GRAVES DISEASE

GRAVES DISEASE
PATHOGENESIS AND CLINICAL FEATURES
DR LAVANYA BONNY
SR, DEPT OF ENDOCRINOLOGY
ST JOHNS MEDICAL COLLEGE
BANGALORE

HISTORY
◦ first report of toxic diffuse goiter- Robert James Graves
◦ 1835- three cases of violent and long palpitations in females, in each of which the same
peculiarity presented - enlargement of the thyroid gland
◦ Caleb Hillier Parry, a physician of Bath, England, had described a similar picture earlier, in 1825,
and noticed protrusion of the eyes as a feature of the syndrome

HISTORY
◦ 1840, in Germany, Carl A. von Basedow described exophthalmos caused by hypertrophy of the
cellular tissue of the orbit
◦ 1886 Moebius proposed that exophthalmic goiter was due to an excessive function of the
thyroid gland.
◦ 1911 Marine proposed treatment of Graves’ disease with iodine in the form of Lugol’s solution

HISTORY
◦ In the early 1940s the ATD thioureas were described, and Astwood introduced them into clinical
use for thyrotoxicosis.
◦ At the same time, physicists and physicians in Boston and in Berkeley started to treat thyrotoxic
patients with radioiodine (131I)
◦ 1956 - long-acting thyroid stimulator (LATS) discovered by Adams and Purves and subsequently
identified as an antibody

EPIDEMIOLOGY
◦ Most frequent cause of thyrotoxicosis in iodine-sufficient countries
◦ Whickham survey in the United Kingdom - prevalence of 1.1% to 1.6% for thyrotoxicosis of all
causes
◦ studies performed in Sweden have shown an incidence of GD between ∼21 and ∼25
cases/100,000 per year

EPIDEMIOLOGY
◦ general prevalence of the disorder - about 1%
◦ about fivefold more prevalent in women than in men
◦ can be observed in people of any age, including children
◦ peaks in the fourth to sixth decades of life

ETIOLOGY
◦ multifactorial disease
◦ complex interplay of genetic, hormonal, and environmental influences
◦ leads to the loss of immune tolerance to thyroid antigens and to the initiation of a sustained
autoimmune reaction.

ETIOLOGY - GENETICS
◦ Twin studies - greater concordance rate of GD in monozygotic than in dizygotic twins
◦ Prevalence of circulating thyroid autoantibodies in siblings of patients - as high as 56% in some
studies
◦ Villanueva et al
◦ 36% of GD with ophthalmopathy have a family history of either GD or autoimmune thyroiditis
◦ 23% of the cases affected first-degree relatives

ETIOLOGY - GENETICS
◦ Autoimmune thyroiditis is frequently observed in siblings of probands with GD as well as the
contrary.
◦ This suggests that the two diseases share some susceptibility genes, but the full expression of
the phenotype depends on other genes and environmental factors

ETIOLOGY - GENETICS
◦ Complex multigenic pattern of inheritance.
◦ Some of the components of the phenotype, such as the presence of antibodies against Tg and
TPO - dominant fashion with high penetrance.
◦ However, these genetic determinants do not appear to be sufficient for full expression of the
disease.

ETIOLOGY - GENETICS
◦ Genes Predisposing to Graves’ Disease
◦ HLA Complex
◦ association of GD with HLA-B8 and a relative risk of 3.9 in white patients
◦ HLADR3 was later shown to increase the risk to a greater extent and was considered the true
determinant of the disease

ETIOLOGY - GENETICS
◦ HLA Complex
◦ Sequencing of the DRβ-1 chain of HLA-DR3 - identification of Arg74 as the critical amino acid
conferring susceptibility to GD
◦ HLA association confers a relatively low risk
◦ HLA locus explains a small fraction of the total genetic predisposition, but is neither the major
nor the only determinant

ETIOLOGY - GENETICS
◦ CD40
◦ member of the TNF receptor family
◦ expressed in B cells and other antigen-presenting cells
◦ involved in B cell activation and proliferation, antibody secretion
◦ C/T polymorphism at the 5’ untranslated region strongly a/w GD

ETIOLOGY - GENETICS
◦ CTLA-4
◦ T lymphocyte surface protein with a major role in downregulation of the immune response
◦ Although CTLA-4 seems to be a genetic determinant of GD, the causative variant remains to be
identified

ETIOLOGY - GENETICS
◦ protein Tyrosine Phosphatase-22 (PTPN22)
◦ PTPN22 is a powerful inhibitor of T cell activation.
◦ A SNP at codon 620 was found to be associated with both GD and autoimmune thyroiditis

ETIOLOGY - GENETICS
◦ Fc Receptor Like (FCRL) 3
◦ association of SNP of FCRL3 with Graves’ disease in Asians as well as in Caucasians

ETIOLOGY - GENETICS
◦ Tg
◦ SNP variant of the Tg promoter predisposes to AITD, by an altered interaction with interferon
regulatory factor-1.
◦ genetic/epigenetic mechanism is involved

ETIOLOGY – ENVIRONMENTAL FACTORS
◦ Infections
◦ Evidence of a recent viral infection in a high percentage of patients with GD
◦ Molecular mimicry explains the association between infections and GD
◦ based on the hypothesis that crossreactions of some microbial antigens with a self-antigen may
cause an immune response to autoantigens

◦ Infections
◦ high prevalence of circulating antibodies against Y. enterocolitica in patients with GD
◦ Yersinia antibodies were found to interact with thyroid structures

◦ Infections
◦ Low-affinity binding sites for TSH were found also in other bacteria - some species of
Leishmania and Mycoplasma.
◦ However, thyroid autoimmunity does not develop in most patients with Yersinia infections
◦ Greater prevalence of serum antibodies against Helicobacter pylori - in pediatric patients with
GD

◦ Infections
◦ “hygiene hypothesis of autoimmunity,” - infections may protect from, rather than precipitate,
autoimmune diseases
◦ Kondrashova et al - reported a significantly reduced prevalence of thyroid autoantibodies in a
population with lower economic standards
◦ may suggest that the hygiene hypothesis may apply to thyroid autoimmune diseases

◦ Stress
◦ psychological stress may be a precipitating factor in GD
◦ Stress is associated with increased ACTH and cortisol secretion, which can in turn determine
immune suppression
◦ Recovery from such immune suppression can be associated with rebound immune hyperactivity,
which could precipitate autoimmunity

◦ Gender
◦ female-to-male ratio ranges from 5 to 10 at any age
◦ risk for developing GD increases fourfold to eightfold in the postpartum year.
◦ Mechanism - abrupt fall in the level of pregnancy-associated immunosuppressive factors
immediately after delivery (rebound immunity)

◦ Gender
◦ Postpartum period is also risk factor for relapse of Graves’ thyrotoxicosis after withdrawal of
ATDs
◦ Women with normal baseline levels of estrogen, but with an increased sensitivity to the
hormone, had a higher prevalence of thyroid autoimmune disorders acc to studies
◦ However, NO clear association between exogenous estrogen administration and GD

◦ Gender
◦ linkage analysis in families with GD - putative susceptibility locus on the long arm of the X
chromosome
◦ This finding could help explain the higher incidence of GD in women and, possibly, in patients
with Turner’s syndrome

◦ Smoking
◦ increased risk for GD and ophthalmopathy in smokers – retrospective analysis
◦ Also risk for for relapse of hyperthyroidism following ATD withdrawal, which is more
pronounced in the female gender.
◦ may be due both to a direct action of smoking metabolites on the immune system or by a
damage induced by smoking metabolites on thyrocyte

◦ Thyroid damage
◦ reports of GD appearing after ethanol injections performed for treatment of autonomous
thyroid nodules
◦ also following radioiodine treatment for toxic adenoma or toxic nodular goiter
◦ May be due to the massive release of thyroid antigens, thereby triggering an autoimmune
response in predisposed individuals

◦ Vitamin D, and Selenium
◦ Decreased levels of serum vitamin D have been reported in Graves’ patients
◦ associated with a higher rate of hyperthyroidism relapse after ATD withdrawal
◦ selenium deficiency has been reported in Graves’ patients compared with control subjects

PATHOGENESIS
◦ TSH-R Antibodies
◦ Assays for TSH-R Antibody
◦ Radioreceptor assay originally used TSH-R solubilized from porcine or human thyroids.
◦ relied on displacement of labeled TSH from solubilized TSH-R by the serum of patients
◦ positive results in 75% to 95% of untreated hyperthyroid Graves’ patients.

PATHOGENESIS
◦ All of these methods were superseded by the second generation radioreceptor assay - employs
a human recombinant TSH-R
◦ higher sensitivity while maintaining a high specificity (99%)
◦ isolation of a human Mab against the TSH-R, called M22, was followed by the development of
an enzyme-linked assay

PATHOGENESIS
◦ Radioreceptor and enzyme-linked assays do not require permanent cell cultures;
◦ they are readily available and are therefore the most frequently used in clinical practice

PATHOGENESIS
◦ functional, stimulating properties of TRAbs can be studied by in vitro bioassays
◦ based on the measurement of cAMP production from cells with a functional TSH-R.
◦ Human thyroid follicular cells,a rat thyroid cell strain (FRTL-5), and Chinese hamster ovary cells
stably transfected with the human TSH-R (CHO-R) have all been used for this purpose

PATHOGENESIS
◦ Advantage of bioassays – give information on the functional properties of TRAbs and, by
modifying the assay design, can also detect TBAbs.
◦ require permanent cell culture equipment and pre-purification of the Ig fraction of serum
◦ not readily available to routine laboratories

PATHOGENESIS
◦ overcome by very sensitive assays in which activation of a transfected firefly luciferase gene by
cAMP produces chemiluminescence in response to TSH-R stimulation by whole serum

PATHOGENESIS
◦ TSAbs interact with the TSH-R in that they act as a potent agonist and thus cause hyperfunction
of the thyroid gland
◦ TSAbs produced mainly by thyroid-infiltrating lymphocytes and lymphocytes in the draining
lymph nodes
◦ a small proportion of hyperthyroid Graves’ patients have undetectable TSAbs - occurrence at a
serum level too low to be detected by current methods.

PATHOGENESIS
◦ Alternatively, restricted intrathyroidal production of TRAbs has been hypothesized.
◦ A positive correlation between TSAb levels and serum T3 levels, serum Tg levels, and goiter size
has been observed.

PATHOGENESIS
◦ TSAbs are oligo- or pauciclonal - suggested a primary defect at the B cell level.
◦ TSAbs can be detected in more than 90% of patients with untreated Graves’ hyperthyroidism.

PATHOGENESIS
◦ Other Antigens
◦ autoantibodies against Tg and TPO are commonly found in GD
◦ autoimmunity against these two antigens - secondary phenomenon with no pathogenetic
implications.

PATHOGENESIS
◦ Other Antigens
◦ insulin-like growth factor-1 receptor (IGF1-R) has a role in the pathogenesis of GD, especially of
its extrathyroidal manifestations (i.e., Graves’ ophthalmopathy)
◦ The receptor is expressed in thyroid epithelial cells as well as in orbital fibroblasts, and
autoantibodies against the receptor have been detected in patients with GD

PATHOGENESIS
◦ Cellular Immunity
◦ Studies of patients with GD showed activated T cells both in the peripheral circulation and in the
thyroid gland
◦ percentage of CD8+ (suppressor/cytotoxic) T cells was found to be much lower in GD than in
autoimmune thyroiditis

PATHOGENESIS
◦ CD4+ T cells are the M.C cells infiltrating the thyroid in autoimmune diseases
◦ comprise a functionally heterogeneous population of T effector cells (Teff) and a smaller
population (10%) of T regulatory cells (Tregs).
◦ Tregs express CD25 (the IL-2 receptor α) and are critical for maintaining peripheral tolerance

PATHOGENESIS
◦ Tregs are usually identified by the expression of Foxp3, a transcription factor necessary for Treg
development.
◦ Tregs typically secrete IL-10 and TGF-β to induce tolerance
◦ role of these cells is to prevent the development of organ-specific autoimmunity

PATHOGENESIS
◦ patients with untreated Graves’ hyperthyroidism have reduced circulating Treg cells
◦ Tregs levels are negatively correlated with the conc. of TRAbs

PATHOGENESIS
◦ another important mechanism of control is central tolerance caused by positive and negative
selection of T cells and B cells in the thymus, where thyroid antigens, including the TSHR, are
expressed.
◦ Regulation of thymic gene expression of the TSHR appears to be potentially important in
susceptibility to GD

PATHOGENESIS
◦ intrathyroidal T cells were found to be predominantly of the TH1 subtype
◦ TH1 cells may also induce antibody production through secretion of IL-10, which in turn
activates B cells

PATHOGENESIS
◦ Chemokines
◦ Chemokines are a group of peptides that induce chemotaxis of different leukocyte subtypes.
◦ Their major function is the recruitment of leukocytes to inflammation sites
◦ IFN-γ inducible chemokines (CXCL9, CXCL10, and CXCL11) and their receptor, CXCR3, play an
important role in the initial stage of autoimmune disorders involving endocrine glands

CLINICAL FEATURES
◦ THYROID
◦ The thyroid gland is usually symmetrically enlarged
◦ nodular glands can be seen, especially in geographic areas of iodine deficiency
◦ Goiter size is widely variable
◦ consistency of the gland is generally firm, although softer than in autoimmune thyroiditis.
◦ Thrills and bruits due to increased blood flow may be present

CLINICAL FEATURES
◦ Skin and Appendages
◦ skin - warm, thin, and moist; palmar erythema is common.
◦ Dermatographism, pruritus and urticaria may also be associated.
◦ Vitiligo is frequently associated
◦ hair - friable, mild diffuse alopecia
◦ Nails - soft and friable with longitudinal striations, and onycholysis

CLINICAL FEATURES
◦ Cardiovascular System
◦ increase in both inotropism and chronotropism of the heart.
◦ vascular resistance is decreased because of peripheral vasodilatation.
◦ The net effect of these changes is increased cardiac output
◦ Increased cardiac workload causes increased oxygen consumption, which in turn can
precipitate angina pectoris

CLINICAL FEATURES
◦ MC symptoms - tachycardia and palpitations.
◦ In patients with heart failure or preexisting coronary disease - dyspnea on exertion or at rest,
chest pain
◦ low exercise tolerance

CLINICAL FEATURES
◦ Accentuated heart sounds
◦ Arrythmia
◦ Systolic murmer
◦ May have associated MVP
◦ Features of cardiac failure

CLINICAL FEATURES
◦ ECG – nonspecific
◦ sinus tachycardia with ST elevation, QT shortening, and PR prolongation.
◦ Atrial fibrillation or flutter - 10% to 25% of patients, especially older adults
◦ reversible in up to 60% upon correction of hyperthyroidism
◦ Ischemic changes
◦ WPW pattern

CLINICAL FEATURES
◦ Gastrointestinal
◦ Increased appetite and weight loss - due to increased catabolism.
◦ Increased GI motility - frequent bowel movements
◦ can be associated with some degree of malabsorption and steatorrhea, which can contribute to
weight loss.
◦ Atrophic gastritis and/or celiac disease of autoimmune origin may be associated.
◦ mild elevations of liver enzymes

CLINICAL FEATURES
◦ Nervous system
◦ Insomnia and irritability are MC
◦ restless and agitated
◦ logorrhea is often present
◦ Concentration ability is decreased.

CLINICAL FEATURES
◦ Nervous system
◦ Fatigability and asthenia
◦ “apathetic thyrotoxicosis” - severe apathy, lethargy, and pseudodementia (in older adult
patients)
◦ In rare cases, true psychoses can be precipitated by thyrotoxicosis

CLINICAL FEATURES
◦ Nervous system
◦ Fine distal tremor - can also be observed on protrusion of the tongue or at the eyelids
◦ Brisk DTR, with a shortened relaxation time.
◦ Clonus can be sometimes elicited.

CLINICAL FEATURES
◦ Nervous system
◦ The characteristic stare - due to autonomic hyperstimulation of the elevator muscle of the lid
and can also be found in the absence of ophthalmopathy.
◦ True thyrotoxic neuropathy has occasionally been reported, characterized by areflexic flaccid
quadriparesis.

CLINICAL FEATURES
◦ Muscle
◦ muscle weakness and easy exhaustion
◦ Severe - atrophy of variable degree
◦ Less than 1% of patients have classic myasthenia gravis
◦ ocular myasthenia gravis may be more frequent
◦ 3% of patients with myasthenia gravis have GD
◦ precipitate crises of periodic hypokalemic paralysis

CLINICAL FEATURES
◦ Skeletal system
◦ increased rate of bone remodeling.
◦ The disproportionate increase in bone resorption over new bone formation leads to net bone
loss
◦ Mild hypercalcemia and increased levels of bone turnover markers

CLINICAL FEATURES
◦ Hematopoietic system
◦ Mild leukopenia with relative lymphocytosis
◦ Normocytic anemia is relatively rare
◦ Pernicious anemia in a small minority
◦ circulating autoantibodies to gastric parietal cells are found in a much higher percentage of
cases - sign of associated gastric autoimmunity.

CLINICAL FEATURES
◦ Hematopoietic system
◦ Aplastic anemia has also been reported
◦ associated with autoimmune thrombocytopenic purpura
◦ Increases in factor VIII levels and fibrinogen

CLINICAL FEATURES
◦ Reproductive system
◦ Females
◦ In severe thyrotoxicosis - oligomenorrhea or amenorrhea.
◦ As a consequence of impaired ovulation, fertility is decreased
◦ almost exclusively occur in women with severe weight loss
◦ Thyrotoxicosis in pregnancy - increased incidence of miscarriage, low– birth-weight infants,
and preeclampsia

CLINICAL FEATURES
◦ Reproductive system
◦ Males
◦ Gynecomastia
◦ erectile dysfunction, reduced sperm count, and reduced libido

CLINICAL FEATURES
◦ Metabolic changes
◦ significant weight loss is a hallmark
◦ increased metabolic rate, with increased heat production
◦ Mitochondrial oxygen consumption increased- Increased mitochondrial activity and numbers

CLINICAL FEATURES
◦ enhanced heat production d/t increase of uncoupling proteins
◦ manifested as a moderate rise in body temperature that is compensated by vasodilatation and
increased sweating.
◦ Heat intolerance and weight loss result from the excessive energy wastage

CLINICAL FEATURES
◦ Peripheral utilization of carbohydrates is increased
◦ primary mechanism - increased cellular transport of glucose
◦ also causes some degree of insulin resistance.
◦ Consequently, DM may be exacerbated.
◦ T1DM can be associated with GD within polyglandular autoimmune syndromes.

CLINICAL FEATURES
◦ Serum cholesterol and TGs are decreased – D/T reduced LDL, in spite of an increase of hepatic
lipogenesis
◦ The conversion of cholesterol to bile acid in the liver is enhanced
◦ LDL receptor number on adipocytes is increased as well.
◦ These phenomena may account for the increased turnover of cholesterol and triglycerides.

CLINICAL FEATURES
◦ Protein metabolism is altered during thyrotoxicosis, with both increased synthesis and
degradation.
◦ In most cases, however, degradation predominates and causes negative nitrogen balance.

CLINICAL FEATURES
◦ Cancer
◦ Increased risk of cancer
◦ Increased cancer mortality
◦ Esp breast and thyroid
◦ Reason unknown

DISTINCTIVE MANIFESTATIONS
◦ Pretibial (or Localized) Myxedema
◦ nonpitting swelling of the pretibial areas, brownish and reddish in color, well delimited, and
containing little free fluid
◦ almost invariably observed only when also Graves’ ophthalmopathy is present.
◦ Can also occur on forearms

◦ Diffuse myxedema refers to the mildest form, with only superficial diffuse edema
◦ Nodular form - Localized areas of more prominent infiltration that assume a papular aspect
◦ Elephantiasis - In the most severe forms

◦ Histopathologic studies
◦ accumulation of hyaluronic acid in the subcutaneous layers
◦ lymphocytic infiltrate may be observed
◦ origin of the mucinous material (hyaluronic acid) appears to be the skin fibroblast
◦ pretibial myxedema is another autoimmune manifestation of GD - almost invariable presence of
serum TRAbs in patients with myxedema

◦ Thyroid acropachy
◦ observed most often in longlasting and usually severe forms of ophthalmopathy and pretibial
myxedema
◦ almost invariably associated with serum TRAbs
◦ clubbing and soft tissue swelling of the last phalanx of the fingers and toes
◦ overlying skin is often discolored and thickened.

◦ Thyroid acropachy
◦ Microscopically, increased GAG deposition in the skin
◦ Subperiosteal new bone formation is also present.

GRAVES DISEASE
DIAGNOSIS AND MANAGEMENT

LABORATORY DIAGNOSIS
◦ HORMONE MEASUREMENTS
◦ TSH is the single most useful test in confirming the presence of thyrotoxicosis
◦ undetectable or low in all patients with thyrotoxicosis of thyroidal origin
◦ Diagnostic accuracy improves when serum TSH, FT4, and TT3 are assessed at the initial
evaluation

◦ HORMONE MEASUREMENTS
◦ ‘‘euthyroid hyperthyroxinemia’’ - cause elevated TT4 conc (and frequently elevated TT3 conc) in
the absence of hyperthyroidism
◦ May be d/t
◦ elevations in TBG or transthyretin
◦ abnormal albumin which binds T4 with high capacity (familial dysalbuminemic
hyperthyroxinemia)
◦ Igs that directly bind T4 or T3

◦ Determination of etiology
◦ If the diagnosis is not apparent based on the clinical presentation and initial biochemical
evaluation, diagnostic testing is done
◦ (1) measurement of TRAb,
◦ (2) determination of the radioactive iodine uptake (RAIU)
◦ (3) measurement of thyroidal blood flow on ultrasonography

◦ Determination of etiology
◦ symmetrically enlarged thyroid, recent onset of orbitopathy, and moderate to severe
hyperthyroidism - GD is likely
◦ thyrotoxic patient with a nonnodular thyroid and no definite orbitopathy -TRAb or RAIU to
distinguish GD from other etiologies.
◦ use of TRAb measurements to diagnose GD compared to RAIU measurements reduced costs by
47% and lead to quicker diagnosis

◦ CIRCULATING AUTOANTIBODIES
◦ TRAb assay is very specific and sensitive for GD.
◦ sensitivity and specificity of the serum TSH-R-Ab concentration measured with second- and
third-generation binding assays were 97 and 98%, respectively
◦ very few false-positive results

◦ TRAb is cost effective because if it is positive it confirms the diagnosis of the most common
cause of thyrotoxicosis.
◦ If negative it does not distinguish among other etiologies, however, and it can be negative in
very mild GD.
◦ If third-generation TRAb assays are not readily available, RAIU is preferred for initial testing

◦ TSAb is a highly sensitive and predictive biomarker for the extrathyroidal manifestations of GD
◦ Also useful as a predictive measure of fetal or neonatal hyperthyroidism
◦ Can be used in nodular variants of GD, which must be differentiated from toxic nodular goiter

IMAGING - RAIU
◦ Useful to rule out silent or subacute thyroiditis, factitious thyrotoxicosis, and type II amiodarone
induced thyrotoxicosis
◦ RAIU results can also be used before radioiodine treatment of hyperthyroidism to calculate the
activity to be administered
◦ can be performed with radioiodine at the time that RAIU is performed or by using
pertechnetate 99m

IMAGING - RAIU
◦ RECOMMENDATION
◦ Scintigraphy of the thyroid is suggested when thyroid nodularity coexists with
hyperthyroidism, and prior to RAI therapy
◦ The pattern of RAIU in GD is diffuse unless coexistent nodules or fibrosis is present.
◦ single TA - focal uptake in the adenoma with suppressed uptake in the surrounding and
contralateral thyroid tissue

IMAGING - RAIU
◦ If autonomy is extensive, the image may be difficult to distinguish from that of GD
◦ GD and nontoxic nodular goiter may coincide - positive TRAb levels and a nodular ultrasound or
heterogeneous uptake images

IMAGING - USG
◦ In hyperthyroid GD, the echoic pattern undergoes diffuse changes.
◦ HYPOECHOIC - because of
◦ reduction in colloid content
◦ increase in thyroid vascularity
◦ lymphocytic infiltrate
◦ This pattern is similar to the one observed in chronic thyroiditis and, when diffuse, is almost
pathognomonic of thyroid autoimmunity

IMAGING - USG
◦ A color-flow or power Doppler examination characterizes vascular patterns and quantifies
thyroid vascularity
◦ Vascularity is significantly increased in untreated GD
◦ typically shows a pulsatile pattern called “thyroid inferno”
◦ multiple small areas of increased intrathyroidal flow seen diffusely throughout the gland

IMAGING - USG
◦ In untreated GD, thyroidal artery flow velocity and PSV are significantly increased.
◦ The PSV can differentiate between thyrotoxicosis owing to GD from subacute thyroiditis or AIT
type 2, where the blood flow is reduced

IMAGING - USG
◦ RECOMMENDATION
◦ US examination, comprising conventional grey scale analysis and color-flow or power
Doppler examination is recommended as the imaging procedure to support the diagnosis
of GD

MANAGEMENT – ANTITHYROID DRUGS
◦ goal of the therapy is to render the patient euthyroid as quickly and safely as possible
◦ Treatment itself might have a beneficial immunosuppressive role, either to primarily decrease
thyroid specific autoimmunity, or
◦ secondarily, by ameliorating the hyperthyroid state, which may restore the dysregulated
immune system back to normal

◦ Thionamides (methimazole, carbimazole, and propylthiouracil) were described and introduced
into clinical practice in the early 1940s.
◦ Carbimazole is rapidly metabolized to MMI and has no properties not shared by MMI

◦ drug concentrations required to inhibit coupling are less than those required to
inhibit iodine organification

◦ Effects on the Immune System
◦ numerous in vitro studies have documented an effect of ATDs on the immune
system.
◦ inhibit lymphocyte transformation
◦ formation of free radicals, which may be important in T cell responsiveness and in
complement-mediated thyroid-cell injury, may be inhibited by MMI
◦ may reduce expression of MHC class II (HLA-DR) molecules on thyroid cells

◦ Induce expression of Fas ligand (FasL) on thyroid cells, which could lead to
activation of Fas on lymphocytes and consequently Fas-induced apoptosis of
these cells
◦ Serum concentrations of ICAM-1, and of some cytokines and soluble cytokine
receptors, also decrease in including those of lL 1 beta, soluble IL-2 receptors,
and soluble lL 6 receptors

◦ ATD can inhibit immune function in vitro, but the concentrations of drug required
may be higher than are attained within the thyroid gland during treatment.
◦ Changes in serum conc of antithyroid antibodies and TSHR-Ab and in T -cell
subsets occur in patients receiving chronic ATD therapy
◦ but changes in thyroid function occur concomitantly, making it impossible to
distinguish cause and effect satisfactorily

◦ CLINICAL CONSIDERATIONS
◦ ATD are indicated as a first-line treatment of GD, particularly in younger subjects, and for short-
term treatment of GD before RAI therapy or thyroidectomy
◦ Both MMI and PTU are very (at least 90%) effective in controlling thyrotoxicosis due to GD

◦ concerns about PTU related hepatotoxicity have led the ATA to recommend that MMI be used
instead of PTU as first line therapy
◦ MMI therapy results in more rapid normalization of serum T4 and T3 concentrations than does
PTU therapy
◦ MMI has more effective long-term control of T3 levels in severe thyrotoxicosis

◦ MMI initial doses of 10– 30 mg daily are used to restore euthyroidism, and then titrated down to
a maintenance level (generally 5– 10 mg daily)
◦ MMI - OD administration and a reduced risk of major S/E compared to PTU.
◦ When more rapid biochemical control is needed in patients with severe thyrotoxicosis, an initial
split dose of MMI (e.g., 15 or 20 mg twice a day) may be more effective than a single daily dose
because the duration of action of MMI may be less than 24 hours

◦ PTU has a shorter duration of action
◦ usually administered two or three times daily
◦ start with 50–150 mg three times daily, depending on the severity of the hyperthyroidism

◦ As thyroid secretion decreases during the first several weeks or months after ATD is initiated, the
dose should be decreased, or hypothyroidism may supervene
◦ If high doses of drug are required for control of thyrotoxicosis, remission is unlikely, and ablative
therapy usually is selected.

◦ BLOCK AND REPLACE REGIMEN - Administration of fixed, relatively high doses of thionamide in
combination with LT4 to prevent iatrogenic hypothyroidism
◦ useful in rare patients who experience changes from hyperthyroidism to hypothyroidism and
vice versa after minimal changes in the dosage of ATD (“brittle hyperthyroidism”)

◦ OUTCOME
◦ in most studies hyperthyroidism recurred in 50% to 80% of patients, depending on the duration
of the follow-up period
◦ Remission rates have been decreasing over time, possibly as a result of increased iodine supply
in the diet

◦ RISK FACTORS FOR RELAPSE
◦ a good predictor of relapse of hyperthyroidism is a positive TSAb test before
discontinuation of medical treatment.
◦ However, even when TSAbs disappear, the chances of relapse are still high, ranging
from 20% to 50%

◦ Most relapses of hyperthyroidism occur within 3 to 6 months after therapy is
discontinued
◦ more than two-thirds of patients who relapse will do so within 2 years

◦ Relapse of hyperthyroidism after a full cycle of thionamides is a strong indication for
alternative treatments such as radioiodine or thyroidectomy
◦ In selected patients (i.e., younger patients with mild stable disease on a low dose of
MMI), long-term MMI is a reasonable alternative approach
◦ If continued MMI therapy is chosen, TRAb levels might be monitored every 1–2 years

◦ RECOMMENDATIONS
◦ MMI (CBZ) should be used in every non-pregnant patient who chooses ATD
therapy for Graves’ hyperthyroidism.
◦ MMI is administered for 12–18 months then discontinued if the TSH and TSH-
R-Ab levels are normal
◦ Measurement of TSH-R-Ab levels prior to stopping ATD therapy is
recommended

◦ RECOMMENDATIONS
◦ Patients with persistently high TSH-R-Ab at 12–18 months can continue MMI
therapy, repeating the TSH-R-Ab measurement after an additional 12 months,
or opt for RAI or thyroidectomy

◦ ADVERSE EFFECTS
◦ In a systematic review of eight studies that included 667 GD patients receiving MMI
or PTU, 13% of patients experienced adverse events
◦ The minor allergic reactions included pruritus or a limited, minor rash in 6% of
patients taking MMI and 3% of patients taking PTU
◦ Hepatocellular injury occurred in 2.7% of patients taking PTU and 0.4% of patients
taking MMI

◦ ADVERSE EFFECTS
◦ Agranulocytosis
◦ Although ATD-associated agranulocytosis is uncommon, it is life-threatening.
◦ PTU at any dose is more likely to cause agranulocytosis compared with low doses of
MMI
◦ Agranulocytosis - granulocyte count less than 250 cells/mm3 (0.25 x 109/L)
◦ usually develops so suddenly that routine monitoring of the leukocyte count is of
little value

◦ ADVERSE EFFECTS
◦ Agranulocytosis
◦ In a patient developing agranulocytosis or other serious side effects while taking
either MMI or PTU, use of the other medication is contraindicated owing to risk of
cross reactivity
◦ alleles HLA-B*38:02 and HLA-DRB1*08:03 or rare NOX3 genetic variants are
independent susceptibility loci for agranulocytosis.

◦ ADVERSE EFFECTS
◦ Agranulocytosis
◦ Treatment
◦ broad-spectrum antibiotics and appropriate supportive measures
◦ granulocyte count usually begins to increase within several days, but may not be
normal for 10 to 14 days.
◦ G-CSF therapy has proven variably effective
◦ Glucocorticoid therapy is probably ineffective

◦ ADVERSE EFFECTS
◦ Hepatotoxicity
◦ MMI hepatotoxicity is typically cholestatic, but hepatocellular disease may be seen
◦ PTU can cause fulminant hepatic necrosis that may be fatal
◦ average PTU dose associated with liver failure was 300 mg/day
◦ median time to develop severe hepatotoxicity after starting PTU was 120 days, with a
range of 1 to 450 days

◦ ADVERSE EFFECTS
◦ Hepatotoxicity
◦ Patients should be warned about the potential for hepatotoxicity, and to discontinue
the drug if they have malaise, jaundice, or dark urine.
◦ PTU should be discontinued immediately if transaminases are >2-3 times ULN and
fail to improve on testing 1 week later

◦ ADVERSE EFFECTS
◦ Hepatotoxicity
◦ Liver function and hepatocellular integrity should be assessed in patients taking MMI
or PTU who experience symptoms
◦ Onset of PTU-induced hepatotoxicity may be acute and rapidly progressive
◦ Routine monitoring of liver function in all patients taking ATDs has not been found to
prevent severe hepatotoxicity

◦ ADVERSE EFFECTS
◦ Vasculitis
◦ PTU and rarely MMI can cause pANCA-positive small vessel vasculitis as well as drug-
induced lupus
◦ The risk increases with duration of therapy as opposed to other adverse effects seen
with ATDs that typically occur early in the course of treatment

◦ ADVERSE EFFECTS
◦ Vasculitis
◦ more common in patients of Asian ethnicity
◦ Children are more likely to develop PTU-related ANCA-positive vasculitis
◦ In most cases, the vasculitis resolves with drug discontinuation
◦ immunosuppressive therapy may be necessary in some

◦ ADVERSE EFFECTS
◦ Other rare side effects of MMI
◦ pancreatitis
◦ hypoglycemia, caused by anti-insulin antibodies (the "insulin autoimmune syndrome"
or "Hirata disease"), typically in Japanese patients
◦ myalgia and high serum creatine kinase concentrations.
◦ MMI can cause a decreased sense of taste , whereas PTU may cause a bitter or
metallic taste

◦ ADVERSE EFFECTS
◦ Management of allergic reactions
◦ Minor cutaneous reactions may be managed with concurrent antihistamine therapy
without stopping the ATD.
◦ Persistent symptomatic minor side effects - cessation of the medication and
changing to RAI or surgery, or switching to the other ATD when RAI or surgery are
not options.
◦ In the case of a serious allergic reaction, prescribing the alternative drug is not
recommended

◦ Monitoring of patients taking ATDs
◦ assessment of serum free T4 and total T3 should be obtained about 2–6 weeks after
initiation of therapy, depending on the severity of the thyrotoxicosis
◦ dose of medication should be adjusted accordingly.
◦ Serum T3 should be monitored because the serum FT4 levels may normalize despite
persistent elevation of serum TT3

◦ Once the patient is euthyroid, the dose of MMI can usually be decreased by 30%–
50%
◦ biochemical testing repeated in 4–6 weeks.

◦ Once euthyroid levels are achieved with the minimal dose of medication- follow up
at intervals of 2–3 months
◦ remission - normal serum TSH, FT4, and TT3 for 1 year after discontinuation of ATD
therapy

◦ If the patient remains euthyroid for more than 1 year (i.e., in remission), thyroid
function should be monitored at least annually
◦ relapses can occur years later, and some patients eventually become hypothyroid

MANAGEMENT – IODINE AND IODINE
CONTAINING COMPOUNDS
◦ Inorganic iodine given in pharmacologic doses (as Lugol’s solution or as SSKI])
decreases its own transport into the thyroid, inhibits iodine organification (the Wolff-
Chaikoff effect), and blocks the release of T4 and T3.
◦ iodine sharply decreases the vascularity of the thyroid in GD

MANAGEMENT – IODINE AND IODINE
CONTAINING COMPOUNDS
◦ iodine is now used only for short periods in the preparation for surgery, after
euthyroidism has been achieved with thionamides.
◦ also used in the management of severe thyrotoxicosis (thyroid storm) because it
inhibits thyroid hormone release acutely.
◦ Lugol’s solution - 3 to 5 drops three times daily
◦ SSKI - 1 to 3 drops three times daily

MANAGEMENT – BETA BLOCKERS
◦ recommended in all patients with symptomatic thyrotoxicosis
◦ especially elderly patients and thyrotoxic patients with resting HR >90 bpm or
coexistent cardiovascular disease
◦ In a RCT of MMI alone versus MMI and a b-blocker, after 4 weeks, patients taking b-
blockers had lower heart rates, less shortness of breath and fatigue, and improved
‘‘physical functioning

◦ In patients with quiescent bronchospastic asthma, or in patients with mild obstructive
airway disease or symptomatic Raynaud’s phenomenon, a b-1 selective agent can be
used cautiously
◦ Oral administration of CCB(verapamil and diltiazem) have been shown to affect rate
control in patients who do not tolerate or are not candidates for b-blockers

◦ High doses of propranolol (40 mg 4 times daily) inhibit peripheral conversion of T4
to T3.
◦ Anticoagulation with warfarin or direct oral anticoagulants should be considered in
all patients with atrial fibrillation.
◦ If digoxin is used, increased doses are often needed in the thyrotoxic state

MANAGEMENT - LITHIUM
◦ beneficial in Graves’ patients undergoing radioiodine therapy
◦ if given on the day of thionamide withdrawal (5 days before radioiodine) for 19 days, lithium has
been found to reduce the extent of thyrotoxicosis either due to thionamide withdrawal before
radioiodine or to radioiodine itself after its administration.
◦ Dose - 900 mg/day, but even doses of 450 mg/day seem to be effective.
◦ d/t direct inhibitory action on hormone release or on intrathyroidal iodine turnover.

MANAGEMENT - GLUCOCORTICOIDS
◦ GC in high doses inhibit the peripheral conversion of T4 to T3
◦ In Graves’ thyrotoxicosis, GC appear to decrease T4 secretion, possibly by immune suppression
◦ the immunosuppressive effect of GC in high doses – used in ophthalmopathy and dermopathy.
◦ In severe thyrotoxicosis or thyroid storm, short-term GC administration as a general supportive
treatment.

MANAGEMENT - RADIOIODINE
◦ RAI has been used since 1941
◦ candidates for RAI are :
◦ Patients with side-effects to or recurrence after a course of ATD
◦ cardiac arrhythmias
◦ thyrotoxic periodic paralysis

◦ Preparation of patients with GD for RAI therapy
◦ b-adrenergic blockade even in asymptomatic patients who are at increased risk for
complications due to worsening of hyperthyroidism (i.e., elderly patients and patients with
comorbidities)
◦ pretreatment with MMI prior to RAI therapy for GD - in patients who are at increased risk for
complications due to worsening of hyperthyroidism.
◦ MMI should be discontinued 2–3 days prior to RAI

◦ In patients who are at increased risk for complications due to worsening of hyperthyroidism,
resuming MMI 3–7 days after RAI administration may be done
◦ Medical therapy of any comorbid conditions should be optimized prior to RAI therapy
◦ includes patients with cardiovascular complications such as AF, HF, or pulmonary hypertension
and those with renal failure, infection, trauma, poorly controlled DM, and cerebrovascular or
pulmonary disease

◦ Patients that might benefit from adjunctive MMI or carbimazole may be those who tolerate
hyperthyroid symptoms poorly.
◦ Such patients frequently have free T4 at 2–3 times ULN
◦ Young and middle-aged patients who are otherwise healthy and clinically well compensated
despite significant biochemical hyperthyroidism can generally receive RAI without pretreatment

◦ In selected patients with Graves’ hyperthyroidism who are allergic to ATDs, the duration of
hyperthyroidism may be shortened by administering iodine (e.g.,[SSKI])
◦ To be given beginning 1 week after RAI administration

◦ Administration of RAI in the treatment of GD
◦ Sufficient activity of RAI should be administered in a single application, typically a mean dose of
10–15 mCi (370–555 MBq), to render the patient with GD hypothyroid
◦ A pregnancy test should be obtained within 48 hours prior to treatment in any woman with
childbearing potential

◦ 131I is the isotope of choice
◦ One microcurie of 131I retained per gram of thyroid tissue delivers approximately 70 to 90 rad.
◦ administered orally as a single dose in a capsule or in water, is rapidly and completely absorbed

◦ Initially, radioiodine causes cellular necrosis that provokes an inflammatory response
◦ Long-term effects include shorter survival, impaired replication of surviving cells with atrophy
and fibrosis, and a chronic inflammatory response resembling autoimmune thyroiditis.

◦ Because of the high proportion of patients requiring retreatment, RAI therapy with low activities
is generally not recommended
◦ Conception should be delayed in women until stable euthyroidism is established

◦ Conception should be delayed 3–4 months in men to allow for turnover of sperm production
◦ In breastfeeding women, RAI therapy should not be administered for at least 6 weeks after
lactation stops to ensure that RAI will not be actively concentrated in the breast tissues.
◦ A delay of 3 months will reliably ensure that lactation-associated increase in breast NIS activity
has returned to normal

◦ Adverse effects of RAI
◦ radiation-induced acute thyroiditis - 3 or 4 days after treatment by pain and swelling in the neck
(rare)
◦ Rx – short course of anti-inflammatory drugs
◦ sialoadenitis.

◦ transient worsening of thyrotoxicosis, due to leakage of stored T 4 and T 3 from disrupted
follicles
◦ Transient exacerbation of preexisting ophthalmopathy may occur in the first few months
◦ no increase in the overall cancer risk after RAI treatment for hyperthyroidism; however, a trend
towards increased risk of thyroid, stomach, and kidney cancer was seen

◦ Acc to studies, thyroid cancer develops in children treated with low, but not with high doses of
I131
◦ suggested to treat children with doses higher than those given to adults for Grave’s
hyperthyroidism.
◦ long-term risk for cancer of other organs - as high as 3% in children
◦ Therefore – RAI only for individuals older than 18 to 20 years of age.

◦ Patient follow-up after RAI therapy for GD
◦ Follow-up within the first 1–2 months after RAI therapy for GD should include an assessment of
free T4, total T3, and TSH.
◦ Biochemical monitoring should be continued at 4- to 6-week intervals for 6 months, or until the
patient becomes hypothyroid and is stable on thyroid hormone replacement

◦ Hypothyroidism may occur from 4 weeks on, with 40% of patients being hypothyroid by 8
weeks and >80% by 16 weeks.
◦ This transition can occur rapidly but more commonly between 2 and 6 months

◦ Beta-blockers that were instituted prior to RAI treatment should be tapered when free T4 and
total T3 have returned to the reference range.
◦ As free T4 and total T3 improve, MMI can usually be tapered

◦ TSH levels may not rise immediately with the development of hypothyroidism and should not
be used initially to determine the need for LT4
◦ When thyroid hormone replacement is initiated, the dose should be adjusted based on an
assessment of free T4

◦ Risk factors for persistence of hyperthyroidism
◦ Large goiter size
◦ rapid iodine turnover
◦ adjunctive therapy with ATD too soon after radioiodine

◦ Treatment of persistent Graves’ hyperthyroidism following RAI therapy
◦ When hyperthyroidism persists after 6 months following RAI therapy, retreatment with RAI is
suggested.
◦ In selected patients with minimal response 3 months after therapy additional RAI may be
considered
◦ In the small percentage of patients with hyperthyroidism refractory to several applications of
RAI, surgery should be considered

MANAGEMENT - SURGERY
◦ INDICATIONS FOR SURGERY
◦ Large goiter
◦ coincident primary hyperparathyroidism
◦ suspicion of malignant nodules
◦ patient wishes to avoid exposure to ATD or RAI
◦ facilities for RAI treatment are not available

◦ Preparation of patients with GD for thyroidectomy
◦ patients should be rendered euthyroid prior to the procedure with ATD pretreatment, with or
without b-adrenergic blockade.
◦ A KI containing preparation should be given in the immediate preop period
◦ Calcium and 25-OH vitamin D should be assessed preoperatively and repleted if necessary, or
given prophylactically

◦ Preparation of patients with GD for thyroidectomy
◦ Thyroid storm may be precipitated by the stress of surgery, anesthesia, or thyroid manipulation
and may be prevented by pretreatment with ATDs
◦ Preoperative KI, SSKI, or Lugol’s solution should be used before surgery in most patients with
GD.
◦ This treatment is beneficial because it decreases thyroid blood flow, vascularity, and
intraoperative blood loss during thyroidectomy

◦ Choice of procedure
◦ If surgery is chosen as the primary therapy for GD, near total or total thyroidectomy is the
procedure of choice
◦ Total thyroidectomy has a nearly 0% risk of recurrence
◦ subtotal thyroidectomy may have 8% chance of persistence or recurrence of hyperthyroidism at
5 years

◦ Complications
◦ hypocalcemia due to hypoparathyroidism (which can be transient or permanent)
◦ recurrent or superior laryngeal nerve injury (which can be temporary or permanent)
◦ postoperative bleeding
◦ complications related to general anesthesia

◦ Postoperative care
◦ Following thyroidectomy for GD oral calcium and calcitriol supplementation administered based
on the lab results
◦ or prophylactic calcium with or without calcitriol can be prescribed empirically
◦ Patients can be discharged if they are asymptomatic and their serum calcium levels corrected for
albumin are 8.0 mg/ dL or above and are not falling over a 24-hour period

◦ Persistent hypocalcemia in the postoperative period - measurement of serum magnesium and
possible magnesium repletion
◦ In addition to reduced serum calcium levels, reduced serum phosphate may be observed in
hungry bone syndrome

◦ LT4 should be started at a daily dose appropriate for the patient’s weight (1.6 microg/kg)
◦ elderly patients require less dose
◦ serum TSH should be measured 6–8 weeks postoperatively

SPECIAL SITUATIONS
◦ IN THE ELDERLY
◦ RECOMMENDATIONS
◦ Older patients who have had atrial fibrillation, cardiac failure, or cardiac ischemic
symptoms precipitated by hyperthyroidism should undergo definitive therapy, usually
RAI.
◦ Long-term MMI (CBZ) should be considered as a satisfactory treatment for older
individuals with mild GD.

SPECIAL SITUATIONS
◦ IN CHILDREN AND ADOLESCENTS
◦ RECOMMENDATIONS
◦ PTU should be avoided in children and adolescents.
◦ Long-term MMI (CBZ) should be the mainstay of treatment in children with GD.
◦ Thyroidectomy is the primary definitive therapy in childhood, but in postpubertal
children RAI can be considered.

SPECIAL SITUATIONS
◦ IMMUNE RECONSTITUTION
◦ The first demonstration of immune reconstitution GD was in multiple sclerosis patients who had
received lymphocyte-depleting alemtuzumab antibody treatment
◦ This treatment causes initial lymphopenia, but 12–24 months later 20–30% of patients
developed TSH-R-Ab-positive GD, as lymphocyte populations recover.

SPECIAL SITUATIONS
◦ A similar pattern of GD has been observed in patients with HIV who have received HAART
◦ May also be seen in bone marrow transplant recipients

SPECIAL SITUATIONS
◦ RECOMMENDATIONS
◦ Graves’ hyperthyroidism precipitated by an immunomodulatory therapy is not a
mandatory indication to stop that precipitating treatment, nor is it a mandatory
indication for definitive therapy for hyperthyroidism.
◦ Sequential monitoring of serum TSH-R-Ab levels can be used to guide the duration of
ATD therapy in patients with immune reconstitution GD

CONTRAINDICATIONS TO A PARTICULAR MODALITY
◦ a. RAI therapy:
◦ Definite contraindications include pregnancy, lactation, coexisting thyroid cancer, or suspicion of
thyroid cancer, individuals unable to comply with radiation safety guidelines
◦ used with informed caution in women planning a pregnancy within 4–6 months.
◦ b. ATDs: Definite contraindications include previous known major adverse reactions to ATDs

CONTRAINDICATIONS TO A PARTICULAR MODALITY
◦ Surgery:
◦ comorbidity such as cardiopulmonary disease, end-stage cancer, or other debilitating disorders,
or lack of access to a high-volume thyroid surgeon.
◦ Pregnancy is a relative contraindication - surgery should only be used when rapid control of
hyperthyroidism is required and ATD cannot be used

EMERGING DRUGS
◦ monoclonal antibodies or small molecules that block TSHR or block the stimulatory effect of
TSHR autoantibodies.
◦ a human anti-TSHR monoclonal antibody (K1-70) is being tested in a phase I trial in patients
with GD and GO.
◦ Iscalimab (antibody targeting CD40, expressed on the surface of thyroid cells and orbital cells)
led to an ~50% response rate when administered to patients with untreated Graves’
hyperthyroidism and is under further study

SUBCLINICAL GRAVES’ HYPERTHYROIDISM
◦ increased risk of coronary heart disease mortality, incident atrial fibrillation, heart failure,
fractures, and excess mortality in patients with serum TSH levels < 0.1 Mu/l
◦ in the presence of TSH-R-Ab indicating “subclinical” GD, the rate of progression to overt
hyperthyroidism is up to 30% in the subsequent 3 years

SUBCLINICAL GRAVES’ HYPERTHYROIDISM
◦ Treatment might be considered in patients older than 65 years with TSH levels of 0.1–0.39 mIU/L
because of their increased risk of atrial fibrillation
◦ RECOMMENDATION
◦ Treatment of SH is recommended in Graves’ patients >65 years with serum TSH levels
that are persistently < 0.1 MU/L
◦ ATD should be the first choice of treatment of Graves’ SH

GRAVES DISEASE

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