Pathology Ch 24 1107-1116
Thyroid Gland
-thyroid gland has 2 lobes connected by an isthmus below/anterior to larynx, and is divided into
lobules of about 20-40 evenly dispersed follicles lines with cuboidal/low columnar epithelium
and filled with thyroglobulin
-TSH released by thyrotropes in anterior pituitary into circulation, and binding of TSH on
follicular epithelium results in G protein signal to increase intracellular cAMP to stimulate
thyroid growth, hormone synthesis, and release of thyroid hormone
-dissociation of thyroid hormone synthesis and release from controlled influence of TSH
signaling is called thyroid autonomy and hyperfunction
-thyroid follicular cells convert thyroglobulin into thyroxine (T4) and less triiodothyronine T3.
-T4 and T3 are released into circulation bound to thyroxine-binding globulin and transthyretin
for transport to peripheral tissues
-in periphery, T4 is converted to T3, and T3 binds thyroid nuclear receptors in target cells with
10-fold affinity than does T4
-interaction of thyroid hormone with nuclear thyroid hormone receptor (TR) results in formation
of a multiprotein receptor-hormone complex that binds thyroid hormone response elements
(TREs) in target genes to regulat transcription
-thyroid hormone upregulates carb and lipid catabolism, stimulates protein synthesis to increase
net basal metabolic rate
-critical in brain development in fetus
-function of thyroid gland can be inhibited by goitrogens: they suppress T3/4 synthesis, causing
level of TSH to rise and cause hyperplasia of thyroid gland (goiter), treated with
propylthiouracil, which also inhibits peripheral deiodination of T4 to T3 to ameliorate
symprtoms of thyroid hormone excess
-Iodide given to people also blocks release of thyroid hormones because it inhibits proteolysis of
thyroglobulin
-thyroid gland contains population of parafollicular (C) cells which synthesize and secrete
Calcitonin to promote absorption of calcium by bone, and inhibits resorption by osteoclasts
Hyperthyroidism – Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels
of T3 and T4 and mostly caused by hyperfunction of thyroid gland
-hyperthyroidism is only ONE cause of thyrotoxicosis (most common)
-Three common causes of thyrotoxicosis are diffuse hyperplasia of thyroid associated with
Graves disease (Most common), hyperfunctional multinodular GOITER, hyperfunctional
adenoma of thyroid
Clinical Course of Hyperthyroidism – cause hypermetabolic state induced by excess thyroid
hormone and overactivity of sympathetic nervous system; increases basal metabolic rate
-skin of patients is soft, warm, flushed due to increased blood flow
-heat intolerance is common, and sweating is increased, increased weight loss
-cardiac manifestations are EARLIEST FEATURE of hyperthyroidism, increased cardiac output,
tachycardia, palpitations, cardiomegaly, increased frequency of atrial fibrillation
-some patients with thyrotoxicosis develop reversible left ventricular dysfunction and
low-output cardiac failure called hyperthyroid cardiomyopathy
-overactivity of sympathetics causes tremor, hyperacticity, anxiety, insomnia, muscle weakness
-Ocular changes are seen through wide, staring gaze and lid lag because of sympathetic
overstimulation of levator palpebrae superioris (seen ONLY IN GRAVES DISEASE)
-thyroid hormone stimulates bone resorption to increase porosity of cortical bone and reduce
volume of trabecular bone to cause osteoporosis
-Thyroid Storm – abrupt onset of severe hyperthyroidism occurs most commonly in patients
with Graves disease and results from acute elevation in catecholamine levels
-Apathetic hyperthyroidism – asymptomatic thyrotoxicosis seen in the elderly where thyroid
hormone excess doesn’t produce too many symptoms
-DIAGNOSIS is made using clinical and lab findings such as measurement of serum TSH
-low TSH value confirmed with measurement of free T4, which is increased
-occasionally, increased levels of T3 are present (toxicosis), where free T4 may be
decreased and direct T3 measurement may be useful
-normal rise in TSH after TRH administration indicates SECONDARY HYPERTHYROIDISM
Hypothyroidism – structural or functional derangement that causes less thyroid hormone being
produced, and is 10x more common in females than males
-can result in a defect anywhere in the hypothalamic-pituitary-thyroid axis
-divided into primary and secondary categories depending whether it arises from intrinsic
abnormality or as a result of pituitary or hypothalamic disease
-Congenital hypothyroidism – most often result of endemic iodine deficiency in diet
-others are inborn errors of thyroid metabolism (dyshormonogenetic goiter) where one of
many steps leading to thyroid hormone synthesis may be deficient, such as:
-iodide transport into thyrocytes, iodide organification (binding of iodide to tyrosines on
thyroglobulin), iodotyrosine coupling to form active T3 and T4
-Mutations in Thyroid Peroxidase most common cause of dyshormonogenetic goiter
-Pendred Syndrome – hypothyroidism and sensorineural deafness caused by mutations in
SLC26A4 gene, whose product, pendrin, is an anion transporter expressed on apical surface of
thyrocytes and in inner ear.
-Thyroid agenesis – absence of thyroid gland or reduced in size (thyroid hypoplasia)
-mutations in transcription factors expressed in developing thyroid and regulating
follicular differentiation such as thyroid transcription factor-2 (TTF-2 or FOXE1), (PAX-8)
have been reported in people with thyroid agenesis
-Thyroid hormone resistance syndrome – rare autosomal dominant disorder caused by
inherited mutations in thyroid hormone receptor which abolish ability of receptor to bind
thyroid hormones and cause patients to be resistant to thyroid hormone (TSH levels high)
-Acquired hypothyroidism – can be caused by surgical or radiation-induced ablation of thyroid
parenchyma; drugs given to intentionally decrease thyroid secretion can cause acquired
hypothyroidism
-Autoimmune hypothyroidism – MOST COMMON CAUSE of hypothyroidism in iodine-sufficient
areas of the world, and vast majority are due to Hashimoto Thyroiditis
-circulating autoantibodies including anti-microsomal, anti-thyroid peroxidase and antithyroglobulin are found, and thyroid is typically enlarged
-can occur in isolation or in conjunction with autoimmune polyendocrine syndrome
(APS) types I and II
-Secondary hypothyroidism is caused by deficiency of TSH or more commonly TRH, such as from
hypopituitarism or hypothalamic damage
-classic clinical manifestations of hypothyroidism include Cretinism and Myxedema
Cretinism – hypothyroidism that develops in infancy or early childhood resulting in impaired
skeletal and CNS development, severe mental retardation, short stature, coarse facial features,
protruding tongue, and umbilical hernia
-normally T3 and T4 cross placenta and are critical to fetal development of fetal thyroid gland; if
maternal deficiency is before development of thyroid gland, mental retardation is severe;
however if it is later in pregnancy, it is not as severe
Myxedema – hypothyroidism developing in older child or adult characterized by slowing of
physical and mental activity; general fatigue, apathy, mental sluggishness, slowed speech, cold
intolerant, overweight
-decreased sympathetic activity results in constipation, decreased sweating
-skin is cool and pale because of decreased blood flow
-reduced cardiac output contributes to shortness of breath and decreased exercise capacity
-thyroid hormones regulate transcription of sarcolemmal genes, such as Ca-ATPases, whose
products are critical in maintaining efficient cardiac output
-hypothyroidism promotes atherogenic profile: increase total cholesterol and LDL levels
-accumulation of matrix substances such as glycosaminoglycans and hyaluronic acid in skin,
subcutaneous tissues, and visceral sites causing peripheral edema, facial features, enlargement
of tongue, and deepening of voice
-measuring serum TSH is MOST SENSITIVE screening test for this disorder
-TSH is increased due to loss of feedback inhibition of TRH and TSH production by
hypothalamus and pituitary
-T4 levels are DECREASED in people with any hypothyroidism
Thyroiditis – inflammation of thyroid gland, which includes diseases that result in acute illness
with severe thyroid pain and manifests as thyroid dysfunction (subacute lymphocytic thyroiditis)
Infectious Thyroiditis – may be acute or chronic
-Acute infections can reach thyroid by hematogenous spread or through direct thyroid
seeding such as through fistula from piriform sinus next to larynx
-other infections, including mycobacterial, fungal, and Pneumocystis infections, are chronic and
frequently occur in immunocompromised patients
-may cause sudden onset of neck pain and tenderness accompanied by fever, chills, and other
signs of infection
Hashimoto Thyroiditis – most common cause of hypothyroidism where iodine levels sufficient,
characterized by gradual thyroid failure because of autoimmune destruction of thyroid gland,
most prevalent between ages 45-65 in women (10:1) compared to men
-Has a strong genetic component associated with polymorphisms in immune regulatory
associated genes, most significant of which is cytotoxic T lymphocyte-associated antigen-4
(CTLA-4), which is a negative regulator of T-cell responses
-CTLA-4 polymorphisms resulting in decreased protein level or function predispose to disease
-another susceptibility locus is protein tyrosine phosphatase-22 (PTPN22) encoding a lymphoid
tyrosine phosphatase thought to inhibit T cell function
PATHOGENESIS – Hashimoto is caused by breakdown of self-tolerance to thyroid auto-antigens;
increased circulating antibodies against thyroglobulin and thyroid peroxidase, resulting possibly
from abnormalities in regulatory T cells (Tregs) or exposure of normally sequestered thyroid
antigens
-progressive depletion of thyrocytes by apoptosis and replacement with mononuclear cell
infiltration and fibrosis occurs
-thyroid cell death is caused by multiple mechanisms, such as:
-CD8 T cell mediated death may cause destruction of thyrocytes
-Cytokine-mediated cell death – Th1 activation leads to inflammatory cytokines IFN-g in
thyroid gland to recruit macrophages to damage follicles
-binding of anti-thyroid antibodies listed above followed by antibody-dependent, cellmediated toxicity
MORPHOLOGY – thyroid is often enlarged, with parenchyma showing mononuclear
inflammatory infiltrate and well-developed germinal centers
-thyroid follicles are atrophic and lined by epithelial cells distinguished by presence of
eosinophilic, granular cytoplasm termed Hürthle cells
-metaplastic response of normally cuboidal epithelium ot ongoing injury
-in fine-needle aspiration biopsy, presence of Hürthle cells in conjunction with lymphocyte
infiltration is characteristic of Hashimoto thyroiditis
-fibrous variant characterized by severe thyroid follicular atrophy and dense keloid-like fibrosis
with broad bands of acellular collagen encompassing residual thyroid tissue
CLINICAL COURSE OF HASHIMOTO – often presents as painless enlargement of thyroid
associated with some hypothyroidism in middle-aged women
-in some cases, can be associated with thyrotoxicosis caused by disruption of thyroid follicles
with secondary release of thyroid hormones where T3/4 is elevated and TSH is diminished; as
hypothyroidism supervenes, T3/4 levels drop and TSH levels increase
Subacute (Granulomatous) Thyroiditis – also referred to as De Quervain Thyroiditis is much
less frequent than Hashimoto and affects more women than men
PATHOGENESIS – believed to be triggered by viral infection, with majority of patients having a
history of upper respiratory infection just before onset of thyroiditis
-disease is seasonal (peaks in the summer)
-one model suggests it results from a viral infection that leads to exposure to a viral or thyroid
antigen which is released secondary to virus-induced host tissue damage; antigen stimulates
cytotoxic T cells to damage thyroid follicular cells
MORPHOLOGY – gland may be uni- or bilaterally enlarged and firm; scattered follicles may be
entirely disrupted and replaced by neutrophils formine microbscesses
-multinucleated giant cells enclose naked pools or fragments of colloid, hence the name
granulomatous thyroiditis
CLINICAL COURSE – most common cause of THYROID PAIN; thyroid inflammation and
hyperthyroidism are transient, diminishing in 2-6 weeks
-all patients have high serum T4 and T3 levels and low TSH DURING THIS PHASE
-after recovery, normal thyroid function returns
Subacute Lymphocytic (Painless) Thyroiditis – presents initially as mild hyperthyroidism,
goitrous enlargement of gland and can occur at any age, more often in women
-resembles postpartum thyroiditis and are variants of Hashimoto thyroiditis where most
patients have circulating anti-thyroid antibodies, and many patients revert to overt
hypothyroidism
MORPHOLOGY – thyroid appears normal and most histologic manifestation is lymphocyte
infiltration with hyperplastic germinal centers within thyroid parenchyma
CLINICAL PRESENTATION – painless goiter, transient overt hyperthyroidism where some
patients transition from hyper to hypothyroidism before recovery
-vast majority of postpartum thyroiditis patients are normal within 1 year
-postpartem thyroiditis can resemble Graves disease, but no ocular manifestation present
Graves Disease – MOST COMMON CAUSE OF ENDOGENOUS HYPERTHYROIDISM, shows:
1. hyperthyroidism due to diffuse hyperfunctional enlargement of thyroid
2. Infiltrative ophthalmopathy with resultant exophthalmos (eyes bulging)
3. Localized, infiltrative dermopathy sometimes called pretibial myxedema
-incidence between 20-40y.o and women 10x more affected than men
-genetic factors are important in this autoimmune hyperthyroid disorder, linked to SNPs in
immune function genes like CTLA4 and PTPN22 and HLA-DR3 allele
PATHOGENESIS – characterized by breakdown in self-tolerance to thyroid auto-antigens, most
importantly the TSH Receptor, the result is production of multiple autoantibodies, including:
1. Thyroid-stimulating immunoglobulin – IgG antibody binds TSH receptor to mimic action
of TSH and stimulates adenylyl cyclase to increase release of thyroid hormones, and
presence of this antibody in serum is specific for graves disease, unlike thyroglobulin or
thyroid peroxidase antibodies
2. Thyroid growth-stimulating immunoglobulins – directed against TSH receptor and are
implicated in proliferation of thyroid follicular epithelium
3. TSH-binding inhibitor immunoglobulins – anti-TSH antibodies prevent TSH from binding
normally its receptor in the thyroid
-Autoimmunity plays a role in development of infiltrative ophthalmopathy that is characteristic
of Graves disease
-volume of the retro-orbital connective tissues is increased for several reasons, including:
1. infiltration of retro-orbital space by mononuclear cells (mostly T cells)
2. inflammatory edema and swelling of extraocular muscles
3. accumulation of extracellular matrix components, specifically hydrophilic
glycosaminoglycans like hyaluronic acid and chondroitin sulfate
4. increased numbers of adipocytes (fatty infiltration)
-ALL of thee place eyeball forward and can interfere with extraocular muscle function
-Orbital preadipocyte fibroblasts express TSH receptor and become target of autoimmune
attack by T cells which secrete cytokines to stimulate fibroblast proliferation and synthesis of
extracellular matrix to perpetuate infiltration of retro-orbital space and ophthalmopathy
MORPHOLOGY of GRAVES – thyroid gland is enlarged because of diffuse hypertrophy and
hyperplasia of thyroid follicular cells
-small papillae form projecting into follicular lumen and encroach on colloid
-lymphoid infiltrates are present of T cells, and fewer B/plasma cells
-Treatment with antithyroid drug propylthiouracil exaggerates epithelial hypertrophy and
hyperplasia by stimulating TSH secretion
-generalized lymphoid hyperplasia occurs throughout the body; heart may be hypertrophied,
and ischemic changes may be present
CLINICAL COURSE OF GRAVES DISEASE – same as most thyrotoxicosis with unique presentation
of diffuse hyperplasia of thyroid, ophthalmopathy, and demopathy; degree of thyrotoxicosis
varies and diffuse enlargement of thyroid is present at all times which may be accompanied by
increased blood flow to produce an audible bruit
-Sympathetic overactivity produces characteristic wide, staring gaze and lid lag, extraocular
muscles are normally weak
-infiltrative dermopathy or pretibial myxedema most common in skin over the shins where it
presents as scaly thickening (only in minority of patients)
-laboratory findings include elevated free T3/4 and DECREASED TSH
-radioactive iodine uptake is increased, and radioiodine scans show diffuse uptake of iodine
-Graves disease is treated with B-blockers to address symptoms related to B-adrenergic tone,
and by measures aimed at decreasing thyroid hormone synthesis, such as thionamides,
radioiodine ablation, and surgical intervention