Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design.

Approximately 10%-15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that "tissue T3 lack" may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection-(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 µg/day or 100 µg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.

The prevalence of diabetes and thyroid related autoantibodies in Sri Lankan children with type 1 diabetes and their unaffected siblings - The utility of a new screening assay.

Background: There is limited information about diabetes and thyroid related autoantibodies in children with type 1 diabetes (T1D) or their siblings in Sri Lanka. Objectives: To assess in T1D children and their unaffected siblings the prevalence of autoantibodies to (1) glutamic acid decarboxylase (GADA), insulinoma associated antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) using 3 Screen ICA™ (3-Screen) and individual ELISA assays; (2) insulin (IAA); and (3) thyroid peroxidase (TPOA), thyroglobulin (TgA) and the TSH receptor (TSHRA). Methods: We selected - (a) consecutive T1D children, and (b) their unaffected siblings of both sexes, from the T1D Registry at Lady Ridgeway Hospital, Colombo. Results: The median age (IQR) of 235 T1D children and 252 unaffected siblings was 11 (8.4, 13.2) and 9 (5.4, 14.9) years respectively, and the duration of T1D was 23 (7, 54) months. (1) T1D children (a) 79.1% were 3-Screen positive; (b) all 3-Screen positives were individual antibody positive (GADA in 74%; IA-2A 31.1%; ZnT8A 38.7%); (c) and were younger (p=0.01 vs 3-Screen negatives); (d) multiple autoantibodies were present in 45.1%; (e) IA-2A (p=0.002) and ZnT8A (p=0.006) prevalence decreased with T1D duration. (f) TPOA and TgA prevalence was higher in T1D children compared to unaffected siblings (28%, p=0.001 and 31%, p=0.004, respectively). (2) Unaffected siblings (a) 6.3% were 3-Screen positive (p=0.001 vs T1D), and 2.4% were positive for IAA; (b) four subjects had two diabetes related autoantibodies, one of whom developed dysglycaemia during follow-up. Conclusions: The 3-Screen assay, used for the first time in Sri Lankan T1D children and their siblings as a screening tool, shows a high prevalence of T1D related Abs with a high correlation with individual assays, and is also a helpful tool in screening unaffected siblings for future T1D risk. The higher prevalence of thyroid autoantibodies in T1D children is consistent with polyglandular autoimmunity.

Acute postprandial gut hormone, leptin, glucose and insulin responses to resistant starch in obese children: a single blind crossover study.

INTRODUCTION: Resistant starch (RS) has beneficial effects on postprandial glucose metabolism in both animals and adults. Hitherto, there have been no studies in children of the acute metabolic and hormonal effects of RS-containing meals. OBJECTIVES: We aimed to compare serial plasma glucose, insulin, gut hormone, leptin profiles and satiety scores in obese children after meals containing variable amounts of RS. METHODS: This was a single blind, non-randomised, crossover study of 20 obese children aged 10-14 years old without comorbidities. Three test meals containing rice (M1), rice cooked with coconut oil (M2), rice cooked in coconut oil with lentils (M3) were given in sequence after a 12-hour fast . Blood samples were analysed for glucose (PG), insulin, leptin, glucagon-like polypeptide (GLP) 1, ghrelin and peptide YY (PYY) at appropriate times between 0 and 180 min. RESULTS: Meal M2 resulted in significantly lower postprandial glucose values compared with meal M1 (maximal incremental glucose, ∆Cmax, p<0.05; area under the curve, ∆AUC0-3, p<0.01) and meal M3 (maximal concentration, Cmax, p<0.01; ∆Cmax, p<0.001, and ∆AUC0-3p<0.01). M2 also produced lower insulin values compared with M1 (p<0.05). Postprandial ghrelin was significantly higher after M1 compared with M3 (p<0.05). PYY, GLP1 and median satiety scores were not significantly different between the three meals. CONCLUSION: This study shows that M2, the meal containing RS alone, induced beneficial effects on acute postprandial glucose, insulin and ghrelin concentrations in obese children without diabetes. Acute postprandial satiety scores were not significantly affected by the three meals. TRIAL REGISTRATION NUMBER: SLCTR/2020/007.

Natural desiccated thyroid for the treatment of hypothyroidism?

Primary hypothyroidism affects about 3% of the general population in Europe. Early treatments in the late 19th Century involved subcutaneous as well as oral administration of thyroid extract. Until the early 1970s, the majority of people across the world with hypothyroidism were treated with natural desiccated thyroid (NDT) (derived from pig thyroid glands) in various formulations, with the majority of people since then being treated with levothyroxine (L-thyroxine). There is emerging evidence that may account for the efficacy of liothyronine (NDT contains a mixture of levothyroxine and liothyronine) in people who are symptomatically unresponsive to levothyroxine. While this is a highly selected group of people, the severity and chronicity of their symptoms and the fact that many patients have found their symptoms to be alleviated, can be viewed as valid evidence for the potential benefit of NDT when given after careful consideration of other differential diagnoses and other treatment options.

Pre-test Cortisol Levels in Predicting Short Synacthen Test Outcome: A Retrospective Analysis.

Objective: Short Synacthen tests (SSTs) are expensive, dependent on Synacthen availability, and need supervision. To reduce SST testing, we examined the utility of pre-test cortisol (Cort0) and related parameters in predicting outcome. Design and Measurements: We retrospectively examined the following in all SSTs; (i) Cort0 (ii) indications (iii) and time and place of testing. Receiver operated characteristic (ROC) curves were devised for Cort0 to obtain the best cut-off for outcome prediction in those who had SSTs between 8 and 10 am (Group 1) and at other times (Group 2). Results: Of 506 SSTs, 13 were unsuitable for analysis. 111/493 SSTs (22.5%) were abnormal. (1) ROC curves predicted - (a) SST failure with 100% specificity when Cort0 was ⩽124 nmol/L (Group 1), or ⩽47 (Group 2); (b) a normal SST with 100% sensitivity when Cort0 ⩾314 nmol/L (Group 1) and ⩾323 nmol/L (Group 2). (2) There was significant correlation between Cort0 and 30-minute cortisol (rs = 0.65-0.78, P < .001). (3) Median Cort0 was lower in those who failed SSTs compared to those who passed (147 vs 298 nmol/L respectively, P < .001). (4) SST failure was commoner in Group 1 vs 2 (P = .001). (5) There was no difference in outcome between out-patient and inpatient SSTs. (6) SST failure was most common for 'steroid related' indications (39.6%, P < .001). Conclusions: This study indicates that (1) Cort0 ⩾ 323 (Group1) and ⩾314 nmol/L (Group 2) predicted a normal SST with 100% sensitivity; (2) Using these cut offs 141/493 (28.6%) tests may have been avoided; (3) supporting evidence should be considered in those with a lower pre-test predictability of failure.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis.

OBJECTIVES: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy. METHODS: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity. RESULTS: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up. CONCLUSIONS: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

Is there a role for natural desiccated thyroid in the treatment of levothyroxine unresponsive hypothyroidism? Results from a consecutive case series.

INTRODUCTION: Some levothyroxine unresponsive individuals with hypothyroidism are prescribed a natural desiccated thyroid (NDT) preparation such as Armour Thyroid® or ERFA Thyroid® . These contain a mixture of levothyroxine and liothyronine in a fixed ratio. We evaluated the response to NDT in individuals at a single endocrine centre in terms of how the change from levothyroxine to NDT impacted on their lives in relation to quality of life (QOL) and thyroid symptoms. METHODS: The ThyPRO39 (thyroid symptomatology) and EQ-5D-5L-related QoL/EQ5D5L (generic QOL) questionnaires were administered to 31 consecutive patients who had been initiated on NDT, before initiating treatment/6 months later. RESULTS: There were 28 women and 3 men. The dose range of NDT was 60-180 mg daily. Age range was 26-77 years with length of time since diagnosis with hypothyroidism ranging from 2 to 40 years. One person discontinued the NDT because of lack of response; two because of cardiac symptoms. EQ-5D-5L utility increased from a mean (SD) of 0.214 (0.338) at baseline, to 0.606 (0.248) after 6 months; corresponding to a difference of 0.392 (95% CI 0.241-0.542), t = 6.82, P < .001. EQ-VAS scores increased from 33.4 (17.2) to 71.1 (17.5), a difference of 37.7 (95% CI 25.2-50.2), t = -4.9, P < .001. ThyPRO scores showed consistent fall across all domains with the composite QoL-impact Score improving from 68.3 (95% CI 60.9-75.7) to 25.2 (95% CI 18.7-31.7), a difference of 43.1 (95% CI 33-53.2) (t = 5.6, P < .001). CONCLUSION: Significant symptomatic benefit and improvement in QOL was experienced by people with a history of levothyroxine unresponsive hypothyroidism treated with NDT, suggesting the need for further evaluation of NDT in this context.

Liothyronine and levothyroxine prescribing in England: A comprehensive survey and evaluation.

INTRODUCTION: The approach to thyroid hormone replacement varies across centres, but the extent and determinants of variation is unclear. We evaluated geographical variation in levothyroxine (LT4) and liothyronine (LT3) prescribing across General Practices in England and analysed the relationship of prescribing patterns to clinical and socioeconomic factors. METHODS: Data was downloaded from the NHS monthly General Practice Prescribing Data in England for the period 2011-2020. RESULTS: The study covered a population of 19.4 million women over 30 years of age, attending 6,660 GP practices and being provided with 33.7 million prescriptions of LT4 and LT3 at a total cost of £90million/year. Overall, 0.5% of levothyroxine treated patients continue to receive liothyronine. All Clinical Commission Groups (CCGs) in England continue to have at least one liothyronine prescribing practice and 48.5% of English general practices prescribed liothyronine in 2019-2020. Factors strongly influencing more levothyroxine prescribing (model accounted for 62% of variance) were the CCG to which the practice belonged and the proportion of people with diabetes registered on the practice list plus antidepressant prescribing, with socioeconomic disadvantage associated with less levothyroxine prescribing. Whereas factors that were associated with increased levels of liothyronine prescribing (model accounted for 17% of variance), were antidepressant prescribing and % of type 2 diabetes mellitus individuals achieving HbA1c control of 58 mmol/mol or less. Factors that were associated with reduced levels of liothyronine prescribing included smoking and higher obesity rates. CONCLUSION: In spite of strenuous attempts to limit prescribing of liothyronine in general practice a significant number of patients continue to receive this therapy, although there is significant geographical variation in the prescribing of this as for levothyroxine, with specific general practice and CCG-related factors influencing prescribing of both levothyroxine and liothyronine across England.

Thyroid Autoimmunity and Dysfunction in Sri Lankan Children and Adolescents After 22 Years of Sustained Universal Salt Iodization.

Background: Sri Lanka introduced universal salt iodization (USI) in 1995 after which we demonstrated a high thyroglobulin antibody (TgAb) prevalence in 1998. However, it is unclear whether thyroid autoimmunity persists in the long term in populations exposed to sustained USI and whether such populations have an excess of thyroid dysfunction. We evaluated the prevalence of thyroid autoantibodies and dysfunction in Sri Lankan children and adolescents after more than two decades of sustained USI. Methods: We selected 10- to 18-year-old subjects of both sexes (randomized cluster sampling) from all 9 provinces of Sri Lanka in this cross-sectional study. Blood, urine, and anthropometric data were collected and thyroid ultrasound scans were performed. Validated statistical methods were used to derive local population-specific reference ranges for all thyroid parameters. We also measured urine iodine concentration (UIC), salt, and water iodine concentrations. Results: Blood and urine samples from 2507 and 2473 subjects respectively, and ultrasound scans from 882 subjects were analyzed. Population-derived upper limits for thyroid peroxidase antibody (TPOAb) and TgAb, and reference ranges for triiodothyronine, thyroxine, and thyrotropin (total and age-year-related groups) were significantly different from manufacturer's reference ranges. Using these derived ranges, the prevalence of TPOAb was 10.3% and TgAb was 6.4%. Of the TPOAb-positive subjects, TPOAb were of low concentration in 66.2% (1-3 times the upper limit of the reference range [ULRR]) and showed the strongest association with subclinical hypothyroidism (SCH) at the highest concentrations (>4 ULRR). The prevalence of SCH was 3%. Median UIC (interquartile range) was 138.5 µg/L (79.4-219.0) with regional variability, and median thyroglobulin was 8.3 ng/mL (4.1-13.5). Goiter prevalence was 0.6% and 1.93% (thyroid volume compared to age and body surface area, respectively). Salt and water iodine concentrations were satisfactory. Conclusions: Sri Lanka has safely and effectively implemented USI with good sources of iodine, leading to sustained iodine sufficiency over more than two decades. The early postiodization TgAb surge (42.1%) has settled (6.4%), and despite a persistently high TPOAb prevalence (10.3%), SCH prevalence remains low (3%). Further studies should be undertaken to monitor thyroid autoimmune dysfunction in Sri Lankan children, using age-specific, population-derived reference ranges.

Trends in costs and prescribing for liothyronine and levothyroxine in England and wales 2011-2020.

INTRODUCTION: Recent prescribing policies in England and Wales have imposed significant restrictions on liothyronine prescribing in general practice driven by the prohibitive costs and uncertain benefits of liothyronine in the management of hypothyroidism. However, the impact of these policies on liothyronine usage and costs is still unclear. METHODS: Data were downloaded from the NHS monthly General Practice Prescribing Data in England and from the Comparative Analysis System for Prescribing Audit (CASPA) in Wales for 2011-2020. Trends over the period in amount and costs of levothyroxine and liothyronine prescribing were analysed. RESULTS: The total medication costs per year for England Wales for hypothyroidism rose from £60.8 million to £129.8 million in 2015-16 and have since reduced to £88.4 million. Levothyroxine prescriptions have been growing above the population growth rate at 0.7%/annum in England and 1.1% in Wales. The costs/patient/year for liothyronine rose from £550 to £3000 in 2015-16 and has since fallen to £2500. Use of liothyronine as a percentage of levothyroxine started to fall in 2015-16 at 7%/annum in England and 3% in Wales. Nevertheless, 0.5% of levothyroxine-treated patients continue to receive liothyronine. All Clinical Commission Groups (CCGs) in England continue to have at least one liothyronine prescribing practice and 48.5% of English general practices prescribed liothyronine in 2019-20. CONCLUSION: In spite of strenuous attempts to limit prescribing of liothyronine in general practice, a significant number of patients continue to receive this therapy. The price differential of liothyronine vs levothyroxine should be examined again in light of the continuing use of liothyronine.

Myositis, rhabdomyolysis and severe hypercalcaemia in a body builder.

SUMMARY: A 53-year-old man who used growth hormone (GH), anabolic steroids and testosterone (T) for over 20 years presented with severe constipation and hypercalcaemia. He had benign prostatic hyperplasia and renal stones but no significant family history. Investigations showed - (1) corrected calcium (reference range) 3.66 mmol/L (2.2-2.6), phosphate 1.39 mmol/L (0.80-1.50), and PTH 2 pmol/L (1.6-7.2); (2) urea 21.9 mmol/L (2.5-7.8), creatinine 319 mmol/L (58-110), eGFR 18 mL/min (>90), and urine analysis (protein 4+, glucose 4+, red cells 2+); (3) creatine kinase 7952 U/L (40-320), positive anti Jo-1, and Ro-52 antibodies; (4) vitamin D 46 nmol/L (30-50), vitamin D3 29 pmol/L (55-139), vitamin A 4.65 mmol/L (1.10-2.60), and normal protein electrophoresis; (5) normal CT thorax, abdomen and pelvis and MRI of muscles showed 'inflammation', myositis and calcification; (6) biopsy of thigh muscles showed active myositis, chronic myopathic changes and mineral deposition and of the kidneys showed positive CD3 and CD45, focal segmental glomerulosclerosis and hypercalcaemic tubular changes; and (7) echocardiography showed left ventricular hypertrophy (likely medications and myositis contributing), aortic stenosis and an ejection fraction of 44%, and MRI confirmed these with possible right coronary artery disease. Hypercalcaemia was possibly multifactorial - (1) calcium release following myositis, rhabdomyolysis and acute kidney injury; (2) possible primary hyperparathyroidism (a low but detectable PTH); and (3) hypervitaminosis A. He was hydrated and given pamidronate, mycophenolate and prednisolone. Following initial biochemical and clinical improvement, he had multiple subsequent admissions for hypercalcaemia and renal deterioration. He continued taking GH and T despite counselling but died suddenly of a myocardial infarction. LEARNING POINTS: The differential diagnosis of hypercalcaemia is sometimes a challenge. Diagnosis may require multidisciplinary expertise and multiple and invasive investigations. There may be several disparate causes for hypercalcaemia, although one usually predominates. Maintaining 'body image' even with the use of harmful drugs may be an overpowering emotion despite counselling about their dangers.

Stable Iodine Nutrition During Two Decades of Continuous Universal Salt Iodisation in Sri Lanka.

Universal salt iodisation (USI) was introduced in Sri Lanka in 1995. Since then, four national iodine surveys have assessed the iodine nutrition status of the population. We retrospectively reviewed median urine iodine concentration (mUIC) and goitre prevalence in 16,910 schoolchildren (6-12 years) in all nine provinces of Sri Lanka, the mUIC of pregnant women, drinking-water iodine level, and the percentage of households consuming adequately (15 mg/kg) iodised salt (household salt iodine, HHIS). The mUIC of schoolchildren increased from 145.3 µg/L (interquartile range (IQR) = 84.6-240.4) in 2000 to 232.5 µg/L (IQR = 159.3-315.8) in 2016, but stayed within recommended levels. Some regional variability in mUIC was observed (178.8 and 297.3 µg/L in 2016). There was positive association between mUIC in schoolchildren and water iodine concentration. Goitre prevalence to palpation was a significantly reduced from 18.6% to 2.1% (p < 0.05). In pregnant women, median UIC increased in each trimester (102.3 (61.7-147.1); 217.5 (115.6-313.0); 273.1 (228.9-337.6) µg/L (p = 0.000)). We conclude that the introduction and maintenance of a continuous and consistent USI programme has been a success in Sri Lanka. In order to sustain the programme, it is important to retain monitoring of iodine status while tracking salt-consumption patterns to adjust the recommended iodine content of edible salt.

Primary therapy of Graves' disease and cardiovascular morbidity and mortality: a linked-record cohort study.

BACKGROUND: Graves' disease is routinely treated with antithyroid drugs, radioiodine, or surgery, but whether the choice of initial therapy influences long-term outcomes is uncertain. We evaluated cardiovascular morbidity and mortality according to the method and effectiveness of primary therapy in Graves' disease. METHODS: In this retrospective cohort study, we identified patients with hyperthyroidism, diagnosed between Jan 1, 1998, and Dec 31, 2013, from a thyroid-stimulating hormone (TSH)-receptor antibody (TRAb) test register in south Wales, UK, and imported their clinical data into the All-Wales Secure Anonymised Information Linkage (SAIL) Databank (Swansea University, Swansea, UK). Patients with Graves' disease, defined by positive TRAb tests, were selected for the study, and their clinical data were linked with outcomes in SAIL. We had no exclusion criteria. Patients were matched by age and sex to a control population (1:4) in the SAIL database. Patients were grouped by treatment within 1 year of diagnosis into the antithyroid drug group, radioiodine with resolved hyperthyroidism group (radioiodine group A), or radioiodine with unresolved hyperthyroidism group (radioiodine group B). We used landmark Kaplan-Meier and Cox regression models to analyse the association of treatment with the primary outcome of all-cause mortality and the secondary outcome of major adverse cardiovascular events (myocardial infarction, heart failure, ischaemic stroke, or death) with the landmark set at 1 year after diagnosis. We analysed the association between outcomes and concentration of TSH using Cox regression and outcomes and free thyroxine (FT4) concentration using restricted cubic-spline regression models. FINDINGS: We extracted patient-level data on 4189 patients (3414 [81·5%] females and 775 [18·5%] males) with Graves' disease and 16 756 controls (13 656 [81·5%] females and 3100 [18·5%] males). In landmark analyses, 3587 patients were in the antithyroid drug group, 250 were in radioiodine group A, 182 were in radioiodine group B. Patients had increased all-cause mortality compared with controls (hazard ratio [HR] 1·22, 95% CI 1·05-1·42). Compared with patients in the antithyroid drug group, mortality was lower among those in radioiodine group A (HR 0·50, 95% CI 0·29-0·85), but not for those in radioiodine group B (HR 1·51, 95% CI 0·96-2·37). Persistently low TSH concentrations at 1 year after diagnosis were associated with increased mortality independent of treatment method (HR 1·55, 95% CI 1·08-2·24). Spline regressions showed a positive non-linear relationship between FT4 concentrations at 1 year and all-cause mortality. INTERPRETATION: Regardless of the method of treatment, early and effective control of hyperthyroidism among patients with Graves' disease is associated with improved survival compared with less effective control. Rapid and sustained control of hyperthyroidism should be prioritised in the management of Graves' disease and early definitive treatment with radioiodine should be offered to patients who are unlikely to achieve remission with antithyroid drugs alone. FUNDING: National Institute for Social Care and Health Research, Wales.

Thyrotrophin receptor antibody concentration and activity, several years after treatment for Graves' disease.

OBJECTIVE: TSH receptor antibodies (TRAb) are responsible for autoimmune hyperthyroid disease (Graves' disease; GD) with TRAb levels tending to decrease following treatment. Measurement of TRAb activity during follow-up could prove valuable to better understand treatment effectiveness. STUDY DESIGN: TRAb concentration and stimulating (TSAb) and blocking (TSBAb) activity of patient serum were assessed following different treatment modalities and follow-up length. METHODS: Sixty-six subjects were recruited following treatment with carbimazole (n = 26), radioiodine (n = 27) or surgery (n = 13). TRAb, TPOAb, TgAb and GADAb were measured at a follow-up visit as well as bioassays of TSAb and TSBAb activity. RESULTS: Forty-five per cent of all patients remained TRAb-positive for more than one year and 23% for more than 5 years after diagnosis, irrespective of treatment method. Overall, TRAb concentration fell from a median (IQR) of 6.25 (3.9-12.7) to 0.65 (0.38-3.2) U/L. Surgery conferred the largest fall in TRAb concentration from 11.4 (6.7-29) to 0.58 (0.4-1.4) U/L. Seventy per cent of TRAb-positive patients were positive for TSAb, and one patient (3%) was positive for TSBAb. TRAb and TSAb correlated well (r = 0.83). In addition, 38/66 patients were TgAb-positive, 47/66 were TPOAb-positive and 6/66 were GADAb-positive at follow-up. CONCLUSIONS: TRAb levels generally decreased after treatment but persisted for over 5 years in some patients. TRAb activity was predominantly stimulatory, with only one patient demonstrating TSBAb. A large proportion of patients were TgAb/TPOAb-positive at follow-up. All treatment modalities reduced TRAb concentrations; however, surgery was most effective.

Thyroid testing in acutely ill patients may be an expensive distraction.

In health, an efficient negative feedback mechanism maintains serum thyroid hormone concentrations within an exquisitely controlled narrow range. Therefore any change that occurs to thyroid hormones in intrinsic thyroid disease is concordant and easy to interpret. Optimal functioning of the many tissues they influence is thereby facilitated.The situation in acute illnesses is different. Mechanisms that operate in these circumstances influence the hypothalamic-pituitary-thyroid axis and its components producing thyroid test results, which are discordant, do not fit recognizable patterns and are difficult to interpret. The yield of abnormalities is also low (about 7%). As many studies indicate, thyroid tests are expensive and consume large amounts of the hospital budget and resources of hospital laboratories. Other studies have shown that when abnormalities are detected, clinicians do not intervene or follow up these subjects. Therefore the clinical utility of thyroid testing in acutely ill patients is debatable. Interventions to change requestor behaviour with regard to thyroid testing in acutely ill subjects and the success of some audit and educational interventions are worthy of note.Thyroid testing in acutely ill patients is often an expensive distraction and is of limited clinical value. Targeted thyroid testing should be offered in this group only to those with: (a) symptoms or signs of thyroid disease e.g. goiter or orbitopathy; (b) risk factors for thyroid disease, previous or family history of thyroid disease;

Improving quality in the preanalytical phase through innovation, on behalf of the European Federation for Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for Preanalytical Phase (WG-PRE).

It is now undeniable that laboratory testing is vital for the diagnosis, prognostication and therapeutic monitoring of human disease. Despite the many advances made for achieving a high degree of quality and safety in the analytical part of diagnostic testing, many hurdles in the total testing process remain, especially in the preanalytical phase ranging from test ordering to obtaining and managing the biological specimens. The Working Group for the Preanalytical Phase (WG-PRE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has planned many activities aimed at mitigating the vulnerability of the preanalytical phase, including the organization of three European meetings in the past 7 years. Hence, this collective article follows the previous three opinion papers that were published by the EFLM WGPRE on the same topic, and brings together the summaries of the presentations that will be given at the 4th EFLM-BD meeting "Improving quality in the preanalytical phase through innovation" in Amsterdam, 24-25 March, 2017.

Should all women be screened for thyroid dysfunction in pregnancy?

The subject of universal thyroid screening in pregnancy generates impassioned debate. Thyroid dysfunction is common, has significant adverse implications for fetal and maternal well-being, is readily detectable and can be effectively and inexpensively treated. Furthermore, the currently recommended case-finding strategy does not identify a substantially proportion of women with thyroid dysfunction thus favoring universal screening. On the other hand subclinical thyroid dysfunction forms the bulk of gestational thyroid disorders and the paucity of high-level evidence to support correction of these asymptomatic biochemical abnormalities weighs against universal screening. This review critically appraises the literature, examines the pros and cons of universal thyroid screening in pregnancy, highlighting the now strong case for implementing universal screening and explores strategies for its implementation.