Publications (53) View all
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Article: Treating the thyroid in the presence of Graves' ophthalmopathy.
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ABSTRACT: The etiology of Graves' orbitopathy (GO) remains enigmatic. Optimal therapeutic choices for the hyperthyroidism associated with Graves' disease (GD) in the presence of GO remain controversial. Whether antithyroid drugs (ATDs), radioiodine (RAI), or thyroidectomy should be favored in such patients remains debated. Pre-therapy variables such as ethnicity, sex, age, thyroid function, level of TSH-receptor antibodies and smoking behavior influence response to therapy. Among the most important management goals are restoring euthyroidism and abstaining from smoking. On average, ATDs and thyroidectomy - independent of extent - do not influence the natural course of GO. RAI can cause de novo development or progression of GO, which is largely preventable with oral steroid prophylaxis. In patients with mild GO, the thyroid treatment is largely independent of GO. Moderate to severe GO should be treated promptly. Deciding whether, in the latter, GD is better treated with ATDs, RAI, or surgery, is based more on expert opinion than on evidence. It is clear that in the individual patient a number of factors, not addressed in any trial, influence the final choice of therapy for GD, including concern of developing or negatively affecting pre-existing GO. Evidently, there is room for improving therapy of GO. Progress using novel drugs such as rituximab, which might potentially influence positively both GD and GO, are impatiently awaited.Best practice & research. Clinical endocrinology & metabolism 06/2012; 26(3):313-24. · 3.89 Impact Factor -
Article: A review of the evidence for and against increased mortality in hypothyroidism.
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ABSTRACT: The lifetime risk of overt hypothyroidism is around 5%, and this disease is usually preceded by subclinical hypothyroidism, which has an even higher prevalence (estimated to be up to 9%). Hypothyroidism has been linked with cardiac dysfunction, atherosclerosis, hypertension and coagulopathy. Intuitively, this increased morbidity is expected to shorten patients' lifespan, but definitive data are lacking on whether either of these hypothyroid states (particularly overt hypothyroidism) increase mortality. Study findings are inconsistent and, overall, the pooled data do not demonstrate increased mortality in patients with either subclinical or overt hypothyroidism. However, none of the available studies was adequately designed to answer this question. This Review discusses major shortcomings in those studies, such as population dissimilarities, hypothyroid state classification and misclassification, the inclusion of nonthyroidal illness, drug interference from concurrent therapies, serious comorbidities (for example, cardiovascular disease), differences in duration of follow-up and the number of levothyroxine-treated individuals. Taken together, the data exhibit little evidence of systematic bias and no strong scientific proof of increased mortality related to either subclinical or overt hypothyroidism. Future studies, however, should take the above-mentioned shortcomings and potential genetic confounding into consideration.Nature Reviews Endocrinology 03/2012; 8(7):417-24. · 9.97 Impact Factor -
Article: The clinical presentation of autoimmune thyroid disease in men is associated with IL12B genotype.
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ABSTRACT: Common variants in the interleukin 12B (IL12B) gene are associated with predominantly inflammatory (Th1) or antibody-mediated (Th2) immune responses. As Hashimoto's disease and Graves' disease are thought to arise from mainly Th1 and Th2 immune responses respectively, we hypothesized that IL12B genotype may influence the clinical presentation of autoimmune thyroid disease. We tested for differences in IL12B genotype between Graves' disease and Hashimoto's disease. We studied a discovery cohort of 203 Australian women and 37 men with autoimmune thyroid disease, a replication cohort of 100 European men and a cohort of 146 Chinese men. We analysed three IL12B variants: rs41292470, in the promoter; rs3212227, in the 3' untranslated region and rs6887695, located 60 kilobases upstream from the coding region. In the discovery cohort, rs41292470 and rs3212227 genotypes did not differ significantly between Hashimoto's disease and Graves' disease. In Australian men (but not women), rs6887695 genotype differed between Hashimoto's disease and Graves' disease, with a minor allele frequency (MAF) of 14% and 41%, respectively (P=0·034). This result was confirmed in the European men (MAF 24% and 41%; P=0·013). On combined analysis of Australian, European and Chinese men (N=285), the difference was highly significant (MAF 23% and 45%; P=3×10(-5) ). In 233 men without thyroid disease, the MAF was 34%, significantly different from Graves' disease (P=0·005) and Hashimoto's disease (P=0·029). In men with autoimmune thyroid disease, a common variant located upstream of the IL12B coding region may influence whether patients present with Graves' disease or Hashimoto's disease.Clinical Endocrinology 12/2010; 74(4):508-12. · 3.17 Impact Factor -
Article: A randomized trial evaluating a block-replacement regimen during radioiodine therapy.
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ABSTRACT: Lack of consensus regarding the antithyroid drug regimen in relation to radioiodine ((131) I) therapy of hyperthyroidism prompted this randomized trial comparing two strategies. Patients with Graves' disease (GD, n = 51) or toxic nodular goitre (TNG, n = 49) were randomized to (131) I either 8 days following discontinuation of methimazole (-BRT, n = 52, median dose: 5 mg) or while on a continuous block-replacement regimen (+BRT, n = 48, median dose 15 mg methimazole and 100 μg levothyroxine). results: Patients in the +BRT group required more radioactivity. In this group, thyroid function did not change in the early post (131) I period, while serum-free T3 index was higher in the -BRT group (P < 0·05). One year posttherapy, the fraction of cured patients (euthyroid or hypothyroid) was 48% and 61% in the +BRT and -BRT group, respectively (P = 0·014 unadjusted; P = 0·004 adjusted), but the outcome depended on the type of disease. In GD, treatment failure in the +BRT group correlated positively with the 24-h thyroid (131) I uptake (P = 0·017), while no correlations existed in the -BRT group. In addition to +BRT allocation, patients with TNG were at higher risk of treatment failure with lower thyroid radiation doses (P = 0·048), higher doses of methimazole (P = 0·026) and lower levels of serum TSH (P = 0·009). A continuous block-replacement regimen results in a stable thyroid function during (131) I therapy but is hampered by the higher amounts of radioactivity required. The study demonstrates that the outcome in GD is highly unpredictable, while treatment failure in patients with TNG is correlated with a number of factors.European Journal of Clinical Investigation 12/2010; 41(7):693-702. · 3.02 Impact Factor -
Article: The pituitary-thyroid axis set point in women is uninfluenced by X chromosome inactivation pattern? A twin study.
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ABSTRACT: The pituitary-thyroid axis (PTA) set point is determined by a combination of genetic and environmental factors. However, despite considerable efforts to characterize the background, the causative genes as well as environmental factors are not well established. Theoretically, as shown for autoimmune thyroid disease, the pattern of X chromosome inactivation (XCI) could offer a novel explanation for the observed variability of the PTA set point in women. To examine the impact of XCI pattern on the PTA set point, we studied whether within-cohort (n = 318 subjects) and within-twin pair (n = 159 pairs) differences in XCI are correlated with serum concentrations of thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). X chromosome inactivation was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid variables were measured using a solid-phase time-resolved fluoroimmunometric assay. Zygosity was established by DNA fingerprinting. In the overall study population (within cohort), no significant correlations were found between TSH [regression coefficient (β) = -0·28 (95% confidence intervals, -0·66 to 0·11), P = 0·158], FT3 [β = -0·25 (-0·85 to 0·34), P = 0·403], FT4 [β = 0·08 (-0·91 to 1·07), P = 0·876] and XCI pattern. Essentially similar results were found in the within-pair analysis. Controlling for confounders such as age, body mass index, smoking and zygosity did not change the findings. In a sample of female twins, we found no evidence of a relationship between XCI pattern and PTA set point.Clinical Endocrinology 11/2010; 73(5):666-70. · 3.17 Impact Factor
