Outcomes in 125 individuals with adrenal incidentalomas from a single centre. a retrospective assessment of the 1 mg overnight and low dose dexamethasone suppression tests.

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.

Performance of a third-generation TSH-receptor antibody in a UK clinic.

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. OBJECTIVE: To evaluate the diagnostic performance of a TRAb assay in a retrospective and subsequently a prospective cohort in a UK centre. DESIGN: A retrospective review of patients with thyroid disease followed by a prospective observational study in consecutive patients with newly found suppressed serum thyrotrophin (TSH). PATIENTS AND MEASUREMENTS: Medical records of 200 consecutive patients with thyroid disorders who had TRAb measured since the introduction of the assay. In a prospective study 44 patients with newly identified hyperthyroidism (TSH < 0·02 mIU/l) had sera assayed for TRAb prior to their clinic appointment at which a final diagnosis was sought. RESULTS: In the retrospective cohort, the manufacturer's cut-off point of TRAb ≥0·4 U/l resulted in a positive predictive value (PPV) of 95%, sensitivity 85%, specificity 94% and negative predictive value (NVP) 79% to diagnose Graves' disease using defined criteria. Receiver operating characteristic (ROC) analysis determined an optimal cut-off point of TRAb ≥3·5 U/l with a 100% specificity to exclude patients without Graves' disease at the cost though of a lower sensitivity (43%). In the prospective study, the sensitivity, PPV, specificity and NPV were all 96% using the ≥0·4 U/l cut-off. When combining hyperthyroid patients from both cohorts the assay sensitivity and specificity at ≥0·4 U/l cut-off were 95% and 92% respectively. A positive TRAb result increased the probability of Graves' disease for a particular patient by 25-35% and only six (2·5%) patients had a diagnosis of hyperthyroidism of uncertain aetiology after TRAb testing. CONCLUSIONS: The assay studied specifically identifies patients with Graves' disease. It is a reliable tool in the initial clinical assessment to determine the aetiology of hyperthyroidism and has the potential for cost-savings.

Benzofuran derivatives and the thyroid.

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.

Best practice in primary care pathology: review 11.

This eleventh best practice review examines two series of common primary care questions in laboratory medicine: (i) thyroid testing, and (ii) hypercalcaemia and hypocalcaemia. The review is presented in the same question-answer format as in the previous reviews. These questions and answers deal with common situations in men and non-pregnant women. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. In the case of the thyroid series, the recommendations are drawn from the 2006 guidelines published by the Association for Clinical Biochemistry, the British Thyroid Association and the British Thyroid Foundation. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence based. They will be updated periodically to take account of new information.

The cost effectiveness of treatment modalities for thyrotoxicosis in a U.K. center.

OBJECTIVE: This study determined the cost effectiveness of treating thyrotoxicosis using thionamide therapy, radioiodine or surgery in the United Kingdom. DESIGN: One hundred thirty-five patients diagnosed with thyrotoxicosis (62% Graves' disease, 7% nodular disease, 5% thyroiditis, and 27% unknown aetiology) referred in 12 months were offered a fully informed choice of treatment modality. Thirteen patients with transient thyrotoxicosis were subsequently excluded from the analysis. Seventy-four patients (61%) received an 18-month course of thionamide therapy, 43 received radioiodine therapy (35%), and 5 had a thyroidectomy (4%) within the first year of diagnosis as their primary treatment. A successful outcome ("cure") was defined as euthyroidism 12 months after thionamide therapy or euthyroidism or hypothyroidism on thyroxine replacement at 24 months following radioiodine or thyroidectomy. Costs were calculated for outpatient attendances, laboratory tests, and initial and subsequent treatments. MAIN OUTCOME: In the thionamide group 73% were "cured" at 30 months after initiating treatment compared to 95% in the radioiodine group and 100% treated by thyroidectomy at 24 months. Cost per "cure" was calculated to be 3,763 pounds (5,644 dollars) per patient who received thionamides, 1,375 pounds (2,063 dollars) per patient given radioiodine and 6,551 pounds (9,826 dollars) per patient who underwent thyroidectomy. CONCLUSION: The most cost-effective primary treatment modality for thyrotoxicosis is radioiodine.

Population screening for autoimmune thyroid disease.

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.

An audit of the management of thyroid cancer in a district general hospital.

OBJECTIVE: Thyroid cancer is the commonest endocrine malignancy yet it appeared to present infrequently to the endocrinologists at this large District General Hospital. The management of well-differentiated thyroid cancer remains controversial with a wide variation in clinical practice. The aim of this survey was to determine the characteristics of the patients diagnosed with thyroid cancer and whether any deficiencies existed in the management of subjects diagnosed with thyroid cancer over a five-year period using standards of care based upon long-term outcome data and recently published USA guidelines. DESIGN AND PATIENTS: Retrospective case-note survey of all patients newly registered with thyroid cancer from 1990 to 1994 in North Staffordshire (estimated total population 450,000). RESULTS: The annual incidence of all thyroid cancer was two per 100,000 of which well-differentiated tumours comprised 70%. Medical records were obtained in 48 new cases (91% of total) identified. Fifteen subjects who presented as surgical emergencies received only palliative treatment and had a poor outcome. Two patients presented with metastatic medullary thyroid carcinoma (3% of total). Thirty-one patients (97% of whom presented with a thyroid nodule) were referred electively to either surgical (n = 22), ENT (n = 2) or endocrinology (n = 7) outpatients with well-differentiated papillary (n = 17) and follicular (n = 14) tumours. Thirteen patients (42%) had fine-needle aspiration cytology performed preoperatively. Of the 22 tumours (71%) greater than 1.5 cm, five (27%) had a total thyroidectomy and two (9%) also had radioiodine ablation. There was inadequate serum thyrotrophin suppression postoperatively in 12 patients (39%) and only five (16%) were being monitored for recurrence with serum thyroglobulin measurements. CONCLUSIONS: Deficiencies in the optimum management of small, well-differentiated thyroid cancers were identified. Improved communication between specialties has led to the development of an agreed management protocol to increase the quality of care offered to patients with thyroid cancer and for auditing the coordinated service in the future.

The prevalence of hyperprolactinaemia and association with markers of autoimmune thyroid disease in survivors of the Whickham Survey cohort.

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 degrees 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 < or = 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 < 0.0001). CONCLUSIONS: This study has demonstrated that a gender-related reference range for serum prolactin is necessary. Pituitary pathology is not common and screening with measurement of serum prolactin is not warranted in middle-aged and elderly subjects. In asymptomatic subjects with modestly elevated serum prolactin levels (< 3 SD above the mean), extensive pituitary imaging and investigation is unwarranted. Autoimmune thyroid disease was not a significant cause of hyperprolactinaemia in this sample.

Does an increase in the sensitivity of serum thyrotropin assays reduce diagnostic costs for thyroid disease in the community?

Many authorities now advocate that the first-line assessment of thyroid function should be measurement of thyrotropin (TSH). The latest serum TSH assays (third generation) are more sensitive than the second generation but the reagents are more costly. We have examined whether overall assay reagent costs would be higher or lower with a third-generation assay, in a laboratory that serves a population of almost 500,000. In a prospective study over six weeks, 505 samples with a second-generation serum TSH less than 0.5 mU/L (303 for screening and 202 for monitoring thyroxine therapy) had an additional third-generation TSH analysis. With a second-generation assay for screening, 11% more free thyroxine (FT4) measurements were required to exclude thyrotoxicosis but there was a 42% saving on the reagent budget compared with a third-generation assay. In patients taking thyroxine, 33% more FT4 measurements were required to exclude over-replacement but the calculated saving in reagent costs was 53%. The costs of all other aspects of the two methods were similar. In this community-based sample, the improvement in sensitivity yielded by the third-generation assay at the lower end of the normal range reduced the number of confirmatory FT4 levels required to exclude thyrotoxicosis or over-replacement with thyroxine, but reagent costs were nevertheless higher than for second-generation assays. In financial terms, there is little justification for use of assays with sensitivity greater than the second generation (0.1 mU/L).

The incidence of diabetes mellitus in an English community: a 20-year follow-up of the Whickham Survey.

The original Whickham Survey documented the prevalence of diabetes and lipid disorders in a sample of 2779 adults aged 18 years and over, which matched the British population structure. The aim of the 20-year follow-up study was to determine the incidence and natural history of diabetes. Outcomes in terms of morbidity and mortality at follow-up were determined in over 97% of the original population. Ninety-four subjects had been identified and treated for diabetes since the first survey, including 17 subjects identified as having a fasting plasma glucose > or = 7.8 mmol l-1 at follow-up. The incidence of diabetes for the total population was 2.2 1000-1 year-1 (95% confidence interval 1.8, 2.6). The risk factors identified at first survey were corrected for age, cut-off at the 95 centile and entered into a log linear model. Those which strongly predicted development of diabetes in the total population were fasting blood glucose (odds ratio (OR) (with 95% confidence intervals) = 2.3 (1.5, 3.5)) and body mass index (OR = 2.2 (1.5, 3.3)) in men, and fasting blood glucose (OR = 2.6 (1.7, 4.1)) and fasting serum triglyceride (OR = 2.8 (1.8, 4.4)) in women. A logit model has enabled the calculation of the probability of developing diabetes 20 years later. It was the characteristics of becoming older such as obesity, hypertriglyceridaemia, and raised fasting blood glucose, rather than age itself, which were associated with the development of diabetes.

The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community.

The original Whickham Survey documented risk factors for cardiovascular disease and the prevalence of thyroid disorders in a sample of 2779 adults that closely matched the British population. A 20-year follow-up study has determined outcomes in terms of morbidity and mortality from ischemic heart disease in over 97% of the original survey population. Analysis of deaths from all causes and from ischemic heart disease showed no association with antithyroid antibody status identified at first survey. A multiple logistic regression using the development of ischemic heart disease in the total population at follow-up as the dependent variable found that the significant predictor variables for men were age, cholesterol, mean arterial blood pressure, smoking history, and skinfold thickness index. For women only age, cholesterol, and mean arterial blood pressure were significant. The presence of autoimmune thyroid disease, as defined by either hypothyroidism, positive antithyroid antibodies, or raised serum thyrotropin at first survey, was not significant. A retrospective cohort study of a subsample of women identified at first survey with positive antithyroid antibodies or raised serum thyrotropin and closely matched controls found no significant association with mortality or development of ischemic heart disease. There is no evidence from this study to suggest that evidence of autoimmune thyroid disease identified 20 years ago is associated with an increased risk of ischemic heart disease.

The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey.

BACKGROUND AND OBJECTIVE: The original Whickham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the incidence and natural history of thyroid disease in this cohort. DESIGN, PATIENTS AND MEASUREMENTS: Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, in addition to death certificates, two-thirds had information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91% were tested for clinical, biochemical and immunological evidence of thyroid dysfunction. RESULTS: Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean incidence (with 95% confidence intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism in women was 0.8/1000 survivors/year (0.5-1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an increase with age in hypothyroidism but no age relation in hyperthyroidism. The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially. The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors identified at first survey. The odds ratios (with 95% confidence intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A logit model indicated that increasing values of serum TSH above 2mU/l at first survey increased the probability of developing hypothyroidism which was further increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism in women. CONCLUSIONS: This historical cohort study has provided incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease identified twenty years earlier.