1 Thyroid Associated Orbitopathy 10 th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology

1

Thyroid Associated Orbitopathy

10th Asia and Oceania Thyroid Association Congress

October 21-23, 2012

Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Medicine,

Kurume University School of Medicine, Kurume, Japan 　

2


Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Medicine,

Kurume University School of Medicine, Kurume, Japan 　

Pathogenesis Role of MRI Treatment

10th Asia and Oceania Thyroid Association Congress

October 21-23, 2012

外眼筋

脂肪組織

涙腺

外眼筋

上眼瞼挙筋

Proptosis

Lid retraction

Abnormal Secretion of Lacrimal fluid

Eyelid

Conj.

Cornea

Extra-ocularMuscle

Optic NerveRetina

Primary Secondary impairmentSiteMüller’s muscle

Lacrimal 　 gland

Extraocular 　 Muscle

Orbital connective tissue

上眼瞼挙筋Lev palpebrae sup

Geneticfactor

Enviromentalfactor

TRAb

Hyperthyroidism Graves’ ophthalmopathy Pretibial myxedema

Robert James Graves(1796~1853)

Graves’ disease Morbus Basedow

Carl von Basedow

Breakdown of immunological tolerance

(1799~1854)

80~90%

25~50%

(Thyroid associated orbitopathy)

En

larg

em

en

t of

eye

mu

scle

s（

mm

2)

ー＋0

200

400

600

800

1000

1200

1400

TNFαgene expression in eye muscle tissue

P < 0.05

0

500

1000

1500

2000

2500

Orb

ital fa

t volu

me

(mm

2)

P < 0.05

IL-4 IL-6 IL-10ー＋＋ー＋

P < 0.05 P < 0.05

Cytokine gene expression in orbital fat tissue

ー

（ Hiromatsu et al. ： JCEM 85:1194, 2000 ）

Increase of orbital fat tissueEnlargement of eye muscle

Expression of TSH-R mRNA in the orbitTSH-R

（ 1.2kb ）

TSH-R (296 bp)

RT-PCR

In situ hybridization

anti-sense sense (Hiromatsu et al. Thyroid 6: 553, 1996)

Gene Array StudiesGene Fold Function

PPAR-g 44.2 Signal transduction

Pro-platelet basic protein 32.9 Cell proliferaion

Collagen type 1a1 28.2 differentiation

Adiponectin 25.0 Metabolism

IL-6 23.9 Cell proliferation

Glycogenin 2 22.4 Glycogen biosynthesis

sFRP-1 18.5 Signal transduction

(Kumar et al.: JCEM 90:4730, 2005)sFRP-1 (secreted frizzled related protein-1)

(Kumar, S. et al. J Clin Endocrinol Metab 2005;90:4730-4735)

sFRP-1 (100 nM) 　 induced adiponectin mRNA (A), leptin mRNA (B), and TSHr mRNA (C) expression

on orbital fibroblasts

sFRP-1 induces adipogenesis and expression of TSHR on orbital fibroblasts.

sFRP-1 (secreted frizzled related protein-1)

Peroxisome Proliferator-Activated Receptor-g in Thyroid Eye Disease: Contraindicaiton for Thiazolidinedion Use?

(Starkey et al: J Clin Endocrinol Metab 88: 55-59, 2003)

57 yr-old male, 8-yr history of type 2 DM

Pioglitazone 30mg/d for 3 months

6wk pre 3m on 3m stop Proptosis rt 19mm 21 20 lt 20 23 22Conj. Redness (-) mild (-)Lid swelling Mild Severe SevereDiplopia (-) Intermittent (-)CAS 6 2

Thiazolidinedione induced Graves’ ophthalmopathy

• Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, Ludgate M. ： Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab. 2003;88:55–9.

• Levin F, Kazim M, Smith TJ, Marcovici E. ： Rosiglitazone-induced proptosis. Arch Ophthalmol. 2005;123:119–21.

• Dorkhan M, Lantz M, Frid A, Groop L, Hallengren B. ： Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes. Clin Endocrinol (Oxf). 2006;65:35–9.

• Lee S, et al. ： Thiazolidinedione induced thyroid associated orbitopathy. BMC Ophthalmol. 2007; 7: 8.

CD34+OF CD34-OFIL-16

RANTES CXCL10

IGF-1R↑

IGF-1R Ab

Migration of T cells

T cellT cell

Macrophages

Adipogenesis

IL-6IL-8

CXCR4

TSHR↑

TSHR Ab

Glycosaminoglycansshort chainhyaluronan

long chainhyaluronan

proliferation

B cellactivation

TSHR Ab IGF-1R Ab

IL-1aIL-8

COX-2CXCL12

CytokineTh1, Th2

IL-1TNFaTGFb

IL-6TNFa

CD40CD40L

B7

TCR

HLA

Th1- ： Leukoregulin,TNFα, IL-1β, INFβ, INFγ, IL-2, IL-12Th2- ： IL-4, IL-5, IL-10Antibody

serumCD34+fibrocytes

Orbital fibroblasts

＋

PPARgTGFbTNFa

_

IL-1bIFNgTGFbTNFa

+

Orbit

preadipocytes

TSHR Ab IGF-1R Ab

CD90 (Thy-1)+ orbital

fibroblasts may differentiate

into myofibroblasts, that

participate in the

development of fibrosis in

late stages of the disease.

Bahn R.S: N Engl J Med 2010; 362:726-738.

Myofibroblast

Thy-1+

OF

TGF-β

FibrosisFibrosisExtraocular muscle

enlargement

Extraocular muscle

enlargement

ExpandedAdiposetissues

ExpandedAdiposetissues

ElevatedTRAb

ElevatedTRAb

Relationships between anti-TSH receptor antibidies and GO

• TRAB ( 1st generation; TBII)• TRAb (2nd generation; hTRAb; TRAb-CT)• TRAb (3rd generation; M22)• TSAb• TSI [Mc4; chimeric TSH-R (amino acid residues

262-335 of human TSH-R replaced by rat LH-R) ]

Anti-TSH receptor Antibodies

TBII

TSAb

TSH-R antibodies　 TBII TSAb

GO （＋） GO （ー） Normal 67% 　　　 85% 　　　　 0%59% 　　　 83% 　　　　 0%

(Hiromatsu et al., Thyroid 6: 553, 1996)

(Nishikawa et al., Acta Endocrinol 129: 213, 1993)

In GO patients there are significant correlation between TRAb and the enlargement of eye muscle.

At the first visit, there is no difference in the prevalence of TRAb between GO and GD without ophthalmopathy.

Enlargement of EM En

larg

em

en

t of

EM

Anti-TSH receptor antibody in GO

Mild GO Severe GO

The novel chimeric(Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R)

TSI level of GO was greater than that of Graves’ disease without ophthalmopathy.Majority of patients with GD had undergone antithyroid treatment and were rendered euthyroid at the time of blood sampling.

chimeric (Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R)

A novel thyroid stimulating immunoglobulin assay

Correlation of the thyroid stimulating lgs in GO with clinical disease activity.

Th2 thyroiditis

　

Shared antigens Between thyroid and orbit

Tg

Hyperthyroidism (Graves’ disease)

Breakdown of immune tolerance

Breakdown of immune tolerance

Genetic factors Genetic factors Enviromentalfactors

Enviromentalfactors

Th1, Th2cytokines

Anti-TSH receptor AbsAnti-TSH receptor Abs

Anti-EM Ab

Tg

adipogenesisTSH receptor ↑

sFRP-1, CYR61G2s

SDH1D

EM antigensG2s

1D

Calsequestrin

TSH receptor

Mild

SeveresmokingCTLA-4

CD40PTPN22

HLA TNFaICAM-1NFkB1FOXP3

IGF-1receptor↑

Greves’ ophthalmopathy

Collagen XIII

IGF-1R Ab

TSI

Infl

amm

atio

n /

fib

rosi

s

genotype Allele frequency

TT TC CC 　　　 T C 　　　　　 OR

n

28(45.2)

81(73.0)

29(46.7)

30(27.0)

5(8.1)

0(0)

85(68.5)

192(86.5)

39*(31.5)

30(13.5)

GO

GDw/ooph

62

111

TNF-α gene polymorphism (T-1031C) and GO

＊ P=0.0001

（ Kamizono et al. Clin Endocrinol 2000; 52:759-764.)

2.9

（日本人）

The C allele frequency is higher in GO patients.

ICAM-1 gene polymorphism

ｃｌａｓｓ ⅢーⅥ

ｃｌａｓｓ０－Ⅱ

ＡＡ

４６

７２

（％）

（４９）

（３６）

ＧＡ

３６

９９

（％）

（３９）

（４９）

ＧＧ

１１

３０

（％）

（１２）

（１５）

　Ａ　（％）

１２８（６９）

２４３（６０）　

　Ｇ　（％）

　５８（３１）

１５９（４０）

χ2=4.925 P=0.0852

χ2=3.825 P=0.0505

Allele frequencyGenotype frequency

ｃｌａｓｓ ⅢーⅥ

ｃｌａｓｓ０－Ⅱ

ＡＡ

４６

７２

（％）

（４９）

（３６）

GA + GG 　（％）

　４７（５１）

１２９（６４）

χ2=4.643 P=0.0312

Ｋ４６９Ｅ (1405 A→G)

The ＡＡ genotype frequency is higher in severe GO .

OR

1.75

OR

1.44

ATA class

NFkB1 gene polymorphism（ -94del ATTG ）

Genotype frequency Allele frequency

Del (%) Hetero (%) Ins (%) Del (%) Ins (%)N

Ⅲ ～Ⅵ

０～Ⅱ ３０１３８（１３％）

１３２（４４％）

１３１（４３％）

１２３２５（２０％）

５９（４８％）３９（３２％）

１０９（４４％）

１３７（５６％）

２０８（３５％）

３９４（６５％）

χ2=6.853 P=0.0325OR 1.76

χ2=7.103 P=0.0077OR 1.51

The -94delATTG polymorphism of the NFkB1 gene is higher in severe GO.

ATA class

PPARγ （ Pro12Ala) 　 gene polymorphism

Genotype Allele

ＣＣ (%) ＣＧ (%) GG (%) Ｃ (%) Ｇ (%)N

Ⅲ ～Ⅵ

０～Ⅱ ２９４２７１（６９％）

２１（８７％）２（ 100 ％）

１２３１２０（３１％）

　３（１３％）　０（０％）２４３（３０％）

　３（１１％）

５６３（７０％）

２５（８９％）

Χ ２＝4.439 P = 0.1087

Fisher’s exact probability testP = 0.0328OR 3.59

Patients with ＣＣ genotype frequently have severe ophthalmopathy.

ATA class

Χ ２＝4.430 P = 0.0381OR 3.39

Summary (1) 1. TSH receptor is a primary autoantigen in GO.

Recent study suggests the presence of GO specific TRAb (Mc4)?

2. The increase of TSH receptor expression through adipogenesis is important in the pathogenesis of GO.

3. CD34+ fibroblasts, which are derived from peripheral blood and expand in the orbit, express TSH receptor in high level.

4. The increase of IGF-1 receptor expression in the orbital fibroblasts may also be important. Activation of IGF-1R leads secretion of IL-16 and RANTES on CD34-

fibroblasts, which enhance recruitment of activated T lymphocytes.

5. CD90 (Thy-1)+ orbital fibroblasts may differentiate into myofibroblasts that participate in the development of fibrosis in late stages of the disease.

6. Gene polymorphisms of the immunomodulator genes (such as TNFa, ICAM-1, NFkB, PPARg and FOXP3 etc) have been proposed as the susceptibility genes for GO.

7. The significance of the presence of anti-eye muscle antibodies, such as SDH, CASQ needs to be confirmed.

　　　



NOSPECS classification of eye changes of Graves’ disease (Thyroid 2:235, 1992)

Class Definition

0 No physical signs or symptoms

I Only signs, no symptoms (upper lid retraction, stare, and eyelid lag)

II Soft tissue involvement (symptoms and signs)

III Proptosis

IV Extraocular muscle involvement

V Corneal involvement

VI Sight loss (optic nerve involvement)

NOSPECS classification of eye changes of Graves’ disease (Thyroid 2:235, 1992)

Class Definition

0 No physical signs or symptoms



III Proptosis

IV Extraocular muscle involvement

V Corneal involvement

VI Sight loss (optic nerve involvement)

MRI 70%

50~75% of patients with

Graves’ disease do not have any signs or symptoms

of GO.

Occult Thyroid Eye DiseaseNo physical signs or symptoms

Enlargement of extra-occular muscles

Occult thyroid eye diseaseCase 1 Case 2

MRI


Total Mild Moderate severe

Lid retraction

1587(79.3) 792(39.6) 620(31.0) 175(8.7)

2000 eyes (%)Inoue et al.

Dalrymple sign (lid retraction)

Case 3 Case 4

von Graefe’s sign

ＲＬＲＬ

Case 5 Case 6

ＲＬＲＬ

Unilateral lid retraction

Case 7 Case 8

MRI



Lid swelling

1354(67.7) 958(47.9) 376(18.8) 20(1.0)

Conjunctiva 642(32.1) 451(22.6) 170(8.5) 21(1.0)


Swelling of upper and lower eyelidCase 9

MRI

III 　 Proptosis

Male 　　 444 eyes

female 1556 eyes

Japanese

Untreated Graves’ disease 　 Symptoms 24.2%

　 Hertel exophthalmometermild 　 39% total 57%

moderate 　１ 3% severe 　 5%

GO patients (4598 eyes) total 85% 　mild 39%

moderate 33% severe 13%

Proptosis alone 18.5%　 + lid lag 46.2%　 + lid swelling 19.0%　 + lid lag and lid swelling 16.3%

Proptosis

R) 13.0 mm L) 13.0 mm R) 17.0 mm L) 17.0 mm

R) 19.0 mm L) 19.0 mm R) 28.5 mm L) 30.5 mm

Proptosis 18mm~<21mm Proptosis ≥21mm

+ lid swelling

+ lid swelling+ lid retraction

Case 11 Case 13

Case 12 Case 14

MRI

IV 　 Extraocular muscle involvement


Diplopia 447(22.3) 237(11.8) 74(3.7) 136(6.8)


Diplopia

Restriction of motion in upward gazeVertical deviation of right eye

Enlargement of right inferior rectus muscle

Case 15

MRI

VI 　 Sight loss (optic nerve involvement)


DON 168(8.4) 147(7.4) 13(0.6) 8(0.4)


Papilledema Papillitis Optic disc atrophy

He complains orbital ache and decreased visual acuity.

Eyelid swellingEyelid eythema Conjunctival rednessProptosis

MRI: 　 The enlargement of superior, inferior, medial and lateral rectus musclesmay compress optic nerve.

T2 immage:The increased T2 relaxation time indicates that GO is in active state.

Case 17

Summary (2)

MRI is • useful for the assessment of GO.• useful for planning of the management of GO.

We strongly recommend MRI for management of GO.



Mild Moderate to severe Sight-threatening (DON ）

i.v. GCs 　 (±OR)

　 prompt decompression

Still active

Iv GCs(±OR)

Rehabilitative surgery

Stable & inactive

Active　　　

Rehabilitative surgery(if needed)

i.v. GCs (±OR)

Stable & inactive

Rehabilitative surgery (if needed)

Inactive

Local injection of GCs or Botulinum toxin

Ophtalmological examination, CAS, QOL

Local measuresWait and see

MRI

Poor response (2 weeks)

MRI

All patients with GO

NOSPECS Class 0 NOSPECS Class I~VI

Restore euthyroid 　 (avoid hypothyroidism)Urge smoking withdrawal

Wait and see

Occult thyroid eye disease

Specialized center

MRI

Inflammation ofUpper eyelids

intractable

Immuno-suppressant ,Decompression

Inflammation of eye muscles

Stable &inactive

Progression

Treatment of Graves’ ophthalmopathy

Sight-threating GO (DTN)

MRI

i.v. Glucocorticoids

i.v. Glucocorticoids( orbital radiation)


Still active

Poor response(2 weeks)

Prompt decompression

Stable and inactive

methylpredonisolone1g/d 3days 　 3 cycles

Pulse therapy

1w

Sight-threating GO (DON)Dysthyroid optic

neuropathy （ DON ） and/or

Corneal breakdown 　　　　　

Pulse therapy Before After

3 cycles

Transantral orbital decompression for Papilledema （ dysthyroid optic neuropathy)

pre

post

Papilledema

6 months after the surgery

Moderately to severe GO

MRI

i.v. Glucocorticoids( orbital radiation)


Stable and inactive

active inactive

Severity

Activity

Immunosuppressive therapy

Severity

Activity

Immunosuppressive therapy

Outcome Outcome

Prediction of outcome of Immunosuppressive treatment

Rehabilitative therapy

Classical Pulse1g/d 3days 　 3 cycles

Irradiation2Gy 10 times

Prednisolone 20mg 15mg 10mg 5mg

Pulse therapyOral steroid

①

1w

Efficacy ：　 77 ％（ Pulse ＋ irradiation ： 88 ％）　 Side effects ： peptic ulcer 、 glucose intolerance 、 osteoporosis

Efficacy ：　 59 ％　 ( 44 ％ in 5 RCT )Side effects ： exacerbation of inflammation 、 Cataract 、 Retinopathy, Tumorgenesis

Fatal liver failure• Acute liver damage occurred in 0.8%, and was lethal in 0.3% of

patients with GO underwent iv GC.• Direct toxic effect? Precipitation of virus-induced hepatitis? AIH?

ANAAIHNone 8Recovery439***

CMV3.2Recovery548

steatosisHBV15.7Recovery557

None17.1Recovery306

None15Recovery455

None17.1Death474

None7.1Death633

ANAsteatosisNone7.8 wkDeath562**

None4 wk after 5 cyclesDeath711*

Liver diseaseVirusTime of diagnosisOutcomeAgeCase

* Weissel et al. Thyroid 10: 521, 2000 ** Marino et al. Thyroid 14: 403, 2004*** Salvi et al. Thyroid 14: 631, 2004

The cumulative dose should be <8g methylprednisolone in one course of therapy. (EUGOGO)

Classical Pulse1g/d 3days 　 3 cycles



Pulse therapyOral steroid

①

1w

Efficacy ：　 77 ％（ Pulse ＋ irradiation ： 88 ％）　 Side effects ： peptic ulcer 、 glucose intolerance 、 osteoporosis

Efficacy ：　 59 ％　 ( 44 ％ in 5 RCT )Side effects ： exacerbation of inflammation 、 Cataract 、 Retinopathy, TumorgenesisMini-pulse

0.5g/d 3days 　 3 cycles



Oral steroid

②1w

Liver dysfunction during and 1 year period after pulse therapy (4 centers, 480 cases)

020406080

100120140160180200220240260280300320340360380400420440460480500520540

前 (ALT) 高値 (ALT) 3(ALT) 6(ALT)

ALT

before 1 month 6months 12 months

NoLiver dysfunction 　（ ALT)

＞ 100 50 ～ 100 total

Methylprednisorone 　１ g/d, 3 days, 3 courses

136　　

　

17cases

12.5 ％ 27cases

19.9 ％ 44cases

32.4 ％

Methylprednisorone 0.5g/d, 3 days, 3 courses

97　

3 3.1 ％ 17 17.5 ％ 20 20.6 ％

Total 233 20 8.6 ％ 44 18.9 ％ 64 27.5 ％Fisher’s exact probability testP=0.0115

c ２＝ 3.913 、 P=0.0479

Ｌｉｖｅｒ　ｆａｉｌｕｒｅ　ａｎｄ　ｓｔｅｒｏｉｄ　ｐｕｌｓｅ　ｔｈｅｒａｐｙ（４ centers ）

Liver dysfunction (ALT>100) was more frequently found in patients with high dose of methylprednisolone (>9g) pulse therapy than in low dose (4.5g). -Dose dependency-

Out of 20 cases with increase of ALT>100, Two cases were HBcAb+, their ALT increased to 639 、 326. Four cases were were HCVAb positive, and their ALT elevated to 223,188,149,124. -Reactivation of hepatitis virus infection –

In 7 out of 11 cases, who were HCVAB positive before pulse therapy, the increase of ALT was observed.

HBV carrier and patietns with past history of HBV infection.

Check HBV-DNA.Avoid pulse therapy.

If ophthalmopathy needs pulse therapy, consult with hepatologists for the use of entecavir.

Check liver function and HBV-DNA every month during and 1 year-period after pulse therapy.

Treatment in inactive stage

Rehabilitative Surgery• Orbital Decompression • Eye Muscle Surgery• Eyelid Surgery

Pre 3 months after surgery

Proptosis

preRt 22mmLt 20mm

postRt 15mmLt 14mm

Rehabilitative Surgery Transantral Orbital Decompression

Case 19

6months afterbefore

Deep Lateral Orbital Decompression

6 months afterbefore

Rt 27mm Lt 28mm Rt 24mm Lt 24mm

Case 20

Rehabilitative Surgery

Eye Muscle Surgery

Removal of the cicatricial tissue of left inferior rectus muscle

Lt 　 upward gaze impairment(enlargement of left inferior rectus muscle)

Case 21

Pre

Post

Rehabilitative SurgeryEyelid Surgery

Lengthening of Levator Muscle

Lenghening of Levator Muscle procedure by using polytetrafluoroethyrene as spacer.

Case 22

Mild GO

MRI

Rehabilitative surgery (if needed)

Stable and inactive

Local measures

active

Inflammation of EM and fat tissues

i.v. glucocorticoids(±orbital radiation

Stable and inactive

Local injection of triamcinolone acetonide and botulinum A toxin

Inflammation ofeyelid

progression

Wait and see

Triamcinolone acetonide injection

Rt ） lid swelling 、 lid lag 、 Graefe’s sign 2 months after the injection

Case 23

Botulinum toxin therapy

Full effect is evident after 2-3 days and persists for 4-6 weeks.

Indication: upper lid retraction

Case 24

Potential Therapeutic Targets in Graves’ ophthalmopathy

Target Current Agent TNF InfliximabTNF receptor EtanerceptIL-1 receptor AnakinraIL-6 receptor TocilizumabTGF-b LerdelimumabOxygen free radicals SeleniumCD20 RetuximabCD3 ChAglyCD3CD28 AbataceptCD154 IDEC-131PPAR-g Selective PPAR modulatorsSomatostatin receptor Octreotide-long acting release

SOM230 Thyrotropin receptor NIDDK/CEB-52

TSHR antagonist (Org-274179-0)

Anti-CD20 monoclonal Ab (rituximab)• Open study ： 9 caces 　 RTX 1000mg iv twice at 2wk interval• 20 cases 　 IVGC methylprednisolone 500mg iv for 16 weeks

Salvi et al. Eur J Endocrinol 2007; 156:33-40

Rituximab (1000mg)

００

０

Anti-CD20 monoclonal Ab (rituximab)

Peripheral depletion of CD20+ cellsSalvi et al. Eur J Endocrinol 2007; 156:33-40

CD20

CD20

B cell

B cell

http://www.eje-online.org/content/vol156/issue1/images/large/33F2.jpeg

Anti-CD20 monoclonal Ab (rituximab)

　　　ＲＴＸＩＶＧＣＲＴＸ　 v.s. ＩＶＧＣＣＡＳ　 4.7 　　　 1.8 4.1 　　　 2.0 　　 better

ＴＲＡｂ　 19.3　 11.5 16.3 9.3 　　　 not significant　 not significant not significant　　

Proposis 　　　 22.4　 20.9 22.6 22.1 　　 not significant significantly decreased significantly decreased

Palpebra 　　　　 improve improve not significant

Side effecs 　 33 ％ 45 ％Recurrence 　 0 ％ 10 ％

Salvi et al. Eur J Endocrinol 2007; 156:33-40

Complete Inhibition of rhTSH-, Graves’ Disease IgG-, and M22-Induced cAMP Production in Differentiated Orbital Fibroblasts by a Low-Molecular-Weight TSHR Antagonist

Clementine J. J. van Zeijl, Chris J. van Koppen, Olga V. Surovtseva, et al.(J Clin Endocrinol Metab 97: E781–E785, 2012)

Clementine J. J. van Zeijl, Chris J. van Koppen, Olga V. Surovtseva, et al.(J Clin Endocrinol Metab 97: E781–E785, 2012)

Summary (3)

1. Liver dysfunction (ALT>100) was more frequently found in patients with high dose of methylprednisolone (>9g) pulse therapy than in low dose (4.5g).

2. Reactivation of viral hepatitis should be considered.

Conclusion

Significant progress has been made in our understanding of the immunogenetic mechanisms leading to GO. 　We hope that these findings may be translated into new therapies and prevention strategies in GO. 　All the patients with GO should benefit from these efforts in near future.

ご清聴ありがとうございました。

Thank you for your attention.

Documents

1 Thyroid Associated Orbitopathy 10 th Asia and Oceania Thyroid Association Congress October 21-23, 2012 Yuji Hiromatsu, M.D., Ph.D. Division of Endocrinology