The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

The Relation Between Thyroid Function and Anemia: A Pooled Analysis of Individual Participant Data.

Context: Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce. Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia. Design: Individual participant data meta-analysis. Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162). Main Outcome Measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women). Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)]. Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups. Conclusion: Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

Thyrotoxicosis associated with the use of amiodarone: the utility of ultrasound in patient management.

Amiodarone is an anti-arrhythmic drug that commonly affects the thyroid, causing hypothyroidism or thyrotoxicosis. Amiodarone-induced thyrotoxicosis (AIT) is caused by excessive thyroid hormone biosynthesis in response to iodine load in autonomously functioning thyroid glands with pre-existing nodular goitre or underlying Graves' disease (type 1 or AIT 1), or by a destructive thyroiditis typically occurring in normal glands (type 2 or AIT 2). Indeterminate or mixed forms are also recognized. The distinction is clinically useful as AIT 1 is treated predominantly with thionamides, whereas AIT 2 is managed with glucocorticoids. We review the tools used to differentiate type 1 from type 2 thyrotoxicosis, with specific reference to the imaging modalities used.

Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts.

IMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline. EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status. RESULTS: Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results. CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Subclinical thyroid disease.

INTRODUCTION: Subclinical thyroid disease is a common finding on testing of thyroid function and its management remains controversial. SOURCE OF DATA: Epidemiological data from large population studies from USA and Europe. AREAS OF AGREEMENT: There is an increased risk of progression to overt hypothyroidism or hyperthyroidism. The treatment of mild thyroid failure is of importance in optimizing pregnancy outcome. AREAS OF CONTROVERSY: Diagnostic criteria differ and there is variation between management guidelines. The difference was found in long-term clinical outcomes between endogenous and exogenous subclinical hyperthyroidism. GROWING POINTS: Meta-analyses have provided epidemiological data in cardiovascular mortality and morbidity in subclinical thyroid disease. Increased use of echocardiography and bone markers in identifying those who benefit from intervention. AREAS TIMELY FOR DEVELOPING RESEARCH: A randomized controlled trial to identify those subjects identified from screening programmes that benefit from intervention in terms of morbidity and mortality.

2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism.

BACKGROUND: Data suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area. METHODS: Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large. RESULTS: SUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research. CONCLUSION: L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

The epidemiology of thyroid disease.

INTRODUCTION: Thyroid disorders are prevalent and their manifestations are determined by the dietary iodine availability. SOURCES OF DATA: Data from screening large population samples from USA and Europe. AREAS OF AGREEMENT: The most common cause of thyroid disorders worldwide is iodine deficiency, leading to goitre formation and hypothyroidism. In iodine-replete areas, most persons with thyroid disorders have autoimmune disease. AREAS OF CONTROVERSY: Definition of thyroid disorders, selection criteria used, influence of age and sex, environmental factors and the different techniques used for assessment of thyroid function. GROWING POINTS: Increasing incidence of well-differentiated thyroid cancer. Environmental iodine influences the epidemiology of non-malignant thyroid disease. AREAS TIMELY FOR DEVELOPING RESEARCH: Iodine supplementation of populations with mild-to-moderate iodine deficiency. An evidence-based strategy for the risk stratification, treatment and follow-up of benign nodular thyroid disease. Is there any benefit in screening adults for thyroid dysfunction?

Should we treat mild subclinical/mild hyperthyroidism? No.

The management of a patient with subclinical hyperthyroidism or mild thyroid over-activity is controversial. Subclinical hyperthyroidism is defined as a serum thyrotrophin (TSH) below the reference range but a normal thyroxine (T4) and triiodothyronine (T3) level in a patient who is either asymptomatic or has only non-specific symptoms. Epidemiological studies report an overall prevalence of approximately 3%, with men and women over 65 years and those in iodine deficient regions having the highest prevalence. Approximately 50% of subjects are taking levothyroxine. The aetiology for those with endogenous subclinical hyperthyroidism is Graves' disease, toxic nodular goitre or rarely a solitary toxic adenoma or thyroiditis. Non-thyroidal illness is an important cause of false positive low serum TSH test results. Subjects with low but detectable serum TSH values (0.1-0.4 mU/L) usually recover spontaneously when re-tested. It has been estimated that in those with an undetectable serum TSH (<0.1 mU/L) conversion to overt hyperthyroidism occurs at a rate up to 5% per year. Advocates of intervening for subclinical hyperthyroidism argue that early treatment might reduce mortality, prevent the later development of atrial fibrillation, osteoporotic fractures, and overt hyperthyroidism but data supporting improvement in outcomes are sparse. No appropriately powered prospective, randomised, controlled, double-blinded trial of intervention for subclinical hyperthyroidism exists. For the vast majority of patients adopting a "wait and see" policy rather than intervention may avoid unnecessary treatment or the potential for harm. Any potential benefits of therapy in subclinical hyperthyroidism must be weighed against the significant morbidity associated with the treatment of hyperthyroidism.

Iodine status of UK schoolgirls: a cross-sectional survey.

BACKGROUND: Iodine deficiency is the most common cause of preventable mental impairment worldwide. It is defined by WHO as mild if the population median urinary iodine excretion is 50-99 µg/L, moderate if 20-49 µg/L, and severe if less than 20 µg/L. No contemporary data are available for the UK, which has no programme of food or salt iodination. We aimed to assess the current iodine status of the UK population. METHODS: In this cross-sectional survey, we systematically assessed iodine status in schoolgirls aged 14-15 years attending secondary school in nine UK centres. Urinary iodine concentrations and tap water iodine concentrations were measured in June-July, 2009, and November-December, 2009. Ethnic origin, postcode, and a validated diet questionnaire assessing sources of iodine were recorded. FINDINGS: 810 participants provided 737 urine samples. Data for dietary habits and iodine status were available for 664 participants. Median urinary iodine excretion was 80·1 µg/L (IQR 56·9-109·0). Urinary iodine measurements indicative of mild iodine deficiency were present in 51% (n=379) of participants, moderate deficiency in 16% (n=120), and severe deficiency in 1% (n=8). Prevalence of iodine deficiency was highest in Belfast (85%, n=135). Tap water iodine concentrations were low or undetectable and were not positively associated with urinary iodine concentrations. Multivariable general linear model analysis confirmed independent associations between low urinary iodine excretion and sampling in summer (p<0·0001), UK geographical location (p<0·0001), low intake of milk (p=0·03), and high intake of eggs (p=0·02). INTERPRETATION: Our findings suggest that the UK is iodine deficient. Since developing fetuses are the most susceptible to adverse effects of iodine deficiency and even mild perturbations of maternal and fetal thyroid function have an effect on neurodevelopment, these findings are of potential major public health importance. This study has drawn attention to an urgent need for a comprehensive investigation of UK iodine status and implementation of evidence-based recommendations for iodine supplementation. FUNDING: Clinical Endocrinology Trust.

Subclinical hypothyroidism and the risk of coronary heart disease and mortality.

CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease. OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched. DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations. RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease. CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

Thyroid dysfunction in a UK hepatitis C population treated with interferon-alpha and ribavirin combination therapy.

OBJECTIVE: To assess the incidence of thyroid dysfunction (TD) in a UK cohort of patients with hepatitis C virus (HCV) infection treated with interferon-alpha (IFNalpha) and ribavirin combination therapy (IFN/RBV). DESIGN, PATIENTS AND MEASUREMENTS: A retrospective study of 288 patients who received IFN/RBV for HCV during a 2-year period from January 2006 was performed. Thyroid function was assessed during a 24-week or 48-week course of IFN/RBV. If serum thyrotrophin (TSH) became undetectable (<0.01 mU/l) and serum free thyroxine (T4) was raised, a diagnostic thyroid isotope scan was performed. RESULTS: Full medical records were examined for 260 patients (172 men, 88 women) included in the study, of whom 22.3% (16.9% of men, 33.0% of women) developed TD during IFN/RBV. In total, 10.4% developed a suppressed serum TSH (0.8% Graves' disease, 9.6% transient thyroiditis) while 11.9% developed an elevated serum TSH with 1.5% becoming permanently hypothyroid and requiring levothyroxine therapy. Women had a relative risk (RR) for developing TD of 1.96 (CI: 1.75-3.03, P = 0.004). A serum TSH > or =1.75 mU/l and a positive thyroid peroxidase (TPO) antibody titre pretherapy were associated with RRs for progression to TD of 6.02 (CI: 2.95-12.78, P < 0.0001) and 4.35 (CI: 2.58-6.52; P < 0.0001), respectively, while combination of baseline TSH and TPO antibody data predicted progression to TD with a sensitivity of 94.7%. CONCLUSIONS: Although TD was common in this cohort, just 2.3% developed TD that required ongoing therapy. Pre-IFN/RBV serum TSH and TPO antibody titre were found to predict progression to TD in this group of patients.

How should we manage patients with mildly increased serum thyrotrophin concentrations?

A mildly increased serum thyrotrophin (TSH) is usually because of mild thyroid failure, and the most common aetiology in iodine-replete communities is chronic autoimmune thyroiditis. It is more common in women, and the prevalence increases with age in both men and women and is associated with the presence of antithyroid antibodies. The majority will have serum TSH levels between 5-10 mIU/l, normal free thyroxine (T4) levels and relatively few symptoms. In 2004, US evidence-based consensus guidelines concluded that there were no adverse outcomes of a mildly increased serum TSH other than a risk of progression to overt hypothyroidism and few data to justify levothyroxine therapy. There is still debate as to what constitutes an increased serum TSH, particularly in older subjects. Although some subjects will progress to overt hypothyroidism, recent data suggest a significant proportion revert to a serum TSH within the reference range without treatment. Two recent meta-analyses have suggested that the possible cardiovascular risks may be more significant in younger adults. Other data suggest that mild thyroid failure may be the only reversible cause of left ventricular diastolic dysfunction. No appropriately powered prospective, randomized, controlled, double-blinded interventional trial of levothyroxine therapy for a mildly increased serum TSH exists. However, treatment in subjects who are symptomatic, pregnant or preconception, aged less than 65 years and older subjects with evidence of heart failure appear justified.

Thyroid hormone resistance.

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited syndrome of reduced end-organ responsiveness to thyroid hormone. Patients with RTH have elevated serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations and normal or slightly elevated serum thyroid stimulating hormone (TSH) level. Despite a variable clinical presentation, the common characteristic clinical features are goitre but an absence of the usual symptoms and metabolic consequences of thyroid hormone excess. Patients with RTH can be classified on clinical grounds alone into either generalized resistance (GRTH), pituitary resistance (PRTH) or combined. Mutations in the thyroid hormone receptor (TR) beta gene are responsible for RTH and 122 different mutations have now been identified belonging to 300 families. With the exception of one family found to have complete deletion of the TRbeta gene, all others have been demonstrated to have minor alterations at the DNA level. The differential diagnosis includes a TSH-secreting pituitary adenoma and the presence of endogenous antibodies directed against thyroxine (T4) and triiodothyronine (T3). Failure to differentiate RTH from primary thyrotoxicosis has resulted in the inappropriate treatment of nearly one-third of patients. Although occasionally desirable, no specific treatment is available for RTH; however, the diagnosis allows appropriate genetic counselling.

Achieving compliance with the European Working Time Directive in a large teaching hospital: a strategic approach.

This paper describes the strategy which achieved European Working Time Directive (EWTD) compliance at the Royal Free Hampstead NHS Trust in medicine and surgery. Compliance with EWTD regulations was assessed by diary card exercise, clinical care assessed through critical incident reports, electronic handover documents and nursing reports, training opportunities assessed by unit training directors, cost controls assessed by finance department analysis, and workload assessed by staff attendance on wards, in casualty and in theatres. There was a change in focus of care to a consultant-led, specialist registrar- (SpR-)driven service extending into evenings and on weekends, coupled with a move to a multi-skilled team for night cover, and to a move from traditional on-call shifts to a full shift system across both medicine and surgery. Compliance with the EWTD was achieved whilst maintaining good standards of clinical care, ensuring training opportunities for doctors in training, controlling payroll costs, removing the need for locums, and reducing workload for both junior doctors and consultants.

Epidemiology and prevention of clinical and subclinical hypothyroidism.

Iodine deficiency is the most common cause of hypothyroidism worldwide. In persons living in iodine-replete areas, causes are congenital, spontaneous because of chronic autoimmune disease (atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis [Hashimoto's thyroiditis]), or iatrogenic because of goitrogens, drugs, or destructive treatment for thyrotoxicosis. Screening for congenital hypothyroidism exists and its use prevents mental retardation. The prevalence of spontaneous hypothyroidism is between 1% and 2% and is more common in older women and 10 times more common in women than in men. A significant proportion of subjects have asymptomatic chronic autoimmune thyroiditis and 8% of women (10% of women over 55 years of age) and 3% of men have subclinical hypothyroidism. Approximately one third of patients with newly diagnosed overt hypothyroidism have received destructive therapy for hyperthyroidism and indefinite surveillance is required. There is not much that can be done to prevent the occurrence of spontaneous autoimmune hypothyroidism, but if identified early, something can be done to prevent progression to overt disease. Controversy exists as to whether healthy adults would benefit from screening for autoimmune thyroid disease because a significant proportion of subjects tested will have evidence of mild thyroid failure. Case finding in women at menopause or visiting a primary care physician with nonspecific symptoms appears justified.