Antithyroid drugs in Graves' hyperthyroidism: differences between "block and replace" and "titration" regimes in frequency of euthyroidism and Graves' orbitopathy during treatment.

PURPOSE: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy. METHODS: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy. RESULTS: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. CONCLUSION: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Current challenges in the pharmacological management of thyroid dysfunction in pregnancy.

INTRODUCTION: Thyroid dysfunction is common in pregnancy and has adverse fetal and maternal health consequences. A number of challenges in the management of gestational thyroid dysfunction remain unresolved including uncertainties in optimal thresholds for correction of hypothyroidism and strategies for pharmacological management of hyperthyroidism. Areas covered: We addressed key challenges and areas of uncertainty in the management of thyroid dysfunction in pregnancy. Expert commentary: Gestational thyroid hormone reference intervals vary according to population ethnicity, iodine nutrition, and assay method and each population should derive trimester specific reference intervals for use in pregnancy. Subclinical hypothyroidism and isolated hypothyroxinaemia are common in pregnancy but there is no consensus on the benefits of correcting these conditions. Although observational studies show potential benefits of levothyroxine on child neurocognitive function these benefits are have not been supported by two controlled trials. Carbimazole should be avoided in the first trimester of pregnancy due to risk of congenital anomalies but recent studies would suggest that this risk is present to a lesser magnitude with propylthiouracil. Current international guidelines recommend the use of propylthiouracil in the first trimester and switching to carbimazole for the remainder of pregnancy but the benefits and practicalities of this approach is unproven.

Thyroxine replacement: a clinical endocrinologist's viewpoint.

BACKGROUND: Hypothyroidism affects 2-5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30-50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval. METHODS: This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement. RESULTS: Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited. CONCLUSION: Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes.

Prognostic significance of thyroglobulin antibody epitopes in differentiated thyroid cancer.

CONTEXT: Thyroglobulin antibodies (TgAbs) are surrogate markers of disease recurrence or persistence in differentiated thyroid cancer (DTC). However, the prognostic significance of TgAb heterogeneity in DTC has not been investigated. OBJECTIVE: To evaluate the relationship between TgAb epitope specificities and clinical outcomes in DTC patients. DESIGN: We studied 61 TgAb-positive patients with DTC, post-thyroidectomy and remnant ablation (7 males, 54 females; age-range 16-80 years, median follow-up duration 8.9 years). TgAb epitope reactivities were mapped using a panel of 10 thyroglobulin (Tg) monoclonal antibodies delineating six antigenic Tg clusters in competitive ELISA studies. Sera from 45 patients with Hashimoto's thyroiditis (HT) and 22 TgAb-positive healthy subjects served as autoimmune and healthy controls. Tg was measured by immunoradiometric assay (IRMA), electrochemiluminescence immunoassay (ECLIA), and RIA, while TgAbs was measured by ELISA and ECLIA methods. RESULTS: Samples from 26 DTC patients showed TgAb epitope restriction similar to HT patients, while 35 patients exhibited nonspecific reactivity comparable to healthy controls. DTC patients with epitope restriction had higher rates of recurrent/persistent disease (81% vs 17%, P < .001), higher median TgAb concentration (887.0 vs 82.0 kIU/L; P < .001), and a higher prevalence of thyroid lymphocytic infiltration (71.4% vs 26.8%; P < .001) compared to patients with nonspecific reactivity. Samples with epitope restriction also had a lower median Tg-IRMA/RIA ratio (3.0% vs 36.0%; P < .001) denoting greater degrees of Tg assay interference. CONCLUSIONS: TgAb epitope restriction is associated with a less favorable prognosis than nonspecific reactivity in DTC patients. TgAb epitope specificities may have prognostic value in DTC.

Trends in hospital admissions with diabetic ketoacidosis in Wales, 1999-2010.

We determined the incidence of diabetic ketoacidosis in Wales using nationwide hospital discharge data. Ketoacidosis admission rate was 24 per 100,000 person years and increased progressively from 1999 to 2010. The highest incidence was seen in 10-29 year olds, highlighting the need for targeted prevention in this age-group.

Serum thyrotrophin at baseline predicts the natural course of subclinical hyperthyroidism.

OBJECTIVE: Optimal therapeutic strategies for subclinical hyperthyroidism are undecided. Overt disease develops in a minority of cases, but the risk factors for progression remain unclear. We examined whether a baseline thyrotrophin (TSH) predicted progression to overt hyperthyroidism in asymptomatic individuals with subclinical hyperthyroidism. DESIGN, PATIENTS AND MEASUREMENTS: This was a retrospective study of 323 patients with subclinical hyperthyroidism seen in our institution from 2003 to 2010 (mean age 71 years, males 26·9%, females 73·1%, mean follow-up duration 32 months, range 6-93 months). Serum TSH and free thyroxine (FT4) were documented at baseline and during follow-up. After excluding individuals with nonthyroid causes of low TSH, patients were grouped according to initial TSH as: TSH 0·10-0·39 mU/l (grade I) and TSH < 0·10 mU/l (grade II). RESULTS: Only 38 patients (11·8%) developed overt hyperthyroidism with annual progression rates of 0·6-3·7%. Most patients reverted to normal thyroid status (31·6%) or remained subclinically hyperthyroid (56·7%). Progression to frank hyperthyroidism was higher in grade II than in grade I patients (20·3% vs 6·8%, P < 0·001, Chi square test). Kaplan-Meier curves showed faster progression rates in grade II than grade I (P < 0·001, log rank test). In stepwise multivariate Cox regression analysis, TSH < 0·1 mU/l was associated with overt hyperthyroidism (hazard ratio 3·4, confidence interval 1·6-7·0), whereas age, gender, FT4 and aetiological diagnosis were not associated with hyperthyroidism. CONCLUSIONS: Thyrotrophin predicts overt hyperthyroidism in asymptomatic individuals with subclinical hyperthyroidism. Patients with TSH < 0·10 mU/l have a higher risk of progressing to hyperthyroidism than those with TSH 0·10-0·39 mU/l.

Adequacy of thyroid hormone replacement in a general population.

BACKGROUND: Suboptimal thyroid hormone replacement may carry harmful health consequences. AIMS: Our objectives were to determine the prevalence and factors associated with inadequate replacement in patients receiving treatment with levothyroxine. DESIGN: Retrospective general practice audit. METHODS: We identified levothyroxine users through electronic searches of primary care records in all 11 practices within a county borough. The adequacy of thyroid hormone replacement was determined from the current serum, serum thyrotropin (TSH) as: (i) adequate replacement (normal TSH; 0.4-4.0 mU/l); (ii) over replacement (low TSH; <0.4 mU/l); and (iii) under replacement (high TSH; >4.0 mU/l). RESULTS: Out of a registered patient population of 58 567, we identified 1037 patients who were first included in the hypothyroidism disease register between January 2004 and December 2009 (mean age 62.4 ± 15.9 years; female 85.9%, male 14.1%). Inadequate replacement was seen in 385 patients (37.2%), comprising 205 patients (19.8%) with over replacement and 180 patients (17.4%) with under replacement. Step-wise logistic regression showed that the factors associated with under replacement were male gender [odds ratio (OR) 2.85, confidence interval (CI) 1.86-4.38; P < 0.001 and younger age (OR 0.88, CI 0.80-0.98; P = 0.02 per 10 year increase in age) while longer duration of treatment was associated with over-treatment (OR 1.06, CI 1.01-1.10). A thyroid function test was performed in the preceding 12 months in 914 patients (88.1%) and appropriate dose adjustments had been made in 81.0% (312/385) of patients with abnormal results. CONCLUSION: Despite frequent monitoring and dose adjustment activities, inadequate thyroid hormone replacement remained a problem in over a third of levothyroxine users in this population.

Thyroid dysfunction in patients with diabetes: clinical implications and screening strategies.

BACKGROUND: Patients with diabetes mellitus are at an increased risk of thyroid disease. The frequency of thyroid dysfunction in diabetic patients is higher than that of the general population and up to a third of patients with type-1 diabetes (T1DM) ultimately develop thyroid dysfunction. Unrecognised thyroid dysfunction may impair metabolic control and add to cardiovascular disease risk in diabetic patients. AIMS: Our aims were to review the current literature on the association between thyroid dysfunction and diabetes mellitus, to highlight relevant clinical implications, and to examine present thyroid disease screening strategies in routine diabetes care. RESULTS: The pleiotropic effects of thyroid hormones on various metabolic processes are now better understood. Uncontrolled hyperthyroidism in diabetic patients may trigger hyperglycaemic emergencies while recurrent hypoglycaemic episodes have been reported in diabetic patients with hypothyroidism. Furthermore, thyroid dysfunction may amplify cardiovascular disease risk in diabetic patients through inter-relationships with dyslipidaemia, insulin resistance and vascular endothelial dysfunction. However, the significance of subclinical degrees of thyroid dysfunction remains to be clarified. While these developments have implications for diabetic patients a consensus is yet to be reached on optimal thyroid screening strategies in diabetes management. CONCLUSIONS: The increased frequency of thyroid dysfunction in diabetic patients and its likely deleterious effects on cardiovascular and metabolic function calls for a systematic approach to thyroid disease screening in diabetes. Routine annual thyroid testing should be targeted at diabetic patients at risk of thyroid dysfunction such as patients with T1DM, positive thyroid autoantibodies or high-normal TSH concentrations.

Can a random serum cortisol reduce the need for short synacthen tests in acute medical admissions?

BACKGROUND: Short synacthen tests (SSTs) are frequently performed in medical inpatients with suspected adrenocortical insufficiency. The utility of a random or baseline serum cortisol in this setting is unclear. We determined random cortisol thresholds that safely preclude SSTs in acute medical admissions. METHODS: We analysed SSTs in acute non-critically ill general medical patients (n = 166, median age 66, range 15-94 y; men 48%, women 52%). The SST was defined according to the 30-min cortisol as 'pass' (>550 nmol/L) or 'fail' (< or =550 nmol/L). Receiver operating characteristics (ROC) curves were generated to determine the predictive value of the basal cortisol for a failed SST. RESULTS: Of 166 SSTs, a pass was seen in 127 (76.5%) tests, while 39 (23.5%) tests failed the SST. ROC curves showed that no single cut-off point of the baseline cortisol was adequately both sensitive and specific for failing the SST despite a good overall predictive value (area under curve 0.94; 95% confidence interval 0.89-0.98). A basal cortisol <420 nmol/L had 100% sensitivity and 54% specificity for failing the SST, while a basal cortisol <142 nmol/L had 100% specificity and 35% sensitivity. Restricting the SST to patients with a basal cortisol <420 nmol/L would have prevented 44% of SSTs while correctly identifying all patients who failed the SST. CONCLUSION: A baseline serum cortisol may prevent unnecessary SSTs in medical inpatients with suspected adrenocortical insufficiency. However, SSTs are still indicated in patients with random cortisol <420 nmol/L, or where the suspicion of adrenal insufficiency is compelling.

Insulin therapy in type 2 diabetes: insulin analogue mix 50, a potential role in reducing postprandial hyperglycaemia and cardiovascular disease.

IMPORTANCE OF THE FIELD: Postprandial hyperglycaemia is becoming topical, with studies suggesting a link to cardiovascular disease. Recently, a number of new therapies for the treatment of type 2 diabetes have become available. AREAS COVERED IN THIS REVIEW: This review looks at the evidence for the potential role of insulin analogue mix 50 to reduce postprandial hyperglycaemia and cardiovascular disease. SEARCH STRATEGY: Medline and Embase databases were searched using the MeSH terms to identify relevant studies from 1980 to 2009. Both original articles and reviews were extracted. Published reference lists were also examined. MeSH terms used for literature searching: human insulins, insulin analogues, insulin analogue mix 50, glycaemia, postprandial glucose, fasting glucose, type 2 diabetes, type 1 diabetes, cardiovascular disease. WHAT THE READER WILL GAIN: The reader is presented with evidence discussing the importance of postprandial hyperglycaemia and studies comparing different insulin regimes and in particular insulin analogue mix 50 and its potential to reduce postprandial glucose surges and reduce cardiovascular disease. TAKE-HOME MESSAGE: Insulin analogue mix 50 is a viable therapeutic option in a sub-group of patients with type 2 diabetes.

The utility of radioiodine uptake and thyroid scintigraphy in the diagnosis and management of hyperthyroidism.

BACKGROUND AND OBJECTIVES: The value and practice of thyroid radionuclide imaging in the diagnosis and management of hyperthyroidism is unsettled. Our objectives were to determine the influence of thyroid uptake and scintigraphy on the diagnosis of hyperthyroidism and the prediction of outcome following radioiodine therapy. PATIENTS AND DESIGN: We reviewed records and scintigraphic studies on 881 hyperthyroid patients carried out between 2000 and 2007. The agreement between the clinical and scintigraphic diagnosis was evaluated by kappa statistics. We determined the relationship between 4-h (123)I uptake and the outcome of (131)I treatment in 626 patients. A multiple logistic regression model was used to determine variables influencing treatment outcome in 1 year. RESULTS: The diagnostic categories were Graves' disease (GD, n = 383), toxic multinodular goitre (n = 253), solitary toxic nodule (n = 164) and Graves' disease coexisting with nodules (n = 81). The mean age of the patients was 58 +/- 17, (M:F 160:721). There was good agreement between clinical and scintigraph diagnosis (K = 0.60, 95% CI 0.57-0.64, P < 0.001); and they were correctly matched in 74%; mismatched in 6% and indeterminate in 20% of patients. Treatment outcome was not associated with scintigraph diagnosis (P = 0.98) or radioiodine uptake at 4 h (P = 0.2). The use of antithyroid medications before treatment predicted treatment failure (odds ratio 2.0, 95% CI 1.2-3.6, P = 0.01). CONCLUSION: Thyroid scintigraphy and uptake studies did not influence diagnosis or treatment outcomes in most cases of hyperthyroidism. Our findings in this retrospective study do not justify their routine use. Selective scanning will reduce cost and exposure to radioisotopes without compromising diagnostic accuracy or treatment outcomes.

Restricted thyroglobulin antibody epitope specificities in subjects with type 1 diabetes mellitus.

OBJECTIVES: Following iodisation in Sri Lanka we observed a high prevalence of thyroglobulin antibodies (TgAbs) in type 1 diabetic (T1DM) patients. The clinical significance of these TgAbs is uncertain. We sought to obtain a detailed epitope analysis of TgAbs in T1DM patients recruited from diabetes clinics and to compare these with TgAb epitope specificities in patients with autoimmune thyroid disease (AITD) and healthy individuals in that country. DESIGN AND METHODS: We used a panel of 10 Tg-MAbs in competitive ELISA reactions in a prospective study of subjects recruited from Colombo, to determine the epitopes recognised by TgAb-positive patients with T1DM (n=58, 34F:24M, median age 16 years), AITD patients (n=42, 33F:9M, median age 37 years) and healthy subjects (n=50, 39F:11M, median age 27 years). The outcomes were a comparison of reactivity with six Tg clusters (I-VI) in these subjects, and the relation of epitope specificity patterns with free thyroxine and TSH. RESULTS: Patients with T1DM and AITD but not healthy control subjects preferentially recognised the immunodominant clusters, I, III and IV. Patients with these narrow epitope specificities had higher median TSH levels (1.60 vs 1.06; P=0.01), and were more frequently positive for antibodies to thyroid peroxidase than those with broad specificities (52.3 vs 7.1%; P=0.004). CONCLUSIONS: The TgAb epitope specificities in euthyroid Sri Lankans with T1DM are similar to AITD patients. TgAb epitope studies may potentially identify T1DM patients at risk of thyroid dysfunction.

Prevalence of thyroid antibodies in Nigerian patients.

BACKGROUND: Thyroid antibody testing is not routinely available in developing countries, and few studies have measured thyroid antibodies in Africans. The significance of thyroid autoimmunity in an African setting is thus unclear. AIM: To determine the prevalence of thyroid antibodies in patients attending a Nigerian teaching hospital. DESIGN: Prospective survey. METHODS: We measured antibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) using an ELISA technique in 104 patients with various thyroid pathologies attending an endocrine referral centre in Lagos, Nigeria. Patients were clinically grouped into Graves' disease (GD) (n = 69), simple non-toxic goitre (SNTG) (n = 21), toxic nodular goitre (TNG) (n = 8) and suspected Hashimoto's thyroiditis (HT) (n = 6). Blood donors without thyroid disease (n = 100) acted as controls. RESULTS: TgAb and TPOAb were found in 4% and 7%, respectively, of healthy adult controls, 11.6 and 76.8% of patients with GD, 25% and 12.5% of patients with TNG and 9.52% and 14.29% of patients with SNTG. TPOAb testing confirmed HT in six patients, and identified two further cases that would have been misdiagnosed without antibody testing. DISCUSSION: Thyroid autoimmunity appears more common in these Nigerian patients than in previous reports from Africa, and TPOAb was significantly associated with auto-immune thyroid disease. The clinical utility of these antibody measurements requires further evaluation in a wider African population.

Peripheral cytokine expression in autoimmune thyroiditis: effects of in vitro modulation by rosiglitazone and dexamethasone.

BACKGROUND: In Hashimoto's thyroiditis (HT), there is evidence for activation of peripheral T-lymphocytes that predominantly express a T helper 1 (T(H)1) cytokine bias. However, the immunomodulatory factors involved in regulating this response have so far received scant attention. In this study, we examine the effects of the glucocorticoid, dexamethasone, and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, rosiglitazone on the expression of interferon (IFN)-gamma (T(H)1) and interleukin (IL)-4 (T(H)2) by activated peripheral CD4(+) and CD8(+) lymphocytes in patients with HT (n = 10) and healthy control subjects (n = 12). METHODS: Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with phorbolmyristate acetate (PMA) and ionomycin in the presence or absence of varying doses of dexamethasone and rosiglitazone (0.01 microM, 1.0 microM, and 100 microM). Cytokine expression was determined by flow cytometry. RESULTS: CD4(+) and CD8(+) IFN-gamma expression was greater in HT than controls (14.87 versus 9.25; p < 0.05 and 21.34 versus 10.16; p < 0.01, respectively). A dose-dependent inhibition of IFN-gamma expression was seen with dexamethasone and rosiglitazone. Inhibition of CD4(+) and CD8(+) IFN-gamma expression with both dexamethasone and rosiglitazone was greater in control subjects than in patients (p < 0.05). There was no significant difference in IL-4 expression between patients and control groups and its expression remained unaffected by either compound. CONCLUSIONS: We show that CD4(+) and CD8(+) T lymphocytes from HT patients express a type 1 cytokine bias that is significantly more resistant to in vitro modulation by rosiglitazone and dexamethasone. Further studies are needed to clarify if this resistance plays a role in the pathogenesis of autoimmune thyroid disease (AITD).

Diuretic-induced hypokalaemia in patients with hypertension.

We describe a 55 year-old woman with longstanding hypertension who developed hypokalaemia following diuretic treatment. Investigations revealed primary hyperaldosteronism due to an adrenal adenoma, and normal blood pressure was restored after surgical removal of the tumour. Primary hyperaldosteronism is a potentially curable cause of hypertension and should be considered in hypertensive patients who present with diuretic - induced hypokalaemia.