Page 985 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 70 Autoimmune Thyroid Diseases 951

GRAVES OPHTHALMOPATHY
Management of GD
The management of hyperthyroid GD can be divided into three Epidemiology
broad categories: medical management, radioiodine (RAI) treat­ GO is the most common extrathyroidal manifestation of GD.
ment, and surgery. 18 It is clinically apparent in 25–50% of those presenting with GD,
although almost all patients have radiological changes consistent
Medical Management—Antithyroid Drugs with GO to some degree. The peak age of incidence is in the
The thionamide drugs (carbimazole, its metabolite methima­ fifth and seventh decades of life. GO precedes thyroid gland
zole, and propylthiouracil) compete with Tg to act as substrates dysfunction in about 20% of patients, arises at the same time
for iodination by TPO. Once iodinated, they are metabolized in 40%, and occurs after diagnosis of thyroid dysfunction in the
peripherally, depleting thyroid iodine stores. When the thyroid remaining 40%. Males, older adults, and smokers are more likely
iodine stores are depleted and the intrathyroidal thionamide to have severe disease. Ninety­three percent of cases of GO occur
concentration is high enough, thyroid hormone synthesis is in those with hyperthyroid GD. However, 3% and 4% of GO
abrogated. Most individuals become euthyroid following 4–8 occurs in hypothyroid and euthyroid patients, respectively. A
weeks of treatment; however, euthyroidism may take longer to proportion of these patients with “euthyroid Graves” will eventu­
achieve in those with poor medication compliance or with a ally become hyperthyroid; however, some will remain hypothyroid
history of recent iodide exposure. Following initial treatment, or euthyroid despite the presence of TSH­R antibodies.
thionamides may either be administered as a fixed high dose,
with levothyroxine supplementation to prevent hypothyroid­ Etiology
ism (known as a “block and replace” regimen), or at progres­ GO shares many etiological factors with GD. Smoking is the major
sively lower doses, titrated to allow adequate thyroid hormone environmental risk factor for GO, with smokers or ex­smokers
generation. Following 6–18 months of thionamide treatment, four times more likely to develop GO compared with lifelong
about 50% of patients will remain in remission following ces­ nonsmokers. The number of cigarettes smoked per day correlates
sation of therapy. There is no improvement in remission rate in with the risk of developing GO, suggesting a “dose­dependent”
individuals with GD who are treated for longer than 18 months. effect. RAI therapy is also known to occasionally cause flare­ups
The mechanism of the thionamide­induced remission in GD of GO. This is thought to be largely related to uncontrolled
remains obscure; however, the lymphocytic infiltrate in the post­RAI hypothyroidism. Smokers and those with active GO
GD thyroid is rapidly abolished by thionamide treatment, and seem particularly susceptible to this complication, and therefore
serum TSH­R and TPO autoantibodies also decrease during RAI is relatively contraindicated in patients with active GO. 19
treatment, suggesting an immunomodulatory effect. It is telling
that several induced murine models of thyroiditis can be amelio­ Immunopathogenesis
rated by thionamide treatment, suggesting an immunomodula­ The molecular mechanism that links thyroid dysfunction with
tory role that is distinct from the antithyroid hormone synthesis GO remains incompletely understood. The TSH­R is widely
action. If the patient’s disease relapses following medical treat­ believed to be the primary autoantigen linking the thyroid and
ment, definitive treatment should be considered, as a second the orbit. Orbital fibroblasts (OFs) have been shown to express
course of thionamide treatment rarely induces prolonged cell­surface TSH­R, and these are thought to be functional because
remission. of the observation that TSH stimulation in vitro results in an
increase in intracellular cAMP. Mechanistically, the orbital changes
Definitive Treatment that occur in GO are better understood. TSH­R autoantibodies
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Radioactive iodine (RAI) therapy ( I) and surgical thyroid­ that bind to the TSH­R on OFs (or possibly other OF receptors,
ectomy are both efficacious treatments for GD, effectively such as the insulin­like growth factor receptor; IGF­1R) are
removing functional thyroid tissue and rendering the patient believed to activate OFs to secrete cytokines and chemokines,
hypothyroid and dependent on levothyroxine replacement over which attract lymphocytes and other inflammatory cells. These
the long term. RAI therapy takes advantage of the thyroid’s infiltrate the orbital tissues, augmenting further the proinflam­
ability to concentrate iodine. RAI is administered orally and matory cytokine environment, causing OFs to proliferate and
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concentrates in the thyroid, primarily emitting beta­radiation to secrete excessive GAGs. GAGs accumulate in the extraocular
to produce local thyrocyte DNA damage. These cells then muscles, increasing their size. These matrix molecules are also
undergo necrotic change, and the thyroid atrophies over the osmotically active, resulting in edema and swelling of surrounding
subsequent year. RAI renders more than 80% of those with GD tissues. In addition, the adaptive arm of the immune system is
hypothyroid and needing long­term thyroid hormone replace­ thought to interact via HLA and CD40 molecules expressed by
ment. RAI is generally well tolerated, and long­term follow­up the OFs to increase the presentation of autoantigens, thus
studies in adults have shown reassuring results with regard to perpetuating the cycle. OFs are also thought to differentiate into
carcinogenicity. RAI is absolutely contraindicated in pregnancy adipocytes, resulting in increased retroorbital fat deposition. The
and is best avoided in those with active, inflammatory GO. Total resulting inflammation gives rise to redness and edema of the
or near­total thyroidectomy is also an effective treatment for orbital tissues, with the cellular proliferation and GAG accumula­
GD and is particularly suitable for individuals with a large tion producing proptosis (protrusion of the eyeball from the
goiter, those with severe hyperthyroidism who cannot tolerate socket), increased intraorbital pressure, and restriction of
thionamides, or in those with active GO when RAI is relatively extraocular eye movements. 20
contraindicated. The complications of thyroidectomy include
change in voice because of intraoperative damage to the recur­ Diagnosis and Clinical Presentation
rent laryngeal nerve and hypocalcemia (often transient) caused When the clinical signs of GO are associated with thyroid dysfunc­
by parathyroid gland damage. tion and/or circulating thyroid autoantibodies, the diagnosis is