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, Gs-
alpha 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 <5%
TSHRAb 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

0- No changes
1- Only lid retraction
2- Soft tissue involvement
3- Proptosis
4- Extraocular muscle involvement
5- Corneal involvement
6- Sight loss due to optic nerve involvement
Pathogenesis of Gravesophthalmopathy

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 TSHR-
expressing fibroblasts results in
cytokine-mediated hydrophilic
glycosaminoglycan production, causing
edema and ultimately fibrosis
 PREVALENCE OF ATRIAL FIBRILLATION IN
ENDOGENOUS OVERT AND SUBCLINICAL
HYPERTHYROIDISM
Group Number With Atrial
Fibrillation
Control (>45 years) 22,300 513 ( 2.3%)
(TSH 0.4 - 4.0 mU/ L)

Overt Hyperthyroidism 725 100 (13.8%)*

(TSH < 0.03 mU/ L)

Subclinical 613 78 (12.7%)*

Hyperthyroidism
(TSH < 0.4 mU/ L)
*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
(Lugols 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 Wolff-
Chaikoff 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