JOURNAL READING

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JOURNAL READING
Graves ophthalmopathy

• R5 ???
• 93/2/4

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• Perspective current medical management of Graves
  ophthalmopathy
• Ophthalmic plastic and reconstructive
  surgery, Vol 18, No.6 p402-408 , 2002
• Management of Graves ophthalmopathy
• Endocrine Reviews 21 (2)168199,2000
• 3. Current Perspective on the Pathogenesis of
  Graves Disease and Ophthalmopathy
• Endocrine Reviews 24 (6) 802-835,2003

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Pathogenesis
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• Pathological finding
• excess glycosaminoglycans (hyaluronan and
  chondroitin sulfate ) accumulation
• expansion of the adipose tissues (adipogenesis)
• Marked infiltration of immunocompetent cells (
  predominantly T lymphocytes , macrophage ,less B
  lymphocytes )

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• Pathogenetic hypothesis ---
• Autoreactive T lymphocytes recognizing an antigen
  ( shared by thyroid and orbit)
• After antigen recognition ? CD4 cell secrete
  cytokines ? amplify the immune reaction (
  activation CD8 or B cells )
• Predominance of T cells with a Th1 profile (
  IL-2, IFr, TNFa)
• Th2 profile ( IL-4, IL-5, IL-10) has been
  reported

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• Cytokines
• induce expression of MHCII, and HSP-72 ?
  important for antigen recognition
• induce expression of intercellular adhesion
  molecule-1 ? important for T cell recruitment
• Stimulate fibroblasts to synthesize and secrete
  GAGs

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Positive selection takes place in the cortex of
the thymus lobules
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Which is the antigen shared by the thyroid and
the orbit ?

• Ans
• The TSH-receptor

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Which is the orbital cell type targeted by T
cells ?

• Ans
• Remains to be defined
• Fibroblasts and adipocytes are more likely

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Genetic and Environmental Contributions to GO
Pathogenesis
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Genetic contributions

• multigenic condition
• HLA , CTLA4 , TCR ß-chain , and Ig heavy chain
  ?small relative risk of GD
• HLA, TNF-ß, CTLA4, and TSHR ?found none to be
  specifically associated with GO
• environmental factors, rather than major genes,
  are likely to be the primary predisposing factors
  to the development of GO.

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Environmental factors

• Induction of an inflammatory response
• cytokines?enhanced/aberrant expression of MHC
  class II and costimulatory molecules ?
  activation of antigen-specific T cells
• Infection
• overexpression of certain self proteins
• Act as B cell or T cell mitogens
• nonspecific activation of lymphocytes

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Environmental factors

• Superantigen
• Activation of a diverse population of T cells
• Polyclonal activation of B cells
• Molecular mimicry
• Two protein sharing common epitopes

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Graves ophthalmopathy

• management

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WHOM TO TREAT ?
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• Graves disease
• most ? mild,nonprogressive ophthalmopathy ?
  often improves spontaneously
• 35 with severe GO
• Severe GO
• treatment according to the severity and activity
  

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Natural history of GO
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Soft tissue involvement is not sufficient to
define GO as severe
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Proposed indicator of the activity of Graves
ophthalmopathy
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Hypothetical relationship between disease
activity and severity in the natural history of
GO -- J clin Endocrinol metab 80345347,1955
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• Ophthalmopathy is nonsevere
• no aggressive medical or surgical treatment
  (??some signs of activity)
• Severe GO ? ?? activity
• active ? likely to respond medical treatment
• Inactive ? surgical treatment
• Duration of eye disease--- less relevant for
  therapeutic decision

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HOW TO TREAT ?
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Nonsevere Graves ophthalmopathy
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Nonsevere Graves ophthalmopathy

• Simple local supportive measures
• Change in sleep position , elevation of the bed ?
  reduce periorbital edema
• Diuretic ??

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Severe Graves ophthalmopathy

• Medical or surgical decompression ??
• Availability of experienced surgeons or
  radiotherapists
• The existence of contraindication to
  glucocorticoid
• European thyroid association ---
• Majority ? select glucocorticoid treatment
• Need consensus guidelines

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Severe Graves ophthalmopathy
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Glucocorticoids

• Anti-inflammatory and immunosuppressive actions
• Decrease glucosaminoglycans synthesis and
  secretion by orbital fibroblasts
• Oral form steroid
• high doses ( prednisone 60100mg/day), prolonged
  periods (several months )
• Problem recurrence of active eye disease
• with cyclosporine ? recurrence was abated
• Respond rate 60 ( 40100)
• Favorable effect on soft tissue changes, optic
  neuropathy ,

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Glucocorticoids

• Intravenous glucocorticoids therapy
• Cumulative dose ranges 1-21g in different studies
  
• Favorable effect inflammatory signs and optic
  nerve involvement
• High respond severe ophthalmopathy , highest
  TSH-R antibody level

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Glucocorticoids

• Local (retrobulbar or subconjunctival ) therapy
• Less satisfactory than systemic steroid
• Side effect local pain, transient ocular
  discomfort ,conjunctivae hemorrhage )
• In case with major contraindication to systemic
  steroids

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glucocorticoids
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Orbital radiotherapy

• Radiotherapy
• nonspecific anti-inflammatory effect
• High radiosensitivity of lymphocytes infiltrating
  the orbital space
• Reduce GAG production
• Beneficial effects
• Rapid progression of eye disease
• Soft tissue inflammatory changes , optic
  neuropathy
• Proptosis , ocular motility dysfunction ? less
  benefit
• Overall favorable effects 60

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Orbital radiotherapy

• Linear accelerators , delivering 4-6 megavolts ,
  4x4 cm lateral field
• Most common delivered dose 20 Gy
• fractionated in 10 daily doses over 2-week
  period
• Side effect
• Transient exacerbation of inflammatory eye signs
  and symptoms ? administrated with glucocorticoids
  
• Cataract
• Radiation retinopathy --- case with DM
  retinopathy is contraindication ??????
• Carcinogenic ?? ( avoid in young lt30 y/o )

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Orbital radiotherapy combined with
glucocorticoids

• Synergistic effects
• Rapid effect of steroid sustained action of
  irradiation
• Prevent transient exacerbation of ocular disease
  
• reduce the prevalence of eye disease recurrence

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Immunosuppressive drugs

• Cyclosporine
• Lower efficacy compared with steroid
• Prummel combination of cyclosporine and
  prednisone ? more effective
• Methotrexate

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plasmapheresis

• Removal of immunoglucobins or immune complexes
• Conflicting results
• No randomized and controlled trials

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Somatostatin analogs

• Somatostatin receptors can be visualized in vivo
  in orbital tissue of Graves disease by Octreoscan
  
• Active GO have a higher orbital uptake of tracer
  (111-In Octreoscan)
• Few , uncontrolled trials
• 0.1 mg subcutaneous octreotid 3 times daily for 3
  months
• Improvement in soft tissue inflammatory ,
  extraocular muscle impairment ( in positive
  octreoscan patients)
• Limitation short half life
• Lanreotide long acting analog ( 40mg every
  other week )

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Intravenous immunoglobulins

• Study ????

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antioxidants

• Oxygen free radicals ? stimulate proliferation of
  orbital fibroblasts and their expression of
  72-kDa heat shock protein
• A nonrandomized ,comparative study
• 1 group (11 cases) with 3-month course of
  allopurinol( 300mg/daily) niconamide
  (300mg/daily), 1 group with placebo
• Improvement of GO in 82 of antioxidant-treat
  patients Vs 27 of placebo

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Cytokine antagonists

• Balazs et al
• Nonrandomized and uncontrolled trials
• 10 patients ? pentoxifylline ( IV 200mg daily for
  10 days ?1800mg daily orally for 4 weeks? 1200mg
  daily until 3-month treatment)
• 80 responded
• Soft tissue change and proptosis ? most
  responsive
• ??? randomized , controlled trials

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colchicine

• Anti-inflammatory
• Inhibit phagocytosis of the macrophage
• Reduce chemotaxis of PMN
• Decrease the expression of IL-2 receptor
• Decrease the formation of leukotrienes
• Stimulate the release of PGE
• Inhibits immunoglobulin secretion
• A recent preliminary uncontrolled report on 6
  patients ? showed favorable results on soft
  tissue change and subjective symptoms

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Rehabilitative surgery

• Extraocular muscle surgery
• Reducing diplopia
• Time when the muscle has undergone fibrotic
  change and disease has been inactive for 4-6
  months
• Require prior decompression surgery
• Most frequent ? the inferior rectus muscle
• Eyelid surgery

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Treatment of Graves hyperthyroidism in patients
with GO
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Treatment of Graves hyperthyroidism in patients
with GO

• The relationship between the type of treatment of
  hyperthyroidism and the outcome of eye disease is
  not completely clear
• antithyroid drug treatment
• radioiodine therapy
• Thyroidectomy
• total thyroid ablation
• GO should not influence the choice of treatment
  for hyperthyroidism

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Antithyroid agents

• Restoration of euthyroidism by thionamides is
  associated with GO improvement
• A direct effect of thionamides or thionamide
  induced normalization of thyroid status ??
• Recent study ? suggest ATD does not affect GO
  course
• Major problem --- recurrence after withdrawal
• young , goitergt 40ml, high TSH-receptor antibody
  at diagnosis

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• Radioiodine therapy
• Few reports radioiodine carries a small but
  definite risk of causing GO progression,
  especially if GO preexists or patients smokes
• can be prevented by concomitant glucocorticoid
  therapy
• in a recent European survey ---
• Treatment of recurrent hyperthyroidism after
  antithyroid drug therapy
• 43 of respondents --- thyroidectomy
• 32 of respondents --- 20 course of ATD
• 25 of respondents --- radioiodine therapy

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• Thyroidectomy
• If GO is well established or long-lasting ? total
  thyroidectomy might not favorably influence GO
  course
• Carry a very low risk of causing GO progression
• Subtotal and total thyroidectomy ??GO outcome
  ??,????
• Glucocorticoid treatment ? not necessary after
  thyroid surgery

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Total thyroid ablation

• may have a beneficial effect on GO course (
  related to ablation of thyroid antigens and
  removal of thyroid autoreactive T lymphocytes )
• Combination of thyroidectomy and radioiodine
  therapy

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