Graves’ Disease Kenneth A. Woeber, MD, FRCPE
Causes of Hyperthyroidism Common
Graves’ hyperthyroidism, exogenous thyroid hormone excess, toxic multinodular goiter, subacute thyroiditis Uncommon toxic adenoma, iodine excess Rare gestational transient thyrotoxicosis, trophoblastic tumors, TSH hypersecretion, ectopic thyoid tissue, constitutively activated TSH-receptor mutations, Gsalpha mutation
Results ofLaboratory Investigations in Graves’ Hyperthyroidism
Serum TSH very low or undetectable Serum T3 and usually serum T4 elevated, with increased T3/T4 ratio Thyroid radioiodine uptake increased, with diffuse pattern on scintiscan TSH receptor antibodies present in serum
Epidemiology of Graves’ Disease
Cause of 50 – 80% of cases of hyperthyroidism Prevalence: 0.6% of population Incidence: 0.5/1000/year Female/male ratio: 5/1 – 10/1 Peak incidence: 40 – 60 years of age Concordance rate: monozygotic twins 35%; dizygotic twins 3% (Brix et al., J Clin Endocrinol Metab 86: 930, 2001) Predisposition: 79% genetic; 21% nongenetic Female siblings and female children have 5 – 8% risk
Pathogenesis of Graves’ Disease
Autoreactive T cells and B cells emerge and infiltrate the thyroid gland (as well as extrathyroidal tissues) and elaborate various cytokines that ultimately lead to production of TSH receptor antibodies (TSHRAb) as a result of: Genetic susceptibility Environmental factors - infections, stress, smoking Endogenous factors - female gender
Susceptibility Genes in Graves’ Disease
HLA-DR gene - DRB1 variant results in altered peptide presentation to T cells CTLA-4 gene - several single nucleotide polymorphisms (SNPs) result in enhanced T cell activation CD40 gene - ? C/T SNP results in enhanced B cell activation TSHR gene - ? several SNPs lead to alterations in TSHR extracellular domain (modified from Jacobson and Tomer, Thyroid 17: 949, 2007)
Manifestations of Graves’ Disease diffuse goiter in >90% overt infiltrative ophthalmopathy in ~50% overt infiltrative dermopathy in 80% TPOAb in ~75% overlap with other autoimmune diseases
Pathogenesis of Graves’ Hyperthyroidism
TSHRAbs stimulate follicular cell hypertrophy and hyperplasia TSHRAbs increase thyroid hormone synthesis and secretion and result in a disproportionate increase in T3 secretion
(Woeber, Thyroid 16: 687, 2006)
NOSPECS Classification of Ocular Manifestations of Graves’ Ophthalmopathy 0123456-
No changes Only lid retraction Soft tissue involvement Proptosis Extraocular muscle involvement Corneal involvement Sight loss due to optic nerve involvement
Pathogenesis of Graves’ophthalmopathy
Characterized by increased orbital fat and increased extraocular muscle volume Orbital preadipocyte fibroblasts express TSHR and expression correlates with eye disease activity TSHRAbs are potent stimulators of adipogenesis in cultures of orbital preadipocyte fibroblasts Infiltration of autoreactive T cells targeted through recognition of TSHR- expressing fibroblasts results in cytokine-mediated adipogenesis and hydrophilic glycosaminoglycan production (modified from Khoo and Bahn, Thyroid 17: 1013, 2007)
Pathogenesis of Infiltrative Dermopathy
Infiltration of autoreactive T cells in cutaneous tissues targeted by TSHRexpressing fibroblasts results in cytokine-mediated hydrophilic glycosaminoglycan production, causing edema and ultimately fibrosis
PREVALENCE OF ATRIAL FIBRILLATION IN ENDOGENOUS OVERT AND SUBCLINICAL HYPERTHYROIDISM Group Control (>45 years) (TSH 0.4 - 4.0 mU/ L)
Number
With Atrial Fibrillation
22,300
513 ( 2.3%)
Overt Hyperthyroidism (TSH < 0.03 mU/ L)
725
100 (13.8%)*
Subclinical Hyperthyroidism (TSH < 0.4 mU/ L)
613
78 (12.7%)*
*p < 0.01 vs Control Group. Adapted from Auer et al., Am Heart J 148:838, 2001
From Vaidya et al. Clin Endocrinol 68: 814, 2008
Methimazole (MMI) or Carbimazole (CMI) vs. Propylthiouracil (PTU) MMI 15 mg once daily as effective as PTU 100 mg three times daily
with lower incidence of minor adverse effects (14 % vs. 52 %) MMI 15 mg twice daily is more effective than 15 mg once daily with higher incidence of minor adverse effects (30 % vs. 14 %) (Nakamura et al., J Clin Endocrinol Metab 92: 2157, 2007) Serious adverse effects are rare with both drugs
– agranulocytosis (baseline WBC) – MPO-ANCA, vasculitis, and lupus-like syndrome – hepatitis (cholestatic with MMI or CMI and necroinflammatory with PTU) (baseline alk. phos. and ALT)
MMI or CMI vs. PTU (cont.)
MMI, CMI, and PTU reduce efficacy of 131I treatment, with larger effect of PTU (Walter et al., BMJ 334: 514, 2007) MMI during gestation may be rarely associated with
congenital malformations (esophageal atresia, choanal atresia, aplasia cutis) (DiGiantonio et al., Teratology 64: 262,. 2001). No associations with PTU have been reported; therefore preferred drug during gestation.
Randomized Prospective Studies on Effect of Carbimazole Treatment Duration
Relapse rate at 2 years was 58% after 6 months compared to 38% after 18 months (Allanic et al., J Clin Endocrinol Metab 70:675, 1990)
Relapse rate at 2 years was 46% after 12 months compared to 54% after 24 months and at 5 years was 86% and 83%, respectively (Garcia-Mayor et al., J Endocrinol Invest 15: 815, 1992).
Relapse rate at 1 year was 59% after 6 months compared to 65% after 12 months (Weetman et al., Q J Med 87: 337, 1994). Relapse rate at 2 years was 36% after 18 months compared to 29% after 42 months (Maugendre et al., Clin Endocrinol 50:127, 1999)
Comparison of Block – Replace regimen with Titration regimen
12 randomised controlled trials revealed no significant difference between the regimens with respect to relapse of Graves’ hyperthyroidism (RR 0.93; 95%CI 0.84 – 1.03) (Abraham et al., Eur J Endocrinol 153: 489, 2005)
Predictors of Relapse young patient male gender cigarette smoking large goiter severe ophthalmopathy undetectable TSH high TSHRAb
Indications for 131I treatment severe thyrocardiac disease toxic nodular goiter adverse reaction to antithyroid drug relapse after 12 to 18 months of antithyroid drug treatment
131I
Treatment of Hyperthyroidism
(Alexander and Larsen, J Clin Endocrinol Metab 87: 1073, 2002)
261 patients treated with 131I providing an average retained dose of 173 uCi/g at 24 h 225 patients (86 %) became hypothyroid or euthyroid at 1 yr, of whom 79 % were on PTU or MMI before 131I; 36 patients (14 %) remained hyperthyroid of whom all had been on PTU or MMI before 131I inverse, asymptotic relationship between retained 131I at 24 h and persistent hyperthyroidism with success rate of ~90 % with doses >138 uCi/g; failure rate of ~10 % did not decline with doses up to 400 uCi/g
Calculation of 131I Dose Target dose = ~150 uCi/g as efficacy not increased with higher dose 131I dose (mCi) = 0.15 multiplied by estimated gland weight (g) divided by fractional uptake of 131I at 24 h
Outcomes of 10-year MMI versus 131I Treatments (Azizi et al., Eur J Endocrinol 152:695,2005)
MMI group (n=26) 100% euthyroid, 50% had goiter 131I group (n=41) 61% hypothyroid, 25% had goiter QoL score, DXA, & Echocardiogram similar Total and LDL cholesterol higher in 131I group
Indications for Thyroidectomy large goiter with compressive manifestations pregnant patient with adverse reaction to antithyroid drug severe infiltrative eye disease (Moleti et al.,
Thyroid 13: 653, 2003; Usula et al., Asian J Surg 31: 115, 2008)
Pharmacological Utility of Iodine (Lugol’s iodine 3 drops t.i.d. or SSKI 1 drop t.i.d.) Abrupt decrease in thyroid hormone secretion due
to transient (~10 days) inhibition of thyroglobulin proteolysis (Wartofsky et al., J Clin Invest 49: 78, 1970) indicated in thyroid storm Transient reduction of thyroid vascularity in Graves’ hyperthyroidism (Erbil et al., J Clin Endocrinol Metab 92: 2182, 2007) - indicated for 10 days before thyroidectomy Inhibition of thyroid hormone synthesis after 131I treatment due to failure of escape from WolffChaikoff effect (Braverman et al., N Engl J Med 281: 816, 1969)
Management of Graves’ Ophthalmopathy
Acute Active Phase dark lenses elevate head of bed artificial tears & ointments diuretics prisms for diplopia glucocorticoids &/or orbital radiotherapy for severe disease (Bartelena J Clin Endocrinol Metab 90: 5497, 2005)
surgical followed by 131I ablation for severe disease (Moleti et al. Thyroid 13: 653, 2003; Uslu et al. Asian J Surg 31: 115, 2008)
Chronic Inactive Phase orbital decompression eye muscle surgery eyelid surgery