Hypothyroidism

Slide 1 · HYPOTHYROIDISM

Mechanisms, causes, morphology and clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Localize hormone deficiency to the thyroid or the central axis.

Distinguish congenital, autoimmune, iatrogenic and central causes.

Explain systemic findings through loss of thyroid-hormone action.

Interpret the TSH–free T₄ patterns of overt and subclinical disease.

Slide 3 · Definition: Deficient thyroid-hormone production

Structural or functional disturbance reduces thyroid-hormone output.

Deficiency may originate in the thyroid, pituitary or hypothalamus.

The common clinical endpoint is insufficient hormone action at tissues.

Slide 4 · Hypothalamic–pituitary–thyroid axis

Hypothalamus

Anterior pituitary

Thyroid follicles

TRH

TSH

Circulating T₄ and T₃

Negative feedback

Slide 5 · How TSH drives thyroid function

TSH binds thyrocyte receptor

Follicular epithelial-cell surface

Gs-protein activation

Receptor-coupled signaling

CAMP increases

CAMP-dependent kinases

Synthesis and release of T₄/T₃

Stimulates thyroid growth as well

Slide 6 · Steps required for thyroid-hormone synthesis

Iodide enters follicle cell

Transport may be genetically defective

Iodine organification

Iodine is bound to tyrosines

Thyroglobulin processing

Hormone residues are coupled/processed

T₄ and T₃ production

Failure of any stage may cause deficiency

Slide 7 · Transport and peripheral hormone activation

Most circulating T₄ and T₃ bind reversibly to plasma proteins.

Free hormone concentrations determine available cellular exposure.

Peripheral deiodination converts much of free T₄ into T₃.

T₃ binds thyroid-hormone nuclear receptors with greater affinity.

Slide 8 · Why deficiency has multisystem effects

Normal hormone action

Stimulates cellular catabolism and protein synthesis.

Increases basal metabolic rate.

Is essential to fetal and neonatal brain development.

Hormone deficiency

Reduced metabolic and autonomic activity.

Slower mental and physical performance.

Developmental vulnerability early in life.

Slide 9 · Disease classification by site of defect

Category

Primary site

Physiologic deficiency

Primary

Thyroid gland

T₄ production impaired

Secondary

Pituitary

TSH deficiency

Tertiary

Hypothalamus

TRH deficiency

Slide 10 · Distribution of hypothyroidism

Primary disease accounts for most hypothyroid cases.

By estimates reported, overt disease affects about 0.3%.

Subclinical disease exceeds 4% in those estimates.

The figures are illustrative source estimates, not universal rates.

Slide 11 · Demographic pattern

Prevalence rises with age.

Hypothyroidism is markedly more frequent in females.

An approximately tenfold female predominance is reported.

Demographic likelihood supplements, but cannot replace, biochemical assessment.

Slide 12 · The four major etiologic pathways

Congenital

Deficient gland or synthetic machinery

Autoimmune

Progressive follicular destruction

Iatrogenic

Therapeutic or drug-related suppression

Central

Pituitary/hypothalamic failure

Slide 13 · Congenital hypothyroidism: Causal categories

Dietary iodine deficiency is an important global cause.

Dyshormonogenetic disease interrupts one or more synthesis steps.

Thyroid agenesis or hypoplasia reduces functional follicular tissue.

These mechanisms converge on inadequate hormone availability from birth.

Slide 14 · Iodine supply and thyroid synthesis

Iodine available

Iodide transport permits substrate entry.

Organification enables hormone synthesis.

T₃/T₄ production supports development.

Dietary iodine deficiency

Insufficient substrate limits biosynthesis.

Compensatory TSH drive may enlarge the gland.

Neurologic consequences depend on developmental timing.

Slide 15 · Dyshormonogenesis: Sites of failure

Iodide transport

Failure to move iodide into thyrocytes

Organification

Failure to bind iodine to thyroglobulin tyrosines

Hormone-forming processing

Failure of synthesis/processing toward active hormone

Slide 16 · Iodide transport: A critical first step

Thyrocytes must import iodide to synthesize iodinated hormones.

An inherited transport defect can impair this entry step.

The downstream synthetic pathway becomes substrate-limited.

This is one recognized mechanism of dyshormonogenetic goiter.

Slide 17 · Iodine organification: A second vulnerable step

Organification attaches iodine covalently to tyrosine residues in thyroglobulin.

An inherited defect prevents normal formation of iodinated intermediates.

Iodide availability alone cannot overcome a block in organification.

Slide 18 · Later hormone-processing defects

Hormone synthesis requires additional processing beyond organification.

Inherited defects at these downstream steps reduce functional T₃ and T₄.

Each biosynthetic lesion can yield the same phenotype: Hormone deficiency.

Slide 19 · Thyroid dysgenesis

Agenesis

Thyroid parenchyma is absent.

Primary hormone output is profoundly limited.

A developmental rather than autoimmune defect.

Hypoplasia

Functional parenchyma is greatly reduced.

Germline developmental-gene defects may be responsible.

PAX8, FOXE1 and TSH-receptor mutations.

Slide 20 · Congenital etiologies: Mechanistic contrasts

Etiology

What is missing or defective

Goiter possible?

Iodine deficiency

Hormone-synthesis substrate

Yes, with sustained TSH drive

Dyshormonogenesis

Hormone-production pathway

Yes

Agenesis/hypoplasia

Development of follicular parenchyma

Not a defining feature

Slide 21 · Why some hypothyroid glands enlarge

Reduced thyroid hormone weakens feedback inhibition.

Pituitary TSH secretion rises in primary hypothyroidism.

Persistent TSH stimulation can produce hyperplastic enlargement.

A goiter is possible in iodine deficiency, biosynthetic defects and Hashimoto thyroiditis.

Slide 22 · Autoimmune hypothyroidism: Principal acquired cause

The leading cause in iodine-sufficient regions is autoimmune thyroid disease.

Most autoimmune cases are associated with Hashimoto thyroiditis.

Progressive follicular destruction gradually compromises hormone production.

Thyroid enlargement may accompany the autoimmune process.

Slide 23 · Hashimoto thyroiditis: Loss of self-tolerance

Autoimmunity targets antigens expressed by thyroid follicles.

Lymphocytic infiltration accompanies progressive tissue injury.

Destruction of thyroid epithelial cells leads to functional failure.

The precise initiating event remains unresolved.

Slide 24 · Thyroid autoantibodies and their interpretation

Anti-TPO

Antibodies against thyroid peroxidase occur commonly.

Formerly termed antimicrosomal antibodies.

Support an autoimmune etiology.

Anti-thyroglobulin

Also occurs in Hashimoto thyroiditis.

Reflects autoimmunity against thyroid components.

Antibody positivity alone does not establish the injury mechanism.

Slide 25 · Immune mechanisms injuring thyroid follicles

Tolerance breakdown

Susceptibility and initiating factors

Activated T lymphocytes

CD8⁺ cells and Th1 responses

Follicular-cell injury

Direct killing, cytokines and macrophages

Loss of thyroid function

Progressive depletion of parenchyma

Slide 26 · CD8⁺ cytotoxic T cells: Direct injury

Activated cytotoxic T cells can recognize thyroid follicular targets.

Cell-mediated cytotoxicity contributes to epithelial-cell destruction.

Cumulative tissue loss reduces the gland’s synthetic reserve.

Slide 27 · Th1-driven inflammatory injury

Activated CD4⁺ Th1 cells

Cellular immune response

IFN-γ production

Proinflammatory cytokine

Macrophage recruitment

Local inflammatory amplification

Follicular damage

Contributes to tissue destruction

Slide 28 · Caution: Antithyroid antibodies are not a proven sole cause

Antibodies against TPO and thyroglobulin are prevalent in Hashimoto disease.

Complement-mediated or antibody-dependent injury is biologically plausible.

Their causal contribution to tissue injury remains uncertain.

Morphologic inflammation reflects several interacting immune mechanisms.

Slide 29 · Histologic progression in Hashimoto thyroiditis

Intact thyroid follicles

Normal glandular architecture

Lymphocytic infiltration

Lymphoid aggregates and germinal centers

Follicular atrophy / oncocytes

Chronic-injury epithelial response

Fibrous replacement

Reduced functioning parenchyma

Slide 30 · Macroscopic morphology in Hashimoto disease

The thyroid is often diffusely enlarged and well demarcated.

Cut surfaces may appear pale, yellow-tan, firm and somewhat nodular.

The goiter may be symmetrical or occasionally localized enough to resemble a mass.

Slide 31 · Microscopic pattern: Schematic, not a specimen

SCHEMATIC

Hallmarks

Dense lymphocytes; Germinal centers

Atrophic residual follicles

Oncocytic (Hürthle) cells

Variable interstitial fibrosis

Slide 32 · Oncocytic transformation is a chronic-injury response

Residual follicular epithelial cells may acquire abundant eosinophilic granular cytoplasm.

These oncocytes were formerly called Hürthle cells.

An oncocyte-rich aspirate with heterogeneous lymphocytes supports Hashimoto thyroiditis.

The finding must be interpreted in its full cytologic context.

Slide 33 · Hashimoto disease: Clinical trajectory

Painless thyroid enlargement often precedes or accompanies dysfunction.

Hypothyroidism usually develops gradually.

A transient thyrotoxic phase may occur when damaged follicles release stored hormones.

This destructive phase is distinct from sustained hormone overproduction.

Slide 34 · Associated autoimmune and other disorders

Hashimoto disease may coexist with type 1 diabetes or autoimmune adrenalitis.

Nonendocrine autoimmune associations include Sjögren syndrome and systemic lupus erythematosus.

There is an increased risk of thyroid extranodal marginal-zone B-cell lymphoma, although rare.

A proposed association with papillary thyroid carcinoma remains controversial.

Slide 35 · Autoimmune polyendocrine context

Autoimmune hypothyroidism can occur in isolation.

Robbins also describes association with autoimmune polyendocrine syndrome types 1 and 2.

Coexisting glandular failure changes clinical assessment and the interpretation of symptoms.

Slide 36 · Iatrogenic etiologies: Interventions and agents

Exposure

Relationship to hypothyroidism

Thyroid surgery

Loss of hormone-producing parenchyma

Radioiodine treatment

Ablation of functional thyroid tissue

External neck irradiation

Radiation-associated thyroid injury

Thionamides

Suppression of new hormone synthesis

Lithium / p-aminosalicylic acid

Drug-associated acquired hypothyroidism

Amiodarone

May cause hypo- or hyperthyroidism

Slide 37 · Postoperative hypothyroidism

Resection of substantial thyroid tissue can reduce total hormone-production capacity.

Thyroid surgery for hyperthyroidism or neoplasia is a recognized cause.

The mechanism is postablative loss of functioning follicles.

Slide 38 · Radiation-associated hypothyroidism

Radioiodine

Used to ablate thyroid tissue in hyperthyroidism.

Loss of functioning follicles may cause persistent deficiency.

External neck irradiation

Radiation exposure can damage the thyroid.

This is a recognized iatrogenic cause distinct from radioiodine.

Slide 39 · Antithyroid drug–associated deficiency

Thionamide exposure

Examples: Methimazole, propylthiouracil

Thyroid-hormone synthesis falls

The intended pharmacologic action can become excessive

Circulating T₄/T₃ declines

Physiologic consequence is hypothyroidism

Slide 40 · Other drug-associated causes

Lithium may be associated with acquired hypothyroidism.

P-Aminosalicylic acid is another listed drug association.

The key etiologic clue is a temporal relationship to medication exposure.

No drug-specific incidence or dose threshold is provided by the source.

Slide 41 · Amiodarone: A bidirectional thyroid disturbance

Hypothyroidism

Amiodarone exposure may be associated with reduced thyroid function.

Symptoms and hormone studies determine functional state.

Hyperthyroidism

The same agent may also be associated with hormone excess.

Drug exposure alone does not specify the biochemical diagnosis.

Slide 42 · Central hypothyroidism: The driving signal is deficient

Pituitary TSH deficiency produces secondary hypothyroidism.

Hypothalamic TRH deficiency produces tertiary hypothyroidism.

Robbins groups the two as central hypothyroidism.

A damaged thyroid gland is not required for this phenotype.

Slide 43 · Pituitary causes of central hypothyroidism

Pituitary tumors may impair thyrotroph function.

Postpartum pituitary necrosis is an established cause of hypopituitarism.

Trauma and nonpituitary tumors may similarly disrupt pituitary function.

Deficient TSH stimulation ultimately lowers thyroid output.

Slide 44 · Hypothalamic causes of central hypothyroidism

Hypothalamic tumors can compromise TRH release.

Traumatic injury, radiation and infiltrative disorders are additional causes.

The resulting pituitary TSH drive is insufficient for normal thyroid output.

Slide 45 · Different laboratory consequences of feedback failure

Primary thyroid failure

Central-axis failure

Thyroid T₄ ↓

Feedback restraint ↓

TSH ↑

TRH/TSH stimulation ↓

Thyroid T₄ ↓

TSH not appropriately ↑

Slide 46 · Primary versus central disease

Feature

Primary hypothyroidism

Central hypothyroidism

Affected level

Thyroid follicles

Pituitary or hypothalamus

TSH pattern

Usually raised

Low or inappropriately normal

Free T₄ in overt disease

Decreased

Decreased

Examples

Hashimoto; postablation

Pituitary or hypothalamic lesion

Slide 47 · Why adult hypothyroidism can be overlooked

Onset is often gradual and insidious.

Patients may experience symptoms for years before a specific endocrine cause is suspected.

Early complaints are nonspecific, including fatigue and mental slowing.

Biochemical evaluation is therefore central to accurate diagnosis.

Slide 48 · Early neurobehavioral manifestations

Generalized fatigue and apathy may be prominent early complaints.

Mental sluggishness may resemble a depressive syndrome.

Advanced hormone deficiency can slow speech and intellectual functioning.

Clinical assessment alone cannot reliably establish the etiology.

Slide 49 · Thermoregulation and metabolic activity

Cold intolerance

Reduced thyroid-hormone action diminishes basal metabolic activity.

Patients may feel cold even in ordinary surroundings.

Changes in weight

Weight gain may accompany reduced metabolic activity.

Weight gain alone is neither sensitive nor specific for hypothyroidism.

Slide 50 · Autonomic and gastrointestinal manifestations

Reduced sympathetic activity contributes to constipation.

Decreased sweating is another characteristic manifestation.

These features accompany generalized slowing of body functions.

Slide 51 · Skin findings reflect reduced peripheral flow

Skin often becomes cool and pale.

These findings partly to reduced cutaneous blood flow.

Distinct nonpitting edema arises from tissue-matrix accumulation rather than ordinary fluid retention.

Slide 52 · Cardiovascular consequences

Thyroid deficiency can reduce cardiac output.

Patients may develop breathlessness and diminished exercise capacity.

Functional effects reflect altered hormone-dependent transcription in cardiomyocytes.

Slide 53 · Molecular basis of reduced cardiac performance

Reduced thyroid hormones

Deficient nuclear-receptor signaling

Altered sarcolemmal gene transcription

Examples: Calcium ATPases and β-adrenergic receptor

Lower cardiac output

Contributes to exercise intolerance and dyspnea

Slide 54 · Lipid effects link hypothyroidism to vascular risk

Reduced thyroid-hormone action

Changes in lipid metabolism

Total cholesterol / LDL rise

Pattern

Proatherogenic milieu

Contributes to cardiovascular morbidity and mortality

Slide 55 · Myxedema: Extracellular matrix accumulation

Glycosaminoglycans and hyaluronic acid accumulate in tissues.

The matrix change involves skin, subcutis and some visceral sites.

Tissue expansion produces a characteristic nonpitting edema.

This morphologic substrate explains several recognizable clinical signs.

Slide 56 · The phenotype of tissue myxedema

Facial and mucosal changes

Facial features become broader and coarser.

The tongue may enlarge.

The voice may deepen.

Tissue mechanism

Matrix substances accumulate in interstitium.

Expansion is not simply dependent edema.

The swelling is characteristically nonpitting.

Slide 57 · Severe hypothyroidism and myxedema coma

Myxedema is historically associated with profound hypothyroidism.

The term is commonly used clinically for severe disease and myxedema coma.

This represents the extreme clinical end of thyroid-hormone deficiency.

The term denotes severe clinical decompensation, not a separate etiologic category.

Slide 58 · Developmental timing determines vulnerability

Thyroid hormone is essential for fetal and neonatal brain development.

Profound deficiency early in development risks severe neurocognitive injury.

The congenital iodine-deficiency discussion links severity to timing during pregnancy.

Developmental disease cannot be interpreted as merely adult myxedema in miniature.

Slide 59 · Age of onset shapes the clinical pattern

Domain

Congenital / early life

Adult onset

Principal vulnerability

Brain and somatic development

Metabolic and functional slowing

Characteristic features

Growth and neurodevelopmental impairment

Fatigue, cold intolerance, constipation

Shared substrate

Insufficient thyroid-hormone action

Insufficient thyroid-hormone action

Slide 60 · Why laboratory testing is essential

Clinical symptoms are common and nonspecific.

Biochemical testing distinguishes overt disease from compensated states.

Weight gain or otherwise unexplained hypercholesterolemia can prompt thyroid assessment.

Clinical context determines whether central disease is plausible.

Slide 61 · Serum TSH in primary hypothyroidism

TSH is the most sensitive screening measure for primary disease.

Falling thyroid hormone releases hypothalamic–pituitary feedback restraint.

The pituitary consequently raises TSH secretion.

The magnitude of TSH elevation should not be mistaken for proof of a specific etiology.

Slide 62 · Free T₄ identifies overt hormone deficiency

Overt hypothyroidism is accompanied by reduced T₄.

A low free T₄ occurs in overt primary or central disease.

Interpreting free T₄ with TSH helps localize the dysfunction.

An isolated TSH result may miss central hypothyroidism.

Slide 63 · Subclinical hypothyroidism: Compensatory phase

TSH is elevated while free T₄ remains normal.

T₃ remains normal in the subclinical phase described here.

This typically represents an early primary form, not central hypothyroidism.

Symptoms may be absent or nonspecific.

Slide 64 · Core biochemical patterns

State

TSH

Free T₄

Primary overt

Elevated

Low

Central overt

Low or inappropriately normal

Low

Subclinical primary

Elevated

Normal

Euthyroid

Appropriate for feedback state

Normal

Slide 65 · Reasoning from TSH and free T₄

Evaluate clinical context

Symptoms, medications, pituitary risk

Assess TSH and free T₄

TSH alone can mislead in central disease

Identify biochemical pattern

Primary, central or subclinical

Localize and investigate cause

Autoimmunity, ablation, congenital or central

Slide 66 · Diagnostic pitfalls

Nonspecific fatigue and slowed cognition may mimic nonendocrine disease.

Normal or low TSH does not exclude a central cause when free T₄ is low.

Goiter can occur in several etiologies and is not itself a diagnosis.

Anti-TPO positivity indicates autoimmunity, not a proven sole injury mechanism.

Slide 67 · Case 1: Progressive fatigue and goiter

CLINICAL PRESENTATION

A middle-aged adult develops insidious fatigue, constipation and painless diffuse thyroid enlargement. TSH is elevated, free T₄ is low, and anti-TPO antibodies are detected.

Which etiologic and functional diagnoses best fit?

Slide 68 · Case 1: Explanation

Overt primary hypothyroidism, likely Hashimoto thyroiditis

Low free T₄ with compensatory high TSH localizes disease to the thyroid.

Autoantibodies and painless diffuse goiter support autoimmune thyroiditis.

The antibodies support etiology; Cell-mediated injury remains central.

Slide 69 · Case 2: Low free T₄ without a TSH rise

CLINICAL PRESENTATION

A patient with a known pituitary mass develops fatigue and cold intolerance. Free T₄ is low but serum TSH is not elevated.

Why is this not reassuringly normal thyroid function?

Slide 70 · Case 2: Explanation

Suspect central hypothyroidism

A pituitary lesion may impair TSH secretion.

TSH is inappropriately normal relative to deficient circulating T₄.

The low free T₄ is the crucial evidence of overt hormone deficiency.

Slide 71 · Case 3: An incidental biochemical abnormality

CLINICAL PRESENTATION

A person evaluated for an unrelated concern has elevated TSH with free T₄ in the reference interval and no distinct hypothyroid syndrome.

How should this biochemical state be classified?

Slide 72 · Case 3: Explanation

Subclinical primary hypothyroidism

The pituitary compensates for declining thyroid reserve by increasing TSH.

Circulating free T₄ remains normal at this stage.

This pattern does not, by itself, specify the underlying etiology.

Slide 73 · Etiology → mechanism → observed pattern

Iodine / enzyme defect

Synthesis limited

Primary pattern

Hashimoto thyroiditis

Follicular destruction

Primary pattern

Postablation

Loss of functioning tissue

Primary pattern

Pituitary / hypothalamus

Low TSH/TRH drive

Central pattern

Slide 74 · Core clinicopathologic synthesis

Hypothyroidism describes deficient hormone production, not a single thyroid lesion.

Primary disease is common and raises TSH through loss of negative feedback.

Autoimmune destruction, congenital disorders and iatrogenic injury have distinct mechanisms.

Central disease is recognized by low free T₄ without an appropriate TSH response.

Systemic findings follow loss of metabolic, cardiovascular and tissue-matrix regulation.

Slide 75 · Reference

Robbins, Cotran & Kumar

Pathologic Basis of Disease, 11th edition (2026)

Chapter 24 · The Endocrine System

Hypothyroidism and directly related thyroid sections