Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1•5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. Findings: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24•0 months (IQR 12•0-60•0, range 0•0-744•0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35•0 years (95% CI 8•3-61•7). Individuals who did not attain head control by age 1•5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3•46, 95% CI 1•76-8•34; log-rank test p=0•0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4•71, 95% CI 1•26-17•58, p=0•021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. Interpretation: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides ...

Context Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Objective Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. Methods In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. Results From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P &lt; 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P &lt; 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. Conclusions Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Background & objectives: Prediabetes is associated with increased prevalence of cardiovascular disease (CVD). In participants with prediabetes, the effects of exercise and metformin were evaluated on high-sensitivity C-reactive protein (hsCRP) and carotid intima-media thickness (CIMT), surrogate markers of atherosclerosis and CVD compared with standard care. Methods: In a pilot randomized control trial, the participants were randomized in to three arms: standard care (STD), intensive lifestyle modification (ILSM) or ILSM and metformin (ILSM+Met) and followed up for six months. Monitoring of ILSM was done by a trained healthcare facilitator. hsCRP, CIMT and other relevant parameters were measured before and after intervention. Results: A total of 103 participants were randomized into three arms and followed up for six months. At six months, there was a reduction from baseline in weight and fasting blood sugar (FBS) ( P <0.01) in all three arms and a reduction in haemoglobin A 1c ( P =0.03) only in the ILSM+Met arm. The differences in hsCRP over six months within the STD, ILSM and ILSM+Met arms were −0.12 (95% confidence interval, −1.81, 2.08), −0.58 (−2.64, 0.43) and −0.11 (−1.84, 1.56), respectively. There was no difference in hsCRP, CIMT (right) or CIMT (left) between the three arms at six months. Interpretation & conclusions: There was a reduction in weight and FBS from baseline in all three arms. There was, however, no difference seen in hsCRP and CIMT in the two intervention arms compared to standard care. Larger studies with long-term follow up need to be done to detect differences in risk markers for CVD in prediabetes.

Context:Our literature search revealed that the use of porcine sequence corticotropin has not been validated against tetracosactide hexaacetate in a healthy population.Aims:To study the efficacy of using porcine sequence corticotropin in comparison with tetracosactide hexaacetate in the evaluation of hypothalamo pituitary adrenal (HPA) axis.Materials and Methods:Fifteen healthy volunteers were enrolled. Serum cortisol was measured at 0 minute in all subjects and at 30 and 60 minutes after tetracosactide hexaacetate 250 μg intravenously. Four weeks later, serum cortisol level was measured at 0 minute and at 30 and 60 minutes following 24 units of porcine sequence corticotropin given intramuscularly.Results:Mean serum cortisol values with tetracosactide were 30.3 (±7.83) μg/dl and 31.27 (±7.36) μg/dl at 30 and 60 minutes, respectively. The mean cortisol values with porcine sequence corticotropin were 26.33 (±5.47) μg/dl and 31.59 (±6.40) μg/dl at 30 and 60 minutes, respectively. All subjects had a response qualified as normal or adequate at 30 minutes itself. Mean peak serum cortisol response was 32.65 (±7.76) μg/dl in tetracosactide group and 31.59 (±6.4) μg/dl in porcine sequence corticotropin group, and the responses in two groups were comparable (P = 0.686). There were no immediate side effects in both groups, with a lower cost of procedure in the porcine corticotropin group.Conclusion:Our study established the efficacy of porcine sequence corticotropin in testing the adequacy of HPA axis in healthy individuals. Our study also revealed that, the intactness of the HPA axis could be confirmed as early as 30 minutes in healthy individuals.

Background:Primary hyperparathyroidism (PHPT) is a common endocrine disease with a variable clinical presentation. PHPT is usually symptomatic at presentation in majority of the patients, especially in developing countries. As the accessibility to investigations, advanced imaging methods and surgical procedures are improving, the clinical profile of the patients with PHPT has undergone a palpable change compared to the earlier description. Hence we decided to look for a change in clinical, imaging and surgical outcomes of PHPT patients from South India.Methods:We collected the data on clinical presentation, biochemistry, radiological features and operative findings of patients with PHPT treated in our hospital from 2011-2015. Cases of PHPT were identified from the laboratory values using the biochemical criteria, after the exclusion of secondary and tertiary hyperparathyroidism cases.Results:Our study identified 54 patients (19 males and 35 females) with age ranging from 16 to 71 years. A Significant proportion(38.9%) of the patients were asymptomatic. Musculoskeletal symptoms (40.7%), renal manifestations (27.7%) and gastrointestinal system involvement (27.7%) constituted the other common modes of presentation. CNS involvement was seen in 3 patients. A palpable nodule in the neck was detected in 4 patients. Interestingly 4 patients were managed for parathyroid crisis at presentation. Biochemical features included hypercalcaemia (100%) and hypophosphatemia (59%) with a mean intact PTH level of 602.0±721.3 pg/ml. Sensitivity of Ultrasonography and Tc99M Sestamibi was 72% and 70.6% respectively for detecting a parathyroid adenoma. Sensitivity of C11 methionine PET-CT was 71.4% in those patients who were negative for other imaging modalities. Forty three patients (79.6%) underwent minimally invasive parathyroidectomy.Conclusion:In South India we have a notable change in the clinical presentation of PHPT from a symptomatic to an asymptomatic state. C11 Methionine PET - CT is an emerging modality for preoperative localisation especially when other imaging modalities are negative and when a minimally invasive parathyroidectomy is desired.