A Systematic Review and Meta-Analysis of the Relationship Between the Radiation Absorbed Dose to the Thyroid and Response in Patients Treated with Radioiodine for Graves' Disease.

Background: Patients with Graves' disease are commonly treated with radioiodine. There remains controversy over whether the aim of treatment should be to achieve euthyroidism or hypothyroidism, and whether treatments should be administered with standard levels of radioactivity or personalized according to the radiation absorbed doses delivered to the thyroid. The aim of this review was to investigate whether a relationship exists between radiation absorbed dose and treatment outcome. Methods: A systematic review and meta-analysis of all reports published before February 13, 2020, were performed using PubMed, Web of Science, OVID MEDLINE, and Embase. Proportion of patients achieving nonhyperthyroid status was the primary outcome. Secondary outcomes were proportion of patients who were specifically euthyroid or hypothyroid. A random-effects meta-analysis of proportions was performed for primary and secondary outcomes, and the impact of the radiation absorbed dose on treatment outcome was assessed through meta-regression. The study is registered with PROSPERO (CRD42020175010). Results: A total of 1122 studies were identified of which 15, comprising 2303 Graves' disease patients, were eligible for the meta-analysis. A strong association was found between radiation absorbed dose and nonhyperthyroid and hypothyroid outcomes (odds ratio [OR] = 1.11 [95% confidence interval {CI} 1.08-1.14] and OR = 1.09 [CI 1.06-1.12] per 10 Gy increase). Higher rates of euthyroid outcome were found for radiation absorbed doses within the range 120-180 Gy when compared with outside this range (n = 1172, OR = 2.50 [CI 1.17-5.35], p = 0.018). A maximum euthyroid response of 38% was identified at a radiation absorbed dose of 128 Gy. Conclusions: The presented radiation absorbed dose-response relationships can facilitate personalized treatment planning for radioiodine treatment of patients with Graves' disease. Further studies are required to determine how patient-specific covariates can inform personalized treatments.

Time-resolved fluorescence immunoassay for urine retinol-binding protein is more sensitive than polyclonal and monoclonal assays.

BACKGROUND: Retinol-binding protein4 (RBP) assays using polyclonal antibodies (pRBP) have major problems of non-linearity of dilution and a very small useable dynamic range. Our objective was to develop a specific assay with a wider dynamic range to detect tubular proteinuria. METHODS: mRBP (monoclonal capture and second antibody with colorimetric detection) and fluoroimmunoassays for RBP (fRBP) (polyclonal capture and monoclonal second antibody with fluorescence detection) were developed and compared with pRBP. Four hundred and eighty-eight patient samples were collected; 290 samples were analysed by mRBP and 198 samples with fRBP and compared with pRBP. RESULTS: mRBP assay has the advantages of better linearity on dilution and wider analytical range over pRBP. It is limited by poor signal in the patients with albuminuria and glomerular proteinuria and inferior discrimination between patient groups. fRBP had an intra-assay and inter-assay CV of <6% and <8%, respectively, and analytical range was 2.3-599 µg/L. fRBP was linear on dilution within the analytical range. Correlation (r) was 0.8722 (95% CI 0.7621 to 0.9333, P< 0.0001); Mann-Whitney test revealed no significant difference (U = 18,877, n = 198, P = 0.5244) asserting that the medians of the two samples were identical. Bland-Altman test between pRBP and fRBP showed a mean negative bias of 16.43 (CI -994 to 1027) µg/mmol. CONCLUSIONS: The combination assay with fluorescence detection (fRBP) proved more discriminatory than a purely monoclonal system especially in patients with significant proteinuria and has advantages of better linearity on dilution and wider analytical range than the existing pRBP assay and compared extremely well with pRBP.

Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry.

BACKGROUND: Multiple major health organisations recommend the use of extracorporeal membrane oxygenation (ECMO) support for COVID-19-related acute hypoxaemic respiratory failure. However, initial reports of ECMO use in patients with COVID-19 described very high mortality and there have been no large, international cohort studies of ECMO for COVID-19 reported to date. METHODS: We used data from the Extracorporeal Life Support Organization (ELSO) Registry to characterise the epidemiology, hospital course, and outcomes of patients aged 16 years or older with confirmed COVID-19 who had ECMO support initiated between Jan 16 and May 1, 2020, at 213 hospitals in 36 countries. The primary outcome was in-hospital death in a time-to-event analysis assessed at 90 days after ECMO initiation. We applied a multivariable Cox model to examine whether patient and hospital factors were associated with in-hospital mortality. FINDINGS: Data for 1035 patients with COVID-19 who received ECMO support were included in this study. Of these, 67 (6%) remained hospitalised, 311 (30%) were discharged home or to an acute rehabilitation centre, 101 (10%) were discharged to a long-term acute care centre or unspecified location, 176 (17%) were discharged to another hospital, and 380 (37%) died. The estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 37·4% (95% CI 34·4-40·4). Mortality was 39% (380 of 968) in patients with a final disposition of death or hospital discharge. The use of ECMO for circulatory support was independently associated with higher in-hospital mortality (hazard ratio 1·89, 95% CI 1·20-2·97). In the subset of patients with COVID-19 receiving respiratory (venovenous) ECMO and characterised as having acute respiratory distress syndrome, the estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 38·0% (95% CI 34·6-41·5). INTERPRETATION: In patients with COVID-19 who received ECMO, both estimated mortality 90 days after ECMO and mortality in those with a final disposition of death or discharge were less than 40%. These data from 213 hospitals worldwide provide a generalisable estimate of ECMO mortality in the setting of COVID-19. FUNDING: None.

Partial nephrogenic diabetes insipidus associated with lithium therapy.

A 40-year-old Caucasian man developed excessive thirst and polyuria particularly at night over the preceding 6 months. He had been taking lithium for 16 years for the treatment of bipolar affective disorder. Investigations revealed subnormal maximum urinary concentrating ability after 8 hours of water deprivation and only a borderline response of urine osmolality to exogenous desmopressin given by intramuscular injection. A plasma copeptin concentration was elevated at 23 pmol/L. These results were consistent with partial nephrogenic diabetes insipidus. He was encouraged to increase his water intake as dictated by his thirst. In addition, he received amiloride with some improvement in his symptoms. Clinicians should be aware of the risk of nephrogenic diabetes insipidus with long-term lithium use and seek confirmation by a supervised water deprivation test augmented with a baseline plasma copeptin. If increased water intake is insufficient to control symptoms, amiloride may be considered.

Metformin in Pregnancy: Mechanisms and Clinical Applications.

Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with less maternal weight gain and a high degree of patient acceptability. A multicentre RCT is currently assessing the addition of metformin to insulin in pregnant women with type 2 diabetes. RCT evidence is also available for the use of metformin in pregnancy for women with Polycystic Ovarian Syndrome and for nondiabetic women with obesity. No evidence of an increase in congenital malformations or miscarriages has been observed even when metformin is started before pregnancy and continued to term. Body composition and metabolic outcomes at two, seven, and nine years have now been reported for the offspring of mothers treated in the MiG study. In this review, we will briefly discuss the action of metformin and then consider the evidence from the key clinical trials.

Dosimetry-based treatment for Graves' disease.

OBJECTIVE: The aim of this retrospective study was to assess the long-term outcome of a personalized dosimetry approach in Graves' disease aiming to render patients euthyroid from a planned thyroid absorbed dose of 60 Gy. PATIENTS AND METHODS: A total of 284 patients with Graves' disease were followed prospectively following administration of radioiodine calculated to deliver an absorbed dose of 60 Gy. Patients with cardiac disease were excluded. Outcomes were analysed at yearly intervals for up to 10 years with a median follow-up of 37.5 months. RESULTS: A single radioiodine administration was sufficient to render a patient either euthyroid or hypothyroid in 175 (62%) patients, the remainder requiring further radioiodine. The median radioactivity required to deliver 60 Gy was 77 MBq. Less than 2% patients required 400-600 MBq, the standard activity administered in many centres. In the cohort receiving a single administration, 38, 32 and 26% were euthyroid on no specific thyroid medication at 3, 5 and 10 years, respectively. Larger thyroid volumes were associated with the need for further therapy. The presence of nodules on ultrasonography did not adversely affect treatment outcome. CONCLUSION: A personalized dosimetric approach delayed the long-term onset of hypothyroidism in 26% of patients. This was achieved using much lower administered activities than currently recommended. Future studies will aim to identify those patients who would benefit most from this approach.

Association between insulin resistance and preeclampsia in obese non-diabetic women receiving metformin.

OBJECTIVES: To examine whether the reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is mediated by changes in insulin resistance. METHODS: This was a secondary analysis of obese pregnant women in a randomised trial (MOP trial). Fasting plasma glucose and insulin were measured in 384 of the 400 women who participated in the MOP trial. Homeostasis model assessment of insulin resistance (HOMA-IR) was compared in the metformin and placebo groups and in those that developed preeclampsia versus those that did not develop preeclampsia. RESULTS: At 28 weeks, median HOMA-IR was significantly lower in the metformin group. Logistic regression analysis demonstrated that there was a significant contribution in the prediction of preeclampsia from maternal history of chronic hypertension and gestational weight gain, but not HOMA-IR either at randomisation (p = 0.514) or at 28 weeks (p = 0.643). CONCLUSIONS: Reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is unlikely to be due to changes in insulin resistance.

Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus.

BACKGROUND: Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned pregnant women without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. The BMI was calculated at the time of study entry (12 to 18 weeks of gestation). The primary outcome was a reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates). Secondary outcomes included maternal gestational weight gain and the incidence of gestational diabetes and of preeclampsia, as well as the incidence of adverse neonatal outcomes. Randomization was performed with the use of computer-generated random numbers. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, -0.71 to 0.92] and 0.17 in the placebo group [interquartile range, -0.62 to 0.89], P=0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes. CONCLUSIONS: Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight. (Funded by the Fetal Medicine Foundation; ClinicalTrials.gov number, NCT01273584; EudraCT number, 2008-005892-83.).

The importance of visceral fat mass in obese pregnant women and relation with pregnancy outcomes.

BACKGROUND: Maternal obesity is a well established risk factor for gestational diabetes but it is not known if the pattern of maternal fat distribution predicts adverse pregnancy outcomes. METHODS: Body composition was assessed by bioimpedance using Inbody 720® in 302 consecutive obese pregnant women attending a weight management clinic. The relation of visceral fat mass and total percentage body fat with the development of gestational diabetes and perinatal outcomes was evaluated. RESULTS: Women developing gestational diabetes (Group 1; n = 72) were older, had higher body mass indices and greater central obesity (waist:hip ratio, visceral fat mass) compared with those remaining normoglycaemic. Visceral fat mass, but not percentage body fat, correlated with fasting glucose in all patients (r = 0.2, p < 0.001) and particularly those in Group 1 (r = 0.35, p = 0.002). Visceral fat mass, but not percentage body fat, also correlated strongly with glycaemia, particularly in Group 1 (r = 0.47, p < 0.0001). Visceral fat mass also showed a weak but significant correlation with baby weight (r = 0.17, p = 0.01). DISCUSSION: Central obesity, as assessed by early pregnancy waist:hip ratio and particularly by visceral fat mass, is a predictor of gestational diabetes in addition to classical risk factors and may help identify those obese patients at increased risk of complications.

Cushing's Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review.

Despite advances in analytic and imaging techniques, the syndrome of ectopic adrenocorticotrophic hormone (ACTH) secretion from a tumour resulting in Cushing's syndrome continues to pose difficult diagnostic and therapeutic challenges. Dynamic testing may be equivocal and radiology indeterminate. We report a patient presenting with Cushing's syndrome associated with ectopic ACTH secretion from a bronchial carcinoid whose management presented diagnostic and therapeutic challenges.

Pregnancy outcomes after metformin treatment for gestational diabetes: a case-control study.

BACKGROUND: There is increasing evidence that metformin is safe and effective in the treatment of gestational diabetes (GDM), although it has not yet been widely accepted for routine practice. We compared pregnancy outcomes in women with gestational GDM treated with metformin or dietary measures alone. METHODS: Women with GDM (324) not adequately controlled by diet received metformin according to protocol based on their home glucose results. Pregnancy outcomes in these women were compared with 175 GDM women treated with diet alone and matched for age and ethnicity. RESULTS: The percentage of macrosomic babies (birth weight [BW] centile >90th centile) and small for gestational age (SGA) (BW <10th centile) in the metformin group was significantly reduced compared with the diet group (12.7% versus 20%; P < 0.05 [macrosomia]; 7.7% versus 14.3% [SGA] P < 0.05). CONCLUSIONS: Metformin treatment had a favourable impact on the rates of macrosomia and SGA despite more severe glucose intolerance at baseline.

Diffuse large B-cell non Hodgkin's lymphoma in a 65-year-old woman presenting with hypopituitarism and recovering after chemotherapy: a case report.

INTRODUCTION: Diffuse large B-cell non Hodgkin's lymphoma may involve the pituitary either as a primary central nervous system lymphoma or, more frequently, as metastasis from systemic lymphoma leading to hypopituitarism. A partial recovery of pituitary function after treatment with chemotherapy has previously been described but complete recovery with cessation of all hormone supplements is excessively rare. We report a patient presenting with anterior hypopituitarism with subsequent complete and sustained recovery of pituitary function after successful treatment of the lymphoma. CASE PRESENTATION: A 65-year-old Caucasian woman with lethargy, loss of appetite and peripheral edema was found to have anterior hypopituitarism. Magnetic resonance imaging showed no mass lesions in the pituitary although a positron emission tomography scan showed abnormal pituitary activity. An abdominal computed tomography scan revealed multiple intra-abdominal lymph nodes, which on histology proved diagnostic of diffuse large B-cell non Hodgkin's lymphoma. She received six cycles of R-CHOP chemotherapy, after which she achieved a complete metabolic response at all known previous sites of the disease, confirmed by positron emission tomography scanning. Concomitant with the tumor response, there was full recovery of adrenal, thyroid and gonadal axes which has persisted at 10 months follow-up. CONCLUSION: Although rare, it is important to recognize lymphomatous infiltration of the pituitary as a potentially reversible cause of hypopituitarism.

Outcome of Pregnancy After Exposure to Radioiodine In Utero.

OBJECTIVE: Radioiodine (131I) therapy is absolutely contraindicated in pregnancy yet reports of inadvertent exposure continue to appear in the literature. In this review, we discuss the risks of fetal exposure and prevention strategies in the light of current guidelines. METHODS: We performed a literature search on MEDLINE using the terms radioiodine, I-131, toxicity, complications and pregnancy and chose the most relevant studies for this review. RESULTS: Before implantation, the major concern is miscarriage and death of the embryo above a radiation threshold of 100mGy (10 rads). Exposure to 131I at this very early stage of pregnancy is unlikely to result in major malformations or thyroid dysfunction in surviving embryos. Exposure later in pregnancy i.e. during thyroidogenesis (from 10 weeks gestation) and organogenesis (from 2 weeks gestation) at similar radiation thresholds may result in fetal thyroid ablation, birth defects and in later life, growth retardation and reduction in IQ. In addition to these deterministic effects, radiation at any dose may increase the risk of cancer (stochastic effect) and recent evidence indicates an increased risk of thyroid cancer many years after in utero exposure. CONCLUSIONS: Clinicians treating women of child-bearing age with radioiodine need to be aware of the risks of fetal exposure to radioiodine and take all measures to avoid inadvertent exposure during pregnancy.

Changes in bone mineral parameters, vitamin D metabolites, and PTH measurements with varying chronic kidney disease stages.

Vitamin D deficiency is associated with an increased risk of many diseases (skeletal and nonskeletal). Emerging data also associate high concentrations of serum parathyroid hormone (PTH) with morbidity and increased mortality in patients both with and without known chronic kidney disease (CKD). Understanding the relationship between vitamin D and PTH and the determinants of PTH is therefore important. We performed a cross-sectional study of 203 patients with varying stages of CKD randomly recruited from the Renal Unit database at our institution. Detailed case review was performed, and samples of fasting blood were taken for biochemical analyses. We measured standard biochemistry, 25-hydroxyvitamin D (25-OHD), 1,25-OHD, and three PTH measurements [1-84 PTH, total PTH, and derived N-terminal truncated, 7-84 PTH (cPTH)]. Vitamin D deficiency was high, with 86% of patients having 25-OHD levels below 30 ng/ml. Estimated glomerular filtration rate (eGFR) was not associated with 25-OHD levels, whereas 1,25-OHD was lower in those with CKD stage 5 versus stage 4, who were not treated with vitamin D metabolites (18 vs. 65 pg/ml, respectively; P < 0.05). All three PTH measurements increased with worsening eGFR, with this finding being more pronounced in those patients who were not treated with vitamin D metabolites. The slope of the regression line of cPTH on eGFR tended to be steeper, -0.90, compared to -0.81 for total PTH and -0.80 for 1-84 PTH (P = 0.06). The ratio of total PTH to cPTH did decrease significantly through the range of CKD stages (P = 0.03). The determinants of PTH were similar for all three PTH measurements, with eGFR having a strong inverse relationship, with weaker relationships for 25-OHD and ionized calcium on multivariate analyses. We confirm that there is a complex relationship between 25-OHD, eGFR, and PTH. Total PTH, 1-84 PTH, and cPTH increase with increasing CKD stages, with a relatively greater increase in cPTH, although the clinical significance of this finding remains uncertain. The three PTH measurements had similar correlations with the biochemical and clinical variables studied, suggesting that either total PTH or 1-84 PTH can be used in clinical practice when evaluating vitamin D and PTH status.

Early and late toxicity of radioiodine therapy: detection and management.

OBJECTIVE: To review the early and late toxicity associated with radioiodine (131I) therapy, highlighting the need for early detection and, where possible, preventive measures. METHODS: We performed a literature search on MEDLINE using the terms radioiodine, 131I toxicity, complications, Graves disease, and thyroid cancer and chose the most relevant studies for this review. Where appropriate, we refer to our own published series of patients as well. RESULTS: Uptake of 131I into the salivary glands, lacrimal glands, fetal thyroid, and adult thyroid accounts for the early toxic effects of radioiodine therapy. Delayed radiation effects to the gonads, bone marrow, and cell nuclei give rise to late complications. Toxicity may also arise from uptake into metastatic tumors located at vulnerable sites, including the spinal cord, brain, and lungs. CONCLUSION: Although radioiodine therapy for benign and malignant thyroid disorders is usually well tolerated, clinicians involved in the management of thyroid disorders need to be aware of the potential toxicity of radioiodine and take all measures to reduce these effects to a minimum.

Thyroid cancer causing obstruction of the great veins in the neck.

BACKGROUND AND AIMS: To report our experience and review the literature of thyroid cancer obstructing the great veins in the neck, highlighting clinical aspects and response to treatment. METHODS: Clinical data were collected from the thyroid cancer register and from follow-up clinic visits of patients referred to the Thyroid Unit at the Royal Marsden Hospital. A Medline literature search was conducted between 1980 and 2007. RESULTS: Of 1448 patients with thyroid cancer on our cancer register and treated in our unit over the last 60 years, we identified five patients, four women and one man, aged 43 - 81 years with a median follow up of 28 (24-78) months in whom tumour had occluded the great veins in the neck. All patients underwent total thyroidectomy and all subsequently received ablative 131I with the exception of patient 3 whose post-operative isotope scan shown no significant 131I uptake. External beam radiotherapy to the neck and upper mediastinum was used for residual disease control in the 5 patients. The median survival was 28 months and the disease-free survival was 24 months. One patient remains asymptomatic but with disease 53 months after initial presentation. Survival in this small series is significantly better than that previously reported for this condition. CONCLUSION: A multimodality therapeutic approach comprising surgery, radioiodine and external beam radiotherapy may give the best results for patients in whom thyroid cancer is occluding the great veins.