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This chapter covers the anatomy and physiology of the thyroid, and the molecular action of the thyroid hormone. It explains tests of hormone concentration and homeostatic control, and rare genetic disorders associated with thyroid hormone metabolism. It covers antibody screens and screening for thyroid disease, ultrasound scanning, fine needle aspiration cytology, computed tomography, positron emission tomography, and other laboratory investigations. It then covers various thyroid-associated diseases, their treatment (medical and surgical when necessary), and any follow-up management programmes.

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 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.

See Fig. 1 for an emergency management summary. Open in a separate window Figure 1 Pituitary apoplexy emergency management summary.

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.

Treatment with amiodarone is associated with changes in thyroid function tests, but also with thyroid dysfunction (amiodarone-induced hypothyroidism, AIH, and amiodarone-induced thyrotoxicosis, AIT). Both AIH and AIT may develop in apparently normal thyroid glands or in the presence of underlying thyroid abnormalities. AIH does not require amiodarone withdrawal, and is treated with levothyroxine replacement if overt, whereas subclinical forms may be followed without treatment. Two main types of AIT are recognized: type 1 AIT (AIT 1), a form of iodine-induced hyperthyroidism occurring in nodular goitres or latent Graves disease, and type 2 AIT (AIT 2), resulting from destructive thyroiditis in a normal thyroid gland. Mixed/indefinite forms exist due to both pathogenic mechanisms. AIT 1 is best treated with thionamides that may be combined for a few weeks with sodium perchlorate to make the thyroid gland more sensitive to thionamides. AIT 2 is treated with oral glucocorticoids. Once euthyroidism has been restored, AIT 2 patients are followed up without treatment, whereas AIT 1 patients should be treated with thyroidectomy or radioiodine. Mixed/indefinite forms of AIT are treated with thionamides. Oral glucocorticoids can be added from the beginning if a precise diagnosis is uncertain, or after a few weeks if response to thionamides alone is poor. The decision to continue or to stop amiodarone in AIT should be individualized in relation to cardiovascular risk stratification and taken jointly by specialist cardiologists and endocrinologists. In the presence of rapidly deteriorating cardiac conditions, emergency thyroidectomy may be required for all forms of AIT. (c) 2018 European Thyroid Association Published by S. Karger AG, Basel

Introduction: Subclinical thyroid disease is acommon finding on testing of thyroidfunction and its management remains controversial.Source of data: Epidemiological datafrom large population studies from USAandEurope.Areas of agreement: There is an increased riskof progression to overthypothyroidism or hyperthyroidism. The treatment of mild thyroid failure is ofimportance in optimizing pregnancyoutcome.Areas of controversy: Diagnostic criteria differand there is variation betweenmanagement guidelines. The differencewas found in long-term clinical outcomesbetween endogenous andexogenoussubclinical hyperthyroidism.Growing points: Meta-analyses have provided epidemiological data incardiovascular mortalityand morbidity in subclinical thyroid disease. Increased useof echocardiographyand bonemarkers in identifying thosewho benefitfromintervention.Areastimely for developing research: A randomized controlled trial to identifythose subjects identified from screening programmesthat benefitfromintervention in terms of morbidityand mortality.

The World Health Organization (WHO) estimates that worldwide 2 billion people, including 285 million school-age children, still have iodine deficiency despite major national and international efforts to increase iodine intake, primarily through the voluntary or mandatory iodization of salt. Iodine deficiency has substantial effects on growth and development and is the most common cause of preventable mental impairment worldwide. Although endemic cretinism had been long recognized to be associated with iodine deficiency, the article from Pharoah, Buttfield and Hetzel in 1971 recognized the importance of severe iodine deficiency and its correction in early pregnancy in a classic interventional epidemiological study. The recent Copenhagen Consensus of 2008 (www.copenhagenconsensus.com) identified salt iodization as the third most important and cost-effective intervention for confronting ten great global challenges. Although the introduction of iodized salt has considerably improved the situation globally in the developing world, iodine deficiency remains an issue in continental Europe where it is estimated that up to 50% of the children live in iodine-deficient communities. Mild iodine deficiency impairs cognition in children, and moderate to severe iodine deficiency in a population reduces the intelligence quotient by 10–15 points. Iodine supplementation pre-pregnancy may prevent this adverse effect on the intellectual development of infants and children. Mild to moderate iodine deficiency occurs in areas that are not immediately recognized as iodine deficient. Iodine deficiency has historically been considered an issue for developing countries rather than industrialized countries such as the UK. Endemic goitre associated with iodine deficiency was at one time widespread in the UK and Medical Research Council surveys in 1924 and 1944 reported visible goitre in up to 50% of the adult women and schoolgirls. No salt iodization programme was adopted in the UK unlike in other European countries. Since the 1940s, significant changes in farming practice in the UK were associated with a rise in the iodine content of milk, particularly during winter months when cattle are dependent on iodine-rich artificial feed. In addition, successive UK governments from the 1940s encouraged increased milk consumption in schoolchildren. By the 1980s, this resulted in the iodine content of milk alone being almost sufficient to meet the recommended daily requirement of 150 mg/day and has been described as an ‘accidental public health triumph’. Although national monitoring of milk iodine content continued, the major concern was to avoid the harmful effects of iodine toxicity rather than deficiency. My interest in thyroid epidemiology was stimulated where as a research fellow in Newcastle-upon-Tyne working with Mike Tunbridge who had led the original Whickham survey documenting the prevalence of thyroid disorders in a representative sample of the UK in the early 1970s. Sixteen percent of the cohort had small but easily palpable diffuse or multinodular goitres. In men, the prevalence of goitre declined with age from 7% in those aged

Introduction: Thyroid disorders are prevalent and their manifestations aredetermined by the dietary iodine availability.Sources of data: Data from screening large population samples from USA andEurope.Areas of agreement: The most common cause of thyroid disorders worldwide isiodine 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 techniquesused for assessment of thyroid function.Growing points: Increasing incidence of well-differentiated thyroid cancer.Environmental iodine influences the epidemiology of non-malignant thyroiddisease.Areas timely for developing research: Iodine supplementation of populationswith mild-to-moderate iodine deficiency. An evidence-based strategy for the riskstratification, treatment and follow-up of benign nodular thyroid disease. Isthere any benefit in screening adults for thyroid dysfunction?

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 (

Background UK national guidelines recommend the measurement of TSH receptor antibodies (TRAb) in certain clinical scenarios. A commercial third-generation TRAb autoantibody M22-biotin ELISA assay was introduced in May 2008 in our centre.

Classical pituitary apoplexy is a medical emergency and rapid replacement with hydrocortisone maybe life saving. It is a clinical syndrome characterized by the sudden onset of headache, vomiting, visual impairment and decreased consciousness caused by haemorrhage and/or infarction of the pituitary gland. It is associated with the sudden onset of headache accompanied or not by neurological symptoms involving the second, third, fourth and sixth cranial nerves. If diagnosed patients should be referred to a multidisciplinary team comprising, amongst others, a neurosurgeon and an endocrinologist. Apart from patients with worsening neurological symptoms in whom surgery is indicated, it is unclear currently for the majority of patients whether conservative or surgical management carries the best outcome. Post apoplexy, there needs to be careful monitoring for recurrence of tumour growth. It is suggested that further trials be carried out into the management of pituitary apoplexy to optimize treatment.

Context: Subclinical hypothyroidism (SCH) is a common condition that has been associated with ischemic heart disease (IHD) in some, but not all, studies. This may be due to differences in study design and the characteristics of participants. Objective: Our objective was to investigate whether age and gender influence IHD prevalence, incidence, and mortality in people with SCH. Data Sources: Computerized (PubMed, EMBASE, and Cochrane Library) and manual searches of the literature to May 2007, published in English, were performed. Study Selection: Epidemiological studies that quantified thyroid status and IHD events in adults were performed. Data Extraction: Two authors independently reviewed articles and abstracted data. Results were compared across two groups based on the minimum age of participants studied (younger than 65 yr and 65 yr or older). Data Synthesis: There were 15 studies included for analysis with 2,531 SCH participants and 26,491 euthyroid individuals. IHD incidence and prevalence were higher in SCH subjects compared with euthyroid participants from studies including those younger than 65 yr, but not studies of subjects aged older than 65 yr [odds ratio (95% confidence interval)]: 1.57 (1.19–2.06) vs. 1.01 (0.87–1.18) and 1.68 (1.27–2.23) vs. 1.02 (0.85–1.22), respectively. Cardiovascular/all-cause mortality was also elevated in participants from the younger than 65-yr studies, but not from the studies of older people: odds ratio 1.37 (1.04–1.79) vs. 0.85 (0.56–1.29). Prevalent IHD was higher in SCH participants of both genders, although this was statistically significant only in women. Conclusions: SCH is associated with increased IHD (both prevalence and incidence) and cardiovascular mortality only in subjects from younger populations. These data suggest that increased vascular risk may only be present in younger individuals with SCH.

Objectives The aims of the study were (i) to investigate the prevalence of overt and subclinical thyroid disease in HIV-positive patients in a London teaching hospital; (ii) to determine risk factors associated with the development of thyroid dysfunction, including highly active antiretroviral therapy (HAART) and individual antivirals, and (iii) to determine the occurrence of thyroid dysfunction longitudinally over 3 years. Methods The study consisted of retrospective analyses of thyroid function tests (TFT) in HIV-positive patients. The period prevalence of and factors associated with clinical and subclinical thyroid dysfunction were investigated. Patients with normal TFT but previous thyroid disease were identified from pharmacy records and included in the overt category. Results A total of 1565 patients (73% of the clinic population) had at least one TFT taken since 2001. Overall, 3584 samples were analysed. Of the patients included in the study, 1233 (79%) were male, 1043 (66%) were white and 365 (23%) were black African, and in 969 (62%) the main risk for HIV was homosexual sex. Median age at baseline was 37 years. Nine hundred patients (58%) were on HAART at the start of the study. Thirty-nine (2.5%) were found to have overt hypothyroidism, and eight (

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.

The management of primary hypothyroidism with levothyroxine (L-T4) is simple, effective and safe, and most patients report improved well-being on initiation of treatment. However, a proportion of individuals continue to suffer with symptoms despite achieving adequate biochemical correction. The management of such individuals has been the subject of controversy and of considerable public interest. The American Thyroid Association (ATA) and the European Thyroid Association (ETA) have recently published guidelines on the diagnosis and management of hypothyroidism. These guidelines have been based on extensive reviews of the medical literature and include sections on the role of combination therapy with L-T4 and liothyronine (L-T3) in individuals who are persistently dissatisfied with L-T4 therapy. This position statement by the British Thyroid Association (BTA) summarises the key points in these guidelines and makes recommendations on the management of primary hypothyroidism based on the current literature, review of the published positions of the ETA and ATA, and in line with best principles of good medical practice. The statement is endorsed by the Association of Clinical Biochemistry, (ACB), British Thyroid Foundation, (BTF), Royal College of Physicians (RCP) and Society for Endocrinology (SFE).

Iodine is an essential component of the thyroid hormones, which play a crucial role in brain and neurological development. At least one-third of the world's population is estimated to be iodine deficient predominantly in developing countries. Recently concern had also been expressed about the iodine status in industrialised countries such as the UK. A recent survey of the UK iodine status found that that more than two-thirds of schoolgirls aged 14-15 years were iodine deficient due to the reduced milk intake. Maternal iodine deficiency in pregnancy is correlated with cognitive outcomes such as intelligence quotient and reading ability in offspring. No randomised trial data exist for iodine supplementation in mild-moderate iodine-deficient pregnant women. It is possible to combine population interventions to reduce population salt intake with salt iodisation programmes in order to maintain adequate levels of iodine nutrition.

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.

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.

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.

Whether or not healthy adults in the community would benefit from screening for autoimmune thyroid disease is controversial. Although the prevalence of unsuspected overt thyroid disease is low, a significant proportion of subjects tested will have evidence of mild thyroid failure or excess. This article assesses whether subclinical thyroid disease is of sufficient clinical importance to warrant screening and, once detected and confirmed, to justify therapy. Population screening for autoimmune thyroid disease is assessed against recently revised screening criteria, using data from epidemiologic studies. Recommendations are proposed that may be applied in any iodine-replete community.

OBJECTIVE Few data exist on the prevalence of hyperprolactinaemia in the community. This study was intended to determine the prevalence of hyperprolactinaemia in a sample closely matched to the current British population aged 38 years and over. DESIGN AND PATIENTS The 1877 survivors at the 20-year follow-up of the Whickham Survey were a cross-sectional sample of the community aged 38 years and over. Serum was frozen and stored at −30°C from 90% of the survivors (751 men, 924 women, median age 58 years (range 38 to 93 years)) who participated in the follow-up survey. MEASUREMENTS Two years after the follow-up survey, serum prolactin concentrations were measured by ELISA/1 step sandwich assay (reference range ≤ 600 mU/l in men and women). A repeat prolactin measurement was made in those subjects who had prolactin levels within the top 2.5% of men and women in this sample. RESULTS At screening, 0.7% of the men and 2.5% of the women had serum prolactin levels greater than 600 mU/l. For men, 2.5% were above 400 mU/l. The prevalence of hyperprolactinaemia, if defined as greater than 400 mU/l in men and greater than 600 mU/l in women on repeat testing, was 1.4% in the men and 1.2% in the women. The aetiology in men was prolactin-raising drugs (n = 3), renal failure (n = 1), microprolactinoma (n = 1), and unknown (n = 2), and in women it was prolactin-raising drugs (n = 7), microprolactinoma (n = 1), and unknown (n = 1). Logarithmic transformation of serum prolactin concentrations produced Gaussian distributions with 95% reference ranges of 60–430 mU/l in men and 40–560 mU/l in women. No significant relationship was found in either sex between hyperprolactinaemia and age or evidence of autoimmune thyroid disease at either survey. In women, there was no association with age, distance beyond the menopause or duration of reproductive years but prolactin levels were slightly higher in those on oestrogen therapy (geometric mean prolactin 226 mU/l compared to 178 mU/l; t-test on log prolactin t = 3.79; P

Nonfunctioning pituitary tumours account for one-third of all pituitary neoplasms, with an incidence of 7–9 new cases/106 every year. They are slow-growing benign monoclonal adenomas that do not cause any hormone hypersecretion syndromes. Symptoms arise from local compression of normal pituitary tissue and surrounding structures. The aim of treatment is the preservation of residual pituitary function and alleviation of local compressive mass effects. The available published series show that nonfunctioning adenomas constitute the underlying diagnosis in 45 % of patients with pituitary apoplexy. Apoplexy occurs more often in macroadenomas, men and with antithrombotic use. Headache, ophthalmoplegia, reduced visual acuity and visual filed defects are common presenting features. ACTH, TSH and gonadotropin deficiencies are frequently present and need to be assessed biochemically in patients with suspected pituitary apoplexy. A low serum prolactin at presentation has been linked with the severity of hypopituitarism postsurgical decompression. Patients with nonfunctioning pituitary adenomas who present with apoplexy have reduced 5-year rates of tumour regrowth (11 %) compared to non-apoplectic surgically treated nonirradiated nonfunctioning pituitary adenomas (18–34 % in different series). In those patients operated for pituitary apoplexy, tumour recurrence seems to be more common in patients with residual post-operative tumour.

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.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.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.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.

Adrenal masses discovered incidentally during imaging studies - adrenal incidentalomas (AIs) - are common and prompt investigations to exclude secretory lesions and malignancy. Their best management strategy is unknown. Our objectives were to identify all outcomes of AI investigation in a UK centre and to assess the performance of the 2 mg low dose (LDDST) and 1 mg overnight dexamethasone (ODST) suppression tests in this setting. Out of 125 patients referred to our centre between 2005 and 2009 with AIs, 16 (12.8%) were diagnosed with secretory adrenal adenomas. 24 patients (23%) failed to suppress on LDDST or ODST using a serum cortisol cut-off of 50 nmol/l for both tests; in 12 this was due to false positive results. 5 patients were diagnosed with adrenal Cushing's syndrome and 7 with subclinical hypercortisolism. The use of a higher post LDDST (83 nmol/l) or ODST (138 nmol/l) cortisol cut-off would have resulted in missing 1 patient with Cushing's syndrome and 4 with subclinical hypercortisolism or 2 patients with Cushing's syndrome and 1 with subclinical hypercortisolism, respectively. In patients who had both tests, the ODST systematically resulted in higher post-test cortisol values compared with the LDDST. The adenoma diameter correlated with and was predictive of the post LDDST cortisol. Our results indicate that altering the post dexamethasone cut-off in accordance to published guidelines changes the performance of the suppression tests. The ODST may result in higher post-test cortisol levels compared to LDDST when used in patients with AIs.

Classic pituitary apoplexy is rare. It occurs in approximately 5% of patients with a pituitary tumour, and for 80% of apoplexy patients is the first presentation of the tumour, although subtle symptoms (eg, of hypogonadism) may have been present for some years. It is important because delays can occur in the diagnosis, which may be associated with morbidity and even mortality.1 Furthermore, early multidisciplinary intervention can improve outcomes in terms of visual function. It is characterised by the sudden onset of severe headache, vomiting, visual impairment and decreased consciousness caused by haemorrhage or infarction of the pituitary gland. These clinical manifestations of pituitary apoplexy are caused by a rapid increase in intrasellar pressure.2 Lateral compression can affect the contents of the cavernous sinus leading to ocular palsies in nearly 70% of patients.3 4 The third cranial (oculomotor) nerve is the most common nerve to be affected. Decreased visual acuity and visual field defects, specifically bitemporal hemianopia are seen in nearly 75% of patients and are caused by upward enlargement of the intrasellar contents, leading to …

Context: The Whickham Survey evaluated vascular events over 20 yr in community-dwelling subjects stratified by thyroid function and thyroid autoantibody status. No association between ischemic heart disease (IHD) and a composite autoimmune thyroid disease group, comprising individuals with subclinical hypothyroidism (SCH), with positive thyroid antibodies or those using levothyroxine, was found. This result appears to be at odds with the findings of other cohort studies. Objective: The objective of the study was to evaluate incident IHD and mortality in participants in relation to their thyroid status. Outcomes, Design, and Participants: Data were reanalyzed assessing incident IHD events and mortality during 20 yr of follow-up in individuals with endogenous SCH (n = 97; TSH 6.0–15 mIU/liter) vs. the euthyroid group (n = 2279), who were IHD free at baseline. Results: Incident IHD was significantly higher in the SCH group [adjusted hazard ratio 1.76 (95% confidence interval 1.15–2.71); P = 0.01]. IHD mortality was also increased in the SCH group [hazard ratio of 1.79 (1.02–3.56); P = 0.05]. These findings lost their significance when subsequent treatment with levothyroxine was excluded from the regression model. There was no difference in all-cause mortality between the groups. Conclusion: In the Whickham Survey, there is an association between incident IHD events and IHD-related mortality with SCH over the 20 yr of follow-up. Furthermore, subsequent treatment of SCH with levothyroxine appears to attenuate IHD-related morbidity and mortality, and this may explain why some other longitudinal studies of SCH have not shown such an association; properly designed controlled trials of treatment of SCH are required to answer this question definitively.

Summary Objective To assess the incidence of thyroid dysfunction (TD) in a UK cohort of patients with hepatitis C virus (HCV) infection treated with interferon-α (IFNα) 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 (

MarkP.J.VanderpumpConsultantPhysicianandHonorarySeniorLecturerinEndocrinologyandDiabetes,DepartmentofEndocrinology,RoyalFreeHampsteadNHSTrust,London,UKSummaryA mildly increased serum thyrotrophin (TSH) is usually becauseof mild thyroid failure, and the most common aetiology iniodine-replete communities is chronic autoimmune thyroiditis. Itis more common in women, and the prevalence increases withage in both men and women and is associated with the presenceof antithyroid antibodies. The majority will have serum TSHlevels between 5–10 mIU/l, normal free thyroxine (T4) levels andrelatively few symptoms. In 2004, US evidence-based consensusguidelines concluded that there were no adverse outcomes of amildly increased serum TSH other than a risk of progression toovert hypothyroidism and few data to justify levothyroxinetherapy. There is still debate as to what constitutes an increasedserum TSH, particularly in older subjects. Although some sub-jects will progress to overt hypothyroidism, recent data suggest asignificant proportion revert to a serum TSH within the referencerange without treatment. Two recent meta-analyses have sug-gested that the possible cardiovascular risks may be more signifi-cant in younger adults. Other data suggest that mild thyroidfailure may be the only reversible cause of left ventriculardiastolic dysfunction. No appropriately powered prospective,randomized, controlled, double-blinded interventional trial oflevothyroxine therapy for a mildly increased serum TSH exists.However, treatment in subjects who are symptomatic, pregnantor preconception, aged less than 65 years and older subjects withevidence of heart failure appear justified.(Received 18 August 2009; returned for revision 11 September2009; finally revised 19 September 2009; accepted 21 September2009)IntroductionSerum thyrotrophin (TSH) is the first-line diagnostic test for hypo-thyroidism. Normal serum TSH levels in thyroid disease-free indi-viduals are typically cited as about 0AE4–4AE0mIU/l.

Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three decades. However amiodarone and its main metabolically active metabolite desethylamiodarone can adversely affect many organs, including the thyroid gland. Amiodarone-induced thyroid disorders are common and often present as a management challenge for endocrinologists. The pathogenesis of amiodarone-induced thyroid dysfunction is complex but the inherent effects of the drug itself as well as its high iodine content appear to play a central role. The non-iodinated dronedarone also exhibits anti-arrhythmic properties but appears to be less toxic to the thyroid. This review describes the biochemistry of benzofuran derivatives, including their pharmacology and the physiology necessary for understanding the cellular mechanisms involved in their actions. The known effects of these compounds on thyroid action are described. Recommendations for management of amiodarone-induced hypothyroidism and thyrotoxicosis are suggested. Dronedarone appears to be an alternative but less-effective anti-arrhythmic agent and it does not have adverse effects on thyroid function. It may have a future role as an alternative agent in patients being considered for amiodarone therapy especially those at high risk of developing thyroid dysfunction but not in severe heart failure.

Clinical focus on hypocalcaemia

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) β 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 TR β 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.

Speakers at the course were given vignettes describing one or more clinical scenarios on which to base their talks, selected because they represent common but challenging problems likely to be encountered by any physician practising in general internal medicine. Three of the subjects covered – weird thyroid function tests, difficult gout, and dementia – are presented here.