Thyrotoxicosis and Thyroiditis

Thyrotoxocosis is the hypermetabolic state caused by increased levels of free T3 &T4.

• Primary- arising from an intrinsic thyroid abnormality
• Secondary- arising from process outside of the thyroid (TSH-secreting pituitary tumor).

Three most important causes of thyrotoxicosis

1. Grave’s disease (Primary thyrotoxicosis)
2. Hyperfunctional multinodular goitre (Secondary thyrotoxicosis)
3. Hyperfunctional adenoma

Clinical course

• Increased Thyroid hormone → increased basal metabolic rate.
• Skin soft warm & flushed due to increased blood flow & peripheral vasodilation.
• Heat intolerance, increased sweating.
• Wt. loss despite increased appetite.

Cardiac manifestations

• Earliest & consistent features of hyperthyroidism.
• increased cardiac output owing to both increased cardiac contractility & increased peripheral O2 requirements
• Tachycardia, arrhythmias & cardiomegaly

Neuromuscular system

• Tremor, hyperactivity, emotional labiality, anxiety & insomnia
• Proximal muscle weakness

Ocular changes — wide staring gaze & lid lag

GI system — hypermotility & diarrhea.

Skeletal system — bone resorption → osteoporosis.

Lab findings

• ↓ TSH
• ↑ free T4 & T3
• Occasionally ↑ T3 predominantly.
• In rare cases of pituitary associated hyperthyroidism, TSH levels are either normal or raised
• ↑ radioactive iodine uptake.

Hypothyroidism

• Thyroid hormone deficiency
• Can result from defect anywhere in the hypothalamic — pituitary — thyroid axis
• Primary & secondary & tertiary

Primary hypothyroidism

• Surgical or radiation induced ablation of thyroid parenchyma
• Autoimmune hypothyroidism
• Iodine deficiency
• Drugs (lithium, iodides, p-aminosalicylic acid)
• In born errors of thyroid metabolism

Secondary hypothyroidism

• Caused by TSH deficiency (pituitary failure)

Tertiary hypothyroidism

• Caused by TRH deficiency (hypothalamic disorders)

Cretinism

• Hypothyroidism that develops in infancy or early childhood
• Less frequent in recent years
• Clinical features — impaired development of the skeletal system & CNS
• Mental retardation, short stature, coarse facial features, protruding tongue & umbilical hernia

Myxedema

• Hypothyroidism developing in the older child or adult
• Characterized by a slowing of physical & mental activity
• Generalized fatigue & mental sluggishness
• Slowing of speech & intellectual function
• Cold intolerant & frequently over weight
• ↓ cardiac output, SOB, ↓exercise capacity
• Constipation & ↓ sweating
• Skin cool & pale
• Histologically — accumulation of glycosaminoglycan & hyaluronic acid in the skin & subcutaneous tissue
• Lab findings — ↑ TSH level & ↓T4 levels

Thyroiditis

• Inflammation of the thyroid gland
• There are following types of thyroiditis:

1. Infectious thyroiditis
2. Hashimoto thyroiditis
3. Subacute thyroiditis
4. Subacute lymphacytic thyroiditis

Infectious thyroiditis

• May acute on chronic
• Hematogeneous spread or direct seeding from fistula (pyriform sinus)
• Sudden onset of neck pain & tenderness accompanied by fever, chills
• Self limited
• Thyroid function is not significantly affected

Hashimoto thyroiditis

• Autoimmune disease
• The most common cause of hypothyroidism
• Characterized by gradual thyroid failure because of autoimmune destruction of the thyroid gland
• Most prevalent between 45 & 65 yrs of age & more common in women. F:M — 20–10:1
• Significant genetic predisposition
• Concordance rate is monozygotic twins 30–60%
• Several chromosomal abnormalities have been associated with thyroid autoimmunity, Turner syndrome, Down syndrome
• Polymorphism in HLA-DR3 & HLA-DR5 alleles are linked to Hashimoto thyroiditis
• Ch. 6p & 12q may harbor genes predisposing to this disorder

Pathogenesis

• HT- autoimmune disease in which the immune system reacts against a variety of thyroid antigens
• Progressive depletion of thyroid epithelial cells which are gradually replaced by mononuclear cell infiltration & fibrosis
• Sensitization of auto reactive CD4+T helper cells to thyroid antigen — initiating event
• CD8+ cytotoxic T cell mediated cell death — cause thyrocyte destruction
• Cytokine mediated cell death : CD4+T cells produce inflammatory cytokines (IFNγ) with resultant activation of macrophages & damage to follicles.
• Binding of antithyroid antibodies (anti- TSH receptor antibodies, antithyroglobulin & antithyroid peroxidase antibodies) followed by antibody dependent cell mediated cytotoxicity.

Morphology

• Thyroid — diffusely enlarged
• The cut surface — pale, yellow tan, firm & nodular
• Micro — extensive infiltration by a mononuclear inflammatory infiltrate (lymphocytes & plasma cells & well formed germinal centers)
• Thyroid follicles are lined by Hurthle cells with abundant eosinophic granular cytoplasm
• Fibrosis

Clinical course

• Painless, symmetric & diffuse enlargement of the thyroid
• Hypothyroidism
• Middle aged women
• May be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles with secondary release of thyroid hormones (Hashitoxicosis) ↑T3 T4 ,↓ TSH
• Later on ↓ T3T4 ↑ TSH
• ↑ risk for other autoimmune diseases
• Increased risk for development of NHL & thyroid neoplasm

Subacute thyroiditis

• Also known as Granulomatous thyroiditis or De Quervain thyroiditis
• Common between 30–50 yrs, M:F = 5–3:1

Pathogenesis

• Believed to be caused by a viral infection
• Majority have H/O URT infection
• Has seasonal incidence
• Have been reported in associated with Coxsaekie virus, mumps, measles, adenovirus
• Viral or thyroid antigen stimulates cytotoxic T lymphocytes & damage follicular cells

Morphology

• Unilaterally or bilaterally enlarged gland & firm, yellow-white
• Micro- patchy changes. Follicles — disrupted & replaced by neutrophils forming microabscesses in early phase
• Later — aggregation of lymphocytes, plasma cells & histiocytes about collapsed & damaged follicles
• Multinucleate giant cells enclose pools of colloid

Clinical course

• May be sudden or gradual presentation
• Pain in the neck & may radiate to the upper neck, jaw, throat or ears particularly when swallowing
• Fever, fatigue, malaise, anorexia & enlargement of thyroid
• Transient hyperthyroidism
• ↑T4 & T3 & ↓serum TSH levels
• Radioactive iodine uptake — low
• Recovery 6–8 wks. TFT→normal

Graves disease

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Graves disease[/caption]

• The most common cause of endogenous hyperthyroidism
• Characterised by

1. Hyperthyroidism owing to hyperfunctional diffuse enlargement of the thyroid
2. Infiltrative ophthalmopathy with resultant exophthalmos
3. Localized infiltrative dermatology (pretibial myxedema) which is present in a minority of patients

• Peak incidence 20–40
• Women being affected upto 7 times more frequently than men

Etiopathogenesis

• Genetic factors are important.
• ↑ incidence among family members of affected patients
• Concordance rate in monozygotic twins — 60%
• Genetic susceptibility to Graves disease associated with presence of HLA-B8 & HLA-DR3
• Polymorphism in cytotoxic T. lymphocyte associated — 4 (CTLA-4) gene are linked
• Additional susceptibility loci localized to ch.6p & ch.20q.
• Graves disease — an autoimmune disorder in which a variety of antibodies may be present in the serum, antibodies to the TSH receptor, thyroid peroxisomes & thyroglobulin
• Antibodies to TSH receptor are central to disease pathogenesis
• Thyroid stimulating immunoglobulin (TSI) — Almost all pts have this AB to TSH receptor
• Thyroid growth stimulating immunoglobulin (TGI) — also directed against the TSH receptor — TGI have been implicated in the proliferation of thyroid follicular epithelium
• TSH — binding inhibitor immunoglobulin (TBII) — they prevent TSH from binding to its receptor on thyroid epithelial cells & also mimic the action of TSH, resulting in the stimulation of follicular cells
• The trigger for the initiation of the autoimmune reaction in Graves disease remains uncertain (likely to be breakdown in helper T cell tolerance resulting in the production of anti TSH autoantibodies)
• A T cell initiated autoimmune phenomenon also plays a role in the development of the infiltrative ophthalmopathy that is characteristic of Graves disease
• Causes of increase in the volume of the retro orbital connective tissue & extra-ocular muscles are:

1. ↑ infiltration of the retro orbital space by mononuclear cells (T cells)
2. Inflammatory edema & swelling of extraordinary muscles
3. Accumulation of extra cellular matrix components such as hyaluronic acid & chondroitin sulfate
4. Increased number of adipocytes

• Recent evidence suggests that orbital preadipocyte fibroblasts express the TSH receptor & T cells become reactive against these fibroblasts & secrete cytokines which stimulate fibroblast proliferation & synthesis of extracellular matrix protein & ↑ surface TSH receptor expression → ophthalmology
• may be associated with other autoimmune diseases (SLE, PA & DM Type 1)

Morphology

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Graves disease: Morphology of thyroid gland[/caption]

• Thyroid gland — symmetrically enlarged
• Diffuse hypertrophy & hyperplasia of follicular cells
• Increase in wt >80gm (N- 15–25gm)
• Gland — smooth & soft with intact capsule
• Micro — Follicular cells –tall and crowded with small papillae & encroach on the colloid
• Colloid within the follicles — pale with scalloped margins
• Lymphoid infiltrates are present throughout the interstitium. Germinal centers are common.
• Changes in extrathyroid tissue include generalized lymphoid hyperplasia
• Heart — hypertrophied
• Orbital tissue — edematous because of the presence of hydrophilic mucopolysaccharides
• Infiltration by lymphocytes & fibrosis
• Orbital muscles — edematous initially but may undergo fibrosis
• Dermopathy — thickening of the dermis due to deposition of glycosaminoglycans & lymphocyte infiltration.

Clinical features

• Palpitation, Dyspnoea on exertion, arrhythmia’s
• Nervousness, irritable, insomnia, depression.
• Heat intolerance
• Eye signs — common (Exopthalamus, Opthalmopathy)
• Goitre –bilaterally symmetrical, firm
• Weight loss in spite of good appetite.
• Hyperdefaecation / diarrhea
• Ammenorrhoea, oligomenorrhoea, loss of libido, gynaecomasia & infertility.
• Skin changes — Vitelligo, Pretibial Myxoedema.
• Myopathy — fatigue, weakness, tremor

Lab findings

• ↑T3, ↑T4, ↓TSH
• Radioisotope thyroid scan — diffuse ↑ radioiodine uptake

Diffuse & multinodular goiter

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Goiter[/caption]

• The compensatory increase in functional mass of the gland is able to overcome the hormone deficiency, ensuring an euthyroid metabolic state in the vast majority of individuals.
• If the underlying disorders is sufficiently severe, the compensatory response may be inadequate to overcome the impairment in hormone synthesis resulting in goitrous hypothyroidism.

Pathogenesis

• ↓TSH stimulation
• ↓Diffuse hyperplastic goitre
• ↓Fluctuation of stimulation of TSH
• ↓Active and inactive follicles
• ↓Active lobule more vascular
• ↓Hemorrhage and central necrosis
• ↓Necrotic lobules coalesce
• ↓Nodule with Iodine free colloid

Diffuse nontoxic (simple) goiter

• Involves the entire gland without producing nodularity.
• Also known as colloid goiter
• Occurs in both an endemic & sporadic distribution
• Endemic goiter occurs in geographic area with low level of iodine
• The lack of iodine leads to decreased synthesis of thyroid hormone & a compensatory increase in TSH leading to follicular cell hypertrophy & hyperplasia & goitrous enlargement
• With increasing dietary iodine supplementation, the frequency & severity of endemic goiter have declined significantly
• Goitrogens — ingestion of substances that interface with thyroid hormone synthesis at some level, such as excessive ca & vegetables belonging to the Brassica & Cruciferae families (cabbage, cauliflower, Brussels sprouts, turnips) have been documented to be goitrogenic.
• Sporadic goiter occurs less frequently
• Female preponderance
• Peak incidence at puberty or in young adult life
• Can be caused by ingestion of goitrogens, hereditary enzymatic defects (dyshormogenetic goiter)

Morphology

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Multinodular goiter[/caption]

• 2 phases: Hyperplastic phase & the phase of colloid involution

Hyperplastic phase:

• diffusely & symmetrically enlarged thyroid gland
• Follicles are lined bycrowded columnar cells & may form projections
• Follicle vary in size, some hugely distended & some small

Phase of colloid involution:

• If dietary iodine increases or if the demand for thyroid hormone decreases, follicular cells involutes to form enlarged colloid rich follicles (colloid goiter)
• The cut surface — brown, glassy and translucent
• Micro — flattened or cuboidal follicular epithelium arcs & colloid is abundant

Clinical course

• Clinically majority — euthyroid
• Enlarged thyroid gland
• T3,T4 — normal, TSH — elevated or at the upper range of normal

Multinodular goiter

• Irregular enlargement of the thyroid
• May be nontoxic or toxic MNG
• Produce the most extreme thyroid enlargements and are frequently mistaken for neoplastic involvement
• Occur both in sporadic & endemic forms
• MNG — may arise because of variations among follicular cells in responses to trophic hormones
• With uneven follicular hyperplasia →accumulation of colloid → rupture of follicles → haemorrhage, scarring, calcification

Morphology

• Multilobulated, asymmetrically enlarged glands with wt>2000 gm.
• May produce pressure on midline structures (trachea & esophagus)
• Sometimes may produce intrathoracic or plunging goiter
• On cut section — irregular nodules containing variable amounts of brown gelatinous colloid
• In older lesions — hemorrhage, fibrosis, calcification & cystic change
• Micro — colloid rich follicles lined by flattened follicular epithelium & areas of follicular hypertrophy & hyperplasia accompanied by degenerative changes.

Clinical course

• Mass effects of the enlarged thyroid gland
• May occur airway obstruction, dysphagia & compression of large vessels in the neck & thorax
• Mostly euthyroid, minority with hyperthyroidism (Plummer syndrome) & not accompanied by ophthalmopathy & dermopathy of Graves disease
• May be associated with hypothyroidism

This lecture note is based on the class note by Dr. Geeta Sayami, Department of Pathology, TU Teaching Hospital.