H. Delshad M.D Endocrinologist - PowerPoint Presentation

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H.

Delshad M.DEndocrinologistResearch Institute for Endocrine SciencesShahid Beheshti University of Medical Sciences

How to treat hyperthyroidism when GO is present

A challenging dilemma

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The most common cause of

thyrotoxicosisIs an autoimmune disorder in which TRAbs stimulate the TSH receptorRobert James Graves, in 1835, was the first to describe the association of a goitre with exophthalmos

Graves Disease

,

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Prevalence : 25 – 40%

Subclinical (CT Scan, MRI): In the majority of patients Sever forms of GO: 3 -5% of all the casesEstimated incidence in the general population: 16 women and 3 men/100000 population/yearThe prevalence has declined in recent years: Patients diagnosed at the same eye clinic 1960 = 57% 1990 = 37% Earlier diagnosis and treatmentDecreased prevalence of smoking ( western Europe) Increased prevalence of smoking : Poland & Hungary since 1989

Increased prevalence of GOGraves orbitopathy)

Thyroid-associated

ophthalmopathy

or

Thyroid eye disease

(

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اوربیتوپاتی گریوز در ایران

مطالعه دکتر عزیزی و همکاران در سال 1380: ● از 560 بیمار با تشخیص پر کاری تیروئید : 117 بیمار مبتلا به اوربیتوپاتی

گریوز بودند. ● سن بالای 40 سال و جنس مرد ، به عنوان عامل خطر ساز بروز بیماری چشمی مطرح شدند. ● در مقایسه با یافته های دیگر کشورها،اوربیتوپاتی گریوز در این بر رسی حدود یک دهه زودتر خود را نشان می داد. مطالعه دکتر بهمنی کشکولی و همکاران :

●

از 850 بیمار دچار پر کاری تیروئید

30 درصد علائم واضح در گیری چشمی

ودرمعاینه دقیق90 درصد دچار علائم چشمی بودند.

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Graves'

orbitopathy

Activity Acute inflammation 6 – 18 monthsSeverity Chronic complicationsActivity Severity

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Activity

Activity

CAS> 3/7

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Swollen

Caruncle

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Severity

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Severity of Graves,

Orbitopathy(EUGOGO: Europian Groups On Graves, Orbitopathy) Degree

Signs and Symptoms Mild 1- Minimal or moderate edema 2- Proptosis < 25 mm Moderate Moderate to sever soft tissue involvement1- and/ or Proptosis > 25 mm2- and/or inconstant diplopia3- and/or corneal point lesion Sever 1- Optic neuropathy 2- Corneal breakdown

N

O

S

P

E

C

S

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Proptosis, Moderate eyelid edema, Moderate eyelid erythema

Conjunctival chemosis Bilateral edema of the caruncles, Proptosis, Slight eyelid edema . Slight eyelid erythema

CAS = 4

Moderate Active

CAS = 2

Mild to moderate inactive

Graves'

orbitopathy

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Inflammation of the

plica (arrow) with diffuse conjunctival redness.

Chemosis. Notice the conjunctiva separated from the sclera and behind the grey line (arrows) and diffuse conjunctival redness.Graves' orbitopathy

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Graves'

orbitopathySever or Malignant Orbitopathy Optic neuropathy and Corneal breakdown

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Graves, Disease

Three effective and safe treatment options:

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New Guideline

2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis Douglas S. Ross, Henry B. Burch, David S. Coope

,M. Carol Greenlee, Peter Laurberg, Ana Luiza Maia, Scott A. Rivkees, Mary Samuels, Julie Ann Sosa, Marius N. Stan, and Martin A. Walter

THYROID

Volume 26, Number 10, 2016

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Graves, Disease

Thyroid Treatment

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Graves, Disease

Thyroid Treatment

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Graves, Disease

Thyroid Treatment

1

Dose it matter for the eyes how the patient is rendered

euthyroid

?

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ATDs (

Thionamides )Improvement in ocular conditions often follows ATDsThis beneficial effect is related to restoration of euthyroidismA major limitation of ATDs : High rate of relapseRecurrence : Reactivation of thyroid autoimmune phenomena and an increase in serum TRAb.Flare up of autoimmune reaction: GO progression

Permanent control of hyperthyroidism is advocated

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Radioiodine ( I

131 )Its effects on GO are controversialRCTs : Progression of GO in 15 – 39% Systematic review of RCTs: I131 is associated with a small but definite risk of appearance or worsening of GO

Progression of GO : Is unlikely in absent or minimally active / inactive GOGO may occur after I131 even in the absence of active GOAcharya et al : Clin Endocrinol , 2008Bartalena et al : 1989 , 1998 , Tallsted et al : 1992 (

N

Engl

J Med )

Traisk

et al ; 2009

( JCEM )

Vannuchi

et al : JCEM , 2009

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100

80 60 40 20

0

Methimazol

( n=

148 )

Radioiodine +

prednisone

( n=

145 )

Improved

Unchanged

Worsened

Outcome of GO after treatment of hyperthyroidism with

MMI , I 131 or I 131+ prednisone in a RCT

Bartalena

L et al. N

Engl

J

Mrd

;1998

% of patients

.

.

.

.

.

.

Radioiodine

(n=150)

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Pathogenic Mechanism

I 131 Thyroid InjuryRelease of Thyroid- Ag Trigger or Exacerbate

Autoimmune ResponsesTransient Hypothyroidism TSH Stimulates TSHR

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Thyroidectomy

Is not a disease-modifying treatment and dose not influence the natural history of GOThyroid injury : ○ Short lasting after surgery ○ Long lasting after Radioiodine

The initiation of LT4 shortly after surgery prevents the occurrence of hypothyroidism

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Progression of GO after different treatment of thyrotoxicosis

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Graves, Disease

Thyroid Treatment

2

Are there any specific criteria to prefer one of the treatment modalities for hyperthyroidism in Graves,

orbitopathy

?

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Any hyperthyroid patient, independent of GO needs ATD.

Choice of subsequent treatment : ○ Mild GO : ─ Continue ATD ─ I131

or surgery after GO is burnt-out ○ Moderate-to- sever GO : ─ Definitive therapy of hyperthyroidism ─ Concomitant treatment for GO, as appropriateNo controlled studies are available to establish whether either approach is better

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Graves, Disease

Thyroid Treatment

3

Is there any risk factor which may predict appearance or worsening of graves,

orbitopathy

after

I

131?

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Recent-onset Hyperthyroidism

Pre- existing orbitopathy, especially if activeSeverity of hyperthyroidism: T3> 325 ng/dlHigh serum TSH or TRAb. : > 8.8 IU/LCigarette smoking Traisk et al. JCEM: 2009In recent-onset newly diagnosed Graves, development of GO:

After I131 : 38% With ATDs : 18% Bartalena et al. N Engl J Med : 1998 With pre-existing orbitopathy : 24% Without eye involvement : 8%

Bartalena

et al. Ann Intern Med : 1998

Non- smokers : 6%

Smokers : 23%

Risk factors

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Non-smokers smokers

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Graves, Disease

Thyroid Treatment

4

Should the presence of GO limit the use of Radioiodine therapy ?

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I

131 carries a small but definite risk of appearance or progression of GO.Is usually observed, when other risk factors are present.Can be prevented by Glucocorticoid therapy.Prednisolone: 0.5 mg /kg/day, for 6 to 8 weeks

Should the presence of GO limit the use of Radioiodine therapy ?

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All

patients: •ATDs •Risk factors for appearance / worsening of GO •Stop smoking •LT4 , 2 weeks after I131GO Absent : Presence of risk factors:

Glucocorticoids coverageGO Present : •Mild orbitopathy → Active and / or presence of risk factors : Glucocorticoids coverage •Moderate to sever orbitopathy : → Active : High dose IV Glucocorticoids ± Orbital radiotherapy → Inactive : Glucocorticoids in the presence of risk factors

Guidelines for

I

131

therapy in patients with GO

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Graves, Disease

Thyroid Treatment

5

Dose transient hypothyroidism following therapy influence the course of Graves,

orbitopathy

?

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Ophtalmopathy

& thyroid stimulation Mechanism: High TSHEarly administration of LT4 (2 weeks after I131)Karlsson et al. Lancet ; 1989 6 of 15 patients showed sever eye disease during transient phase

of Hypothyroidism after I131○ Stimulation of thyroid cells and over expression of thyroid antigens○ Binding of TSH to orbital TSHRs Dose transient hypothyroidism following therapy influence the course of Graves,

orbitopathy

?

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Graves, Disease

Thyroid Treatment

6

Has total thyroid ablation a role in the management of hyperthyroidism in GO ?

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Graves,

orbitopathy : ♠ Autoimmune reactions against autoantigens ♠

Intrathyroidal autoreactive T-Lyphocytes infiltrate the orbitRemoval of thyroid Ags and autoreactive T-Lymphocytes may be beneficial for GO.Catz B, Perzik SL. Am J Surg ; 1969 , Werner SC et al. N Eng J Med ; 1967De Groot L J et al. Orbit ; 1996 ,

Moleti

M et al. Thyroid ; 2003

Has total thyroid ablation a role in the management of hyperthyroidism in GO ?

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70

6050403020100

.

.

.

.

.

.

.

.

Near-total

thyroidectomy

( n=

30 )

Near-total

thyroidectomy

+

Radioiodine ( total thyroid ablation)

( n=

30 )

Improved

Stable

worsened

Overall outcome of GO after treatment of hyperthyroidism with

near-total

thyroidectomy

with and without radiotherapy in patients also given IVGC in a RCT

P= 0.0014

Menconi

F et al. JCEM ;2007

% of patients

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Thyroid Treatment

Advantages Disadvantages Thionamides No effects of GOFluctuation of thyroid function may be detrimental for GORecurrence of hyperthyroidism and possible worsening of GO

Radioiodine Depletion of autoreactive T-lymphocytesAntigen deprivationPossible appearance or worsening of GOThyroidectomy Depletion of autoreactive T-lymphocytes

Antigen deprivation

Surgical

risk

Advantages and disadvantages of different treatments of hyperthyroidism

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Orbital decompression