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
- Grave’s disease (Primary thyrotoxicosis)
- Hyperfunctional multinodular goitre (Secondary thyrotoxicosis)
- 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:
- Infectious thyroiditis
- Hashimoto thyroiditis
- Subacute thyroiditis
- 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
[caption id=”attachment_770" align=”alignnone” width=”300"]
Graves disease[/caption]
- The most common cause of endogenous hyperthyroidism
- Characterised by
- Hyperthyroidism owing to hyperfunctional diffuse enlargement of the thyroid
- Infiltrative ophthalmopathy with resultant exophthalmos
- 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:
- ↑ infiltration of the retro orbital space by mononuclear cells (T cells)
- Inflammatory edema & swelling of extraordinary muscles
- Accumulation of extra cellular matrix components such as hyaluronic acid & chondroitin sulfate
- 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
[caption id=”attachment_769" align=”alignnone” width=”300"]
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
[caption id=”attachment_768" align=”alignnone” width=”225"]
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
[caption id=”attachment_778" align=”alignnone” width=”300"]
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.