Thyroid autoantibody profiles in ophthalmic dominant and thyroid dominant Graves' disease differ and suggest ophthalmopathy is a multiantigenic disease.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) occurs in 25-50% of patients with Graves' disease (GD) and is occasionally seen in hypothyroid Hashimoto's disease or euthyroid individuals. The link between TAO and hyperthyroidism remains unclear. We hypothesized that qualitative or quantitative differences in thyroid antibodies might determine individual predisposition to these features. METHODS: In a prospective study over 3 years, thyroid antibody levels were measured in all patients diagnosed at the Singapore National Eye Centre to have GD. These patients had no known history of thyroid disease, presented with eye complaints and diagnosis was made by an ophthalmologist. A total of 31 patients were identified. Antibody levels were compared against 71 consecutive patients referred to a thyroid clinic (TC) for thyrotoxic symptoms in whom the diagnosis of GD was confirmed by a thyroidologist. FINDINGS: Thyroid autoantibody profiles of patients diagnosed at the ophthalmology centre (OC) and TC differed markedly. OC patients had significantly higher TSI (P = 0.003) but lower TPOAb (P = 0.008) and TgAb levels (P < 0.001). In contrast, TC patients had higher free T4 (P = 0.048) and higher TBII levels (P < 0.001). Antibody levels were correlated with four parameters of ophthalmopathy--chronic lid retraction, lid swelling, proptosis and extraocular myopathy (EOM). On univariate logistic regression analysis, TSI was a positive predictor and TPOAb and TgAb negative predictors of all four features. In the absence of TgAb, the odds ratios for individual TAO features ranged from 2.8 to 7.9, with corresponding values of 3.9-10.2 when TPOAb was absent. In stepwise logistic regression analysis, TSI was the strongest independent predictor of all aspects studied: lid fullness P = 0.001, proptosis P = 0.001, lid retraction P = 0.008, EOM P = 0.009. Among smokers, TPOAb were significantly lower (P = 0.044) but no association between smoking and the other antibodies was observed. INTERPRETATION: The study demonstrates markedly different thyroid autoantibody profiles in newly diagnosed GD patients with ophthalmic dominant as opposed to thyroid dominant features. It suggests differing antibody patterns are associated with predisposition to hyperthyroidism and orbitopathy. In addition, an association between smoking and low TPOAb levels was noted.

EMG myokymia as a cause of ptosis in hypothyroidism.

Ptosis is known to be associated with thyroid disorders. We describe two biochemically corrected hypothyroid patients presenting with isolated bilateral ptosis. EMG of the orbicularis oculi showed continuous grouped motor unit potentials. In the absence of obvious aetiology, it is hypothesised that focal demyelination of terminal branches to the orbicularis oculi may play a role in the generation of the discharges.

Thyroid diseases in pregnancy.

INTRODUCTION: Changes in thyroid function in pregnancy encompass both hyper- and hypothyroidism. Failure to maintain euthyroidism may place both mother and foetus at higher risk of adverse obstetrical outcomes. This review examines the differences between physiological and pathological thyroid dysfunction during pregnancy and their management. METHODS: Data were obtained from relevant clinical studies and review articles listed in MEDLINE. Additional cross-references from selected articles were identified. RESULTS: In hyperthyroidism, the challenge lies in differentiating gestational transient thyrotoxicosis (GTT) from actual pathological states during the first trimester. GTT is thought to be due to elevation of isoforms of human chorionic gonadotropin (hCG) which may exert potent thyrotrophic effects. While thionamides are safe, the lowest possible dose should be used together with close monitoring of maternal thyroid function in order to avoid over-treatment. Surgery for thyroid nodules may be safely performed during the second trimester. Conversely, diagnosing hypothyroid states, particularly subclinical hypothyroidism and postpartum thyroiditis (PPT), require a high index of suspicion. High levels of thyroid peroxidase antibodies (TPOAb) and thyroid stimulating hormone (TSH) in early pregnancy may be predictive of PPT and subsequent permanent hypothyroidism. Clinicians must recognise the need to increase thyroxine replacement as maternal hypothyroidism may adversely affect the IQ scores of children. The association between thyroid autoimmunity and recurrent abortions remain unclear. CONCLUSION: Regardless of the aetiology of thyroid dysfunction, the key to management lies in individualized therapy in close collaboration with the obstetrician.

Prevalence of gestational thyrotoxicosis in Asian women evaluated in the 8th to 14th weeks of pregnancy: correlations with total and free beta human chorionic gonadotrophin.

OBJECTIVES: The prevalence of gestational transient thyrotoxicosis (GTT) in Europeans evaluated during the 8th to 14th weeks of pregnancy is 2-3%. However, there is evidence that GTT may be more common in some Asian populations. The aims of this study were to evaluate the prevalence of thyroid hormone abnormalities in Asian women in their 8th to 14th weeks of pregnancy using highly sensitive free T4 and TSH assays and to correlate these with total and free beta-hCG levels. DESIGN AND PATIENTS: One hundred and eighty-four consecutive unselected Asian (Singaporean) pregnant women seen at ante-natal clinics for the first time and who were in their 8th to 14th weeks of pregnancy were tested. MEASUREMENTS: Serum free T4, free T3, TSH, total beta-hCG and free beta-HCG levels were measured on the Vitros ECi system (Johnson & Johnson Ortho-Clinical Diagnostics, Amersham, UK) which employs chemiluminescent immunochemical technology. This free T4 assay is free of biases related to serum binding capacity. The TSH assay used was a third generation assay. Thyrotrophin-receptor antibody (TRAb) levels were measured using LUMItest TRAK (BRAHMS Diagnostica, Berlin, Germany). RESULTS: Two subjects (1.1%) were found to have Graves' disease. Elevated free T4, free T3, total T3 and suppressed TSH were seen in 14.8%, 3.3%, 26.4% and 33.0% of the remaining 182 pregnant women, respectively. Total and free beta-hCG correlated negatively with TSH (r = -0.30, P < 0.0001 and r = -0.29, P < 0.0001, respectively), positively with fT4 (r = 0.283, P < 0.001 and r = 0.253, P < 0.001) and fT3 (r = 0.273, P < 0.001 and r = 0.204, P < 0.01). 11.0% of cases had gestational thyrotoxicosis (GT) defined as elevated free T4 (> 19.1 pmol/l), suppressed TSH (< 0.36 mIU/l) and TRAb levels within the reference interval (0-0.9 U/l). The prevalence of GT was significantly higher in patients tested at 8-11 weeks compared to those evaluated at 12-14 weeks (14.4% vs. 4.7%, P < 0.05). Total beta-hCG (P = 0.0002), free beta-hCG (P < 0.0001) and free T4 (P = 0.02) levels were higher and TSH levels (P = 0.01) lower in patients tested at 8-11 weeks. Significant positive correlations between both total and free beta-hCG with free T4 were seen at 8-11 weeks but not in patients tested at 12 weeks or later. TT3 levels were similar in the two groups. CONCLUSIONS: Using sensitive assays, the prevalence of gestational thyrotoxicosis in Asian women was found to be 11.0% and was significantly higher in subjects at 8-11 weeks of gestation than at 12-14 weeks. The positive correlation between hCG and free T4 seen in patients tested at 8-11 weeks was absent in patients tested at later stages of the first trimester. Future studies investigating the entity of gestational thyrotoxicosis, at least in Asian patients, should focus on patients at earlier stages of gestation than currently practised.

Two Chinese families with Pendred's syndrome--radiological imaging of the ear and molecular analysis of the pendrin gene.

We report two families in whom the index cases satisfied the classical diagnostic criteria of Pendred's syndrome. In family I, two siblings were deaf, and one was normal. In family II, both parents and two offspring were deaf. Computed tomography scans performed in five of six of these deaf individuals showed enlarged vestibular aqueducts in all cases, and Mondini cochlea only in family II. Affected members in family I were compound heterozygotes inheriting the paternal allele with a novel mutation S398del in exon 10 and a maternal allele with two mutations IVS13+9C-->G in intron 13, in addition to H723R. In family II, the mother and one child carried both the novel intronic IVS8-2A-->G and H723R mutations, whereas the father and index case were homozygous for the IVS8-2A-->G mutation. A perchlorate discharge test was positive in 50% of cases tested. In conclusion, we concur that radiological and molecular studies should be performed for confirmation of Pendred's syndrome. We report, for the first time, a Pendred's syndrome family in which affected members had three mutations, as well as a second family in whom the intermarriage of two Pendred's syndrome patients resulted in Pendred's syndrome offspring.

Graves' ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels.

The aims of this study were to (a) determine the prevalence of patients without elevated thyroid hormone levels in Graves' ophthalmopathy (GO) using current generation free thyroid hormone assays, (b) measure the prevalence of thyrotropin receptor antibodies (TRAb) in these cases, and (c) identify possible predictors of hyperthyroidism. Over a 30-month period, 1020 cases of thyroid eye disease were evaluated, of which only 19 (1.9%) met the diagnostic criteria. Ten (1%) had subclinical thyrotoxicosis, 7 (0.7%) were euthyroid, and 2 (0.2%) were hypothyroid as determined by a third-generation thyrotropin (TSH) assay. TRAb levels were measured in 16 of these 19 patients. The prevalence of TRAb varied according to the assay used. Polyethylene glycol-extracted thyroid-stimulating immunoglobulin (PEG-TSI), unfractionated thyroid-stimulating immunoglobulin (uTSI), first-generation porcine TSH-binding inhibitory immunoglobulin (pTBII), and second-generation human TSH-binding inhibitory immunoglobulin (hTBII) assays were positive in 93.8%, 50%, 18.8%, and 81.3% of patients, respectively. TRAb was detected by at least one method in all patients. Patients were followed up for 15 to 45 months. Hyperthyroidism developed in 4 patients (25%). Suppressed TSH levels and elevated TBII were predictors of hyperthyroidism. When sensitive assays are used, the prevalence of GO patients without elevated thyroid hormone levels is extremely low. The sensitivities of assays for TRAb detection differ substantially in these cases. PEG extraction improves the detection rate of TSI (p = 0.02), and hTBII assays improve the detection of TBII in these patients (p = 0.002). The high prevalence of TRAb in such cases supports a role for these antibodies in the pathogenesis of thyroid-associated eye disease.

Thyrotoxicosis due to the simultaneous occurrence of silent thyroiditis and Graves' disease.

Silent thyroiditis (ST) and Graves' disease (GD) are two clinical entities belonging to the wide spectrum of autoimmune thyroid diseases (AITD). The two diseases are closely linked because sequential development of GD followed by ST, or the reverse course of events, ie, ST followed by GD, have been documented. However, the pathogenetic basis of the above association remains unknown. Some authors have suggested that the concomitant existence of ST and activation of GD can occur in thyrotoxic postpartum women with normal radioiodoine uptake. The simultaneous occurrence of the two diseases in different parts of the same thyroid gland has, however, to our knowledge, not been documented. We report the case of a 40-year-old thyrotoxic female with atypical presentation of GD. The titers of the antithyrotropin receptor antibodies were elevated and her initial 99mTc-pertechnetate thyroid scan showed the coexistence of ST and GD in different parts of the thyroid gland. Through serial thyroid scans, we document the recovery from ST in parts of the gland and demonstrate the progression to Graves' hyperthyroidism in the entire gland.

Differences in the levels of TSH-binding inhibitor immunoglobulins in goitrous and agoitrous autoimmune thyroiditis after twelve months of L-thyroxine therapy.

OBJECTIVE: The aims were to study the prevalence of TSH binding inhibitor immunoglobulins (TBII) in newly diagnosed patients with autoimmune hypo-thyroidism, to determine if clinical and biochemical parameters in these patients differed, and to study the course of these antibodies after 12 months of L-thyroxine (LT4) therapy. SUBJECTS AND DESIGN: In a prospective study, 111 consecutive patients with newly diagnosed auto-immune hypothyroidism were enrolled. Patients were divided into groups according to the presence or absence of a goitre and TBII levels. Clinical and biochemical differences in these patients were analysed. Patients were then treated with L-thyroxine (LT4) for 12 months and changes in their TBII monitored. MEASUREMENTS: Free T4 and TSH levels were measured at baseline and then 6-weekly during the titration of LT4 doses. Once TSH levels had normalized, these measurements were performed 3 monthly. TBII levels were measured in patients at baseline and 12 months. Thyroid stimulating blocking antibody (TSBAb) levels were measured 12-18 months after initiation of LT4 therapy. RESULTS: Twenty patients were TBII-positive, 10 goitrous and 10 agoitrous. Agoitrous TBII-positive patients were found to have similar characteristics: these included TBII levels > 100 U/l, potent thyroid stimulating blocking antibody (TSBAb) activity and a tendency for TBII levels to remain unchanged or to rise after LT4 therapy. The degree of hypothyroidism seen in these cases was significantly greater than in all other groups. In contrast, goitrous TBII-positive patients were heterogenous, most did not have significant TSBAb activity and TBII disappeared in 5 out of 10 cases after a year of LT4 treatment. While TBII disappeared in 6 of the 20 patients after a year, remission of hypothyroidism occurred in only 3 cases. CONCLUSIONS: The degree of hypothyroidism in agoitrous TSH-binding inhibitor immunoglobulins-positive patients appears to be more severe than that seen in other forms of AIT. The differences in thyroid stimulating blocking antiboby activity and response to LT4 therapy in agoitrous and goitrous autoimmune thyroiditis suggest that the TSH-binding inhibitor immunoglobulins in these patients are fundamentally different. The disappearance of TSH-binding inhibitor immunoglobulins in hypothyroid patients was not accompanied by the reversal of hypothyroidism in 50% of patients.

A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family.

Activating mutations of the TSH receptor (TSH-R) have been reported to result in toxic adenomas, multinodular goiters, sporadic neonatal hyperthyroidism, and familial autosomal dominant nonautoimmune hyperthyroidism. To date, all descriptions of such mutations, whether somatic or genomic, have been confined to the Caucasian population. We describe a Chinese family in whom a germline proline to serine substitution in position 639 resulted in familial thyrotoxicosis. This constitutively activating mutation has been previously described in a hyperfunctioning thyroid nodule. The three children in this family developed thyrotoxicosis during childhood; their father was diagnosed as thyrotoxic at the age of 38 yr. Two of the children and the father had mitral valve prolapse (MVP) associated with mitral regurgitation. There was a close temporal relationship between the onset of thyrotoxicosis and the diagnosis of mitral valvular disease in these patients. An increased prevalence of MVP has been reported in Graves' disease and chronic lymphocytic thyroiditis, but the pathophysiological mechanisms linking MVP and autoimmune thyroid disease are still not understood. This is the first report of an association between activating TSH-R mutations and MVP. We postulate that TSH-R activation may increase the clinical expression of MVP in genetically predisposed individuals.

The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy.

Among Graves' Disease (GD) patients, we have observed an unexpectedly high prevalence of antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb) negativity in those with severe ophthalmopathy. To study the possible role of thyroid autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO), TPOAb, TgAb, thyroid-stimulating immunoglobulin (TSI), and thyrotropin-binding inhibitory immunoglobulin (TBII) levels were measured, and the presence or absence of GO was assessed by a single observer in 100 consecutive patients with newly diagnosed, untreated GD who were nonsmokers. Ophthalmopathy was present in 43 patients. TSI levels (p = 0.001), and the prevalence of TPOAb-negativity (p = 0.002) were significantly higher in patients with ophthalmopathy compared to those without. Logistic regression analysis showed that TSI levels (p = 0.005) and the absence of TPOAb (p = 0.0025) were independent predictors of GO. No correlation between TBII or TgAb and eye disease was found. The prevalence of GO increased with each quartile of TSI levels. The prevalence was 20%, 36%, 52%, and 64% in the first, second, third and fourth quartiles of TSI, respectively. The odds ratio of GO (with 95% confidence intervals) when TSI levels were above the median level (1640%) was 3.6 (1.5-8.0), when TPOAb was negative it was 5.0 (1.7-14.4), and with both risk factors it was 36.6 (4.3-313.5). The prevalence of ophthalmopathy in this last group was 92.9%. The combination of negative TPOAb and high TSI levels appears to be associated with a markedly increased risk of clinically evident ophthalmopathy.

Cushing's syndrome in a patient with a corticotropin-releasing hormone-producing pheochromocytoma.

OBJECTIVE: To present the first case of Cushing's syndrome attributable solely to ectopic production of corticotropin-releasing hormone by a pheochromocytoma. METHODS: We summarize the clinical features and results of laboratory investigations in a patient with symptoms characteristic of Cushing's syndrome. RESULTS: Although Cushing's syndrome is usually caused by ectopic production of adrenocorticotropic hormone (ACTH), our current patient had clinical and biochemical evidence of hypercortisolism in conjunction with "normal" ACTH levels and nonsuppressible serum and urinary cortisol levels on low-dose and high-dose dexamethasone suppression testing. An abdominal computed tomographic scan revealed a 7.7-cm mass in the left adrenal gland. Light microscopic examination and immunohistochemical staining showed a pheochromocytoma with mild cortical hyperplasia. Immunostaining was positive for corticotropin-releasing hormone but negative for ACTH. CONCLUSION: To our knowledge, this is the first case of Cushing's syndrome in a patient with pheochromocytoma caused only by ectopic secretion of corticotropin-releasing hormone without accompanying secretion of ACTH.

Thyroid storm presenting as jaundice and complete heart block.

Thyroid storm is a difficult diagnosis in "apathetic" variant of hyperthyroidism. The clinical features may not be evident. Abnormal atrioventricular (AV) conduction, such as complete heart block, in thyrotoxicosis is uncommon. We report a case of a 16-year-old girl presenting with fever, jaundice, heart failure and complete heart block in whom the diagnosis of thyroid storm was initially missed because of the unusual presenting features. Prompt resolution of the conduction abnormality occurred when treatment with carbimazole, intravenous iodide and dexamethasone was instituted.

Thyroid stimulating hormone receptor antibody levels in Singaporean patients with autoimmune thyroid disease.

Stimulating thyrotrophin receptor antibodies (TRAbs) have been identified as the antibodies responsible for the pathogenesis of Graves' disease (GD) while blocking TRAbs have been implicated as the cause of hypothyroidism in some patients with chronic lymphocytic thyroiditis (CLT). TRAb positivity in patients with other thyroid disorders such as silent thyroiditis, toxic multinodular goitre and subacute thyroiditis has been reported but the role of TRAb in these disorders is unclear. A study was carried out to determine the prevalence of TRAb positivity in Singaporean patients with a spectrum of thyroid diseases. TRAb levels were measured in 181 patients with GD, 54 patients with CLT (37 goitrous and 17 agoitrous), 16 patients with thyroid nodules, 11 patients with subacute thyroiditis, 1 patient with hyperthyroidism due to a human chorionic gonadotrophin (HCG)-secreting tumour, 2 patients with thyroid stimulating hormone-secreting tumours and 2 patients with amiodarone-induced dysthyroidism. Using a cut-off of 10.0 U/L, TRAb levels were found to be positive in 79.0% of GD patients, 9.2% of CLT patients (euthyroid and hypothyroid) and no patients with other thyroid disorders. TRAb was a more sensitive marker of GD than anti-thyroglobulin antibodies (53.2%) but not anti-microsomal (78.3%) antibodies. TRAb levels > 10.0 U/L appear to be highly specific for autoimmune thyroid disease.

Aldosterone to renin ratios in the evaluation of primary aldosteronism.

Primary aldosteronism, though an uncommon cause of hypertension, causes significant morbidity, making it important to diagnose and treat this condition. Its evaluation requires complex and time consuming investigative procedures in order to confirm the diagnosis and to differentiate between the subtypes of aldosterone producing adenoma and idiopathic hyperaldosteronism. Often, the values of renin and aldosterone are equivocal, and the diagnosis of primary aldosteronism is in doubt. In this study, we examine the use of aldosterone to renin ratios in confirming the diagnosis of primary aldosteronism when the usual criteria of suppressed renin and elevated aldosterone are not met. We have found that an aldosterone to renin ratio of 50 has a 100% specificity and 92% sensitivity for detecting primary aldosteronism. Also, an aldosterone to renin ratio of > 2000 is suggestive of an aldosterone producing adenoma.

Diagnostic difficulties associated with phaeochromocytoma--4 case illustrations.

The diagnosis of phaeochromocytoma can be extremely difficult with 40%-76% of cases escaping diagnosis during life. Until recently, the only available biochemical test for the detection of phaeochromocytoma in Singapore has been the 24-hour urinary vanillyl mandelic acid (VMA). Urinary VMA has been reported to have a high specificity (85%-100%) but variable sensitivity (28%-90%) in the diagnosis of this disease. In 1993, high performance liquid chromatography (HPLC) assays for the measurement of urinary catecholamines and metanephrines were introduced at the Singapore General Hospital. Since 1993, 4 cases of phaeochromocytoma have been detected at our institution. We report here, the diverse clinical presentations of these patients. The urinary-free catecholamine and catecholamine metabolite levels of these patients were compared with corresponding levels from 12 non-phaeochromocytoma patients. Using the reference value of 65.6 mumol/day, we found the urinary VMA to be a highly sensitive (100%) test with a specificity of only 31%. In contrast, a urinary total metanephrine level > or = 9,000 nmol/day was both sensitive (100%) as well as specific (100%).

Abnormal thyroid and adrenocortical function test results in intensive care patients.

A prospective, cohort study of 75 consecutive patients requiring management in the medical intensive care unit (MICU) of the Singapore General Hospital was carried out over a five-month period to determine thyroid and adrenocortical profiles and evaluate their use in predicting patient outcome. Up to 88% of patients had at least one abnormal thyroid function and 77% had abnormal adrenocortical function test results. There were significantly lower triiodothyronine, thyroxine and free thyroxine, but not thyrotropin levels, and higher cortisol levels in non-survivors compared to survivors (all P < 0.01). Of the endocrine parameters, triiodothyronine and cortisol concentrations were independent predictors of outcome. The overall predictive accuracy of combining these two variables on admission into the MICU was 74%. The APACHE II (acute physiology and chronic health evaluation II) score alone predicted outcome with 71% accuracy, and in combination with triiodothyronine and cortisol levels improved accuracy to 84%. The use of dopamine alone predicted outcome with 74% accuracy, and in combination with triiodothyronine and cortisol levels, improved accuracy to 84%. Measurements of total triiodothyronine and cortisol concentrations on admission to the MICU, and consideration of the use of dopamine improve on the APACHE II score in outcome prediction.

Diabetic retinopathy--results of a two year screening programme in two medical units in Singapore.

Three hundred patients with Diabetes Mellitus from 2 medical units in Singapore were screened for retinopathy over a 24 month period. Prevalence of retinopathy in this population was 38% with sight-threatening retinopathy in 17%. Risk factors associated with retinopathy included a longer duration of disease, the presence of hypertension, nephropathy and poor glycaemic control. Prevalence of retinopathy was higher in females. Malays and Indians had higher prevalence of retinopathy than Chinese.