Hyperprolactinemia Due to Prolactinoma has an Adverse Impact on Bone Health with Predominant Impact on Trabecular Bone: A Systematic Review and Meta-Analysis.

BACKGROUND: No meta-analysis has holistically analysed and summarized the effect of prolactin excess due to prolactinomas on bone mineral metabolism. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for studies having patients with hyperprolactinemia due to prolactinoma and the other being a matched control group. The primary outcome was to evaluate the differences in BMD Z-scores at different sites. The secondary outcomes of this study were to evaluate the alterations in bone mineral density, bone mineral content and the occurrence of fragility fractures. RESULTS: Data from 4 studies involving 437 individuals was analysed to find out the impact of prolactinoma on bone mineral metabolism. Individuals with prolactinoma had significantly lower Z scores at the lumbar spine [MD -1.08 (95 % CI: -1.57 - -0.59); P < 0.0001; I2 = 54 % (moderate heterogeneity)] but not at the femur neck [MD -1.31 (95 % CI: -3.07 - 0.45); P = 0.15; I2 = 98 % (high heterogeneity)] as compared to controls. Trabecular thickness of the radius [MD -0.01 (95 % CI: -0.02 - -0.00); P = 0.0006], tibia [MD -0.01 (95 % CI: -0.02 - -0.00); P=0.03] and cortical thickness of the radius [MD -0.01 (95 % CI: -0.19 - -0.00); P = 0.04] was significantly lower in patients with prolactinoma as compared to controls. The occurrence of fractures was significantly higher in patients with prolactinoma as compared to controls [OR 3.21 (95 % CI: 1.64 - 6.26); P = 0.0006] Conclusion: Bone mass is adversely affected in patients with hyperprolactinemia due to prolactinoma with predominant effects on the trabecular bone.

Nebulised magnesium sulphate as an adjuvant to the treatment of acute exacerbation of COPD: A systematic review and meta-analysis of randomised controlled trials with trial sequential analysis.

The purpose of this meta-analysis was to evaluate the efficacy of nebulised magnesium in the treatment of acute exacerbation of COPD. PubMed and Embase databases were searched for randomised controlled trials comparing any dose of nebulised magnesium sulphate with placebo for treatment of acute exacerbation of COPD, published from database inception till 30 June 2022. Bibliographic mining of relevant results was performed to identify any additional studies. Data extraction and analyses were done independently by review authors and any disagreements were resolved through consensus. Meta-analysis was done using a fixed-effect model at clinically significant congruent time points reported across maximum studies to ensure comparability of treatment effect. Four studies met the inclusion criteria, randomly assigning 433 patients to the comparisons of interest in this review. Pooled analysis showed that nebulised magnesium sulphate improved pulmonary expiratory flow function at 60 minutes after initiation of intervention compared to placebo [median difference (MD) 9.17%, 95% confidence interval (CI) 2.94 to 15.41]. Analysis of expiratory function in terms of standardised mean differences (SMD) revealed a small yet significant positive effect size (SMD 0.24, 95% CI 0.04 to 0.43). Among the secondary outcomes, nebulised magnesium sulphate reduced the need for ICU admission (risk ratio 0.52, 95% CI 0.28 to 0.95), amounting to 61 fewer ICU admissions per 1000 patients. No difference was noted in the need for hospital admission, need for ventilatory support, or mortality. No adverse events were reported. Nebulised magnesium sulphate improves pulmonary expiratory flow function and reduces the need for ICU admission in patients with acute exacerbation of COPD.

Treatment options in people with COVID19: Selecting the best armamentarium against the novel virus.

Novel coronavirus disease (COVID-19) infection is a global pandemic, of high infectivity, variable mortality, with currently no established treatment. This review summarizes different molecules which are being evaluated for COVID19 treatment. PubMed and Medline, search for articles published to March 2020 was done using terms "COVID19" OR "corona-virus 2019" OR "2019-nCoV" or "severe acute respiratory syndrome coronavirus" AND "treatment". As of today, we have >350 RCTs happening with different agents. COVID19 treatment agents can be broadly classified into immuno-modulators (prevent hyperimmune-activation and cytokine storm) and anti-viral therapies (prevent virus entry, replication or viricidal). Hydroxychloroquine/chloroquine, Interferon-l, glucocorticoids, interleukin antagonists, Ulinastatin, intravenous immunoglobulins, plasmapheresis are main immunomodulators showing initial positive outcomes. Umifenovir. Lopinavir/Ritonavir, Ribavirin, remdesivir and Ravipiravir are some of the major antiviral agents showing initial encouraging results. It may be concluded that the most successful regimen is going to be multi-drug therapy, a combination of immunomodulatory agent with anti-viral agent.

Vitamin D, Thyroid Autoimmunity and Cancer: An Interplay of Different Factors.

BACKGROUND AND AIMS: In spite of large volume of data linking Vitamin D with cardiovascular morbidity, autoimmunity, cancer, and virtually every organ system, Vitamin D and thyroid is a lesser-known aspect of Vitamin D in clinical practice. This article intends to highlight the current literature on the impact of Vitamin D status and supplementation on thyroid autoimmunity and cancer. METHODS: References for this review were identified through searches of PubMed for articles published to from 1950 to August 2019 using the terms "thyroid" [MeSH Terms] AND "Vitamin D" [MeSH Terms] OR "thyroid" [All Fields] AND "Vitamin D" [All Fields]. RESULTS: Significant inverse correlation was documented between anti-thyroid peroxidase antibody (TPOAb) and serum 25-hydroxy-Vitamin D (25OHD). TPOAb positivity is more prevalent in Vitamin D deficient individuals. A large volume of medical literature is available from observational studies linking Vitamin D with thyroid autoimmunity. Data from interventional studies documenting beneficial effects of Vitamin D on thyroid autoimmunity is also available, but lesser than that from observational studies. Short-term high dose oral Vitamin D supplementation reduces TPOAb titers. Certain Vitamin D receptor (VDR) gene polymorphism have been linked to increased occurrence of autoimmune thyroid disorders (AITD). Vitamin D deficiency, decreased circulating calcitriol has been linked to increased thyroid cancer. Certain VDR gene polymorphisms have been linked with increased as well as decreased occurrence of thyroid cancer. Data is scant on use of Vitamin D and its analogues for treating thyroid cancer. CONCLUSION: In spite of large volume of medical literature from observational studies linking Vitamin D with thyroid autoimmunity and cancer, meaningful concrete clinical data on impact of Vitamin D supplementation on hard clinical end points in these disorders is lacking, and should be the primary area of research in the next decade.

18F-Fluorocholine-Positron Emission Tomography/Computerised Tomography is Useful in Localising 99mTc-Sesta-methoxyisobutylisonitrile-Negative Parathyroid Cyst Causing Normocalcemic Primary Hyperparathyroidism.

Parathyroid cysts are extremely rare and are rarely associated with primary hyperparathyroidism (PHPT), which are difficult to localise, as they are 99mTc-sesta-methoxyisobutylisonitrile (sestaMIBI) negative. We report for the first time the utility of 18F-fluorocholinepositron emission tomography/computerised tomography (PC-PET/CT) in localising parathyroid cyst causing normocalcemic PHPT. A 76-year-old lady with progressively worsening osteoporosis from 2014-2017 (in spite of annual zolendronic acid infusions, daily calcium and vitamin-D supplementation) with persistently normal serum calcium and vitamin D, but elevated parathyroid hormone, had normal sestaMIBI scans of the neck on multiple occasions. FC-PET/CT finally revealed soft tissue uptake, suggestive of right superior parathyroid adenoma/ hyperplasia. Surgical removal of the culprit lesion resulted in resolution of hyperparathyroidism, histopathologic evaluation of which revealed a cystic lesion lined by chief cell variant parathyroid cells without any nuclear atypia, capsular or vascular invasion. FC-PET/CT is useful in localising culprit parathyroid lesions, especially when they are sestaMIBI negative. PC-PET/CT is useful in localising parathyroid hyperplasia and ectopic parathyroids, which are frequently missed by sestaMIBI. There is an urgent need for comparative studies between sestaMIBI and FC-PET/CT in PHPT. We report for the first time the usefulness of FC-PET/CT in localising sestaMIBI-negative functional parathyroid cyst causing normocalcemic PHPT.

Occult phosphaturic mesenchymal tumour of femur cortex causing oncogenic osteomalacia - diagnostic challenges and clinical outcomes.

BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes.

Neonatal Endocrine Labomas - Pitfalls and Challenges in Reporting Neonatal Hormonal Reports.

This review highlights pitfalls and challenges in interpreting neonatal hormone reports. Pre-analytical errors contribute to nearly 50% of all errors. Modern chemiluminescence assay are more accurate, have lower risk of Hook's effect, but continue to have problems of assay interference. Liquid chromatography mass spectroscopy is gold standard for most hormone assays. Neonatal hypoglycemia diagnostic cut-offs are lower than adults. Random growth hormone testing is of value in diagnosing growth hormone deficiency in neonates. 17-hydroxy-progesterone testing in first three days of life for congenital adrenal hyperplasia (CAH) remains a challenge due to cross-reactivity with maternal circulating steroids, prematurity and lack of adrenal maturation. Both T4 and TSH testing is encouraged after 48 hours of delivery for diagnosing neonatal hypothyroidism; repeat testing should be done immediately for confirmation of diagnosis. There is an urgent need to develop age- sex- and ethnicity-based normative data for different hormone parameters in neonates. Laboratory should develop their own neonatal references and avoid using ranges from manufacturers. In neonatal endocrinopathies, the clinical scenario should primarily dictate the treatment formulation with hormonal assay to supplement treatment.

The increasing problem of subclinical and overt hypervitaminosis D in India: An institutional experience and review.

OBJECTIVE: The aim of this study was to determine the changes in serum vitamin D distribution at an institute in India over the past 6 y and compare it with global trends. METHODS: We conducted an audit of 25-hydroxyvitamin D (25-OHD), calcium, and plasma intact parathyroid hormone (iPTH) reporting from January 2011 to February 2016. References for review were identified through searches of PubMed, Medline, and Embase for articles published until February 2016 using keywords "hypervitaminosis D" (MeSH Terms) OR "vitamin D toxicity" (All Fields) OR "vitamin-D intoxication" (All Fields). RESULTS: Reports of 25-OHD from 5527 patients were analyzed. Calcium and iPTH were available for 5501 (99.5%) and 1787 (32.3%) patients, respectively. Vitamin D deficiency and insufficiency were observed in 59.4 and 77.3%. Hypervitaminosis D (25-OHD >250 nmol/L) was noted in 225 (4.1%) patients, of whom 151 (2.7%) had vitamin D intoxication (25-OHD >375 nmol/L). We found that 46.22% (104 of 225) patients with hypervitaminosis D and 62.25% (94 of 151) with vitamin D intoxication had elevated calcium or suppressed iPTH. Orthopedic, pediatric, and surgery patients had the highest rates of hypervitaminosis D (7.9, 7.2, and 7% respectively; P < 0.001). An increasing trend for hypervitaminosis D was observed (1.48, 3.62, 3.90, 4.78, 6.21, and 7.82% in 2011, 2012, 2013, 2014, 2015, and 2016, respectively). A similar steady upward trend in 25-OHD has been reported in Ireland, England, Canada, and Australia. However, hypervitaminosis D reports are scant and have not increased over the years in the developed world. CONCLUSION: There is a global secular trend of increases in 25-OHD over years. There is a disturbing trend of increased hypervitaminosis D at an Indian institute. Empiric, unmonitored, prolonged vitamin D supplementation, using non-recommended supraphysiological doses, especially when administered intramuscularly, should be discouraged.

Vitamin D supplementation reduces thyroid peroxidase antibody levels in patients with autoimmune thyroid disease: An open-labeled randomized controlled trial.

BACKGROUND AND AIMS: Although Vitamin D deficiency has been linked to autoimmune thyroid disorders (AITD), the impact of Vitamin D supplementation on thyroid autoimmunity is not known. This study aimed to evaluate the impact of Vitamin D supplementation on thyroid autoimmunity (thyroid peroxidase antibody [TPO-Ab] titers) in patients with newly diagnosed AITD in a randomized controlled trial. MATERIALS AND METHODS: One hundred two patients with newly diagnosed AITD (TPO-Ab > 34 kIU/L and/or sonographic evidence of thyroiditis) patients were randomized into Group-1 (intervention group) and Group-2 (control group). Group-1 received cholecalciferol 60,000 IU weekly and calcium 500 mg/day for 8 weeks; Group-2 received calcium 500 mg/day for 8 weeks. Responders were defined as ≥25% fall in TPO-Ab titers. Individuals with at least 3-month follow-up were analyzed. Trial is registered at ctri.nic.in (CTRI/2015/04/005713). RESULTS: Data from 100 AITD patients (68 with thyroid stimulating hormone [TSH] ≤10 mIU/L, 32 with TSH > 10 mIU/L), 93% having Vitamin D insufficiency, were analyzed. TPO-Ab titers were highest among patients in the lowest 25-hydroxyvitamin D quartile (P = 0.084). At 3 months follow-up, there was significant fall in TPO-Ab in Group-1 (-46.73%) as compared to Group-2 (-16.6%) (P = 0.028). Sixty-eight percentage patients in Group-1 were responders compared to 44% in Group-2 (P = 0.015). Kaplan-Meier analysis revealed significantly higher response rate in Group-1 (P = 0.012). Significantly greater reduction in TPO-Ab titers was observed in AITD with TSH ≤ 10 mIU/L compared to TSH > 10 mIU/L. Cox regression revealed Group-1 followed by TPO-Ab and free tetraiodothyronine levels to be a good predictor of response to therapy (P = 0.042, 0.069, and 0.074, respectively). CONCLUSION: Vitamin D supplementation in AITD may have a beneficial effect on autoimmunity as evidence by significant reductions in TPO-Ab titers.

Vitamin-D supplementation in prediabetes reduced progression to type 2 diabetes and was associated with decreased insulin resistance and systemic inflammation: an open label randomized prospective study from Eastern India.

Vitamin-D supplementation in vitamin-D insufficient/deficient prediabetes individuals is associated with significantly lower progression to diabetes (6/55 vs. 13/49; p=0.04) and higher reversal to normoglycemia (23/55 vs. 10/49; p=0.02), associated with decreased insulin resistance and systemic inflammation (TNFα and IL6). Baseline vitamin-D and 2h blood glucose independently predicted progression to diabetes.

Primary hyperparathyroidism masquerading as rickets: diagnostic challenge and treatment outcomes.

Primary hyperparathyroidism (PHPT) is extremely uncommon among children and is more likely to be associated with genetic syndromes, multiglandular involvement, and more severe symptoms. Rickets can very rarely be the presenting feature of PHPT in children. Rickets was diagnosed in a 12-year-old girl presenting with short stature, genu valgum, eversion deformity at the ankle joints, and flat feet. Radiograms showed generalized osteopenia, widening of the distal ends of the long bones along with splaying, cupping and fraying. Biochemical evaluation revealed low serum calcium (7.8 mg/dL), low phosphorus (1.4 mg/dL), vitamin-D deficiency [25-hydroxy-vitamin-D (25(OH)D): 8.7 ng/mL], and elevated intact parathyroid hormone (PTH, 811 pg/mL). Re-evaluation due to lack of clinical improvement following vitamin-D and calcium supplementation revealed hypercalcemia 11.9 mg/dL, normal 25(OH)D 41 ng/mL, persistence of elevated PTH 632 pg/mL. A 99mTc-sestamibi scan showed increased uptake at the lower pole of the right lobe of the thyroid. A right inferior parathyroidectomy was performed. Histopathology revealed chief cell type parathyroid adenoma. Last evaluated 4 months after surgery, the bone pains and proximal weakness had resolved, with significant improvement in the patient's quality of life. Rickets in the setting of PHPT often masks the classical phenotype of PHPT. In a child with rickets, lack of improvement following vitamin-D supplementation, hypercalcemia at presentation or following vitamin-D supplementation are warning signs which necessitate further evaluation to rule out PHPT.

Endocrine labomas.

Laboratory endocrinology forms an integral part of 21(st) century endocrinology. Perhaps, no other specialty of medicine is as closely associated with laboratory as endocrinology. This review intends to highlight the challenges faced by an endocrinologist before interpreting a hormone assay report. This review by no means is holistic but intends to highlight some of the pitfalls of laboratory endocrinology and arouse further interest in this important but neglected section of endocrinology. Lack of standardization, as well as rigorous implementation is some of the major challenges facing endocrine assays in our country. It is essential to be aware not only of the details of the method of analysis of a hormone, the pre-analytical requisites, but also disease-specific analytical issues to prevent unnecessary concern both for the patient, as well as the treating physician, as well as needless investigations. Problems with interpretation of serum prolactin, thyroglobulin, steroid hormone assays, rennin assay and vitamin-D assay have been highlighted.

Cretinism revisited.

OBJECTIVE: Cretinism is a condition of severely stunted physical and mental growth due to untreated congenital hypothyroidism. It has been largely eliminated in the developed world, though we still continue to see cases in India. CASE REPORT: A 22-year-old male was brought to our Endocrine clinic by his brother due to his "not growing up". The patient was 83 cm in height (SDS - 16.98) and weighed 13.9 kg (<3(rd) percentile). He had dull look, puffy face with thick lips, macroglossia, and umbilical hernia. There was sexual infancy with prepubertal testes (<3 ml). He could sit without support, but could not stand, or walk without support and could only talk in monosyllables. He was born full term by normal vaginal delivery, and cried immediately after birth. The developmental milestones were delayed, and not achieved till date. He is the eldest of seven siblings, rest six of whom have no complaints. An X-ray of hand was done showing bone age of less than 1 year. A thyroid profile showed TSH >150 IU/ml, free T4 and T3 below the assay range. Ultrasound of neck showed absent thyroid tissue in neck. Iodine-131 uptake scan was consistent with thyroid aplasia. Diagnosis was myxematous cretinism due to thyroid aplasia was made, and patient was started on thyroxine supplementation. CONCLUSION: This case represents the most severe form of untreated congenital hypothyroidism presenting as severely stunted physical and mental growth with delayed bone and sexual maturation.

Idiopathic hypoparathyroidism and systemic sclerosis: An association likely missed.

Hypoparathyroidism in systemic sclerosis is extremely rare with only a single case reported till date. Idiopathic hypoparathyroidism with systemic sclerosis was diagnosed in a 59-year-old gentleman who had presented with recurrent seizures, instability of gait, skin thickening and tightening over both legs and forearms, and arthritis. Examination was significant for positive Trousseau sign and cerebellar ataxia. Evaluation revealed bilateral symmetrical cerebellar and basal ganglia calcification, sensorineural deafness, low serum calcium, elevated serum phosphorus, normal magnesium, normal vitamin D, low plasma parathyroid hormone, high titer of thyroid peroxidase antibody, positive centromere pattern antinuclear antibody, strongly positive anti-topoisomerase-1 (Scl-70) antibody, nonvisualization of parathyroids on neck ultrasonography and skin biopsy suggestive of hyperkeratosis, increased collagen in dermis, and perivascular lymphomononuclear cell infiltration compatible with scleroderma. Last evaluated 10 months after the diagnosis, his ataxia had improved, he remained seizure-free, Trousseau sign was negative, and he had low-normal calcium calcium with calcium carbonate and calcitriol supplementation and switch from phenytoin to valproate. Further studies are warranted to study the use of serum calcium as a screening test for hypoparathyroidism in patients with systemic sclerosis.

The role of garlic in hepatopulmonary syndrome: a randomized controlled trial.

BACKGROUND: Increased nitric oxide production in cirrhosis has been commonly implicated in the genesis of hepatopulmonary syndrome (HPS). Initial studies suggested that garlic, a constituent of the daily diet, may have a role in the treatment of HPS by altering nitric oxide production. OBJECTIVE: To evaluate the effects of oral garlic supplementation on arterial blood gas parameters, and overall morbidity and mortality in patients with HPS. METHODS: Twenty-one and 20 HPS patients were randomly assigned to receive either oral garlic supplementation or placebo, respectively, and were evaluated monthly over a period of nine to 18 months. RESULTS: After nine months, garlic supplementation was associated with a 24.66% increase in baseline arterial oxygen levels (83.05 mmHg versus 66.62 mmHg; P<0.001), compared with only a 7.37% increase (68.75 mmHg versus 64.05 mmHg; P=0.02) among subjects in the placebo group. There was also a 28.35% decrease in alveolar-arterial oxygen gradient (21.35 mmHg versus 29.77 mmHg; P<0.001) among patients with HPS who received garlic, in contrast with only a 10.73% decrease (29.11 mmHg versus 32.61 mmHg; P=0.12) among those in the placebo group. After nine months, the arterial oxygen level was significantly higher (83.05 mmHg versus 68.75 mmHg; P<0.001) and the alveolar-arterial oxygen gradient was significantly lower (21.35 mmHg versus 29.11 mmHg; P<0.001) among patients receiving garlic compared with those receiving placebo. Reversal of HPS was observed in 14 of 21 patients (66.67%) on garlic supplementation (intent-to-treat analysis) and in one of 20 patients (5%) on placebo. Two of 21 patients undergoing garlic supplementation died during follow-up in contrast to seven of 20 patients who were on placebo. CONCLUSIONS: Garlic supplementation may be beneficial in patients with HPS for the reversal of intrapulmonary shunts as well as reducing hypoxemia and mortality.