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Graves' ophthalmopathy (GO) is characterized by swelling of orbital fat and extraocular muscles, but little attention has been given to differential involvement of fat and muscles. Advancements in imaging allow rather accurate measurements of orbital bony cavity volume (OV), fat volume (FV) and muscle volume (MV), and are the topics of this review. Ratios of FV/OV and MV/OV neutralize gender differences. In adult Caucasian controls, mean values ± SD of FV/OV are 0.56 ± 0.11 and of MV/OV are 0.15 ± 0.02. FV increases substantially and MV decreases slightly with advancing age, requiring age-specific reference ranges. In 95 consecutive untreated Caucasian GO patients, both FV and MV were within normal limits in 25%, increased FV but normal MV was present in 5%, normal FV but increased MV was detected in 61%, and both increased FV and MV was evident in 9%. Increased FV was associated with more proptosis and longer GO duration. Increased MV was associated with older age, more severe GO (more proptosis and diplopia, worse eye muscle ductions), higher TBII and current smoking. At the cellular and molecular level differential involvement of fat and muscles might be related to differences between fibroblast phenotypes and cytokine profiles in each compartment, to different orbital T cell subsets during the course of the disease and to peroxisome proliferator activator receptor-γ polymorphisms and modulation of 11β-hydroxysteroid dehydrogenase-1. Enlarged muscles are apparently a rather early phenomenon in GO, whereas increases in fat mass occur relatively late. Why a minor subset of GO patients presents with an increase of only fat remains poorly understood.
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Background: Alcohol consumption has been identified as a protective factor for some autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. Objective: We hypothesized that alcohol consumption would reduce the risk of developing autoimmune thyroid disease (AITD). Study design: Two nested case-control studies in the prospective Amsterdam AITD cohort. Follow-up was 5 years, with annual assessments. In study A, we compared alcohol consumption between cases (subjects who during follow-up remained euthyroid but developed thyroid peroxidase antibodies (TPO-Ab), called event) and controls (subjects who remained euthyroid and TPO-Ab-negative). In study B, we compared alcohol consumption between cases (subjects who during follow-up developed overt hypothyroidism, called event) and controls (subjects who did not develop overt hypothyroidism). For each case, 2 controls were selected, matched for age, duration of follow-up and smoking behavior at baseline and at the time of event. Results: In study A, alcohol consumption did not differ between cases and controls at any time point. In study B, the number of subjects consuming >10 units of alcohol per week was not different between cases and controls at study entrance (8.3 vs. 14.5%, NS), but lower at 1 year before (5.3 vs. 19.7%, p = 0.041) and at the time of event (6.7 vs. 23.7%, p = 0.044); respective odds ratios are 0.54 (0.14–2.06), 0.23 (0.05–1.04) and 0.23 (0.05–1.06). Conclusion: Alcohol consumption is not associated with de novo development of TPO-Ab, but is lower in subjects who developed overt hypothyroidism. The data suggest alcohol consumption may protect against overt autoimmune hypothyroidism.
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Background: 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. Methods: 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. Results: 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. Conclusion: 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.
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Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.
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Objective
Pregnancy is a state of physiological inflammation facilitating implantation. Early isolated hypothyroxinaemia (IH) and increased inflammation (including obesity) have been associated with severe obstetric complications. The current study evaluated the association between IH, low ferritin and inflammation parameters (interleukin 6 (IL-6), C-reactive protein (CRP), human chorionic gonadotrophin (hCG) and obesity. Moreover, the course of these parameters throughout pregnancy was evaluated in relation to IH.
Methods
In the cross-sectional study (A) at 12 weeks, 2759 women participated and 2433 participated in the longitudinal study (B) with assessments at 12, 20 and 28 weeks gestation. At the first trimester, 122 (4.4%) IH women (free thyroxine (FT4) <5th percentile, normal TSH levels) were compared with 2114 (76.6%) reference women (FT4 between tenth and 90th percentiles, normal thyrotrophin (TSH) levels), in study B these figures were 99 (4.1%) and 1847 (75.9%), respectively.
Results
Cross-sectionally, compared to reference women, IH was independently associated with low ferritin (<5th percentile, OR: 2.6, 95% CI: 1.4–4.9), high CRP (>95th percentile: OR: 1.9, 95% CI: 1.04–3.7), low hCG (<median, OR: 2.1, 95% CI: 1.40–3.16), obesity (BMI > 30, OR: 1.7, 95% CI: 1.12.9) and higher age (OR: 1.1, 95% CI: 1.04–1.15). Longitudinally, compared to reference women, women with IH at 12 weeks gestation showed persistently and significantly lower ferritin and hCG levels, and persistently higher CRP and IL-6 levels throughout gestation.
Conclusion
Gestational IH could be viewed as a condition of increased inflammation, as reported in non-thyroidal illness syndrome. Less favourable inflammation parameters and low iron status during early gestation in IH women seem to persist throughout gestation.
