reference range for bone mineral density for the healthy population of India. Methods This is a cross-sectional study of 825 subjects (men 380, women 445) (median age: 41 years, IQR 32–55 years), recruited by a house-to-house survey. The population was stratified into decade-wise groups and biochemical measurements including renal and liver function tests, glycated hemoglobin, serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density were performed in all the subjects. The T-scores for men aged > 50 years and post-menopausal women were calculated based on the data generated from this study in young men and women aged 20–40 years. Results According to the BMD manufacturer’s data, which is based on the western population, 70% of the Indian men (> 50 years) and 48% of the post-menopausal Indian women had osteopenia while 18% of the men and 25% of the women had osteoporosis. However, according to the re-calculated T-scores from the current study, only 56% and 7.2% of men and 33% and 5% of women had osteopenia and osteoporosis, respectively. An age-related decline in bone mineral density, as seen in the western population, was also seen in both Indian men and women. Conclusion We have established a reference database for BMD in healthy Indian adult population, which may have clinical implications for the diagnosis and intervention strategies for the management of osteoporosis.
Primary hyperparathyroidism(PHPT)is clinically characterised by Pentad of PHPT.PHPT is also ass... more Primary hyperparathyroidism(PHPT)is clinically characterised by Pentad of PHPT.PHPT is also associated with various gastrointestinal manifestations viz constipation, acid peptic disease, pancreatitis and cholelithiasis, however all of these are sparsely reported with PHPT. Gastrointestinal manifestations are less specific and literature is silent on cause and effect relationship. Recently, we have shown that constipation (38%) is the most common GI manifestation followed by acid peptic disease (30%), cholelithiasis( 28%%) pancreatitis( 22%) and from PHPT reg istry of our department(n =300 ). PHPT pancreatitis often remains undiagnosed for long period due to lack of awareness and low index of suspicion. Pancreatitis in PHPT is multifactorial and curative parathyroidectomy prevents recurrence of pancreatitis. The aim of present review is to increase awareness amongst clinicians and gastroenterologists about gastrointestinal manifestations of PHPT.
The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice gui... more The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India. Purpose In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines, the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country. Methods The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians, researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guidelines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India. Results Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diagnostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice. Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential, which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/ absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy. Conclusions Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India.
Introduction: Focused parathyroidectomy is the gold standard treatment for primary hyperparathyro... more Introduction: Focused parathyroidectomy is the gold standard treatment for primary hyperparathyroidism (PHPT) due to single gland disease with a comparable success rate as that of conventional four gland exploration. It is also associated with fewer surgical complications. Despite these benefits, there is still controversy about the high recurrence following the focused approach. Aim: The aim was to analyse our experience regarding the success rate of focused parathyroidectomy for PHPT. Methods: This was a retrospective analysis of 192 patients of PHPT between January 2017 and August 2020 who underwent focused parathyroidectomy without intraoperative parathormone analysis, and had a minimum follow up of six months. Demographic profile, biochemical (pre and postoperative), radiological, operative and histological detail of all patients were recorded. Parathyroidectomy was considered curative if the patient maintained normal serum calcium and parathormone (PTH) levels six months after...
The Journal of Clinical Endocrinology & Metabolism, 2020
Aim Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorig... more Aim Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorigenesis, but the underlying mechanism remains elusive. Accordingly, we aimed to explore the epigenetic changes (DNA methylation and histone modifications) involved in CaSR regulation in sporadic parathyroid adenomas and correlate epigenetic state with disease indices. Experimental Design Forty sporadic parathyroid adenomas and 10 control parathyroid tissues were studied. Real-time quantitative PCR (qPCR) for mRNA and immunohistochemistry for protein expression of CaSR were performed. The methylation status of the CaSR promoter 2 was determined by bisulphite sequencing analysis of sodium bisulphite-converted DNA. To determine the role of histone modifications in the CaSR regulation, chromatin immunoprecipitation-qPCR assay was performed. Results Real-time qPCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P < 0.0001) in parathyroid adenomas. Immunohistochemistry r...
Background: Focused parathyroidectomy is the adequate treatment for primary hyperparathyroidism f... more Background: Focused parathyroidectomy is the adequate treatment for primary hyperparathyroidism for localised disease. Adequacy of resection is confirmed by the availability of intraoperative parathormone assay (iOPTH). In the absence of availability of iOPTH assay, the radio guided surgery is an option. The aim of this study was to evaluate the feasibility of radioguided parathyroidectomy in tertiary care centre in India and to compare the overall success rate, operative time, hospital stay and postoperative outcome between focused open and radioguided parathyroidectomy.Methods: This was a prospective study which included 30 primary hyperparathyroidism patients with a single gland disease localised on Tc99m Sesta MIBI scan. Patients were randomized into two equal groups, and they underwent focused open or radioguided parathyroidectomy. Patients were followed up for three months.Results: All patients achieved biochemical cure as evident by the normalization of serum calcium and para...
Inorganic phosphate is a vital constituent of cells and cell membranes, body fluids, and hard tis... more Inorganic phosphate is a vital constituent of cells and cell membranes, body fluids, and hard tissues. It is a major intracellular divalent anion, participates in many genetic, energy and intermediary metabolic pathways, and is important for bone health. Although we usually think of phosphate mostly in terms of its level in the serum, it is needed for many biological and structural functions of the body. Availability of adequate calcium and inorganic phosphate in the right proportions at the right place is essential for proper acquisition, biomineralization, and maintenance of mass and strength of the skeleton. The three specialized mineralized tissues, bones, teeth, and ossicles, differ from all other tissues in the human body because of their unique ability to mineralize, and the degree and process of mineralization in these tissues also differ to suit the specific functions: locomotion, chewing, and hearing, respectively. Biomineralization is a dynamic, complex, and lifelong process by which precipitations of inorganic calcium and inorganic phosphate divalent ions form biological hard tissues. Understanding the biomineralization process is important for the management of diseases caused by both defective and abnormal mineralization. Hypophosphatemia results in mineralization defects and osteomalacia, and hyperphosphatemia is implicated in abnormal excess calcification and/or ossification, but the exact mechanisms underlying these processes are not fully understood. In this review, we summarize available evidence on the role of phosphate in biomineralization. Other manuscripts in this issue of the journal deal with other relevant aspects of phosphate homeostasis, phosphate signaling and sensing, and disorders resulting from hypo-and hyperphosphatemic states.
Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2020
Background and aims: The novel coronavirus disease (COVID-19) pandemic and the resulting nationwi... more Background and aims: The novel coronavirus disease (COVID-19) pandemic and the resulting nationwide lockdowns have posed a major challenge to the management of pre-existing and newly diagnosed endocrine disorders. Herein, we have summarized the management approaches of common endocrine disorders amid the ongoing pandemic. Methods: We have performed an extensive literature search for articles in PubMed, EMBASE and Google Scholar databases till 25 May 2020, with the following keywords: "COVID-19", "diabetes mellitus", "thyroid disorders", "primary adrenal insufficiency", "Cushing's syndrome", "pituitary tumors", "vitamin D 00 ", "osteoporosis", "primary hyperparathyroidism", "hypoparathyroidism", "management", "treatment" and "guidelines" with interposition of the Boolean operator "AND". Results: We have summarized the most feasible strategies for the management of diabetes mellitus, thyroid disorders, primary adrenal insufficiency (including congenital adrenal hyperplasia), Cushing's syndrome, pituitary tumors, osteoporosis, primary hyperparathyroidism and hypoparathyroidism amid the constraints laid down by the raging pandemic. In general, medical management should be encouraged and surgical interventions should be deferred whenever possible. Ongoing medications should be continued. Sick-day rules should be sincerely adhered to. Regular contact with physicians can be maintained through teleconsultations and virtual clinics. Conclusions: Considering the burden of endocrine disorders in the general population, their management needs to be prioritized amid the ongoing COVID-19 pandemic.
Hypophosphatasia is an inborn error in metabolism characterized by low serum alkaline phosphatase... more Hypophosphatasia is an inborn error in metabolism characterized by low serum alkaline phosphatase (ALP) activity resulting from deactivating mutations in TNSALP (also known as ALPL), the gene that encodes the 'tissue-specific' isoenzyme of ALP. The disease exhibits significant clinical heterogeneity that spans from death in utero to only dental complications in adult life. Herein, we report a 47-year-old woman presenting with fracture of shaft of left femur. She had been complaining of pain in both of her thighs for the past 3 years. In addition, she gave a history of premature loss of teeth. Review of old radiographs revealed pseudo-fractures involving the lateral cortices of the femora on both sides. Biochemical panel revealed hyperphosphatemia, persistently low total alkaline phosphatase (ALP) and low-normal bone turnover markers. Screening of her siblings revealed low ALP in her younger sister and brother who were otherwise free from any major dento-arthro-osseous complaints. Sanger sequencing showed a novel, heterozygous, missense mutation in exon 5 at position 311 (c.311a > g;p.104 Asn > Ser) of ALPL gene in the three members. The patient underwent open reduction and intramedullary nailing of left femur along with prophylactic nailing on right side. This case report represents the first genetically confirmed kindred of adult hypophosphatasia from the Indian subcontinent.
Objective: Present a case of an atypical parathyroid adenoma in the mediastinum as a part of mult... more Objective: Present a case of an atypical parathyroid adenoma in the mediastinum as a part of multiple endocrine neoplasia type 1 (MEN1). Methods: Clinical, laboratory, imaging, and histolopathogic analyses were performed. Results: A 50-year-old man who was diagnosed with chronic kidney disease secondary to bilateral nephrolithiasis was referred for evaluation of incidentally detected hypercalcemia. He had an acromegaloid facies and lipomas over the forehead. Laboratory evaluation revealed hypercalcemia (3.33 mmol/L), hyperphosphatemia, and elevated intact parathyroid hormone level (215 pmol/L). Serum insulin-like growth factor 1 was elevated and growth hormone was non-suppressible on oral glucose load. Contrast-enhanced magnetic resonance imaging of the sella showed a pituitary microadenoma. A scan using 99mTc-Sestamibi and combined positron emission and computed tomography using fluorocholine F-18 revealed a mediastinal ectopic parathyroid adenoma, thereby attributing hypercalcemia to primary hyperparathyroidism. A clinical diagnosis of MEN1 was made. Genetic analysis revealed an A>T substitution at cDNA 253 in exon 2 of the MEN1 gene. He underwent median sternotomy and a 3 × 3-cm mass was excised, weighing 14 g. Histopathology showed parathyroid tissue with moderate pleomorphism, pushing margins, fibrous trabeculae, atypical mitoses, and low Ki-67 index, suggestive of atypical parathyroid neoplasm. After surgery the patient became normocalcemic. On follow-up, he is asymptomatic without any evidence of recurrence of primary hyperparathyroidism. Conclusion: Parathyroid involvement in MEN1 is almost exclusively in the form of benign hyperplasia. Atypical parathyroid adenomas and parathyroid carcinomas in MEN1 are very rare, limited to only a few anecdotal case reports to which ours contributes a new case. (AACE Clinical Case Rep. 2018;4:e383-e387) Abbreviations: CKD = chronic kidney disease; iPTH = intact parathyroid hormone; MEN1 = multiple endocrine neoplasia type 1
Primary hyperparathyroidism (PHPT) is a rare endocrine disease in the pediatric population. Spora... more Primary hyperparathyroidism (PHPT) is a rare endocrine disease in the pediatric population. Sporadic parathyroid adenomas remain the most common cause of pediatric PHPT. Parathyroid carcinoma (PC) is an extremely rare cause of pediatric PHPT. We report a 16-year-old boy presenting with a nonhealing fragility fracture of the right leg along with florid features of rickets. Examination revealed a neck mass, mimicking a goiter. Biochemical findings were consistent with PHPT. Imaging was suggestive of a right inferior parathyroid mass infiltrating the right lobe of thyroid. The patient underwent en bloc surgical excision of the parathyroid mass along with the right lobe of thyroid. Histopathology was suggestive of a PC. He achieved biochemical remission with normalization of serum calcium and parathyroid hormone levels. At follow-up, there was no biochemical or imaging evidence of recurrence or metastasis. Genetic analysis revealed heterozygous germline deletion of CDC73. An extensive l...
Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and ... more Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and elevated levels of parathyroid hormone. The primary cause for PHPT is a benign overgrowth of parathyroid tissue causing excessive secretion of parathyroid hormone. However, the molecular etiology of PHPT is incompletely defined. Here, we demonstrate that semaphorin3d (Sema3d), a secreted glycoprotein is expressed in the developing parathyroid gland in mice. We also observed that genetic deletion of Sema3d leads to parathyroid hyperplasia, causing PHPT. In vivo and in vitro experiments using histology, immunohistochemistry, biochemical, RT-qPCR, and immunoblotting assays revealed that Sema3d inhibits parathyroid cell proliferation by decreasing the epidermal growth factor receptor (EGFR)/Erb-B2 receptor tyrosine kinase (ERBB) signaling pathway. We further demonstrate that EGFR signaling is elevated in Sema3d-/parathyroid glands and that pharmacological inhibition of EGFR signaling can partially rescue the parathyroid hyperplasia phenotype. We propose that since Sema3d is a secreted protein, it may be possible to use recombinant Sema3d or derived peptides to inhibit parathyroid cell proliferation causing hyperplasia and hyperparathyroidism. Collectively, these findings identify Sema3d as a negative regulator of parathyroid growth.
The Journal of Clinical Endocrinology & Metabolism, 2019
Context: Fibrogenesis imperfecta ossium (FIO) is a rare and progressive skeletal bone disorder of... more Context: Fibrogenesis imperfecta ossium (FIO) is a rare and progressive skeletal bone disorder of undetermined etiology. Given its rareness, the pathogenesis of FIO remains elusive and no effective treatment exists. Based on review of all published cases and our collective experience of FIO, we offer a comprehensive approach for the diagnosis and management of this complex and fatal disorder. Design: A review of electronic and print medical literature comprising case reports and articles retrieved from PubMed database up to March 2018 was conducted using the search term "fibrogenesis imperfecta." In addition, references from retrieved case reports and articles were screened for articles containing information on FIO and differential diagnoses. Results: Twenty-six articles containing information concerning 29 cases were identified. We reviewed the clinical and pathophysiologic features of all published cases. Comprehensive information on FIO is lacking in the literature. Diagnostic approach, in an attempt to gain insight into the disease, differed depending on the advancements in science and tools available at the time of patient identification. The response to various treatments used has been widely variable. Conclusion: The dearth of information on FIO and low index of suspicion may lead to delayed or missed diagnoses and management. The fundamental skeletal defect appears to be an abnormality in organic matrix of bone characterized by defective mineralization of the abnormal collagen. Research focused on the identification of pathogenetic factors is needed. Although long-term outcomes of GH therapy are yet to be ascertained, short-term effectiveness appears promising.
Primary hyperparathyroidism (PHPT) is considered a state of insulin resistance. However, it is un... more Primary hyperparathyroidism (PHPT) is considered a state of insulin resistance. However, it is unclear whether the state of insulin resistance and adverse levels of adipocytokines are reversed in PHPT patients who have undergone curative parathyroidectomy. Ten consecutive patients with PHPT were studied at baseline and three months after curative parathyroid surgery in this prospective interventional study. Fasting blood calcium, intact parathyroid hormone (PTH), glucose, insulin, adiponectin and leptin concentrations were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA- IR) and insulin sensitivity, by the quantitative insulin sensitivity check index (QUICKI). Four out of the ten patients were male. The mean age of the patients was 32.40 +/- 11.42 years, and the mean body mass index was 23.70 +/- 5.19 kg/m2. The HOMA-IR value was found to be higher, while the QUICKI value was significantly lower before surgery in patients ...
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Papers by sanjay bhadada