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Summary Table

Category	Detail
Risk Factors	Women (5:1 female-to-male ratio), age 20 to 40, family history of autoimmune thyroid disease, other autoimmune conditions (type 1 diabetes, celiac disease, vitiligo), smoking (strong risk factor for ophthalmopathy), recent physiologic stress or postpartum period
Etiology	Autoimmune production of thyroid-stimulating immunoglobulin (TSI), an IgG antibody that activates the TSH receptor
Patient Presentation	Heat intolerance, weight loss despite increased appetite, palpitations, anxiety, tremor, frequent bowel movements, menstrual irregularity (oligomenorrhea), fatigue
Classic Physical Exam	Diffuse, nontender goiter with an audible bruit; exophthalmos and lid retraction; pretibial myxedema (nonpitting edema over the shins); fine resting tremor; warm and moist skin; brisk deep tendon reflexes; tachycardia or atrial fibrillation
Key Diagnostic Results	Suppressed TSH with elevated free T4 and/or free T3; positive TSI or thyrotropin receptor antibody (TRAb); diffusely increased uptake on radioactive iodine uptake scan (RAIU)
Management	Methimazole (first-line antithyroid drug), propranolol for symptomatic relief, radioactive iodine ablation as definitive therapy, thyroidectomy when both are contraindicated or refused
Keywords	"Diffuse goiter with bruit," "exophthalmos," "pretibial myxedema," "thyroid-stimulating immunoglobulin," "diffusely increased uptake"

1. Pathophysiology

Graves disease is an autoimmune disorder in which B lymphocytes produce thyroid-stimulating immunoglobulin (TSI), an autoantibody directed against the TSH receptor on thyroid follicular cells. Unlike TSH itself, TSI is not subject to negative feedback from circulating thyroid hormones. The result is continuous, unregulated stimulation of the thyroid gland, leading to excessive synthesis and secretion of T3 and T4.

Because TSI activates the same receptor as TSH, the entire gland is stimulated uniformly. This explains the diffusely enlarged, hyperactive thyroid seen on exam and the diffusely increased uptake on radioactive iodine scanning. The gland becomes hypervascular due to increased metabolic demand, producing the characteristic thyroid bruit on auscultation. This bruit is a key discriminator: a nodular goiter (as in toxic multinodular goiter or Plummer disease) does not produce a diffuse bruit in the same way.

The systemic effects of thyrotoxicosis result from excess thyroid hormone acting on nearly every organ system. T3 increases basal metabolic rate (weight loss, heat intolerance), upregulates beta-adrenergic receptors in the heart (tachycardia, palpitations, risk of atrial fibrillation), increases gut motility (frequent stools), and accelerates bone turnover. The hyperdynamic cardiovascular state is the reason beta-blockers are first-line symptomatic therapy.

Graves ophthalmopathy is distinct from the thyrotoxicosis itself. TSH receptors are also expressed on orbital fibroblasts and adipocytes. TSI-mediated activation of these cells triggers an inflammatory cascade with glycosaminoglycan deposition and edema within the extraocular muscles and retro-orbital fat. The resulting increase in orbital volume pushes the globe forward, causing proptosis. This process is independent of thyroid hormone levels, which is why ophthalmopathy can worsen even after the patient becomes euthyroid or hypothyroid.

Pretibial myxedema follows a similar mechanism: TSH receptor-bearing fibroblasts in the dermis of the pretibial region are activated by TSI, causing localized glycosaminoglycan accumulation. The resulting skin changes are thickened, waxy, nonpitting plaques over the anterior shins. This finding is essentially pathognomonic for Graves disease.

2. Classification and Clinical Manifestation

Thyrotoxicosis Severity

Severity	Clinical Features
Mild	Resting heart rate under 100 bpm, modest weight loss, mild tremor, no cardiovascular compromise
Moderate	Resting heart rate 100 to 120 bpm, notable weight loss (more than 10% of body weight), impaired daily function, early atrial fibrillation
Severe / Thyroid Storm	Heart rate above 140 bpm, high-grade fever, altered mental status (agitation, delirium, coma), seizures, jaundice, heart failure. Burch-Wartofsky score above 45 is diagnostic of thyroid storm

Graves Ophthalmopathy Classification (Werner / NO SPECS)

Class	Findings
0	No signs or symptoms
1	Only signs (lid retraction, stare, lid lag), no symptoms
2	Soft tissue involvement (periorbital edema, conjunctival injection, chemosis)
3	Proptosis (exophthalmos measured by Hertel exophthalmometry, more than 20 mm or more than 2 mm asymmetry)
4	Extraocular muscle involvement (diplopia, restricted gaze, most commonly inferior rectus then medial rectus)
5	Corneal involvement (exposure keratopathy from incomplete lid closure)
6	Sight loss from compressive optic neuropathy (reduced color vision, afferent pupillary defect)

Eponymous Signs in Graves Ophthalmopathy

Sign	Description
Von Graefe sign	Upper eyelid lag on downward gaze: the lid does not follow the globe smoothly when the patient looks down
Dalrymple sign	Widened palpebral fissure at rest due to upper eyelid retraction, giving a "staring" appearance
Stellwag sign	Infrequent or incomplete blinking
Rosenbach sign	Fine tremor of the closed eyelids
Joffroy sign	Absence of forehead wrinkling when the patient looks up (loss of frontalis contraction)
Mobius sign	Failure of convergence: inability to maintain adduction of both eyes when focusing on a near object
Gifford sign	Difficulty everting the upper eyelid due to edema and fibrosis
Sainton sign	Nystagmus on extreme lateral gaze
Jellinek sign	Brownish hyperpigmentation of the upper eyelid creases
Ballet sign	Restriction or paralysis of one or more extraocular muscles
Enroth sign	Edematous swelling of the lower eyelid
Kocher sign	Spasmodic retraction of the upper lid on fixation, revealing sclera above the limbus during attentive gaze

The most commonly tested eponymous signs in a clinical exam setting are Von Graefe sign (lid lag), Dalrymple sign (lid retraction), and Mobius sign (convergence failure). Von Graefe sign is particularly high-yield because it is often described in vignettes as "the patient's upper eyelid does not follow the globe on looking downward."

Other Manifestations

Manifestation	Key Features
Pretibial myxedema	Nonpitting, thickened, "peau d'orange" plaques over the anterior shin. Present in roughly 1 to 5% of patients. Essentially pathognomonic for Graves
Thyroid acropachy	Digital clubbing, soft-tissue swelling of the hands and feet, periosteal new bone formation. Rare. Virtually diagnostic of Graves when present
Onycholysis (Plummer nails)	Separation of the nail plate from the nail bed, beginning distally

3. Diagnostic Workup

Test	Role	Expected Finding
TSH	Best initial test for any suspected thyroid disorder	Suppressed (often undetectable, below 0.01 mIU/L)
Free T4	Confirms overt hyperthyroidism	Elevated
Free T3 / Total T3	May be the only elevated hormone in early disease (T3 thyrotoxicosis)	Elevated, sometimes disproportionately
TSI / TRAb	Confirms autoimmune etiology; distinguishes Graves from other causes	Positive (elevated)
Radioactive iodine uptake (RAIU)	Distinguishes causes of thyrotoxicosis based on gland activity	Diffusely increased uptake (typically 35 to 95%)
Thyroid ultrasound with Doppler	Alternative when RAIU is contraindicated (pregnancy, breastfeeding)	Diffuse enlargement with increased vascularity ("thyroid inferno")
Anti-TPO antibodies	Supportive but not confirmatory; present in many autoimmune thyroid conditions	Often positive, but nondiagnostic on its own

TSH is always the first test ordered when hyperthyroidism is suspected. A suppressed TSH prompts measurement of free T4 (and free T3 if free T4 is normal but clinical suspicion remains high). If both TSH suppression and elevated free T4 confirm thyrotoxicosis, the next question becomes: what is the cause?

This is where TSI (or TRAb) and RAIU become critical. TSI is the most useful serologic test because a positive result is essentially diagnostic of Graves disease and eliminates the need for a nuclear scan in many clinical settings. However, RAIU remains the gold standard imaging test for differentiating Graves from other causes of thyrotoxicosis. The expected pattern in Graves is diffusely elevated uptake across the entire gland.

RAIU Differential

Condition	RAIU Pattern
Graves disease	Diffusely increased (homogeneous)
Toxic multinodular goiter	Patchy, heterogeneous increased uptake (multiple hot nodules with suppressed intervening tissue)
Toxic adenoma	Single focal "hot" nodule with suppressed surrounding tissue
Subacute thyroiditis / Painless thyroiditis	Diffusely decreased or near-zero uptake (preformed hormone is leaking, not being newly synthesized)
Factitious thyrotoxicosis (exogenous T4 intake)	Diffusely decreased or near-zero uptake with suppressed thyroglobulin

This RAIU pattern table is one of the highest-yield items in thyroid testing. The critical teaching point: low or absent RAIU in a thyrotoxic patient means the thyroid is not actively making new hormone. The hormone is either leaking from an inflamed gland (thyroiditis) or being taken exogenously.

In pregnant patients, RAIU is absolutely contraindicated (radioactive iodine crosses the placenta). The workup relies on TSI/TRAb for diagnosis. Thyroid ultrasound with Doppler showing increased vascularity ("thyroid inferno" pattern) can also support the diagnosis noninvasively.

4. Management and Treatment

Clinical Scenario	Treatment	Key Details
Symptomatic relief	Propranolol	20 to 40 mg every 6 to 8 hours; controls tachycardia, tremor, anxiety. Also inhibits peripheral T4-to-T3 conversion at higher doses
Antithyroid drug (first-line)	Methimazole	Starting dose 10 to 30 mg once daily depending on severity. Titrate to euthyroid state over 4 to 6 weeks. Continue for 12 to 18 months, then attempt taper
Antithyroid drug in first trimester of pregnancy	Propylthiouracil (PTU)	100 to 150 mg three times daily. Used only in the first trimester due to methimazole's teratogenicity (aplasia cutis, choanal atresia). Switch to methimazole after the first trimester
Definitive therapy (most common in the US)	Radioactive iodine (I-131) ablation	Single oral dose. Destroys thyroid tissue. Results in permanent hypothyroidism requiring lifelong levothyroxine. Contraindicated in pregnancy, breastfeeding, and moderate-to-severe active ophthalmopathy
Surgery	Total thyroidectomy	Indicated for very large goiters, coexisting suspicious nodules, inability to tolerate antithyroid drugs, or patient preference. Requires preoperative euthyroid state
Thyroid storm	PTU + iodine + beta-blocker + glucocorticoids + supportive care	PTU first (blocks new synthesis and peripheral conversion), then iodine given at least 1 hour after PTU (Wolff-Chaikoff effect blocks hormone release). Hydrocortisone 100 mg IV every 8 hours
Ophthalmopathy (mild)	Lubricating eye drops, sunglasses, elevate head of bed	Supportive measures
Ophthalmopathy (moderate-to-severe / active)	IV glucocorticoids (methylprednisolone), orbital radiation, or teprotumumab	Teprotumumab is an IGF-1 receptor inhibitor, now considered first-line for moderate-to-severe active Graves ophthalmopathy
Ophthalmopathy (sight-threatening)	Emergent surgical orbital decompression	Indicated for compressive optic neuropathy not responding to IV steroids

Methimazole is the preferred antithyroid drug in nearly all cases because of its once-daily dosing, faster onset of action, and lower risk of hepatotoxicity compared to PTU. The one exception is the first trimester of pregnancy, where methimazole is avoided due to its association with aplasia cutis and embryopathy (choanal atresia, esophageal atresia). PTU is used during this window and then switched to methimazole after the first trimester.

A key adverse effect of both antithyroid drugs is agranulocytosis (absolute neutrophil count below 500). This occurs in roughly 0.2 to 0.5% of patients and typically presents with sudden high fever and severe pharyngitis. Patients must be instructed to stop the medication immediately and present for an urgent complete blood count if they develop fever or sore throat. This counseling point is frequently tested.

PTU carries an additional risk of hepatic necrosis (potentially fatal), which is the primary reason it is not first-line outside of early pregnancy and thyroid storm.

Radioactive iodine (I-131) is the most commonly used definitive therapy in the United States. It ablates the hyperactive thyroid tissue, and most patients develop permanent hypothyroidism within 6 to 12 months, requiring lifelong levothyroxine replacement. The critical contraindication to remember is moderate-to-severe active Graves ophthalmopathy: RAI can worsen eye disease because the destruction of thyroid tissue releases TSH receptor antigens, amplifying the autoimmune orbital inflammation. If RAI is chosen in a patient with mild ophthalmopathy, concurrent glucocorticoid prophylaxis (prednisone 0.3 to 0.5 mg/kg/day, tapered over 2 to 3 months) is recommended.

Thyroid storm management follows a strict sequence. The order matters:

PTU first (blocks new hormone synthesis and peripheral T4-to-T3 conversion)
Iodine (potassium iodide or Lugol solution) given at least 1 hour after PTU. The delay is critical: if iodine is given before the thionamide has blocked organification, the iodine load can paradoxically fuel new hormone synthesis (Jod-Basedow phenomenon). Once organification is blocked, excess iodine acutely inhibits hormone release via the Wolff-Chaikoff effect
Beta-blocker (propranolol IV or esmolol if hemodynamically unstable)
Glucocorticoids (hydrocortisone 100 mg IV every 8 hours) to block peripheral T4-to-T3 conversion and to treat possible concurrent adrenal insufficiency
Supportive care: cooling blankets (avoid aspirin as an antipyretic because it displaces T4 from thyroid-binding globulin, increasing free hormone levels), IV fluids, ICU monitoring

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Toxic multinodular goiter (Plummer disease)	Also causes hyperthyroidism with goiter and suppressed TSH	Older patient (over 50), nodular goiter (not diffuse), no ophthalmopathy or pretibial myxedema, RAIU shows patchy heterogeneous uptake rather than diffuse
Toxic adenoma	Hyperthyroidism with a thyroid mass	Single palpable nodule, RAIU shows one "hot" focus with suppressed surrounding tissue, no extrathyroidal manifestations
Subacute (de Quervain) thyroiditis	Early phase causes thyrotoxicosis with elevated free T4	Painful, tender thyroid after a viral illness, elevated ESR, low or absent RAIU (hormone is leaking, not being made). Self-limited
Painless (silent) thyroiditis / Postpartum thyroiditis	Thyrotoxicosis with a nontender gland, can mimic mild Graves	Low RAIU (distinguishes from Graves). Often occurs postpartum. No ophthalmopathy. TSI/TRAb negative
Factitious thyrotoxicosis	Suppressed TSH and elevated T4, mimics any cause of hyperthyroidism	No goiter, low RAIU, and importantly low thyroglobulin (exogenous T4 suppresses thyroglobulin production). Graves has elevated thyroglobulin
TSH-secreting pituitary adenoma	Elevated free T4 similar to Graves	TSH is not suppressed (inappropriately normal or elevated). This is the hallmark: central hyperthyroidism. MRI pituitary shows adenoma
Hashimoto thyroiditis (hashitoxicosis phase)	Transient thyrotoxicosis with positive thyroid antibodies	Anti-TPO and anti-thyroglobulin antibodies are dominant (not TSI). Thyrotoxicosis is transient and eventually progresses to hypothyroidism. RAIU is low or variable, not diffusely elevated

The single most tested discrimination is between Graves and subacute thyroiditis: both can present with thyrotoxicosis, but the presence of thyroid tenderness and a low RAIU points firmly toward thyroiditis. Graves has a nontender goiter with a bruit and a high RAIU.

6. Traps and High-Yield Pearls

The most common way students lose points on Graves disease questions involves the RAIU interpretation. A thyrotoxic patient with low or absent RAIU is not Graves, regardless of how textbook the other symptoms appear. Test-writers exploit this by describing a patient with weight loss, tremor, and tachycardia but then revealing a near-zero uptake scan, expecting you to pivot away from Graves toward thyroiditis or factitious intake.

A second frequent trap is the sequence of treatment in thyroid storm. Students often select iodine as the first intervention because they recall the Wolff-Chaikoff effect. However, iodine must never be given before a thionamide has blocked organification. The tested principle: PTU first, iodine at least one hour later.

The ophthalmopathy and RAI interaction is another high-yield trap. A patient with moderate-to-severe active Graves ophthalmopathy is not a candidate for radioactive iodine ablation without glucocorticoid cover, and in truly severe cases, RAI should be avoided altogether in favor of surgery. Vignettes may describe worsening proptosis after RAI treatment, and the expected answer is that this was a predictable consequence of RAI in active eye disease.

Students also confuse methimazole teratogenicity with a blanket contraindication in pregnancy. The nuance is trimester-dependent: PTU in the first trimester, then switch to methimazole for the remainder of pregnancy. If a vignette places a pregnant patient in the second or third trimester, methimazole is the correct answer.

Finally, remember the agranulocytosis counseling point. If a patient on methimazole or PTU develops sudden fever and sore throat, the next best step is to stop the drug and check a CBC with differential immediately. Do not restart the same agent. This clinical scenario is a classic "next best step" question format.

The core competency being tested across Graves disease questions is your ability to integrate the pathophysiology (TSI-driven receptor activation) with the diagnostic workup (RAIU patterns), distinguish it from its look-alikes using one or two discriminating features, and sequence the management correctly in both routine and emergent settings.

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