Graves Disease

Slide 1 · Graves Disease

Autoimmune thyroid hyperfunction and extrathyroidal lesions

Mechanism • Morphology • Clinicopathologic correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain how stimulating TSH-receptor autoantibodies create primary hyperthyroidism.

Recognize the characteristic thyroid and extrathyroidal morphology.

Integrate clinical findings, hormone tests, antibodies, and uptake patterns.

Distinguish Graves disease from other major causes of thyrotoxicosis.

Slide 3 · Graves disease: Receptor-driven hyperthyroidism

TSH-receptor autoantibody

Follicular cell stimulation

Excess T₃ / T₄

An autoimmune disorder in which TSH-receptor stimulation drives excess thyroid hormone production.

Produces diffuse enlargement and hyperfunction of the thyroid gland.

Characteristic extrathyroidal lesions are orbitopathy and, less commonly, dermopathy.

Slide 4 · Hyperthyroidism versus thyrotoxicosis

Concept

Thyrotoxicosis

Hyperthyroidism

Meaning

Hormone excess in tissues

Increased gland production

Graves disease

Present

Present

Destructive thyroiditis

May be present

Not the cause

Slide 5 · Normal hypothalamic–pituitary–thyroid feedback

Hypothalamic TRH promotes pituitary TSH secretion.

TSH binds the follicular-cell receptor and stimulates hormone synthesis and release.

T₃ and T₄ suppress TRH and TSH by negative feedback.

Hypothalamus / TRH

Pituitary / TSH

Thyroid / T₃ + T₄

T₃/T₄ inhibit TRH and TSH

Slide 6 · TSH receptor: A cAMP-linked signaling pathway

TSH receptor

Gs protein

Adenylyl cyclase / cAMP

Hormone synthesis + growth

TSH receptor activation couples to Gs-protein signaling.

Increased intracellular cAMP activates downstream effector pathways.

Follicular-cell growth and thyroid hormone production increase.

Slide 7 · Why excess thyroid hormone produces symptoms

T₄ → T₃

Nuclear thyroid-hormone receptor

Altered gene transcription

Hypermetabolic state

T₄ is converted in peripheral tissues to the more active T₃.

Thyroid hormone receptors regulate target-gene expression.

Increased metabolic activity and β-adrenergic responsiveness generate the clinical syndrome.

Slide 8 · Causes of thyrotoxicosis: Source matters

Mechanism

Examples

Typical gland output

Increased synthesis

Graves; toxic nodules

Increased

Hormone leakage

Granulomatous / painless thyroiditis

Not increased

Outside source

Exogenous thyroid hormone

Not increased

Slide 9 · The characteristic Graves clinical triad

Diffuse toxic goiter

Infiltrative ophthalmopathy

Pretibial dermopathy

The three manifestations do not necessarily coexist in every patient.

Slide 10 · Epidemiologic profile

Peak incidence occurs between 20 and 50 years of age.

Females are affected approximately 5–10 times more frequently than males.

The disease is the leading cause of endogenous hyperthyroidism.

Clinical / pathologic inference

The demographic pattern increases suspicion; Laboratory and etiologic tests establish the diagnosis.

Slide 11 · Graves disease is an autoimmune receptoropathy

Loss of immune tolerance

TSH-receptor autoantibodies

Receptor signaling changes

Multiple thyroid-directed autoantibodies may circulate.

The most pathophysiologically important target is the TSH receptor.

Autoantibody effects on the receptor can be stimulating or blocking.

Slide 12 · Stimulating and blocking TSH-receptor antibodies

Receptor antibody

Functional effect

Possible phenotype

Stimulating

Mimics TSH signaling

Hyperthyroidism

Blocking

Opposes receptor activation

Hypothyroidism in some patients

Slide 13 · Thyroid-stimulating immunoglobulin (TSI)

TSI antibody

TSH receptor

Continued stimulation

TSI is the most common antibody subtype described in Graves disease.

TSI in approximately 90% of patients.

TSI directly mimics the action of pituitary TSH at the receptor.

Slide 14 · A ligand mimic bypasses normal feedback

TSI occupancy stimulates the thyroid even when pituitary TSH is low.

Normal feedback appropriately decreases circulating TSH.

Autoantibody-driven receptor signaling nevertheless persists.

↑ TSI at TSH receptor

↑ Thyroid T₃ / T₄

↓ Pituitary TSH

Autoantibody stimulation persists

Slide 15 · The direct mechanism of hormone excess

TSI binds TSHR

↑ Adenylyl cyclase

↑ cAMP signaling

↑ T₃ / T₄ + growth

TSI binds to the TSH receptor on follicular epithelial cells.

Receptor activation increases adenylyl cyclase activity.

Enhanced signaling drives thyroid hormone release and follicular growth.

Slide 16 · Autoantibody specificity: TSI versus anti-TPO

Antibody

Main significance

TSI / stimulating TRAb

Direct receptor-mediated hyperfunction

Anti-thyroid peroxidase

Marker of thyroid autoimmunity

Anti-thyroglobulin

Marker of thyroid autoimmunity

Slide 17 · Genetic susceptibility is substantial, not deterministic

Monozygotic twin concordance is reported at approximately 30–40%.

Dizygotic twin concordance is less than 5%.

Incomplete concordance supports influences beyond inherited genotype.

Clinical / pathologic inference

Twin concordance demonstrates heritable predisposition but does not establish a single-gene disorder.

Slide 18 · Immune-function loci in Graves susceptibility

Immune regulatory variants

Altered susceptibility

Thyroid autoimmunity

Robbins implicates variants associated with CTLA4, PTPN22, and IL2RA.

These loci have roles in immune regulation.

Their shared associations support an autoimmune predisposition.

Slide 19 · TSHR genetic variation contributes to risk

Genome-wide association studies implicate TSHR susceptibility variants.

This connects the principal autoantigen with inherited disease risk.

Susceptibility variants are not themselves diagnostic of active Graves disease.

Clinical / pathologic inference

TSHR is simultaneously the principal pathogenic autoantibody target and a susceptibility locus.

Slide 20 · Why Graves and Hashimoto disease overlap

Feature

Graves disease

Hashimoto thyroiditis

Dominant outcome

Hyperfunction

Destructive failure

Principal mechanism

TSHR stimulation

Immune follicular injury

Common clinical course

Thyrotoxicosis

Hypothyroidism

Slide 21 · Orbitopathy involves a distinct immune tissue response

Activated CD4⁺ T cells

Cytokine signaling

Orbital fibroblasts

Matrix + tissue expansion

Activated CD4⁺ helper T cells contribute to retro-orbital inflammation.

Secreted cytokines stimulate fibroblast proliferation and matrix synthesis.

The resulting change occurs outside the thyroid gland.

Slide 22 · Fibroblast matrix synthesis drives orbital swelling

Cytokines

Orbital fibroblasts

Hydrophilic GAG accumulation

Edema / tissue expansion

Stimulated fibroblasts increase extracellular matrix glycosaminoglycans.

Hyaluronic acid and chondroitin sulfate bind water.

Hydrophilic matrix expansion contributes to edema and tissue volume increase.

Slide 23 · Four contributors to increased orbital volume

Mononuclear inflammatory-cell infiltration, principally T cells.

Extraocular-muscle inflammation and edema.

Hydrophilic glycosaminoglycan accumulation in connective tissue.

An increase in retro-orbital adipocytes.

Immune infiltration

Muscle edema

GAG accumulation

Adipose expansion

Slide 24 · Exophthalmos reflects restricted orbital space

Retro-orbital connective tissue and extraocular muscles expand.

Orbital contents displace the globe anteriorly.

The same process may compromise extraocular-muscle function.

Normal

Graves orbit

Expanding tissue → globe displacement

Schematic — not a specimen

Slide 25 · Orbital inflammation may evolve into fibrosis

Inflammatory infiltration

Edema / muscle swelling

Fibrosis in later disease

Early orbital muscles and connective tissue are edematous.

Continued inflammation may lead to fibrosis of involved muscle.

Late structural change helps explain persistent ocular dysfunction.

Slide 26 · Exophthalmos and lid lag are not equivalent

Finding

Underlying basis

Exophthalmos

Infiltrative orbital tissue expansion

Lid lag

Sympathetic stimulation of eyelid elevation

Staring gaze

Sympathetic overactivity

Slide 27 · Pretibial myxedema is an infiltrative dermopathy

Dermal fibroblast-associated matrix accumulation thickens the skin.

Glycosaminoglycan deposition and lymphocyte infiltration underlie the lesion.

Clinical involvement occurs in a minority of Graves patients.

Epidermis

Thickened dermis

Glycosaminoglycans + lymphocytes

Schematic — not a specimen

Slide 28 · Gross thyroid morphology: Diffuse and symmetrical

The thyroid is usually diffusely enlarged and symmetric.

Diffuse follicular epithelial hypertrophy and hyperplasia increase gland mass.

Weights over 80 g are not uncommon.

Diffuse enlargement

Symmetrical lobes

Schematic — not a specimen

Slide 29 · Gross cut surface in Graves disease

Parenchyma is classically soft and brown-red.

The gland may appear beefy deep red on gross examination.

This diffuse pattern contrasts with nodular and heterogeneous goiters.

Diffuse enlargement

Symmetrical lobes

Schematic — not a specimen

Slide 30 · Follicles respond to chronic receptor stimulation

The epithelial lining becomes taller and more cellular.

Crowded cells narrow the space available for luminal colloid.

The picture reflects active hormone production and resorption.

Follicular epithelium

Colloid

Schematic — not a specimen

Slide 31 · Untreated Graves: Tall columnar follicular cells

Follicular epithelial cells are typically tall rather than flat.

Increased cell height and crowding are distributed diffusely.

The appearance is best assessed with untreated-tissue context.

Follicular epithelium

Colloid

Schematic — not a specimen

Slide 32 · Intraluminal epithelial projections

Crowded follicular epithelium forms small projections into follicle lumens.

Some hyperplastic folds encroach substantially on luminal colloid.

The projections are an epithelial response to trophic stimulation.

Follicular epithelium

Colloid

Schematic — not a specimen

Slide 33 · Graves micropapillae lack fibrovascular cores

Feature

Graves epithelial fold

True papilla

Core

No fibrovascular core

Fibrovascular core present

Context

Diffuse follicular hyperplasia

Requires broader tumor assessment

Slide 34 · Scalloped colloid signals active resorption

Follicular cells actively resorb thyroglobulin-rich colloid.

Luminal colloid becomes pale with irregular scalloped edges.

Scalloping should be interpreted together with epithelial hyperplasia.

Follicular epithelium

Colloid

Resorption scalloping

Schematic — not a specimen

Slide 35 · Interstitium contains lymphoid inflammation

Predominantly T-cell lymphocytes occur between follicles.

Scattered B cells and mature plasma cells also occur.

The inflammatory infiltrate reinforces the autoimmune pathogenesis.

Follicular epithelium

Colloid

Interstitial lymphocytes

Schematic — not a specimen

Slide 36 · Germinal centers may be conspicuous

Lymphoid aggregates may develop germinal centers.

Germinal centers are common in Graves thyroid tissue.

They are not exclusive to Graves: Correlation with endocrine function matters.

Clinical / pathologic inference

Autoimmune thyroid histology must be integrated with the gland’s functional state.

Slide 37 · Morphologic sequence: Signal to follicle

Receptor activation

Follicular growth

Tall epithelium + scalloping

Diffuse hyperplasia

TSH-receptor stimulation promotes growth and endocrine activity.

Follicles develop crowded tall epithelium and resorption vacuoles.

The integrated finding is diffuse hyperplastic activity.

Slide 38 · Iodine treatment alters the histologic pattern

Iodide therapy

Reduced hormone release

Epithelial involution

Colloid accumulation

Preoperative iodide can cause involution of stimulated follicular epithelium.

Colloid accumulates as thyroglobulin release is blocked.

Pretreatment may therefore partially obscure untreated morphology.

Slide 39 · Propylthiouracil can accentuate hyperplasia

PTU: Inhibits synthesis

Reduced circulating hormone

Compensatory TSH

Enhanced epithelial changes

Exaggerated epithelial hypertrophy and hyperplasia after PTU.

Reduced hormone synthesis can induce compensatory trophic signaling.

Medication history is essential when interpreting thyroidectomy morphology.

Slide 40 · Histology depends on treatment context

Setting

Epithelial appearance

Colloid

Untreated

Tall / crowded

Scalloped

Iodide treated

Involution

Accumulated

PTU treated

Hyperplasia may increase

Variable

Slide 41 · Generalized lymphoid tissue can respond

Graves disease may cause lymphoid hyperplasia beyond the thyroid.

Thymic enlargement is especially described in younger patients.

This reflects systemic immune activation rather than a thyroid malignancy.

Clinical / pathologic inference

Thymic enlargement can accompany autoimmune hyperthyroidism in younger patients.

Slide 42 · Cardiac pathology is clinically important

Thyroid hormone excess

↑ Cardiac demand

Tachycardia / output

Hypertrophy / ischemia

Sustained thyrotoxicosis increases cardiac workload.

Cardiac hypertrophy may develop with long-standing disease.

Ischemic changes are especially relevant with preexisting coronary artery disease.

Slide 43 · Histologic substrate of orbital disease

Edema and hydrophilic matrix are present in orbital connective tissue.

Lymphocytes infiltrate the expanded retro-orbital tissue.

Extraocular muscle fibrosis can appear in later disease.

Normal

Graves orbit

Expanding tissue → globe displacement

Schematic — not a specimen

Slide 44 · Skin pathology: Dermal glycosaminoglycans

Infiltrative dermopathy produces dermal thickening.

Glycosaminoglycans accumulate among connective-tissue elements.

Lymphocytic infiltration is also observed.

Epidermis

Thickened dermis

Glycosaminoglycans + lymphocytes

Schematic — not a specimen

Slide 45 · Diffuse goiter may produce a bruit

Thyroid enlargement is generally diffuse rather than nodular.

Marked gland hyperactivity increases thyroid blood flow.

In some patients, vascular flow is sufficient to produce an audible bruit.

Diffuse enlargement

Symmetrical lobes

Schematic — not a specimen

Slide 46 · Metabolic consequences of excess thyroid hormone

↑ Metabolic rate

↑ Heat production

Sweating + heat intolerance

Weight loss

Increased basal metabolic rate causes heat intolerance and sweating.

Weight loss may occur despite increased appetite.

Peripheral vasodilation gives the skin a warm, flushed quality.

Slide 47 · Cardiovascular presentation of thyrotoxicosis

Tachycardia and palpitations may occur early.

Increased output and cardiac contractility contribute to physiologic strain.

Atrial fibrillation and heart failure particularly affect vulnerable older adults.

Clinical / pathologic inference

Cardiovascular findings can be the presenting clue to thyroid hormone excess.

Slide 48 · Adrenergic overactivity drives neurobehavioral signs

Thyroid hormone excess

↑ β-adrenergic tone

Tremor / anxiety / palpitations

Tremor, anxiety, insomnia, and emotional lability are characteristic.

Restlessness and impaired concentration can be prominent.

These effects are often controlled rapidly by β-adrenergic blockade.

Slide 49 · Muscle, gut, and skeletal consequences

Proximal muscle weakness and reduced muscle mass may occur.

Intestinal hypermotility can cause increased stool frequency.

Increased bone resorption raises the risk of osteoporosis and fractures.

Proximal weakness

Hypermotility

Bone resorption

Catabolic effects

Slide 50 · Ocular complications can persist after control

Exophthalmos may persist or progress despite treatment of thyrotoxicosis.

Extraocular muscle dysfunction may affect eye movements.

Severe exposure can damage the corneal surface.

Normal

Graves orbit

Expanding tissue → globe displacement

Schematic — not a specimen

Slide 51 · Typical pretibial clinical findings

Dermopathy occurs in only a minority of Graves patients.

Skin over the shins becomes thickened, indurated, and sometimes scaly.

The lesion is mechanistically distinct from ordinary hypermetabolic skin warmth.

Epidermis

Thickened dermis

Glycosaminoglycans + lymphocytes

Schematic — not a specimen

Slide 52 · Associated autoimmune disorders

Graves patients have an increased risk of other autoimmune conditions.

Pernicious anemia, type 1 diabetes, Addison disease, and systemic lupus erythematosus.

Autoimmune clustering is consistent with shared immune susceptibility.

Clinical / pathologic inference

The coexistence of another autoimmune disease does not alter the mechanism of Graves hyperthyroidism.

Slide 53 · Thyroid storm: Acute decompensation

Known thyrotoxicosis

Acute physiologic stress

Severe systemic hypermetabolism

Thyroid storm

A sudden severe thyrotoxic state may arise in Graves disease.

Potential triggers include infection, surgery, drug cessation, and other stress.

Fever and disproportionate tachycardia indicate a medical emergency.

Slide 54 · Apathetic hyperthyroidism in older adults

The expected hyperadrenergic manifestations can be blunted.

Unexplained weight loss or worsening cardiac disease may dominate.

A suppressed TSH may reveal the disorder despite few classic symptoms.

Clinical / pathologic inference

The absence of obvious tremor or agitation does not exclude thyrotoxicosis in older patients.

Slide 55 · Biochemical pattern of primary Graves disease

Serum TSH is typically decreased due to negative feedback.

Free T₄ and/or T₃ are elevated during overt thyrotoxicosis.

The low TSH level does not imply that the thyroid gland is unstimulated.

↑ TSI at TSH receptor

↑ Thyroid T₃ / T₄

↓ Pituitary TSH

Autoantibody stimulation persists

Slide 56 · T₃-predominant thyrotoxicosis

Some hyperthyroid patients show predominantly increased circulating T₃.

Free T₄ may not be elevated in that setting.

Measuring T₃ can clarify low-TSH presentations with nondiagnostic free T₄.

Clinical / pathologic inference

TSH screening should be followed by the appropriate free-hormone measurements.

Slide 57 · TSI and TSH-receptor antibody testing

Low TSH + high T₃/T₄

Measure TSI / TRAb

Evidence for autoimmune TSHR activation

TSI detects stimulating receptor-directed immunoglobulin activity.

TSH-receptor antibody assays provide etiologic evidence for Graves disease.

Antibody type and functional effect are important conceptual distinctions.

Slide 58 · Radioiodine uptake: Diffusely increased in Graves

Persistent receptor activation increases iodine trapping throughout the gland.

Radioiodine studies show a diffuse increase in uptake.

The distribution helps separate Graves from focal toxic nodules and thyroiditis.

Diffuse Graves

Focal nodule

Thyroiditis

Conceptual patterns; Not radionuclide scans

Slide 59 · Integrated diagnostic reasoning

Suppressed TSH + ↑ hormones

Clinical phenotype

TSI / TRAb or diffuse uptake

Graves disease

Establish thyrotoxicosis biochemically with TSH and free thyroid hormones.

Identify a diffuse, hypervascular goiter and any characteristic extrathyroidal features.

Support etiology with receptor antibodies or a diffuse uptake pattern.

Slide 60 · Major causes of primary thyrotoxicosis

Disease

Gland pattern

Functional driver

Graves

Diffuse symmetric

TSHR autoantibodies

Toxic adenoma

Solitary hot nodule

Autonomous nodule

Toxic MNG

Multinodular

Autonomous nodules

Slide 61 · Graves versus diffuse nontoxic goiter

Feature

Graves

Diffuse nontoxic goiter

Typical function

Hyperthyroid

Usually euthyroid

Growth stimulus

Stimulating TSHR antibody

Compensatory TSH

Colloid

Often scalloped

Often abundant in involution

Slide 62 · Graves versus Hashimoto thyroiditis

Feature

Graves

Hashimoto

Mechanism

Receptor stimulation

Follicular destruction

Epithelium

Tall / hyperplastic

Oncocytic change

Function

Usually hyperthyroid

Usually hypothyroid

Slide 63 · Graves versus destructive thyroiditis

Feature

Graves

Destructive thyroiditis

Source of hormone

Increased production

Leakage of stored hormone

Radioiodine uptake

Diffusely increased

Decreased

TSHR autoantibody

Supports diagnosis

Not the causal mechanism

Slide 64 · Therapeutic mechanisms address different targets

Intervention

Immediate target

β-blocker

Adrenergic symptoms

Methimazole / PTU

Thyroid hormone synthesis

Radioiodine / surgery

Functional thyroid tissue

Slide 65 · Symptom control is not suppression of autoimmunity

β-blocker

↓ Adrenergic manifestations

Symptomatic improvement

β-blockade improves palpitations, tachycardia, tremor, and anxiety.

It does not neutralize TSH-receptor autoantibodies.

Hormone synthesis or functional gland mass must also be addressed.

Slide 66 · Antithyroid drugs act on hormone synthesis

Thionamide

↓ New hormone synthesis

↓ Circulating hormone

Methimazole and propylthiouracil inhibit thyroid hormone biosynthesis.

Propylthiouracil also impedes peripheral T₄-to-T₃ conversion.

Therapy may change the histology subsequently observed in resection specimens.

Slide 67 · Definitive options target the gland

Option

Core effect

Radioiodine

Destroys functional thyroid cells

Thyroidectomy

Removes thyroid tissue

Clinical choice

Requires individual assessment

Slide 68 · Orbitopathy may not track hormone normalization

Thyroid biochemical control

≠

Immediate orbital resolution

The orbit has a locally sustained immune and matrix-remodeling component.

Controlling thyroid hormone does not always reverse established structural changes.

Clinical assessment must separately consider thyroid function and eye involvement.

Slide 69 · Case 1: Interpret the biochemical phenotype

A 31-year-old patient has weight loss, tremor, palpitations, and diffuse thyroid enlargement.

TSH is suppressed; Free thyroid hormone concentrations are increased.

A vascular goiter and exophthalmos are noted. What mechanism best unifies these findings?

Discussion question

Identify the driver of gland hyperfunction and the separate basis of exophthalmos.

Slide 70 · Case 1: Mechanism-based answer

TSHR stimulation

Diffuse thyroid hyperfunction

Thyrotoxicosis + orbitopathy

Stimulating immunoglobulins bind the TSH receptor and activate follicular cells.

Diffusely increased thyroid synthesis produces a low-TSH, high-hormone state.

Orbital tissue inflammation and glycosaminoglycans account for exophthalmos.

Slide 71 · Case 2: Recognize a treated thyroid specimen

A thyroidectomy specimen shows diffuse enlargement with hyperplastic follicles.

Epithelial cells are tall and crowded; Colloid has scalloped margins.

What additional history can substantially modify these morphologic clues?

Discussion question

Describe two medication-related changes before interpreting the specimen.

Slide 72 · Case 2: Treatment history changes morphology

Exposure

Morphologic influence

Iodide

Epithelial involution; more colloid

Propylthiouracil

May intensify epithelial hyperplasia

Slide 73 · Integrated pathology summary

Cause: Activating TSH-receptor autoantibodies produce diffuse thyroid hyperfunction.

Thyroid: Symmetric enlargement, tall epithelial cells, scalloped colloid, lymphoid infiltrates.

Outside gland: Immune-associated orbital and dermal glycosaminoglycan accumulation.

Diagnosis: Low TSH, elevated free hormones, receptor antibodies, and diffuse uptake.

Slide 74 · Primary reading and source context

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Chapter 24, The Endocrine System: thyroid physiology, hyperthyroidism, Graves disease.

Graves disease section, printed pages 984–985; contextual material on pages 979–986.