Graves Disease Scott Gabbard

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Graves DiseaseScott Gabbard
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Overview

• Graves Disease is a syndrome of
• hyperthyroidism
• goiter
• opthalmopathy
• myxedema
• Prevalence 1 in 89
• Incidence 1 in 2000 per year

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Pathogenesis

• B-lymphocytes from thyroid tissue secrete Thyroid
  Stimulating Hormone Receptor Antibodies (TSHR-Ab)

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Immunology????

• CD4 Cells
• Humoral Immune System stimulates B-cell
  proliferation and antibody production
• Cytokines IL-4, 5, 6, 10
• Activation Receptor complexes with HLA class II
  molecules and co-stimulatory molecules

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Immunology of Graves

• CD8 Cells
• Cell Mediated Immunity Activation of macrophages
  and NK cells. Cytotoxic T-cells are also able to
  induce apoptosis in infected body cells.
• Cytokines IFN-gamma and TNF-beta
• Activation Receptor complexes with HLA class I
  molecules and co-stimulatory molecules

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Immunology

• Graves disease is primarily a CD4-Th2 type of
  autoimmune disease (likely due to
  thyroid-specific co-stimulation molecules)
• These cells secrete IL-4 and IL-5 --gt this
  activates antibody production by B-cells

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Predisposing Factors

• Genetics
• Up to 40 concordance in monozygotic twins (lt5
  in dizygotics)
• Sex
• Women to men ratio is 71
• Effects of estrogen vs. decreased testosterone?
• Smoking
• Relative risk 2
• Pregnancy
• Due to rebound from diminished T-cell and B-cell
  function during pregnancy?

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Predisposing Factors

• Infection
• Yersinia
• Serum of many patients with Graves contains
  antibodies that react with antigens derived from
  Yersinia entercolitia (molecular mimicry)
• Subacute thyroiditis
• Rubella
• Stress
• Drugs
• Amiodarone
• due to direct thyroid cell damage which releases
  thyroid antigens to the immune system
• Iodine

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Clinical Manifestations

• Skin
• Warm, smooth skin
• Onycholysis (loosening of nail bed)
• Thinning hair
• Myxedema
• Increased amounts of hyaluronic acid and
  chondroitin sulfate in the dermis layer

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Myxedema
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Graves Opthalmopathy

• Exopthalmos/Lid lag
• Pathogenesis
• T-cell cytokines increase glycosaminoglycan
  secretion by fibroblasts
• This leads to volume increases in extraocular
  muscles and retro-orbital adipose and connective
  tissue
• Risk factors
• Genetics
• Smoking

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Exophthalmos
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Clinical manifestations

• Metabolic
• Weight loss
• Hyperglycemia
• Antagonism to peripheral action of insulin
• Decreases in HDL and LDL
• Respiratory
• Respiratory muscle weakness
• Exacerbation of reactive airways disease

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Clinical manifestations

• GI
• Increased gut motility
• Malabsorption
• Urinary
• Increased frequency
• Bone
• Increased bone resorption -gt increased porosity
  of cortical bone

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Clinical manifestations

• Neuropsych
• Psychosis/agitation
• Emotional lability
• Tremor

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Diagnosis

• Physical exam
• Everything I was just talking about
• Goiter
• Elderly patients will not necessarily have
  palpable thyroid
• Thyroid function testing
• Low TSH (lt0.05)
• Increased T4, T3
• Occasionally (5) patients may have normal T4
  but elevated free T3 (T3 toxicosis)

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Diagnosis

• Radionuclide scan
• Normal thyroid uptake is 15-30
• Graves disease homogenous increased uptake

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Treatment

• Two objectives to treatment
• Ameliorate symptoms
• Decrease thyroid hormone synthesis

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Symptom alleviation

• Beta-blockers
• Start with atenolol (25-50mg per day)
• Beta-1 specific
• Single dose daily

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Treatment

• Thyroid specific treatment
• Thionamides (methimazole and PTU) - reduce
  oxidation and organification of iodide (PTU also
  inhibits deiodination of T4 to T3)
• Methimazole preferred because of longer duration
  than PTU
• Start with 20mg PO Qday

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Treatment

• Radioiodine
• 131-I administered by capsule or solution
• Rapidly incorporated into thyroid tissue, beta
  emissions result in local tissue damage
• Most patients (80) will become hypothyroid in
  6-18 weeks
• Women must have negative hCG before this
  treatment
• Radioiodine may precipitate or worsen
  opthalmopathy (controversial)
• Steroids for three months may prevent worsening
  of opthalmopathy

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Treatment

• Surgery
• Indications
• Large obstructive goiter
• Pregnant patients who cannot tolerate thionamides
• Rapid restoration of euthyroidism

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References

• Uptodate.com
• Davies, T. Pathogenesis of Graves Disease and
  Pathogenesis and Clinical features of Graves
  opthalmopathy
• Ross, D. Diagnosis of hyperthyroidism and
  Overview of the clinical manifestations of
  hyperthyroidism in adults
• Kasper et al. (2005) Harrisons Principles of
  Internal Medicine (pp 2113-2115) McGraw-Hill
• Merckmedicus.com