1. Hyperthyroidism: Diagnosis, Management and Long-term Consequences Hyperthyroidism: Diagnosis, Management and Long-term Consequences Kristien Boelaert Senior Lecturer in Endocrinology Consultant Endocrinologist Queen Elizabeth Hospital Birmingham, UK Centre for Endocrinology, Diabetes & Metabolism University of Birmingham, UK

2. Overview  Diagnosis of hyperthyroidism/thyrotoxicosis  Influence of endogenous/environmental factors on phenotype  Symptoms and signs of hyperthyroidism according to age  Co-existing autoimmune diseases  Management: Treatment with 131 I – The Birmingham experience  Long-term consequences:  Association with mortality  Weight changes following Rx

3. Family history  Family history: 47.7% females – 40.0% males  Inverse relationship between age at diagnosis – number of relatives with thyroid dysfunction  FH of hyperthyroidism more common than hypothyroidism (p<0.001) Manji, Boelaert et al. (2006) JCEM 91, 4873

4. Associated autoimmune diseases Boelaert et al. (2010) Am J Med 123, 183.e1  2791 subjects with Graves’ disease

5. Age at diagnosis of Graves’ Disease Median age at presentation (y) T1DM RA PA CD Vitiligo IBD None N 31 88 39 25 40 25 2571 *** * ** * Boelaert et al. (2010) Am J Med 123, 183.e1

6. Number of reported symptoms according to age Number of patients (%) 0-2 symptoms 3-4 symptoms 5 or more symptoms P < 0.001 Boelaert et al. (2010) JCEM 95, 2715

7. Outcome according to dose regimen (%) Cure Hypothyroidism *** **  1278 patients treated with 131 I for hyperthyroidism  Single fixed dose of 131 I Outcome following 131 I therapy Boelaert et al. (2009) Clin End 70, 129

8. Factors predicting cure of hyperthyroidism Boelaert et al. (2009) Clin End 70, 129

9. Hyperthyroidism and mortality - Outstanding questions  Is mortality related to underlying aetiology - ? higher in toxic nodular hyperthyroidism (Metso et al. (2007) JCEM 92, 2190)  Is outcome affected by treatment modality?  What is the influence of biochemical control of hyperthyroidism on outcome?  How do pre-existing co-morbidities affect outcome? Brandt et al. (2011) Eur J Endo 165, 491

10. SMR according to treatment modality Cause of deathOverallWhilst on Thionamide Rx Following 131 I Not hypothyroid Following 131 I Hypothyroid SMR P P P All causes Males Females 1.15 1.26 1.11 1.30 1.36 1.27 0.006 0.10 0.07 1.24 1.34 1.21 0.02 0.11 0.06 1.02 1.1 0.95 0.85 0.57 0.60 Comorbidity absent Comorbidity present 0.95 1.52 1.03 1.68 0.84 <0.001 1.09 1.48 0.48 0.002 0.81 1.43 0.08 0.01 Sinus Rhythm Atrial fibrillation 1.07 1.59 1.18 1.74 0.18 0.006 1.17 1.53 0.11 0.02 0.92 1.51 0.43 0.08 Circulatory deaths1.201.370.051.190.221.120.45 Boelaert et al. (2012) JCEM resubmitted

11. HR (95% CI)P- Value Gender Male Female 1.00 0.72 (0.55-0.93)0.01 Cause of hyperthyroidism Graves’ disease TN hyperthyroidism Indeterminate 1.00 0.92 (0.63-1.18) 0.86 (0.67-1.28) 0.36 0.64 Cardiac rhythm at presentation Sinus rhythm Atrial fibrillation 1.00 1.50 (1.08-2.08)0.02 Co-morbidities Absent Present 1.00 1.58 (1.23-2.03)<0.001 Serial fT4 per 10 pmol/l increment1.21 (1.03-1.42)0.02 Treatment Whilst on antithyroid drugs After 131 I – not taking T4 After 131 I – on T4 1.00 0.94 (0.69-1.27) 0.72 (0.54-0.97) 0.67 0.03 Multivariate within cohort analysis Boelaert et al. (2012) JCEM resubmitted

12. Control of hyperthyroidism Boelaert et al. (2012) JCEM resubmitted

13. Comparison with background population Proportion of females (%) Normal BMI Overweight Obese *** Normal BMI Overweight Obese Proportion of males (%) *** Normal BMI Overweight Obese * Proportion of males (%) Proportion of females (%) Boelaert et al. (2012) in preparation PRESENTATION DISCHARGE

14. Weight change during FU Boelaert et al. (2012) in preparation

15. VariableCoefficient95% CIP-value 131I treatment No Yes 0 0.810.57 to1.04 <0.001 Levothyroxine RX No Yes 0 0.360.11 to 0.61 <0.001 Serial fT4 (pmol/l) 10-22 22-30 > 30 0 -0.66 -2.01 -0.90 to -0.41 -2.30 to -1.71 <0.001 Serial TSH <0.1 0.1-0.3 0.3-4.5 4.5-10.0 >10.0 -1.21 -0.40 0 0.65 1.00 -1.42 to -0.99 -0.76 to –0.33 0.39 to 0.91 0.71 to 1.28 <0.001 0.03 <0.001 Multi-level model to predict weight

16. Parameters associated with weight gain Boelaert et al. (2012) in preparation Interaction with 131 IInteraction with levothyroxine InteractionCoefficient95% CIP-valueCoefficient95% CIP-value Gender Male Female 2.09 0.43 1.7-2.47 0.18-0.68 <0.0011.25 0.04 0.82-1.68 -0.24-0.32 <0.001 Aetiology GD TN 1.55 0.34 1.24-1.86 -0.08-0.75 <0.0010.89 -0.24 0.54-1.24 -0.81-0.32 <0.001 BMI category Normal Overweight Obese 0.57 1.05 1.02 0.28-0.86 0.70-1.40 0.60-1.44 0.016 0.052 0.05 0.70 0.63 -0.27-0.37 0.30-1.10 0.13-1.14 0.007 0.042 fT4 (pmol/l) 22-29.6 29.7-39.8 39.9-58.2 >58.2 -0.20 0.52 1.23 1.69 -0.60-0.19 0.12-0.93 0.85-1.61 1.33-2.05 0.005 <0.001 -0.05 0.05 0.93 0.84 -0.52-0.41 -0.40-0.49 0.50-1.35 0.40-1.29 0.75 0.001 0.004

17. Summary of weight gain study Boelaert et al. (2012) in preparation  Treatment of hyperthyroidism associated with significant weight gain  131 I treatment and hypothyroidism associated with small amount of excess weight gain  Uncontrolled hyperthyroidism results in less weight gain  Males, GD subjects, higher BMI category and more severe hyperthyroidism associated with higher risk of weight gain from 131 I

18. Conclusions  Clinical presentation of hyperthyroidism widely varied – may be missed in elderly  Think of associated autoimmune diseases if response to treatment poor  Higher doses of 131 I may be required in certain patient groups  131 I-induced hypothyroidism is associated with reduced risk of mortality  131 I associated with small but definite increase in weight gain