Current Management And Changing Trends Of Treatment For Thyrotoxicosis

Session 5: Breast & Endocrine Current Management And Changing Trends Of Treatment For Thyrotoxicosis Win Meyer-Rochow Waikato DHB, Hamilton

Management And Changing Trends Of Treatment For Thyrotoxicosis Win Meyer-Rochow FRACS, PhD Endocrine Surgeon Waikato Hospital

Changing trends Thyroid disease support groups Better Informed patients Patient right for choice of treatment Consumer driven Awareness of adverse outcomes from ATD and I131 Improved outcomes from surgery over time Change of Endocrinology Practice

Outline Current treatment options Advantages of surgery Published international data Waikato Experience Cost effectiveness of thyroidectomy

Thyrotoxicosis new cases Waikato region 18 months n=353 (5% declined FSA excluded) Graves disease 54.4% Toxic multinodular goitre 17% Thyroiditis 13.4% Amiodarone induced 3.4% Solitary toxic nodule 3.2% Iodine associated 2.5% Uncertain 6% Incidence of thyrotoxicosis International data ranges 22-81 per 100,000 pa Waikato region 72.6 per 100,000pa (CI: 65.5-80.4) Tamatea et al 2016 (manuscript in progress)

Thyrotoxicosis Management Often delay to diagnosis Emotional and physical disturbance Significant disruption to personal life and work

Thyrotoxicosis - Management Initiate medical treatment Inform patient of treatment options: 1. Antithyroid drugs 2. Radioiodine 3. Thyroidectomy

Graves Disease 1. Antithyroid drugs 2. Radioiodine 3. Thyroidectomy

Carbimazole / Propylthiouracil Imprecise guess work! May fail to achieve control despite high doses Adjustment of dosage over time Blood tests 6-12 weekly Ongoing specialist input Graves Disease: 12 to 18 months trial for remission At least 58% fail to achieve long-term remission Risk of significant drug reactions Liver Dysfunction: 1/200-1/400 Liver failure; 1/2000-1/4000 Agranulocytosis 0.1 1.7% 4% fatal Significant side effects of ATDs in 10% Benker et al. Clin Endocrinol (Oxf) 1998;49:451-7 N Engl J Med Apr 2009;360:15 Nakamura et al. JCEM 2013 Mohlin et al. Eur J Endocrinol 2014;170:419-27

Carbimazole Drug interactions ( eg warfarin, digoxin, theophylline) Crosses the placenta Excreted in breast milk Teratogenic - choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis Andersen et al. JCEM 2013

Propylthiouracil Not recommended in children Drug interactions ( eg warfarin, digoxin, theophylline) Recommended in 1st trimester in pregnancy but not the 2 nd or 3 rd Crosses the placenta Excreted in breast milk Danish Data: Teratogenic Major cardiac anomalies, urinary system malformations, face and neck malformations Andersen et al. JCEM 2013 Benavides et al. Plos One 2012

Propylthiouracil Not recommended in children Drug interactions ( eg warfarin, digoxin, theophylline) Recommended in 1st trimester in pregnancy but not the 2 nd or 3 rd Stagnaro-Green et al. ATA guidelines 2011 Crosses the placenta Excreted in breast milk Teratogenic Major cardiac anomalies, urinary system malformations, face and neck malformations Side effects: Skin rash Increased skin pigmentation Agranulocytosis Thrombocytopenia Severe liver failure Death

Radioactive Iodine Indications Definitive treatment of Graves disease Failure to achieve cure 25% at 12/12 Metso et al. Clin Endo 2004;61;641-648 Contraindications Compressive symptoms Graves ophthalmopathy Inadequate contraception Women wishing to conceive Pregnancy / Lactation Social circumstances Adverse reaction to iodine Incontinence Patient desire to avoid radiation

Complications of I131 Increased risk primary hyperparathyroidism Increased risk of malignancy Established for doses used in thyroid cancer Thyrotoxicosis conflicting data Biologically plausible Breast (RR 1.53), stomach (RR 1.75), kidney (RR 2.32) Flare of ophthalmopathy Flare of thyrotoxicosis Iodine load Radiation thyroiditis Acute enlargement thyroid risk of airways compromise Radiation exposure to household members Colaco et al. Am J Surg 2007 Sawka et al. Thyroid. 2009 Metso et al. Cancer 2007 Acharya et al. Clin Endocrinol 2008 Lee et al. Nucl Med Commun 2009 McDermott et al. Am J Med 1983 Wilson et al. Med J Aust 1995

Surgery The quick fix! Precise and definitive Rapid prep achievable with Lugol s Iodine (Wolff Chaikoff effect) Removal of concomitant pathology Short hospital stay Low risk of complications ~1% Cost-effective Small incision with good cosmesis Predictable thyroid replacement Discharge back to GP care at 6 weeks

Solitary Toxic Nodule

Graves Disease

Toxic Multinodular Goitre

Intra-operative Vascular gland Dense thyroid tissue High extension of superior poles Difficult surgical planes Identification of parathyroid glands Recommended Procedure: Near Total / Total Thyroidectomy If Sub-total then Dunhill procedure

Surgery social benefits No restriction from loved ones No restriction from pregnancy / breast feeding / childcare Less traumatic for patient / family / young children Rapid return to work

Surgery other benefits More rapid decline of TRAb Prospective randomised trial Laurberg et al. Eur J Endocrinol 2008 n=47 n=36 n=48

TRAb induced Foetal Thyrotoxocosis and Goitre

Surgery other benefits More rapid decline of TRAb No deterioration / possibly beneficial for ophthalmopathy

Cochrane Review: Thyroid surgery for Graves disease Liu ZW, Masterson L, Fish B, Jani P, Chatterjee K, 2015 5 RCT s with Graves disease patients n=886 1988-2004 Total Tx 172, 383 bilat sub total Tx, Dunhill procedure 309, unspec 22 Total Tx more effective than subtotal at preventing recurrence 0/150 versus 11/200 (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001 Dunhill procedure was more likely to prevent recurrence when compared to bilateral subtotal Tx 20/283 versus 8/309 (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01 Total thyroidectomy greater risk permanent hypoparathyroidism 8/172 versus 3/221 (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01

Cochrane Review: Thyroid surgery for Graves disease Liu ZW, Masterson L, Fish B, Jani P, Chatterjee K, 2015

Influence of experience on performance of individual surgeons in thyroid surgery Duclos et al. BMJ, 2012 Prospective cross sectional multicentre study April 2008 Dec 2009 28 thyroid surgeons 5 high volume (>500/yr) French academic centres Total 3574 total thyroidectomies (average 124 per surgeon)

Influence of experience on performance of individual surgeons in thyroid surgery Duclos et al. BMJ, 2012

Complications of Thyroid Surgery Anaesthetic mortality- 1.1 per million population per year Anesthesiology. Apr 2009; 110(4): 759 765 Recurrence after total / near total thyroidectomy 0% Low risk of surgical complications Thyroid storm 0% Surgical site infection 0.36% Recurrent Laryngeal nerve injury 0.9% Post-operative bleeding risk 1.3% Hypoparathyroidism >6months 1.6% (long term 0.9%) J Surg Res, 2000;190(2):161-5 Hormones, 2010;9(4):318-25

Retrospective review Dec 2001-Nov 2011 117 operations for Grave s disease 52 (44%) performed in final year of the study Sub-total thyroidectomy in 2 patients (2%) Thyroid cancer identified in 8 (6.8%) 1 post op bleed 1 RLN injury (0.85%) 2 permanent hypoparathyroidism (1.7%)

Waikato Regional Thyrotoxicosis Patients 2002-2013 Retrospective review 801 patients (591 RAI / 210 surgery) Total Thyroidectomy 100% remission RAI 20% required >1 dose (range 1-4) RAI 35% Maori required >1 dose (range 1-4) Surgical complications wound infection n=2 (1%) Haematoma n=2 (1%) RLN injury n=1 (0.5%) permanent hypoparathyroidism n=7 (3%) (1.9% at 1 year postop) Tamatea et al 2016 (manuscript in progress)

Euthyroid rates after treatment for thyrotoxicosis Surgery: 1 year 52.9% 2 years 61.6% RAI: 1year 46% 2 years 51.1% : 5-10 years no significant difference Tu akoi et al, 2016 (manuscript in progress)

Aust N Z J Obstet Gynaecol. 2014 Aug;54(4):317-21. doi: 10.1111/ajo.12196. Epub 2014 Feb 27. Pregnancy after definitive treatment for Graves' disease--does treatment choice influence outcome? Elston MS1, Tu'akoi K, Meyer-Rochow GY, Tamatea JA, Conaglen JV. Surgery (n=12, 22 pregnancies) Radioiodine (n=17, 27 pregnancies) Median age at definitive treatment 28 yrs (21-38) 31 yrs (21-40) P value Median time from Rx to pregnancy 19.6 mths (3-113) 32 mths (0.5-96) 0.224 Not referred to endocrinology 19/22 (86%) 15/27 (56%) 0.02 Euthyroid at conception 13/19 (68%) 5/23 (22%) 0.002 Pregnancy outcome 14 live births 2 miscarriages 4 terminations 1 unknown 21 live births 6 miscarriages 2 terminations (one for major congenital anomaly)

Thyroid Surgery for Graves Disease Cost-Effective Analysis Actual cost per cure : $5,644 per patient who received thionamides, $2,063 per patient given radioiodine $9,826 per patient who underwent thyroidectomy

Thyroid Surgery for Graves Disease Cost-Effective Analysis Treatment efficacy and complication data literature review Cost analysis using health care model Outcomes measured in quality-adjusted life-years (QALY) Total thyroidectomy most effective ATM life-long least cost-effective RAI less costly but lowest QALYs Total Thyroidectomy highest QALYs and incremental cost-effectiveness J Am Coll Surg, 2009;209:170-179

Summary: Surgery is a reasonable alternative to I131 Resource restraints require selective approach Patients not responding to or tolerating medical treatment Severe ophthalmopathy Pregnant / lactating/ parents with young children Those unlikely to respond to 1 st dose of I131 (Maori/ polynesian / large goitre) Young patients Women of child bearing age wishing to conceive in near future Patients living in extended family environment Experienced high volume surgeon with low complication rate Total / Near Total Thyroidectomy