endocrine system

Pathology (dr. Yabut)

Endocrine Pathology – Part 1 (from Book)

09 January 08

THE ENDOCRINE SYSTEM contains highly integrated & widely distributed grp of organs that

orchestrates a state of metabolic equilibrium or homeostasis 3 types of signaling: autocrine, paracrine, endocrine

HORMONES: secreted molecules act on target cells distant from their site of synthesis Endocrine hormone : frequently carried by blood from site of

release to its target FEEDBACK INHIBITION: activity of target tissue often downregulates the activity of the gland that secretes the stimulating hormone

HORMONE CLASSIFICATION (based on nature of receptors)1. Hormones that trigger biochemical signals upon interacting w/ cell-surface receptors 2 Groups:

a) Peptide hormones – GH and Insulinb) Small molecules – Epinephrine

binding of hormones w/ cell-surface receptors leads to: in intracellular signaling molecules or Second Messengers

(e.g. cAMP) prod’n of mediators from membrane phospholipids (e.g.

inositol 1,4,5-triphosphate or IP3

shifts in the intracellular levels of ionized calcium- elevated levels of one or more of these can control proliferation, differentiation, survival, and functional activity of cells by regulating the expression of specific genes2. Hormones that diffuse across the plasma membrane & interact w/ intracellular receptors in the cytosol or nucleus hormone-receptor complexes bind specifically to recognition

elements in DNA w/c affects the expression of spec. target genes steroids (e.g. estrogen, progesterone, glucocorticoids thyroxine

Processes that disturb normal activity of endocrine system:a. impaired synthesis or release of hormonesb. abnormal interactions b/n hormones & target tissuesc. abnormal responses of target organs

General Classification of Endocrine Diseasesa. diseases of underproduction or overproduction of hormones

& their resulting biochemical & clinical consequencesb. dse assoc w/ development of mass lesions (functional or

assoc w/ overprod’n or underprod’n of hormones)

PITUITARY GLAND small, bean-shaped organ measures 1cm (greatest diameter), weighs abt 0.5gm; enlarges

during pregnancy located at the base of the skull; lies nestled w/n the sella turcica

near the otic chiasm & cavernous sinuses attached to the hypothalamus by the pituitary stalk plays a critical role in the regulation of most of other endocrine

glands Two morphologically & functionally distinct components: anterior

lobe & posterior lobe

ANTERIOR PITUITARY (ADENOHYPOPHYSIS) abt 80% of the gland embryologically from Rathke pouch (an extension of

developing oral cavity) has a portal vascular system – conduit for transport of

hypothalamic releasing hormones from hypothalamus to the pituitary

hypothalamic neurons- have terminals in the median eminence where hormones are released into the portal system, from where they traverse the pituitary stalk and enter the ant pituitary

Positive-acting Releasing Factors – controls prod’n of most pituitary hormones

EXCEPT PROLACTIN – w/c is INHIBITORY through the axn of Dopamine

Pituiatry Growth Hormone – receives both stimulatory & inhibitory influences via the hypothalamus

Five cell types in the adenohypophysis by immunostaining:1- Somatotrophs: growth hormone (GH) – acidophils - constitute ½ of all hormone-producing cells in the ant pituitary2- Lactotrophs (Mammotrophs): Prolactin (Prl) - acidophils.3- Corticotrophs: proopiomelanocortin (POMC) precursor for

adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), b-endorphin, and b-lipotropin

- basophils. 4- Thyrotrophs: thyroid stimulating hormone (TSH) - basophils.5- Gonadotrophs: basophils

a. follicle stimulating hormone (FSH) - stimulates formation of Graafian follicles in the ovary

b. luteinizing hormone (LH) – induces ovulation & formation of corpora lutea in the ovary

POSTERIOR PITUITARY (NEUROHYPOPHYSIS) consists of PITUICYTES (modified glial cells) and AXONAL

PROCESSES (extending from nerve cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus thru the pituitary stalk to the posterior lobe

neurons in the supraoptic & paraventricular nuclei produce ADH (vasopressin) & oxytocin

hormones are stored in the AXON TERMINALS; released into circulation w/ appropriate stimuli

2b1 (joysharcamsyna) & goldie 1 of 25

Pathology – Endocrine Pathology by Dr. Yabut of 25

OXYTOCIN – stimulates contraction of smooth muscle cells in the gravid mammary glands

ADH (Vasopressin) – nonpeptide; synthesized in the supraoptic nucleus; released from the axon terminals to the general circulation;

STIMULI: plasma oncotic pressure, left atrial distention, exercise, certain emotional states

from an outpouching of the floor of 3rd ventricle w/c grows downward alongside the ant lobe

HAS DUAL CIRCULATION: in contrast to ant pituitary; composed of arteries & veins and a portal venous system linking the hypothalamus & the anterior lobe

CLINICAL MANIFESTATIONS OF PITUITARY DISEASE1. HYPERPITUITARISM from excess secretion of trophic hormones caused by: pituitary adenoma, hyperplasia, Ca of ant pituitary,

secretion of hormones by nonpituitary tumors, certain hypothalamic disorders

2. HYPOPITUITARISM from deficiency of trophic hormones caused by: ischemic injury, surgery or radiation, inflammatory

reactions Nonfunctional Pituitary Adenomas – may encroach upon &

destroy adjacent normal ant pituitary parenchyma & cause hypopituitarism

3. LOCAL MASS EFFECTS RADIOGRAPHIC ABNORMALITIES OF THE SELLA TURCICA

including: sellar expansion, bony erosion, disruption of diaphragma sella

close proximity of optic nerves and chiasm to the sella

expanding pituitary lesions often compress decussating fibers in the optic chiasm

visual field abnormalities (classically, defects in lateral (temporal)

visual fieldsBITEMPORAL HEMIANOPSIA

Pituitary adenomas can produce SSX of ELEVATED ICP (intracranial pressure): headache, N/V

PITUITARY APOPLEXY: On occasion, ACUTE HEMMORHAGE into an adenoma is assoc w/ rapid enlargement of the lesion; can cause sudden death

4. Disease of the posterior pituitary often come to clinical attention usually due to or of ADH

PITUITARY ADENOMAS and HYPERPITUITARISM ADENOMA ARISING IN THE ANTERIOR LOBE – most common

cause of hyperpituitarism Other less common causes: hyperplasia and Ca of anterior

pituitary, secretion of hormones by extrapituitary tumors, hypothalamic disorders

PITUITARY ADENOMAS FUNCTIONAL – assoc w/ hormone excess & clinical

manifestations thereof SILENT – immunohistochemical &/or ultrastructural demo of

hormone prod’n @ the tissue level only, w/o clinical symptoms of hormone excess

both are usually composed of a single cell type & produce single predominant hormone

classified on the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue sections

some can secrete 2 hormones (GH & prolactin – most common combination)

rarely plurihormonal may be hormone-negative, based on absence of

immunohistochemical & ultrastructural demo of lineage-specific differentiation

silent & hormone-negative may cause hypopituitarism responsible for abt 10% of intracranial neoplasms discovered incidentally in up to 25% of routine autopsies usually found in adults; peak incidence 30s to 50s most occur as isolated lesions microadenoma - <1cm macroadenomas - >1cm

Genetic abnormalities assoc w/ Pituitary Adenomas majority are monoclonal in origin; arise from single somatic cell;

some plurihormonal tumors may arise from clonal expansion of primitive stem cells

G-protein mutations – possibly the best characterized molecular abnormalities

G-proteins critical role in signal transduction transmit signals from cell-surface receptors (GHRH

receptors) to intracellular receptors (adenyl cyclase) w/c then generate 2nd messengers (cAMP)

heterotrimeric proteins, composed of a specific α-subunit that binds guanine nucleotide & interacts w/ both cell-surface & IC receptors

β- & γ-subunits – noncovalently bound to specific α-subunit

Gs – stimulatory G-protein; exists as an inactive protein in basal states, w/ GDP bound to guanine nucleotide-

binding site of Gs α on interaxn w/ ligand-bound cell-surface receptors, GDP

dissociates & GTP binds to Gs α, thus activating the G-protein

activation of Gs α cAMP generation potent mitogenic stimulus for various endocrine cell types cellular proliferation & hormone synthesis & secretion

activation of Gs α & cAMP generation = transient bcoz of an intrinsic GTPase activity in the α-subunit w/c hydrolizes GTP into GDP

mutation in the α-subunit interferes w/ intrinsic GTPase activity constitutive activation of activation of Gs α , persistent cAMP generation & unchecked cellular proliferation

gsp oncogene – mutant form of GNAS1; in minority of corticotroph adenomas; absent in thyrotroph, lactotroph, & gonadotroph adenomas

Multiple endocrine neoplasia (MEN) syndrome – familial disorder assoc w/ tumors & hyperplasia of multiple endocrine organs

MEN-1 – subtype; caused by germ line mutations of MEN1 gene on chromosome 11q13

Molecular abnormalities present in aggressive or advanced pituitary adenomas include: activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene


MORPHOLOGY (Pituitary Adenoma) soft, well-circumscribed lesion that may be confined to the sella

turcica larger lesions typically extend superiorly thru the diaphragm sella

into the suprasellar rgn compression of optic chiasm & adjacent structures (e.g. cranial nerves)

expansion of adenoma erodes sella turcica & anterior clinoid process

INVASIVE ADENOMAS – in 30% of cases adenomas are not grossly encapsulated & infiltrate adjacent bone, dura, & brain (rarely) but no distant metastasis

HISTOLOGIC uniform, polygonal cells arrayed in sheets or cords reticulin is sparse soft, gelatinous consistency nuclei may be uniform or pleomorphic mitotic activity usually modest cytoplasm – acidophilic, basophilic, chromophobic depends on

type&amount of secretory product w/n the cells CELLULAR MONOMORPHISM & the ABSENCE of a SIGNIFICANT

RETICULIN NETWORK DISTINGUISH PITUITARY ADENOMAS FROM NON-NEOPLASTIC ANTERIOR PITUITARY PARENCHYMA

PROLACTINOMAS (LACTOTROPH ADENOMAS) most frequent type of hyperfunctioning pituitary adenoma (30% of

clinically recognized cases) range from small microadenoma to large, expansile tumors assoc w/

substantial mass effect microscopically, composed of weakly acidophilic or chromophobic

cells (sparsely granulated prolactinoma) rare prolactinomas are strongly acidophilic (densely granulated

prolactinoma) have a propensity to undergo DYSTROPHIC CALCIFICATION, ranging

from isolated psammoma bodies to extensive calcification of virtually the entire tumor mass (“pituitary stone”)

Prolactin secretion of func. adenoma is characterized by its: EFFICIENCY – even microadenomas secrete sufficient

prolactin to cause hyperprolactinemia PROPORTIONALITY – serum prolactin concentrations tend to

correlate w/ the size of the adenoma PROLACTINEMIA

serum levels of Prolactin Cause: amenorrhea, galactorrhea, loss of libido, infertility

dx made readily in women than men (20-40yrs) bcoz of sensitivity of meses to disruption by hyperprolactinemia

HYPERPROLACTINEMIA: may result from causes other than prolactin-secreting pituitary adenomas

physiologic hyperprolactinemia in pregnancy serum prolactin throughout pregnancy peak at delivery nipple stimulation (suckling in lactating women) & response to stress prolactin LACTOTROPH HYPERPLASIA pathologic hyperprolactinemia; when there is interference w/ normal dopamine inhibition of prolactin secretion w/c may occur as a result of damage to the dopaminergic neurons of the hypothalamus, pituitary stalk axn, or drugs that block dopa receptors on lactotroph cells STALK EFFECT: any mass in the suprasellar may disturb normal inhibitory influence of the hypothalamus on prolactin secretion resulting in hyperprolactinemia Drugs that cause HyperPRL: dopamine receptor antagonists (neuroleptic drugs such as phenothiazines, haloperidol); Anti-HPN such as Reserpine, w/c inhibit dopamine storage Other causes: estrogens, renal failure, hypothyroidism

Tx: surgery (transsphenoidal) bromocriptine (dopamine receptor agonist) radiation

a mild elevation in serum prolactin in a px w/ a pituitary adenoma DOES NOT necessarily indicate a prolactin-secreting tumor

GROWTH HORMONE (SOMATOTROPH ADENOMAS) GH-secreting tumors – 2nd most common type of functioning

pituitary adenoma 40% express a mutant GTPase-deficient α-subunit of the G-

protein, Gs

2 types of GH-containing adenomas (histologic) Densely granulated – cells are monomorphic, acidophilic,

retain strong cytoplasmic GH reactivity, cytokeartin staining in perinuclear distribution

Sparsely granulated – chromophobe cells w/ nuclear & cytologic pleomorphism, retain focal & weak GH reactivity

Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor (IGF-1 or somatomedin C) w/c causes many of the clinical manifestations

Gigantism; GH excess occurs in children (before closure of epiphyses). generalized increase in body size disproportionately long arms and legs

Acromegaly; adult onset excess growth hormone (GH) Þ enlargement of the skull, facial bones, jaw, hands, feet, soft tissues & organs. diabetes, hypertension, muscle weakness, arthritis, gonadal dysfunction, cardiovascular disease HYPEROSTOSIS - bone density; spine&hips PROGNATHISM – enlargement of the jaw resulting to protrusion w/ broadening of lower face

dx of pituitary GH excess relies on documentation of serum GH & IGF-1

failure to suppress GH prod’n in response to an oral load of glucose is one o fthe most sensitive tests for acromegaly

TREATMENT:Goals: to restore GH levels to normal & to decrease symptoms referable to a pituitary mass lesion while not causing hypopotuitarism


- surgically, radiation therapy, drug therapy

CORTICOTROPH CELL ADENOMAS usually small microadenomas at time of dx most often basophilic & occasionally chromophobic +PAS: presence of carbohydrate in pre-

opiomelanocorticotropin (POMC), the ACTH precursor molecule

variable immunoreactivity for POMC & ACTH & β-endorphin

Cushing’s disease. ACTH secretion of cortisol from the adrenal glands

hypercortisolism moon face, buffalo hump, truncal obesity, abdominal striae diabetes mellitus, hirsutism and amenorrhea (ACTH stimulates

androgen secretion) increased skin pigmentation (MSH is secreted with pituitary

ACTH), hypertension, muscle weakness

Nelson Syndrome when large destructive adenomas develop in pts after surgical

removal of the adrenal glands for tx of Cushing syndrome occurs due to loss of inhibitory effect of adrenal corticosteroids

on pre-existing corticotroph microadenoma hypercortisolism does not develop w/ mass effects of pituitary tumor hyperpigmentation bcoz of stimulatory effect of other

products of ACTH precursor on melanocytes

OTHER ANTERIOR PITUITARY ADENOMAS pituitary adenomas may elaborate >1 hormone some cases, unusual plurihormonal adenomas are capable of

secreting multiple hormones; usually aggressive

LESS FREQUENT FUNCTIONING ADENOMAGONADOTROPH (LH-producing & FSH-producing)

diffcult to recognize bcoz of inefficient & variable hormone prod’n & secretory products do not cause recognizable clinical syndrome

commonly in middle-aged men & women when they are large enough

Neurologic symptoms: impaired vision, headaches, diplopia, pituitary apoplexy

pituitary hormone deficiencies such as impaired secretion of LH w/c causes energy&libido due to testosterone & amenorrhea in premenopausal women

paradoxically assoc w/ 2º gonadal hypofunction most are large w/ chromophobic cells neoplastic cells demonstrate immunoreactivity for common

gonadotropin α-subunit & the β-FSH & β-LH subunits FSH – usual predominant secreted hormone “Null Cell Adenomas” - hormone-negative adenomas

THYROTROPH (TSH-producing) rare (only 1%) chromophobic or basophilic rare cause of hyperthyroidism

NONFUNCTIONING PITUITARY ADENOMA

comprise both clinically silent counterparts of the func adenoma and true hormone-negative adenomas

approx 25% in the past, classified as “null cell adenomas” bcz of inability to

demo markers of differentiation MASS EFFECTS – typical presentation lesions may also compromise the residual ant pituitary

sufficiently to cause hypopituitarism may occur as a result of gradual enlargement of adenoma or

after abrupt enlargement of the tumor bcoz of acute hemorrhage (pituitary apoplexy)

pituitary CA are rare; most not functional range from well-differentiated (resemble atypical adenoma) to

poorly diff (variable degrees of pleomorphism & the characteristic features Ca in other locations)

Dx requires demo of metastasis to lymph nodes, bone, liver,..

HYPOPITUITARISM refers to secretion of pituitary hormones w/c can result from

diseases of the hypothalamus or pituitary hypofunction of ant pituitary occurs when 75% of the

parenchyma is lost/absent may be congenital or result of variety of acquired abnormalities

intrinsic to the pituitary accompanied by evidence of posterior pituitary dysfunction in

the form of diabetes insipidus (DI) is almost always of hypothalamic origin

Causes of Hypofunction Tumors & other Mass Lesion

pituitary adenomas benign tumors arising w/n sella 1º & metastatic malignancies cysts any mass lesion in sella can cause damage by exerting pressure

on adjacent pituitary cells Pituitary Surgery or Radiation

excision of adenoma may extend to nonadenomatous pituitary radiation used to prevent regrowth of residual tumor after

surgery can damage nonadenomatous pituitary Pituitary Apoplexy

sudden hemorrhage into the pituitary gland often occurring into a pituitary adenoma

causes the sudden onset of excruciating headache, diplopia owing to pressure on oculomotor nerves, hypopituitarism

severe cases, can cause CV collapse, loss of consciousness, sudden death

true neurosurgical emergency Ischemic necrosis of the Pituitary & Sheehan Syndrome

impt cause of pituitary insufficiency Sheehan Syndrome or Post-partum necrosis of ant pituitary –

most common form of clinically significant ischemic necrosis of ant pituitary

Rathke Cleft Cyst lined by ciliated cuboidal epith w/ occasional goblet cells & ant

pituitary cells can accumulate proteinaceous fluid & expand, compromising

the normal gland Empty Sella Syndrome

results from any condition that destroys part or all of the pituitary gland (e.g. ablation of pituitary by surgery or radiation)


refers to the presence of an empty sella turcica not filled w/ pituitary tissue

PRIMARY EMPTY SELLA – defect in the diaphragma sella that allows the arachnoid matter & CSF to herniated into the sella expansion of sella & compression of pituitary- affected patient are obese women w/ hx of multiple pregnancies- may be assoc w/ visual field defects & occ w/ endocrine abnormalities such as hyperprolactinemia SECONDARY EMPTY SELLA – a mass (pituitary adenoma)

enlarges the sella, but is surgically removed or undergoes spontaneous necrosis leading to loss of pituitary func. hypopituitarism can result from the tx of spontaneous infarction

Genetic Defetcs mutations in pit-1 (pituitary transcription factor), result in

combined deficiency of GH, prolactin, & TSH d/o that interfere w/ the delivery of pituitary hormone-

releasing factors from the hypothalamus may also cause hypofunction of ant. pituitary (e.g. pituitary tumors)

any disease involving the hypothalamus can alter secretion of 1 or more of the hypothalamic hormones that influence secretion of the corresponding pituitary hormones

any of these conditions can also secretion of ADH diabetes insipidus (DI)

Hypothalamic lesions that cause hypopituitarism:a. TUMORS:

benign lesions that arise from hypothalamus (e.g. craniopharyngiomas);

malignant tumors that metastasize (e.g. breast&lung Ca) hypothalamic hormone deficiency can ensue when brain or

nasopharyngeal tumors are treated w/ radiationb. INFLAMMATORY D/O & INFECTIONS sarcoidosis, tuberculous meningitis can cause ant pituitary hormone

deficiency & DI clinical manifestations of ant. pituitary hypofunc depend on SPECIFIC

hormone/s that are lacking GH deficiency pituitary dwarfism GnRH deficiency amenorrhea & infertility in women; libido,

impotence, & loss of pubic or axillary hair in men TSH def symptoms of hypothyroidism ACTH def symptoms of hypoaldrenalism prolactin def failure of post-partum lactation Melanocyte-stimulating hormone (MSH) – from the anterior

pituitary; synthesized from the same precursor of ACTH Pallor – one of the manifestations of hypopituitarism due to loss of

stimulatory effects of MSH on melanocytes

POSTERIOR PITUITARY SYNDROMES

DIABETES INSIPIDUS (DI) due to ADH deficiency CENTRAL DI different from NEPHROGENIC DI w/c is a result of renal tubular

unresponsiveness to circulating ADH clinical manifestations are similar w/c include:

excretion of large volumes of DILUTE urine w/ inappropriately LOW specific gravity

serum Na & osmolality are due to excessive renal loss of free water thirst & polydipsia

excessive urination (polyuria) due to inability of kidneys to resorb water properly from the urine

can result from: head trauma, tumors, inflammatory d/o or surgical procedures of the hypothalamus & pituitary;

can also be idiopathic pt who can drink water compensate for urinary losses pt who are obtunded, bedridden, limited ability to obtain water

may develop life-threatening dehydration

SYNDROME of INAPPROPRIATE ADH (SLADH) SECRETION ADH excess resorption of excessive amts of free water

HYPONATREMIA Frequent causes :

secretion of ectopic ADH by malignant neoplasms (particularly SCC of the lungs) non-neoplastic dses of the lungs local injury to the hypothalamus or post. pituitary

Clinical manifestations : hyponatremia, cerebral edema, resultant neurologic

dysfunction Total body water is Blood volume remains Normal peripheral edema does not develop

HYPOTHALAMIC SUPRASELLAR TUMORS neoplasms in this location may induce hypofunction or

hyperfunction of the anterior pituitary, DI, or combinations of these most commonly implicated lesions are:

gliomas & craniopharyngiomas

CRANIOPHARYNGIOMA thought be derived from vestigial remnants of Rathke pouch slow-growing tumors; acct for 1-5% of intracranial tumors small minority arise w/in the sella; but most are Suprasellar w/ or w/o an intrasellar extension w/ bimodal age distribution: 1st peak @ 5-15 yrs then 2nd peak in adults @ 60 yrs – older Children usually present w/ endocrine deficiencies such as growth retardation; Adults w/ visual disturbances pituitary hormonal deficiencies, including DI, are common pts have an excellent recurrence-free & overall survival tumors>5cm higher recurrence rate adamantinomatous tumors higher frequency of brain invasion but does not necessarily correlate w/ an adverse prognosis malignant transformation into squamous Ca are rare & usually occurs postradiation

THYROID GLAND consists of 2 bulky lateral lobes connected by a relatively thin

Isthmus located below & anterior to the larynx Wt of normal adult thyroid = 15 – 25 gm normal structural variations include: presence of pyramidal lobe w/c

is a remnant of the thyroglossal duct above the isthmus has a rich intraglandular capillary network supplied by Superior &

Inferior thyroidal arteries nerve fibers from Cervical Sympathetic Ganglia indirectly influence

thyroid secretion by acting on blood vessels


divided by thin, fibrous sepate into lobules composed of abt 20-40 evenly dispersed follicles

Normal follicle size = 50 -500 µm follicles: lined by cuboidal to low columnar epith, filled w/ PAS-

positive thyroglobulin develops from an evagination of the developing pharyngeal epith

that descends as part of the thyroglossal duct from the foramen cecum @ the base of the tongue to its normal position in the anterior neck

Ectopic thyroid tissue- commonly located @ the base of the tongue (lingual thyroid) or at other sites abnormally high in the neck

Excessive descent - substernal thyroid glands clinical significance of lesions lies in distinguishing them from

metastatic thyroid Ca or primary thyroid malignancy Total Migration Failure - pts w/ lingual thyroids in w/c the ectopic

thyroid tissue is the ONLY thyroid tissue thus removal of lingual thyroid results to Symptomatic Hypothyroidism

Malformations of branchial pouch differentiation – intrathyroidal sites of the thymus or parathyroid glands

these deviations bcome evident in pts who has total thyroidectomy & subsequently develops hypoparathyroidism

TSH – released by thyrotrophs in the Ant. Pituitary into the circulation inresponse to trophic factors from hypothalamus

binding of TSH & its receptor on the thyroid follicular epithactivation and conformational change in the receptor association w/ a stimulatory G-protein

activation of G-protein in intracellular cAMP stimulates thyroid growth, hormone synthesis & release via cAMP-dependent protein kinases

Thyroid Autonomy & hyperfunction – results from dissociation of thyroid hormone synthesis & release from the controlled influence of TSH-signaling pathways

Thyroid follicular epith cells – convert thyroglobulin into T4

(thyroxine) & lesser amts of T3 (triiodothyronine) T4 and T3 – released into systemic circulation where most of these

peptides are reversibly bound to circulating plasma proteins such as TBG (thyroxine-binding globulin) & transthyretin for transport to peripheral tissue

Binding proteins – maintain serum unbound (“free”) T4 &T3 w/in narrow limits; ensure hormones are readily available to the tissues

in the periphery, majority of free T4 is DEIODINATED to T3

T3 – binds to thyroid hormone nuclear receptors in target cells w/ 10x> affinity than T4 & proportionately > activity

The interaxn of thyroid hormone w/ its nuclear thyroid hormone receptor (TR) results inte formation of a multi-protein hormone-receptor complex that binds to thyroid hormone response elements (TREs) in target genes, regulating their transcription.

Cellular effects of Thyroid hormone: up-regulation of carbohydrate & lipid catabolism & stimulation of protein synthesis in wide range of cells

Net result = in Basal Metabolic Rate Impt Func of Thyroid hormone: in brain dev’t, since absence of TH

during fetal & neonatal periods may profoundly interfere w/ intellectual growth

Thyroid gland is one of the most responsive organs & contains the largest store of hormones of any endocrine gland

responds to stimuli & in constant state of adaptation gland ↑in size & becomes more active during: pregnancy, puberty, &

presence of 6easurement stress from any source functional lability is reflected in transient hyperplasia of thyroidal

epithelium

at this time, thyroglobulin is resorbed; follicular cells bcome tall & more columnar, sometimes forming small, infolded buds, or papillae INVOLUTION – happens when stress abates; height of epith falls, colloid accumulates, follicular cells return to normal size & architecture failure of this balance b/n hyperplasia & involution can produce major or minor deviations from usual histo

GOITROGENS – various chemical agents w/c can inhiit the normal func of thyroid gland; suppress T4 & T3 levels →↑TSH → hyperplastic enlargement of gland (goiter)

PROPYLTHIOURACIL – antithyroid agent; inhibits oxidation of iodide; blocks prod’n of thyr. hormone; (parenthetically) inhibits peripheral deiondination of circulating T4 into T3 thus ameliorating symptoms of thyr. hormone excess

IODIDE – given to pts w/ thyroid hyperfunc; blocks the release of thyroid hormones thru diff mechanisms; (in large doses) inhibit proteolysis of thyroglobulin thus thyr hormone is synthesized 7 incorporated w/n increasing amts of colloid, but not released into the blood

PARAFOLLICULAR CELLS (C CELLS) – synthesize & secrete calcitonin w/c promotes absorption of calcium by the skeletal system & ihibits resorption of bone by osteoclast

PATHOLOGY most dse of thyroid are amenable to medical or surgical tx Include: excessive release of thyroid hormones (hyperthyroidism);

those assoc w/ thyroid hormone deficiency (hypothyroidism); mass lesions of the thyroid

HYPERTHYROIDISMTHYROTOXICOSIS hypermetabolic state caused by ↑ circulating levels of T4 & T3 often referred to as Hyperthyroidism bcoz most 6easur cause is

hyperfunction of thyroid gland (in other conditions) oversupply is related to either ecessive release

of preformed thyroid hormone (e.g. thyroiditis) or an extrathyroidal source

so, hyperthyroidism is only one (most common) cause of thyrotoxicosis

3 most common causes of thyrotoxicosis (also assoc w/ hyperfunc of the gland):

- Diffuse hyperplasia of the thyoid assoc w/ Graves’ Dse (accts for 85%of cases)- hyperfunctional multinodular goiter- hyperfunctional adenoma of the thyroid

The term Primary & Secondary Hyperthyroidism are used to designate hyperthyroidism arising from an intrinsic thyroid abnormality & that arising from processes outside the thyroid such as TSH-secreting pituitary tumor

CLINICAL COURSE clinical manifestations: protean; changes referable to

Hypermetabolic state induced by excess thyroid hormone and also those related to overactivityof 6easurement nervous system (i.e. increase in the β-adrenergic “tone)

excessive levels of thyr hormone → ↑basal metabolic rate


skin: warm, soft, lushed due to ↑blood flow & peripheral vasodilation to ↑heat loss

heat intolerance is common; ↑sweating due to higher levels of calorigenesis; weight loss despite ↑appetite

CARDIAC manifestations: among the earliest & most consistent feature

↑CO due to ↑ cardiac contractility & ↑peripheral oxygen requirements

tachycardia, palpitations, cardiomegaly are common arrythmias (Atrial fib) occur frequently/more common in elderly pts CHF may develop esp in older pts MYOCARDIAL changes: foci of lymphocytic & eosinophilic infiltration;

mild fibrosis in th interstitium; fatty changes in myofibers; ↑size & no. of mitochondria

THYROTOXIC DILATED CARDIOMYOPATHY- condition in w/c some pts develop reversible diastolic dysfunction & “low-output” failure

overactivity of sympathetic nervous system → tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, insomnia

THYROID MYOPATHY (common)- proximal muscle weakness w/ ↓muscle mass

Ocular changes: wide, staring gaze, lid lag (due to sympathetic overstimulation of levator palpebrae superioris)

True Thyroid Ophthalmopathy assoc w/ proptosis – seen only in graves’ disease

sympathetic hyperstimulation of GIT – hypermotility, malabsorption, diarrhea

Skeletal system: thyroid hormone stimulates bone resorption → ↑porosity of cortical bone & ↓vol of trabecular bone

Net Effect: Osteoporosis; ↑risk of fractures in pts w/ chronic hyperthyroidism

Other findings: atrophy of skeletal muscle; fatty infiltration & focal interstitial lymphocytic infiltrates; minimal liver enlargement due to fatty changes in hepatocytes; generalized lymphoid hyperplasia w/ lymphadenopathy

THYROID STORM abrupt onset of severe hyperthyroidism occur most commonly in pts w/ underlying Graves’ dse & probably

results from acute elevation in catecholamine levels (e.g. during infections, surgery, cessation of antithyroid medication, any form of stress)

pts often febrile, w/ tachychardia untreated pts die of cardiac arrythmias =( APATHETIC HYPERTHYROIDISM

refers to thyrotoxicosis in the elderly; old age & various comorbidities may blunt the typical features

Dx is usually made in during lab work-up for unexplained wt loss or worsening of CV dse

Dx of hyperthyroidism is made using both clinical & lab The measurement of serum TSH concentration using sensitive TSH

(sTSH) assays provides the most useful single screening test for hyperthyroidism

low TSH – confirmed w/ measurement of free T4 w/c is ↑ In some pts, hyperthyroidism results from predominantly from ↑

circulating levels of T3 (“T3 toxicosis”) free T4 levels may be decreased; direct 7easurement of serum T3 may be useful

in rare cases of Pituitary (Secondary) Hyperthyroidism, TSH levels are either normal or raised

TRH STIMULATION TEST – deterimining TSH levels after injection of TRH used in the evaluation of cases of suspected hyperthyroidism w/ equivocal changes in the baseline serum TSH level

Normal rise in TSH after TRH injection excludes 2˚hyperthryoidism confirmed dx of thyrotoxicosis followed by measurement of

radioactive iodine uptake by thyroid gland to determine etiology E.g.

◦ in Graves’ – there may be diffusely uptake in the whole gland

◦ toxic adenoma - uptake in a solitary nodule

◦ thyroiditis - uptake Therapeutic options:

β-blockers to control symptoms induced by adrenegic tone Thionamide to block new hormone synthesis Iodine sol’n to block the release of thyroid hormone and agents that inhibit peripheral conversion of T4 to T3 Radioiodine incorporated in thyroid tissue, results in ablation of thyroid func over a period of 6-18 wks

HYPOTHYROIDISM caused by any structural or functional derangement that interferes

w/ the prod’n of adequate levels of thyroid hormone can result from a defect anywhere in the hypothalamic-pituitary-

thyroid axis also divided into 1º or 2º hypothyroidism Primary Hypothyroidism – accts for majority of the cases; can be

Thyroprivic (due to absence or loss of thyroid parenchyma) or Goitrous (due to enlargement of thyroid gland under the influence of TSH)

Causes of Primary Hypothyroidism:1. Surgical or Radiation-induced ablation of thyroid parenchyma

total thyroidectomy fro the tx of hyperthyroidism of a primary neoplasm can lead to hypothyroidism

gland may be ablated by radiation (radioiodine administered for tx of hyperthyroidism, or exogenous irradiation such as external radiation therapy to the neck)

2. Autoimmune Hypothyroidism most common cause of goitrous hypothyroidism in iodine-

sufficient areas vast majority of cases are due to Hashimoto thyroiditis circulating antibodies, incl. anti-TSH receptor autoantibodies are

commonly found some pts may have circulating anti-TSH antibodies but do not

present the goitrous enlargement or lymphocytic infiltrate characteristic of Hashimoto

3. Drugs given intentionally to thyroid secretion e.g. methimazole & propylthiouracil agents used to treat nonthyroid conditions e.g. lithium, p-aminosalicylic acid

4. Inborn errors of thyroid metabolsim uncommon cause of goitrous hypothyroidism

(dyshormonogenetic goiter) Any deficiency on the ff step of Thyroid hormone synthesis:

a. iodide transport defectb. organification defectc. dehalogenase effectd. iodotyrosine coupling defect

PENDRED SYNDROME – deficiency in the process of organification of iodine w/c involves binding of oxidized iodide


w/ tirosyl residues in thyroglobulin, wherein goitrous hypothyroidism is accompanied by sensorineural deafness

5. Thyroid Hormone Resistance Syndrome rare, autosomal dominant d/o cause: inherited mutations in the TR w/c abolish the ability of

the receptor to bind thyroid hormones pts have generalized resistance to thyroid hormone despite high

circulating levels of T4&T3 TSH levels are high since pituritary is also resistant to feedback

from thyroid hormones Thyroid Agenesis – complete absence of thyroid parenchyma Thyroid Hypoplasia – gland is reduced in size newly recognized cause: mutations in the TSH receptor assoc w/

hypoplastic thyroid gland Mutations in 2 Transcription factors that are expressed in the

developing thyroid & regulate follicular differentiation (thyroid transcription factor-2 or TTF-2 and Paired Homeobox-8 or PAX-8) reported in pts w/ thyroid agenesis

Thyroid agenesis caused by TTF-2 mutations is usually assoc w/ CLEFT PALATE

6. Secondary Hypothyroidism is caused by TSH deficiency, & Tertiary (Central) Hypothyroidism is caused by TRH deficiency

can result from any of the causes of hypopituitarism frequent cause: Pituitary Tumor other causes: postpartum pituitary necrosis; trauma;

nonpituitary tumors Tertiary (Central) hypothyroidism – can be caused by any d/o

that damages the hypothalamus or interferes w/ hypothalamic-pituitary portal blood flow, thereby preventing delivery of TRH to the pituitary

can result from: hypothalamic damage from tumors, trauma, radiation therapy, infiltrative dse

Clsssic clinical manifestations: CRETINISM & MYXEDEMA

CRETINISM hypothyroidism that develops in infancy or early childhood Gk. Chrétien; Christian or Christlike; they were so mentally retarded

as to be incapable of sinning.. in the past, occurred primarily in areas w/ endemic dietary iodine

deficiency but became much less frequent in recent years due to widespread supplementation of foods w/ iodine

may also be due to inborn errors in metabolism 9e.g. enzyme deficiencies) that interfere w/ the biosynthesis of normal levels of thyroid hormone (sporadic cretinism)

Clinical features: impaired dev’t of skeletal system & CNS manifested by severe mental retardation, short stature, coarse facial features, protruding tongue, umbilical hernia

severity of mental impairment appears to be related to time of occurrence of thyroid deficiency in utero

since T4&T3 normally cross the placenta & are critical to fetal brain dev’t maternal thyroid deficiency before fetal thyroid gland dev’t severe mental retardation

reduction in maternal thyroid hormones later in pregnancy after fetal thyroid developed allows normal brain dev’t

MYXEDEMA (Gull Disease) hypothyroidism in older child or adult clinical manifestations vary w/ age Clinical features: slowing of physical & mental activity Initial symptoms: generalized fatigue, apathy, mental sluggishness

(may mimic depression in the early stages)

speech & intellectual func become slowed Pts are listless, cold-intolerant, frequently overweight Reduced CO probably contribute to shortness of breath &

exercise capacity constipation & sweating (due to sympathetic activity skin is cool & pale due to blood flow

Histologic: accumulation of matrix substances such as glycosaminoglycans &

hyaluronic acid in the skin, subcutaneous tissue & some visceral sites edema, broadening & coarsening of facial features, enlargement of tongue, deepening of voice

Laboratory: measurement of serum TSH level most sensitive screening test

for this d/o TSH level is in 1ºhypothyroidism due to loss of feedback

inhibition of TRH prod/n by the hypothalamus & TSH prod/n by pituitary

TSH level is NOT in pts w/ hypothyroidism due to 1ºhypothalamic or pituitary dse

T4 levels are in pts w/ hypothyroidism of ANY ORIGIN

THYROIDITIS inflammation of the thyroid gland; encompasses a diverse grp of d/o

characterized by some form of thyroid inflammation include conditions that result in acute illness w/ severe thyroid pain

(e.g. infectious thyroiditis, subacute granulomatous thyroiditis) and; d/o in w/c there is relatively little inflammation & illness is

manifested primarily by thyroid dysfunction (e.g. subacute lymphocytic thyroiditis & fibrous (Reidel) thyroiditis)

INFECTIOUS THYROIDITIS either acute or chronic Acute infections: reach the thyroid via hematogenous spread or thru direct seeding of the gland, such as via a fistula from the piriform sinus adjacent to the larynx Chronic: frequently occur in immunocompromised pts; includes mycobacterial, fungal, Pneumocystis infections sudden onset of neck pain & tenderness in the area of the gland accompanied by fever, chills, & other signs of infection can be self-limited or can be controlled w/ appropriate therapy thyroid func usually not significantly affected there are few residual effects except for possible small foci of scarring

HASHIMOTO THYROIDITIS CHRONIC LYMPHOCYTIC THYROIDITIS most common cause of hypothyroidism in iodine-sufficient areas characterized by: Gradual Thyroid Failure due to autoimmune

destruction of thyroid gland in 1912, Hashimoto reported pts w/ goiter & intense lymphocytic

infiltration of the thyroid (struma lymphomatosa) most prevalent b/n 45-65 yrs more common in women; female predominance 10:1 to 20:1 can also occur in children; major cause of NONENDEMIC GOITER in

children pattern of inheritance in non-Mendelian; likely to be influenced by

subtle variations in the functions of multiple genes concordance rate: 30-60% (monozygotic twins); up to 50% of

asymptomatic 1º relatives of Hashimoto pts have circulating antithyroid antibodies


Chromosomal abnormalities assoc w/ Hashimoto: Turner Syndrome – have a high prevalence of circulating

antithyroid antibodies; 20% develops subclinical or clinical hypothyroidism that is indistinguishable from Hashimoto

Down Syndrome (Trisomy 21) - risk of developing Hashimoto & hypothyroidism

link b/n polymorphism in HLA-DR3 & HLA-DR5 alleles and Hashimoto was reported but association is weak

genomewide linkage analyses provided eveidence on several susceptible loci such as on chromosome 6p & 12q may harbor genes predisposing to this d/o

PATHOGENESIS autoimmune disease; immune system reacts against a variety of

thyroid antigens Overriding feature: PROGRESSIVE DEPLETION OF THYROID

EPITHELIAL CELLS w/c are gradually replaced by mononuclear cell infiltration & fibrosis

Initiating event: Sensitization of autoreactive CD4+ T-helper cells to thyroid antigens

Hashimoto thyroiditis, Subacute thyroiditis, Graves disease

EFFECTOR MECHANISMS for THYROCYTE DEATH : a. CD8+ cytotoxic T cell-mediated cell death

may cause thyrocyte destruction by Exocytosis of perforin/granzyme granules or Engagement of death receptors specifically CD95 (Fas) on the target cell

b. Cytokine-mediated cell death CD4+ T cells produce inflammatory cytokines such as IFN-γ in

the immediate thyrocyte milieu recruitment & activation of macrophages & damage to follicles

c. Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, antihtyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity (ADCC)

CLINICAL COURSE painless enlargement of the thyroid usually assoc w/ some degree of

hypothyroidism in a middle-aged woman enlargement of gland is symmetric & diffuse but may be sufficiently

localize din some cases (suspicion of neoplasm) usual course: develops gradually HASHITOXICOSIS - in some cases of Hashimoto, it may be preceded

by transient thyrotoxicosis caused by disruption of thyroid follicles w/ 2º release of thyroid hormones

during this phase: free T4 & T3; TSH; radioactive iodine uptake

as hypothyroidism supervenes, T4 & T3 progressively fall accompanied by compensatory in TSH

pts w/ Hashimoto are at risk for developing other concomitant autoimmune dses: both endocrine (type 1 diabetes, autoimmune adrenalitis) & nonendocrine ( SLE, myasthenia gravis, Sjögren syndrome) and also B-cell non-Hodgkin lymphoma

there is no established risk for developing thyroid epithelial neoplasms

MORPHOLOGY thyroid often diffusely enlarged capsule is intact and gland is well-demarcated from adjacent

structures cut surface is pale, yellow-tan, firm, somewhat nodular Histologic: extensive infiltration of parenchyma by a Mononuclear

Inflammatory Infiltrate containing small lymphocytes, plasma cell, well-developed germinal centers

thyroid follicles are atrophic, lined in many areas by epithelial cells w/ presence of abundant eosinophilic, granular cytoplasm termed Hürthle cells metaplastic response of the normally low cuboidal follicular epith to ongoing injury

FNAB: (+) Hurthle cells in conjunction w/ a heterogenous pop’n of lymphocytes (characteristic of Hashimoto)

“Classic” Hashimoto – interstitial connective tissue is & may be abundant

FIBROUS VARIANT: severe thyroid follicular atrophy & dense “keloid-like” fibrosis, w/ broad bands of acellular collagen encompassing residual thyroid tissue

fibrosis does not extend beyond the capsule remnant thyroid parenchyma demonstrates features of chronic

lymphocytic thyroiditis

SUBACUTE (GRANULOMATOUS) THYROIDITIS aka De Quervain thyroiditis occurs much less frequently than Hashimoto most common b/n 30-50 yrs female predominance of 3:1 to 5:1

PATHOGENESIS believed to be caused by a viral infection or a postviral inflammatory

process majority of pts have Hx of upper respi. infection has seasonal incidence, peaking in the summer clusters of cases have been reported in assoc w/ coxsackievirus,

mumps, measles, adenovirus, & other viral illnesses pathogenesis is unclear but one model suggests that it results from:

a viral infection provides an antigen (viral or thyroid antigen) that is released 2º to virus-induced host tissue damage antigen stimulates cytotoxic T lymphocytes damage thyroid follicular cells

immune response is virus-initiated & not self-perpetuating so the process is limited

CLINICAL COURSE may be sudden or gradual pain in the neck w/c may radiate to upper neck, jaw, throat, or ears

particularly when swallowing variable enlargement of thyroid accompanied by fever, fatigue,

malaise, anorexia, & myalgia


thyroid inflammation & hyperthyroidism are transient (diminishing w/in 2-6 wks even w/o tx)

may be followed by a period of transient, asymptomatic hypothyroidism (2-8wks) but recovery is virtually complete

the transient hyperthyroidism si due to disruption of thyroid follicles & release of excessive thyroid hormone

nearly all pts have high serum T4&T3 w/ low TSH radioactive iodine uptake is low due to suppression of TSH after recovery, in 6-8wks, normal thyroid fnc returns

MORPHOLOGY gland may be unilaterally or bilaterally enlarged & firm w/ an intact

capsule may be slightly adherent o surrounding structures involved areas are firm & yellow-white instead of the normal

rubbery, brown thyroid tissue Histologic: changes are patchy & depend on disease stage early in the active inflammatory phase: scattered follicles may be

entirely disrupted & replaced by neutrophils forming microabscesses more characteristic features appear later in the form of aggregations

of lymphocytes, histiocytes, plasma cells about collapsed & damaged thyroid follicles

multinucleate giant cells enclose naked pools or fragments of colloid granulomatous

later stages: chronic inflammatory infiltrate & fibrosis may replace foci of injury

SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS aka Painless Thyroiditis or Silent Thyroiditis an uncommon cause of hyperthyroidism mild hyperthyroidism or goitorus enlargement of gland (or both) can occur at any age but often seen in middle-aged adult & more

common in women esp during postpartum period (postpartum thyroiditis)

pathogenesis is unknown autoimmune basis has been suggested bcoz some pts have levels

of antibodies to thyroglobulin & thyroid peroxidase or; family hx of thyroid autoimmune dse

occasionally, dse develops into overt chronic autoimmune thyroiditis several yrs later

no particular viral or other agent

CLINICAL COURSE Hyperthyroidism – principal clinical manifestation symptoms develop over 1-2 wks and last from 2-8wks before

subsiding palpitations, tachycardia, tremor, weakness, fatigue (common

findings of hyperthyroidism) thyroid gland not usually tender but is minimally & diffusely enlarged no infiltrative ophthalmopathy nor other manifestations of Graves pts w/ one episode of postpartum thyroiditis are at risk of

recurrence ff subsequent pregnancies minority of pts progress to hypothyroidism some pts have no SSX, the d/o is detected incidentally during routine

thyroid testing Laboratory: during periods of thyrotoxicosis elevated T4andT3,

depressed TSH levels

Riedel Thyroiditis less common form of thyroiditis rare idiopathic d/o

characterized by extensive fibrosis involving the thyroid & contiguous neck structures

presence of a hard & fixed thyroid mass clinically simulates a thyroid Ca

may be assoc w/ idiopathic fibrosis in other sites of the body such as the retroperitonium

presence of circulating antithyroid antibodies in most pts suggests an autoimmune etiology

Palpation Thyroiditis caused by vigourous clinical palpation of the thyroid gland results in multifocal follicular disruption assoc w/ chronic

inflammatory cells & occasional giant cell formation abnormalities of thyroid fnc are not present

MORPHOLOGY except for possible mild enlargement, thyroid appears normal on

gross inspection Histologic: lymphocytic infiltration w/ hyperplastic germinal centers

w/in the thyroid parenchyma & patch disruption & collapse of thyroid follicles

fibrosis & Hurthle cell metaplasia not commonly seen

GRAVES DISEASE in 1853, Graves reported observations of a dse characterized by

violent and long continued palpitations in females assoc w/ enlargement of thyroid gland

most common cause of endogenous hyperthyroidism TRIAD OF CLINICAL FINDINGS:

HYPERTHYROIDISM – hyperfunctional, diffuse enlargement of thyroid

INFILTRATIVE OPHTHALMOPATHY – w/ resultant exophthalmos

Localized infiltrative DERMOPATHY – also called PRETIBIAL MYXEDEMA

has peak incidence b/n 20-40 yrs, women 7x more affected than men

genetic susceptibility to Graves assoc w/ presence of major histocompatibility haplotypes, specifically HLA-B8 & HLA-DR3

polymorphisms in the cytotoxic T-lymphocyte-associated-4 (CTLA-4) gene are also linked

HLA proteins – critical component of antigen presentation to T cells CTLA-4 – inhibitory receptor that prevents T-cell responses to self-

antigens genomewide linkage analyses: additional susceptiblility loci localized

to chromosome 6p (also linkes w/ Hashimoto) & chromosome 20q

PATHOGENESIS autoimmune d/o in w/c a variety of antibodies may be present in the

serum include antibodies to TSH receptor, thyroid peroxisomes, and

thyroglobulin AUTOANTIBODIES TO TSH RECEPTOR – central to disease

pathogenesis specific effects of antibodies depend on w/c TSH receptor epitope

they are directed against: Thyroid-Stimulating Immunoglobulin (TSI)

serum from Graves pts conatin long-acting thyroid stimulator (LATS) – long-acting bcoz it stimulate thyroid fnc more slowly than TSH


LATS proved to be an IgG antibody that binds to TSH receptor & mimics the axn of TSH stimulating adenyl cyclase release of thyroid hormones

all pts have detectable levels of this autoantibody TSI is relatively specific for Graves

Thyroid growth-stimulating immunoglobulins (TGI) also directed against TSH receptor have been implicated in the proliferation of thyroid follicular

epithelium TSH-binding inhibitor immunoglobulins (TBII)

prevent TSH from binding normally to its receptor on thyroid epithelial cells

some forms of TBII mimic the axn of TSH stimulation of thyroid epithelial cell activity

some may also inhibit thyroid cell function possible coexistence of both stimulating & inhibitory

immunoglobulins in the serum explains why some pts spontaneously develop episodes of hypothyroidism

trigger for initiation of autoimmune reaction in Graves remains uncertain, but most likely due to breakdown in helper T-cell tolerance, resulting in prod’n of anti-TSH autoantibodies

Graves Ophthalmopathy T-cell mediated autoimmune phenomenon plays a role in the

dev’t of infiltrative ophthalmopathy volume of retro-orbital connective tissues & extraocular muscles

is owing to several causes: marked infiltration of retro-orbital space by mononuclear

cells (Tcells) inflammatory edema & swelling of extraocular muscles accumulation of extracellular matrix components (specifically

hydrophilic glycosaminoglycans GAGs such as hyaluronic aicd & chondroitin sulfate)

numbers of adipocytes (FATTY INFILTRATION) these changes displace the eyeball forward & can interfere w/

func of extraocular muscles Orbital Preadipocyte Fibroblasts – express the TSH receptor thus

becoming targets of autoimmune attack T cells reactive against these fibroblasts secrete cytokines

stimulate fibroblast proliferation & synthesis of extracellular matrix proteins (GAGs) & surface TSH receptor expression immune response perpetuation progressive infiltration of retro-orbital space & ophthalmopathy

autoimmune d/o of the thyroid span a continuum; Graves (hyperfunction of thyroid) to Hashimoto (hypothyroidism)

there are families w/ coexistence of both there is histologic overlap b/n autoimmune thyroid d/o

(prominent intrathyroidal lymphoid cell infiltrates w/ germinal center formation)

in both d/o, frequency of other autoimmune dse (SLE, pernicious anemia, type 1 diabetes, Addison dse) is increased

CLINICAL COURSE include changes referable to thyrotoxicosis as well as those uniquely

w/ Graves (diffuse hyperplasia of the thyroid, ophthalmopathy, dermopathy)

diffuse enlargement of thyroid is present in all cases of Graves thyroid enlargement may be accompanied by flow of blood thru

the hyperactive gland producing an audible bruit sympathetic overactivity wide, staring gaze & lid lag

ophthalmopathy results in abnormal protrusion of the eyeball (Exophthalmos)

extraocular muscles are often weak exophthalmos may persist or progress despite tx of thyrotoxicosis may result to corneal injury

Infiltrative Dermopathy or Pretibial Myxedema – most common in skin overlying the shins; presents as scaly thickening & induration of the skin (present only in minority)

skin lesions may be pigmented papules or nodules & often have an orange peel texture

Laboratory: Elevated free T4&T3; Depressed TSH Radioactive iodine uptake is - due to ongoing stimulation of

thyroid follicles by TSI diffuse uptake of iodine Tx include:

decreasing the symptoms of hyperthyroidism that are induced by β-adrenergic tone (e.g tachycardia, palpitations, tremulousness, anxiety)

measures aimed at decreasing thyroid hormone synthesis such administration of Thionamides (e.g. propylthiouracil), radioiodine ablation, surgical intervention

MORPHOLOGY thyroid gland usually symmetrically enlarged due to diffuse

hypertrophy & hyperplasia of thyroid follicular epith cells gland usually smooth & soft, capsule is intact in weight to over 80gm not uncommon parenchyma has soft, meaty appearance resembling normal

muscles HISTOLOGIC: dominant feature is TOO MANY CELLS follicular epith cells in untreated cases are tall & crowded crowding often results to formation of small papillae

project into follicular lumen & encroach on the colloid sometimes filling the follicles

papillae lack fibrovascular cores colloid w/in lumen is pale, w/ scalloped margins lymphoid infiltrates (T cells, w/ fewer Bcells & mature plasma

cells) – present throughout the interstitium germinal centers are common preoperative therapy – alters morphology of the thyroid preoperative administration of iodine involution of

epithelium & accumulation of colloid by blocking thryoglobulin secretion

Tx w/ PTU exaggerates the epithelial hypertrophy & hyperplasia by stimulating TSH secretion

Changes in extrathyroidal tissue include:generalized lymphoid hyperplasiaheart may be hypertrophied ischemic changes may be present (esp in pts w/ CAD) in pts w/ ophthalmopathy – tissues of orbit are edematous due to

the presence of hydrophilic mucopolysaccharides; plus infiltration by lymphocytes & fibrosis

dermopathy characterized by thickening of the dermis due to deposition of GAGs & lymphocyte infiltration

DIFFUSE and MULTINODULAR GOITERS GOITER – enlargement of the thyroid; most common manifestation

of throid disease reflect impaired synthesis of thyroid hormone most often caused by

dietary iodine insufficiency


impaired thyroid hormone synthesis compensatory rise in serum TSH hypertrophy & hyperplasia of thyroid follicular cells gross enlargement of thyroid gland

compensatory increase in functional mass is able to overcome hormone deficiency ensures EUTHYROID metabolic state

if underlying d/o is sufficiently severe (e.g. congenital biosynthetic defect or endemic iodine deficiency), compensatory responses may be inadequate Goitrous Hyperthyroidism

degree of thyroid enlargement is proportional to level & duration of thyroid hormone deficiency

DIFFUSE NONTOXIC (SIMPLE) GOITER diffusely involves the entire gland w/o producing nodularity Colloid Goiter – bcoz the enlarged follicles are filled w/ colloid occurs in both endemic and sporadic distributionENDEMIC GOITER in areas where soil, water, & food have low iodine levels when goiters are present in more than 10% of the pop’n lack of iodine synthesis of thyroid hormone &

compensatory in TSH follicular cell hypertrophy & hyperplasia & goitrous enlargement

Goitorgens – substance that interfere w/ thyroid hormone synthesis (e.g excessive calcium & vegetables belonging to Brassica and Crucifera families [cabbage, cauliflower, Brussels sprouts, turnips, cassava])

cassava contains THIOCYANATE w/c inhibits iodide transport w/in the thyroid

SPORADIC GOITER occurs less frequently female preponderance & peak incidence at puberty or in young

adult Causes: goitrogens hereditary enzymatic defects that interfere w/ thyroid

hormone synthesis all are transmitted as Autosomal-recessive conditions in most cases, cause of sporadic goiter is not apparent

CLINICAL COURSE pts are clinically euthyroid clinical manifestations are primarily related to mass effects from the

enlarged thyroid gland T4&T3 levels are normal TSH is usually elevated or at the upper range of normal in children, dyshormogenetic goiter, caused by congenital

biosynthetic defect, may induce cretinism

MORPHOLOGY 2 Phases identified Hyperplastic Phasethyroid gland is diffusely & symmetrically enlarged increase is usually modest; gland rarely exceeds 100-150gmfollicles are lined by crowded columnar cells w/c may pile up &

form projections similar in Gravesaccumulation is not uniform; some follicles are hugely distended

while some remain small Phase of Colloid Involution if dietary iodine or demand for thyroid hormone stimulated follicular epith involutes to form an enlarged, colloid-rich gland (Colloid Goiter)

cut surface of thyroid is usually brown, somewhat glassy, translucent

follicular epithelium is flattened & cuboidal; colloid is abundant during periods of involution

MULTINODULAR GOITER irregular enlargement of the thyroid due to recurrent episodes of

hyperplasia & involution virtually, all long-standing simple goiters convert into multinodular

goiters may be nontoxic or may induce thyrotoxicosis (toxic multinodular

goiter) produce the most extreme thyroid enlargements & are more

frequently mistaken for neoplastic involvement than any other form of thyroid disease

occur in both endemic & sporadic form may arise bcoz of variations among follicular cells in response to

external stimuli such as trophic hormones cells w/in follicles w/ growth advantage perhaps bcoz of intrinsic

genetic abnormalities develop into clones of proliferating cells formation of nodule w/ autonomous growth

both polyclonal & monoclonal nodules coexist w/in the same multinodular goiter

mutations in proteins of the TSH-signaling pathway that lead to constitutive activation of this pathway have been identified in a subset of autonomous thyroid nodules

uneven follicular hyperplasia generation of new follicles, uneven accumulation of colloid, tensions, stresses rupture of follicles & vessels hemorrhages, scarring, calcification

scarring adds to tensions nodularity stromal framework may enclose areas of expanded parenchyma

nodularity

CLINICAL COURSE dominant clinical features: caused by Mass Effects of the enlarged

gland large neck mass airway obstruction, dysphagia, compression of large vessels in the

neck & upper thorax most pts are euthyroid PLUMMER SYNDROME - in a minority of pts, a hyperfunctioning

nodule may develop w/in a long-standing goiter hyperthyroidism (toxic multinodular goiter)! not accompanied by infiltrative ophthalmopathy & dermopathy

may be assoc w/ clinical evidence of hypothyroidism radioiodine uptake is uneven (varied levels of activity) hyperfunctioning nodules concentrate radioiodine and appear “hot” goiters are also of clinical significance due to their ability to mask or

to mimic neoplastic diseases arising in the thyroid

MORPHOLOGY multilobulated, asymmetrically enlarged glands can reach up to 2000gm pattern of enlargement is quite unpredictable & may involve one

lobe far more than the other lateral pressure on midline structures such as trachea & esophagus

INTRATHORACIC or PLUNGING GOITER – in some cases, goiter grows behind the sternum & clavicles

occasionally, most of it is hidden behind the trachea & esophagus in some cases, one nodule may stand out as to appear like a solitary

nodule


Cut section: irregular nodules contain variable amts of brown, gelatinous colloid

regressive changes occur frequently, particularly in older lesions; include areas of hemorrhage, fibrosis, calcification, cystic changes

Microscopic: colloid-rich follicles lined by flattened, inactive epithelium & areas of follicular epithelial hypertrophy & hyperplasia accompanied by degenerative changes

NEOPLASMS of the THYROID solitary thyroid nodule is a palpably discrete swelling w/in an

otherwise apparently normal thyroid gland single nodules are abt 4x more common in women incidence of thyroid nodule increases throughout life possibility of neoplastic dse is of major concern in pts w/ thyroid

nodules majority of solitary nodules prove to be localized, non-neoplastic

conditions (e.g. nodular hyperplasia, simple cysts, or foci of thyroiditis) or benign neoplasms such as follicular adenomas

benign neoplasms : thyroid Ca ratio is 10:1 Clinical criteria for determining the nature of a thyroid nodule:

Solitary Nodules – more likely to be neoplastic than multiple nodules

Nodules in younger pts – more likely neoplastic than those in older pts

Nodules in males – more likely to be neoplastic than in females

A history of radiation treatment to the head & neck rgn is assoc w/ an increased incidence of thyroid malignancy

Nodules that take up radioactive iodine in imaging studies (hot nodules) – more likely to be benign than malignant

morphologic evaluation of a given thyroid nodule thru FNAB & histologic study of surgically resected parenchyma provides the most definitive info about its nature

ADENOMAS typically discrete, solitary masses derived from follicular epithelium follicular adenomas various terms have been proposed on the Classification of

Adenomas based on degree of follicle formation and Colloid content: Simple Colloid Adenomas (macrofollicular adenomas) – common

form; resemble normal thyroid tissue Fetal or Microfollicular, Embryonal or Trabecular – recapitulate

stages in the embryogenesis of the normal thyroid mixed patterns are common; most of these benign tumors are

nonfunctional follicular adenomas can be difficult to distinguish from dominant

nodules of follicular hyperplasia or follicular Ca although majority are nonfunctional, a small portion produce

thyroid hormones & cause clinically apparent thyrotoxicosis TOXIC ADENOMAS – functional adenomas that produce thyroid

hormone independent of TSH & is an example of Thyroid Autonomy (same as toxic multinodular goiters)

PATHOGENESIS TSH receptor signaling pathway impt in pathogenesis of toxic

adenomas “gain of function” or activating somatic mutations in 1 of 2

components of this signaling system (most often TSH receptor or α-subunit of Gs ) chronic overprod’n of cAMP generates cells w/ growth advantage clonal expansion of follicular epith cells that

can autonomously produce thyroid hormone symptoms of thyroid excess

CLINICAL FEATURES many thyroid adenomas present as unilateral painless mass often

discovered during routine P.E. larger masses produce local symptoms such as difficulty in

swallowing most adenomas take up less radioactive iodine than normal thyroid

parenchyma on radionuclide scanning: adenomas are “cold” nodules up to 10% of “cold” nodules eventually prove to be malignant malignancy is rare in “hot” nodules in minority of cases, adenomas may be hyperfunctional, producing

SSx of hyperthyroidism (toxic adenoma) on radionuclide imaging: hyperfunctioning adenomas are “hot”

nodules compared to paranodular thyroid tissue w/c is deprived of thyrotropin stimulation

hot adenomas occasionally have TSH dependence & may be induced to regress by administration of thyroid hormones w/c suppress TSH secretion

Ultrasonography & FNAB – for preoperative evaluation of suspected adenomas

THE DEFINITIVE DX OF ADENOMAS CAN BE MADE ONLY AFTER CAREFUL HISTOLOGIC EXAM OF RESECTED SPECIMEN

suspected adenomas are removed to exclude malignancy thyroid adenomas, including atypical adenomas have excellent

prognosis & do not recur or metastasize abt 20% of follicular adenomas have point mutations in the RAS

family of oncogenes w/c are also identified in 30-40% of follicular Ca possiblity that some adenomas may progress to Ca

MORPHOLOGY solitary, spherical, encapsulated lesion, well-demarcated ave. of abt 3cm (some are smaller or grow up to 10cm) on resected specimens: adenoma bulges from cut surface &

compress adjacent thyroid gray-white to red-brown, depending on the cellularity of the

adenoma & its colloid content neoplastic cells are demarcated from adjacent parenchyma by a

well-defined, intact capsule These features are impt in distinguishing adenoma from

Multinodular Goiters w/c have multiple nodules, less compression of thyroid, & lack of well-formed capsule

Areas of hemorrhage, fibrosis, calcifications, & cystic changes similar to those in multinodular goiters are COMMON in follicular adenomas (esp in larger lesions)

Microscopically: cells often form uniform-appearing follicles that contain colloid

follicular growth pattern is distinct from the adjacent non-neoplastic thyroid UNLIKE in multinodular goiters wherein growth patterns of maybe similar

epithelial cells of follicular adenomas reveal little variation in cell & nuclear morphology

mitotic figures are rare; mitotic activity needs careful exam to exclude follicular Ca

papillary change is not typical; if extensive, may raise suspicion of an Encapsulated Papillary Ca

OXYPHIL or HURTHLE CELL CHANGE - occasionally, neoplastic cells acquire bright eosinophilic granular cytoplasm


HURTHLE CELL ADENOMA – clinical presentation & behavior of a follicular adenoma w/ oxyphilia

Other variants of Follicular adenomas: CLEAR CELL FOLLICULAR ADENOMA (extensive clear cell change of cytoplasm) & SIGNET-RING CELL FOLLICULAR ADENOMA (adenomas w/ signet-ring features)

ENDOCRINE ATYPIA - similar to endocrine tumors @ other anatomic sites, benign follicular adenomas may occasionally exhibit focal nuclear pleomorphism, atypia, prominent nucleoli; doesn’t constitute a feature of malignancy

ATYPICAL FOLLICULAR ADENOMAS – adenomas that can demonstrate cellularity, more extensive variation in cellular size & nuclear morphology, & even mitotic activity

HALLMARK OF ALL FOLLICULAR ADENOMAS: PRESENCE OF AN INTACT, WELL-FORMED CAPSULE ENCIRCLING THE TUMOR

OTHER BENIGN TUMORS solitary nodules of the thyroid gland may also prove to be cysts great preponderance represent cystic degeneration of a follicular

adenoma while the remainder probably arise in multinodular goiters often filled w/ brown, turbid fluid containing blood, hemosiderin

pigment, & cell debris additional benign rarities include dermoid cysts, lipomas,

hemangiomas, teratomas (seen mainly in infants)

CARCINOMAS mostly occur in adults, although papillary Ca may present in

childhood female preponderance noted among pts who develop thyroid Ca in

early & middle adult yrs related to expression of estrogen receptors on neoplastic thyroid epithelium

cases presenting in childhoos\d & late adulthood are equally distributed among males & females

most thyroid Ca are well-differentiated lesions Major Subtypes & relative frequencies: PAPILLARY Ca: 75-85% of cases FOLLICULAR Ca: 10-20% of cases MEDULLARY Ca: 5% of cases ANAPLASTIC Ca: <5% of cases

most thyroid Ca are derived from the follicular epithelium EXCEPT FOR MEDULLARY Ca w/c is derived from the parafollicular or C cells

PATHOGENESIS - there are several factors, genetic & environmental, implicated in the pathogenesis of thyroid Ca

GENETIC FACTORS impt in both familial & nonfamilial (sporadic) forms of thyroid Ca Familial medullary Ca – accts for most inherited cases of thyroid

Ca Familial Nonmedullary thyroid Ca (papillary & follicular variants)

– very rare distinct genes are ivolved in the histologic variants of thyroid Ca

FOLLICULAR THYROID Ca (FTC) approx ½ of FTC harbor mutations in the RAS family of oncogenes

(HRAS, NRAS, & KRAS) NRAS mutations are most common recently, unique translocation has been described b/n PAX8 (paired

homeobox gene impt in thyroid dev’t) & PPARγ1 (peroxisome

proliferators-activated receptor γ1; nuclear hormone receptor implicated in terminal differentitaiton of cells)

PAX8- PPARγ1 fusion is present in approx 1/3 of FTC, specifically those Ca w/ t(2;3)(q13;p25) translocation permits juxtaposition of portions of both genes

follicular Ca appear to arise by at least 2 distinct & virtually nonoverlapping molecular pathways: tumors carry either a RAS mutation or a PAX8-PPARγ1

both genetic abnormalities rarely present in same case

PAPILLARY THYROID Ca (PTC) appear to arise by multiple distinct, nonoverlapping molecular

pathways1) one involves arrangements of tyrosine kinase receptors RET or NTRK1 (neurotrophic tyrosine kinase receptor 1)2) another involves activating mutations in the BRAF oncogene3) 3rd pathway involves RAS mutations (10-20% of PTC) suggests relation w/ follicular adenomas

RET – located on chromosome 10q11 NTRK – located on chromosome 1q21 both belong to the family of receptor tyrosine kinases that transduce

extracellular signals fro cell growth & differentiation & exert many of their downstream effects thru MAP kinase signaling pathway

neither receptor is normally expressed on the surface of thyroid follicular cells

either a paracentric inversion of chromosome 10 or a reciprocal translocation b/n chromosomes 10 & 17 places tyrosine kinase domain of RET under the transcriptional control of active genes on these chromosomes

ret/PTC (ret/papillary thyroid Ca) – novel fusion genes present in approx 1/5 of PTC

frequency of ret/PTC rearrangements is in papillary Ca arising in children w/ radiation exposure

paracentric inversions or translocations of NTRK1 that activate its tyrosine kinase domain present in 5-10% of PTC

1/3 to ½ of PTC harbor mutation in the BRAF gene, w/c encodes a signaling intermediary in the MAP kinase pathway

chromosomal rearrangement of the RET & NTRK1 genes & mutations of BRAF have redundant effects on thyroid epith PTC demonstrate only one of these abnormalities

MEDULLARY THYROID Ca (MTC) arise form C cells in the thyroid familial MTC occur in multiple endocrine neoplasia type 2 (MEN-2) assoc w/ germ-line RET protooncogene mutations that affect

residues in the cysteine-rich extracellular or intracellular tyrosine kinase domains constitutive activation of the receptor

RET mutations detectable in approx 95% of families w/ MEN-2 remaining few cases, mutations may arise in hard-to-detect

promoter sequences or intronic sites RET mutations are also seen in nonfamilial (sporadic) MTC no ret/PTC translocations

ANAPLASTIC Ca highly aggressive & lethal tumors can arise de novo or by “dedifferentiation” of a well-differentiated

papillary or follicular Ca inactivating point mutations in the p53 tumor suppressor gene are

common (rare in well-differentiated thyroid Ca)


ENVIRONMENTAL FACTORS EXPOSURE TO IONIZING RADIATION – major risk factor

predisposing to thyroid Ca particularly in the 1st 2 decades in the past, radiation therapy is used for tx of head & neck lesions in

infants & children including reactive tonsillar enlargement, acen, tinea capitis 9% developed thyroid malignancies several decades postexposure

importance of radiation as major risk was highlighted due to in incidence of PTC in children in Marshall Islands after atomic bomb testing

Long-standing multinodular goiter has been suggested as a predisposing factor in some cases since iodine-deficiency related endemic goiter have higher prevalence of follicular Ca

no conclusive evidence to relate thyroiditis w/ increased risk of thyroid epith Ca

PAPILLARY CARCINOMA most common form of thyroid cancer occur at any age but most often in 20s-40s acct for majority of thyroid Ca assoc w/ previous exposure to

ionizing radiation

CLINICAL COURSE present as asymptomatic thyroid nodules first manifestation may be a mass in a cervical lymph node presence of isolated cervical nodal metastases does not appear

influence the generally good prognosis the carcinoma, usually a single nodule, moves freely during

swallowing & is not distinguishable from a benign nodule hoarseness, dysphagia, cough, or dyspnea suggests advanced

disease in minority of cases, hematogenous metastases are present at time

of Dx, usually in the lung radionuclide scanning & FNAB – employed to separate benign from

malignant thyroid nodules papillary lesions are “cold” masses on scintiscans FNAB – due to improvements in cytologic analysis, this became a

reliable test for distinguishing benign from malignant nodules nuclear features often nicely demonstrated in aspirated specimens have excellent prognosis, w/ 10-yr survival rate in excess of 95% 5%-20% have local or regional recurrences 10%-15% have distant metastases prognosis depends on several factors: age (less favorable in pts older

than 40), presence of extrathyroidal extension, and presence of distant metastases (stage)

MORPHOLOGY solitary or multifocal lesions some may be well-circumscribed & encapsulated some may infiltrate adjacent parenchyma w/ ill-defined margins lesions may contain areas of fibrosis & calcification & are often cystic cut surface may appear granular & sometimes contain grossly

discernible papillary foci definitive dx can be made only after microscopic examination

CHARACTERISTIC HALLMARKS of PAPILLARY NEOPLASMSa) papillary Ca can contain branching papillae having a fibrovascular

stalk covered by a single to multiple layers of cuboidal epith cells in most neoplasms epithelium covering the papillae consists

of well-differentiated, uniform, orderly, cuboidal cells or;

may be w/ fairly anaplastic epith showing considerable variation in cell & nuclear morphology

papillae of papillary Ca differ from those seen in areas of hyperplasia

neoplastic papillae are more complex & have dense fibrovascular cores

b) nuclei of papillary Ca chromatin finely dispersed chromatin w/c imparts an optically clear or empty appearance ground glass or Orphan Annie eye “Pseudo-inclusions” or Intranuclear inclusions appearance

of the invaginations of the cytoplasm in x.s. Dx of papillary Ca is based on these nuclear features even in

the absence of papillary architecture c) PSAMMOMA BODIES concentrically calcified structures often

present w/in the lesion, usually w/in the cores of papillae; strong indication of a Papillary Ca almost never found in follicular & medullary Ca whenever a psammoma body is found w/in a lymph node or

perithyroidal tissues a hidden papillary Ca must be considered

d) - foci of lymphatic invasion by tumor are often present; - involvement of blood vessels is relatively uncommon particularly

in smaller lesions; - Metastases to adjacent cervical lymph nodes are estimated to

occur in ½ of the cases

Variant Forms of Papillary Caa) ENCAPSULATED VARIANT constitutes abt 10% of all papillary neoplasms usually confined to the thyroid well encapsulated, rarely presents w/ vascular or lymph node dissemination can be easily confused w/ benign adenoma has excellent prognosis

b) FOLLICULAR VARIANT has characteristic nuclei of Papillary Ca but has an almost totally

follicular architecture may be encapsulated, psammoma bodies may be seen still behave biologically as usual papillary Ca as long as they

meet the criteria for Dx of papillary Ca True Follicular Ca – lacks these nuclear features, frequently

demonstrates capsular & vascular invasion, has less favorable prognosis

c) TALL CELL VARIANT marked by tall comunar cells w/ intensely eosinophilic

cytoplasm lining the papillary structures cells are at least 2x as tall as they are wide tumors tend to occur in older people & are usually large w/

prominent vascular invasion, extrathyroidal extension, & cervical & distant metastases

recently demonstrated that more than ½ harbor a ret/PTC translocation potential than the ret/PTC observed in usual papillary thyroid Ca

presence of this genetic abnormality might result in more aggressive behavior

d) DIFFUSE SCLEROSING VARIANT unusual variant occurs in younger individuals including children


tumors do not present w/ a mass but rather w/ a BILATERAL GOITER

characteristic “gritty” sensation to cut surface of the lesion due to the presence of abundant psammoma bodies

prominent papillary growth pattern, intermixed w/ solid areas containing nests of squamous cells (Squamous Morules)

neoplastic cells exhibit classic nuclear features of a papillary neoplasm

extensive, diffuse fibrosis throughout the thyroid often assoc w/ prominent lymphocytic infiltrate, simulating Hashimoto

neoplastic cells have peculiar propensity to invade intrathyroidal lymphatic channels nodal metastases are present in almost all cases

e) HYALINIZING TRABECULAR TUMORS a grp that includes both adenomas & Ca recently been considered as a variant based on the presence of

ret/PTC gene rearrangement in 30%-60% of these tumors “organoid” growth pattern w/ nests & trabeculae of elongated

tumor cells w/in a fibrovascular stroma at first glance, may resemble an extra-adrenal paraganglioma both intra- & extracellular hyalinization are prominent & confer

a pink hue on the tumor on LPO nuclear features resemble those seen in classic papillary Ca &

psammoma bodies may be present well-encapsulated (Ca demonstrate capsular &/or vascular

invasion)

FOLLICULAR CARCINOMA 2nd most common form; 10%-20% of all thyroid Ca tend to present in women & at an older age than papillary Ca; peak

incidence in 40s-50s incidence is in areas of dietary iodine deficiency suggests

nodular goiter may predispose to the dev’t of the neoplasm high frequency of RAS mutations in follicular adenomas & Ca

suggests that the 2 may be related tumors

CLINICAL COURSE present as slowly enlarging painless nodules most frequently “cold” nodules; in some rare cases, better-

differentiated lesions may be hyperfunctional, take up radioactive iodine & appear “warm” on scintiscan

have little propensity for invading lymphatics regional lymph nodes are rarely involved

vascular invasion is common w/ spread to the bone, lungs, liver, & elsewhere

prognosis is largely dependent on the extent of invasion & stage at presentation

widely invasive follicular Ca not infrequently develop metastases; up to ½ succumb to their dse in 10 yrs in contrast to minimally invasive follicular Ca w/c has a 10yr survival rate greater than 90%

most are treated w/ Total Thyroidectomy followed by administration of radioactive iodine

Rationale: metastases are likely to take up the radioactive element w/c can be used to identify & ablate such lesions pts are usually treated w/ thyroid hormone after surgery to

suppress endogenous TSH bcoz any residual follicular Ca may respond to TSH stimulation

MORPHOLOGY

single nodules that may be well-circumscribed or widely infiltrative

sharply demarcated lesions may be difficult to distinguish from follicular adenoma by gross exam

larger lesions may penetrate the capsule & infiltrate well beyond the thyroid capsule into the adjacent neck

gray to tan to pink, & on occasion, somewhat translucent when large, colloid-filled follicles are present

central fibrosis & foci of calcification (degenerative changes) are sometimes present

Microscopically: composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid

in other cases, follicular differentiation may be less apparent; nests or sheets of cells w/o colloid may be present

occasional tumors are dominated by Hurthle cells (cells w/ abundant granular, eosinophilic cytoplasm)

nuclei lack the features typical of papillary Ca psammoma bodies are not presentNote: absence of these details bcoz some papillary Ca may appear almost entirely follicular follicular lesions w/ nuclear features typical of papillary Ca

must be treated as papillary Ca nuclear features are of little value in distinguishing follicular

adenomas from minimally invasive follicular CaNote: requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular &/or vascular invasion criterion for vascular invasion is applicable only to capsular vessels

& vascular spaces beyond the capsule presence of tumor plugs w/in intratumoral blood vessels little

prognostic significance lymphatic spread is uncommon extensive invasion of adjacent thyroid parenchyma or

extrathyroidal tissues dx of Ca in widely invasive follicular Ca Histologic: have a greater proportion of solid or trabecular growth

pattern, less evidence of follicular differentiation, & mitotic activity

MEDULLARY CARCINOMA neuroendocrine neoplasms derived from C cells of the thyroid cells of medullary Ca secrete CALCITONIN (same as normal C cells);

its measurement impt in dx & postop follow-up of pts in some instances, tumor cells elaborate other polypeptide

hormones such as somatostatin, serotonin, & vasoactive intestinal peptide (VIP)

tumors arise sporadically in abt 80% of cases remaining occurs in the setting of MEN syndrome 2A or 2B or as

familial tumors w/o an assoc MEN syndrome (FMTC) cases assoc w/ MEN-2 occur in younger pts & may even arise during

childhood in contrast, sporadic medullary Ca & FMTC lesions of adulthood

(peak incidence in 40s-50s)

CLINICAL COURSE sporadic cases most often present as a mass in the neck, sometimes

assoc w/ local effects such as dysphagia, or hoarseness in some, initial manifestations are those of paraneoplastic syndrome caused by secretion of a peptide hormone (e.g. diarrhea owing to VIP secretion)

hypocalcemia not a prominent feature despite presence of raised calcitonin levels


for early detection of tumors in familial cases – screening relatives for elevated calcitonin or RET mutations

all mEN-2 kindred carrying RET mutations given prophylactic thyroidectomy to preclude dev’t of medullary Ca, the major risk factor for poor outcomes in these families

sometimes, only histo finding in resected thyroid of asymptomatic carriers is the presence of C cell hyperplasia or small (<1cm) “micromedullary” Ca

recent studies show specific RET mutations correlate w/ aggressiveness of medullary Ca & propensity of MEN-2 pts to develop other coincident endocrine tumors

MORPHOLOGY arise as solitary nodule or multiple lesions involving both lobes of the

thyroid sporadic neoplasms tend to originate in one lobe bilaterality & multicentricity – common in familial cases larger lesions often contain areas of necrosis & hemorrhage & may

extend thru the capsule of the thyroid tumor tissue is firm, pale gray to tan, & infiltrative Microscopically: composed of polygonal to spindle-shaped cells w/c

may form nests, trabeculae, & even follicles small, more anaplastic cells are present in some tumors & may be

the predominant cell type Acellular Amyloid Deposits – derived from altered calcitonin

molecules; present in the adjacent stroma in many cases calcitonin is readily demonstrable w/in the cytoplasm of tumor cells

as well as in stromal amyloid by immunohistochemical methods EM: variable #s of membrane-bound electron-dense granules w/in

the cytoplasm of neoplastic cells Multicentric C-cell Hyperplasia – one peculiar feature of familial

medullary Ca; present in surrounding thyroid parenchyma (usually absent in sporadic lesions)

precise criteria for defining C cell hyperplasia not established so; presence of multiple prominent clusters of C cells scattered

throughout the parenchyma – raise specter of familial tumor Foci of C-cell hyperplasia are believed to represent the precursor

lesions form w/c medullary Ca arise

ANAPLASTIC CARCINOMA undifferentiated tumors of thyroid follicular epithelium aggressive tumors; mortality rate: 100% tumors acct for fewer than 5% of all thyroid Ca mean age = 65 yrs abt ½ of pts have a Hx of multinodular goiter 20% - have Hx of differentiated Ca another 20%-30% have concurrent differentiated thyroid tumor,

frequently a papillary Ca these findings led to the proposal that: anaplastic Ca develops by

dedifferentiation from more differentiated tumors as a result of one or more genetic changes including loss of p53 tumor suppressor gene

CLINICAL COURSE usually present as a rapidly enlarging bulky neck mass in most cases, dse has already spread beyond the thyroid capsule

into adjacent neck structures or has metastasized to the lungs at the time of presentation

Compression and Invasion Symptoms dyspnea, dysphagia, hoarseness, cough common

no effective therapy; dse is almost uniformly fatal

metastases to distant sites are common in most cases, death occurs in less than 1 yr as a result of aggressive

growth & compromise of vital structures in the neckMORPHOLOGY composed of highly anaplastic cells w/c may take one of several

histologic patterns:1. large, pleomorphic giant cells, including occasional osteoclast-like

multinucleate giant cells2. spindle cells w/ sarcomatous appearance3. mixed spindle & giant cells4. small cells resembling those in SCC arising at other sites

unlikely that a true small cell Ca exists in the thyroid significant # of these small cell tumors were proven to be medullary

Ca or malignant lymphomas w/c may also occur in thyroid but have better prognosis

foci of papillary or follicular differentiation may be present in some tumors suggest origin form better differentiated Ca

CONGENITAL ANOMALIESTHYROGLOSSAL DUCT OR CYST most common clinically significant congenital anomaly persistent sinus tract may remain as a vestigial remnant of the

tubular dev’t of the thyroid part of this tube obliterated leaves small segments forms

cysts occur at any age & might not become evident until adulthood mucinous, clear secretions may collect w/in these cysts to form

either spherical masses or fusiform swellings, rarely over 2-3cm present in the midline of the neck anterior to trachea segments of duct & cysts that occur high in the neck lined by

stratified squamous epithelium (identical w/ covering of posterior tongue in the region of foramen cecum)

anomalies that occur in the lower neck more proximal to the thyroid are lined by epithelium resembling thyroidal acinar epithelium

subjacent to the lining epithelium there is an intense lymphocytic infiltrate

superimposed infection may convert these lesions into abscess cavities and rarely give rise to cancers

PARATHYROID GLANDS derived from developing pharyngeal pouches that also give rise to

the thymus four glands normally lie in close proximity to the upper & lower poles

of each thyroid lobe but may also be found anywhere along the pathway of descent of

pharyngeal pouches (carotid sheath, thymus, elsewhere in anterior mediastinum)

10% of individuals have only 2-3 glands (in adult) yellow-brown, ovoid encapsulated nodule weighing approx

35-40mg composed mostly of CHIEF CELLS

vary from light to dark pink w/ H&E depending on their GLYCOGEN content

polygonal, 12-20mm; have central, round, uniform nuclei

contain secretory granules of PTH sometimes have water-clear appearance due to

lakes of glycogen OXYPHIL CELLS & Transitional Oxyphils

found throughout the normal parathyroid


either singly or in small clusters slightly larger than chief cells acidophilic cytoplasm tightly packed w/ mitochondria glycogen granules are also present secretory granules are sparse or absent

(infancy&childhood) composed almost entirely of solid sheets of chief cells

amt of stromal fat increases up to age 25, max: 30% of gland then plateaus

precise proportion of fat determined largely by constitutional factors: obese individuals have more adipose tissue in their glands

LEVEL OF FREE (IONIZED) CALCIUM in the bloodstream – controls activity of the gland; rather than trophic hormones secreted by the hypothalamus & pituitary

levels of free calcium stimulate synthesis & secretion of PTH CIRCULATING PTH

84-amino acid linear polypeptide derived by sequential cleavage in the chief cell of a larger pre-pro form

biologic activity resides w/in 34 residues at the amino terminus

smaller nonfunctional fragments also circulate (lacks the critical amino-terminal domain); biologically inert, contains epitopes that react in certain radioimmunoassay for PTH

PTH RECEPTOR 7-transmembrane G-

protein-coupled receptor binding of hormone

activation of stimulatory G-protein (Gs) adenylate cyclase-mediated generation of cAMP

this pathway assumes clinical significance when abnormalities of the Gs protein result in either hyperactivity or hypoactivity of the parathyroid gland

METABOLIC FUNCTIONS OF PTH (in supporting serum calcium levels) activates osteoclasts mobilization of calcium from bone increases renal tubular reabsorption of calcium conservation of

free calcium increases conversion of Vit. D to its active dihyroxy from in the

kidneys increases urinary phosphate excretion lowering serum

phosphate levels augments GI calcium absorption

net result of these activities levels of free calcium inhibits further PTH secretion in a classic feedback loop

HYPERCALCEMIA one of a number of changes induced by elevated levels of PTH relatively common complication of malignancy, occurring both w/

solid tumors, such as lung, breast, head & neck, renal Ca & w/ hematologic malignancies such asmultiple myeloma

MALIGNANCY IS THE MOST COMMON CAUSE OF CLINICALLY APPARENT HYPERCALCEMIA

primary hyperthyroidism – more common cause of asymptomatic elevated blood calcium

prognosis is poor in pts w/ malignancy-assoc hypercalcemia since it most commonly occur in pts w/ advanced Ca

hypercalcemia of malignancy is due to bone resorption & subsequent release of calcium

2 Major Mechanismsby w/c this can occur:

OSTEOLYTIC METASTASES metastatic tumor cells as well as stromal cells in the vicinity of

metastases release a variety of soluble mediators induce local osteolysis by promoting differentiation of committed osteoclast precursors into mature cells

recently, critical osteoclastogenic pathway has been discovered involves RANK (osteoblast cell-surface receptor; receptor

activator of nuclear factor κB), its ligand RANKL, & Osteoprotegerin (a decoy receptor for RANKL)

decoy receptor – soluble receptor that competes w/ the true receptor, in this case RANK, for binding the ligand w/c is RANKL

RANKL – aka osteoclast differentiation factor; by binding w/ RANK it promotes all aspects of osteoclast fnc (proliferation, differentiation, fusion, & activation); it is secreted by tumor cells & peritumoral stromal cells in metstatic foci & cause osteolysis

Osteoprotegerin – inhibits this pathway of osteoclastogenesis & has emerged as a possible therapeutic agent in Ca pts w/ hypercalcemia of malignancy

PTH-RELATED PROTEIN RELEASE OF PTHrP - most frequent cause of hypercalcemia in

nometastatic solid tumors (particularly squamous cell Ca) classically, PTHrP-induced hypercalcemia was known as

“HUMORAL HYPERCALCEMIA of MALIGNANCY” to distinguish it from hypercalcemia arising from osteolytic metastases

PTHrP contributes to hypercalcemia of malignancy irrespective of the presence or absence of metastases


this protein is immunologically distinct from PTH yet similar enough to permit binding to identical receptors & simulation of 2nd messengers (notably cAMP)

accts for ability of PTHrP to induce most of actions of PTH including in bone resorption & inhibition of proximal tubule phosphate transport

PATHOLOGY abnormalities include both hyper- & hypofunction tumors usually come into attention bcoz of EXCESSIVE SECRETION OF

PTH rather than mass effects

HYPERPARATHYROIDISM occurs in 2 major forms – primary & secondary; less commonly, tertiary form 1st condition: represents autonomous, spontaneous overprod’n of

PTH latter 2 conditions typically occur as secondary phenomena in pts w/

chronic renal insufficiency

PRIMARY HYPERPARATHYROIDISM one of the most common endocrine d/o impt cause of hypercalcemia Frequency of various parathyroid lesions underlying the

hyperfunction:Adenoma: 75-80%Primary Hyperplasia (diffuse or nodular) 10-15%Parathyroid Ca: less than 5%

usually a dse of adults more common in women than in men (3:1) in more than 95% of cases, this d/o is caused by Sporadic

Parathyroid Adenomas or Sporadic Hyperplasia familial syndromes are a distant second but provided unique insight

in the pathogenesis of primary hyperparathyroidism

GENETIC SYNDROMES ASSOCIATED w/ FAMILIAL PRIMARY HYPERPARATHYROIDISMa) MULTIPLE ENDOCRINE NEOPLASIA – 1 (MEN-1) MEN1 gene on chromosome 11q13 – tumor suppressor gene

inactivated in a variety of MEN-1-related parathyroid lesions (incl: parathyroid adenomas & hyperplasia)

MEN1 mutations have also been described in sporadic parathyroid tumors

b) MULTIPLE ENDOCRINE NEOPLASIA – 2 (MEN-2) caused by activating mutations in the tyrosine kinase receptor

RET, on chromosome 10q primary hyperparathyroidism occurs as a component of MEN-2A

c) FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH) autosomal-dominant d/o enhanced parathyroid function due to decreased sensitivity to

extracellular calcium mutations in parathyroid CASR (calcium sensing receptor) on

chromosome 3q – primary cause for this d/o pts w/ homozygous CASR mutations – severe

hyperparathyroidism in neonatal period CASR mutations not described in sporadic tumors

most sporadic parathyroid adenomas are monoclonal suggests they are true neoplastic outgrowths from a single abnormal progenitor cell

sporadic parathyroid hyperplasia is also monoclonal when assoc w/ a persistent stimulus for parathyroid growth (refractory secondary or tertiary parathyroidism)

2 Molecular Defects:a) PARATHYROID ADENOMA 1 (PRAD1) PRAD1 encodes cyclin D1 (major regulator of cell

cycle) pericentromeric inversion on chromosome 11

relocation of PRAD1 protooncogene so it is positioned adjacent to the 5’ flanking region of the PTH gene (on 11p)

Consequence: regulatory element from PTH gene 5’ flanking sequence directs overexpression of cyclin D1 protein force cells to proliferate

10-20% of adenomas have this clonal genetic defect cyclin D1 is overexpressed in approx 40% of

parathyroid adenomas suggests other mechanisms that can lead to its activation

b) MEN1 20-30% of parathyroid tumors not assoc w/ MEN-1 syndrome

demonstrate mutations in both copies of MEN1 gene spectrum of MEN1 mutations identical to that in familial

parathyroid adenoma

CLINICAL COURSEPRIMARY HYPERPARATHYROIDISM presents in 1 of 2 general ways

it may be asymptomatic & be identified after a routine chemistry profile

patients may have the classic clinical manifestations of primary hyperparathyroidism

Asymptomatic Hyperparathyroidism blood tests for unrelated conditions serum calcium levels

routinely assessed early detection of clinically silent hyperparathyroidism

level of serum ionized calcium – most common manifestation of primary hyperparathyroidism

primary hyperparathyroidism – most common cause of asymptomatic hypercalcemia

malignancy – most common cause of clinically apparent hypercalcemia in adults (must be excluded by appropriate clinical & lab tests in pts w/ suspected hyperparathyroidism)

pts w/ 1º hyperparathyroidism – serum PTH levels are inappropriately elevated for the level of serum calcium; but in hypercalcemia, PTH levels are low to undetectable bcoz of nonparathyroid dses

in pts w/ hypercalcemia caused by PTHrP secretion by nonparathyroid tumors radioimmunoassays specific for PTH & PTHrP can distinguish b/n the 2

Other lab alterations referable to PTH excess: hypophosphatemia & urinary excretion of both calcium & phosphate

secondary renal dse may lead to phosphate retention w/ normalization of serum phosphates

Symptomatic Primary Hyperparathyroidism


SSx of hyperparathyroidism reflect the combined effects of PTH secretion & hypercalcemia

traditionally assoc w/ a constellation of symptoms that included “painful bones, renal stones, abdominal groans, & psychic moans”

Symptomatic Presentation w/ Diverse Clinical Manifestationsa) Bone Disease

- includes bone pain 2º to fractures of bones weakend by osteoporosis or osteitis fibrosa cystica

b) Nephrolithiasis (renal stones)- occurs in 20% of newly diagnosed pts; w/ attendant pain & obstructive uropathy- chronic renal insufficiency & variety of abnormalities in renal func are found, including polyuria & 2º polydipsia

c) Gastrointestinal disturbances- constipation, nausea, peptic ulcer, pancreatiits, gallstones

d) CNS alterations- depression, lethargy, eventually seizures

e) Neuromuscular abnormalities- complaints of weakness & fatigue

f) Cardiac manifestations- aortic or mitral valve calcifications (or both)

nephrolithiasis & bone dse most directly related to hyperparathyroidism

fatigue, weakness, constipation – attributable to hypercalcemia pathogenesis of other manifestations still poorly understood

MORPHOLOGY changes include those in the parathyroid glands, as well as other

organs affected by elevated levels of calciumParathyroid Adenomas almost always solitary & may lie near the thyroid gland or in an

ectopic site ave: 0.5 – 5.0 gm well-circumscribed, soft, tan to reddish-brown; invested by a delicate

capsule glands outside adenoma are usually normal in size or somewhat

shrunken bcoz of feedback inhibition by elevation in serum calcium Microscopically: predominance of fairly uniform, polygonal chief

cells w/ small, centrall-placed nuclei at least a few nests of larger cells containing oxyphil cells are present Oxyphil Adenoma – uncommon type wherein oxyphils comprise the

whole adenoma Chief cells arranged in various patterns; follicles same as in thyroid

are present in some cases mitotic figures are rare rim of compressed, nonneoplastic parathyroid tissue, generally

separated by a fibrous capsule is often visible at the edge of the adenoma

Endocrine Atypia – bizarre & pleomorphic nuclei even w/in adenomas; not uncommon; should not be used for defining malignancy

Primary Hyperplasia may occur sporadically or as a component of MEN syndrome frequent asymmetry w/ apparent sparing of 1 or 2 glands making the

distinction b/n hyperplasia & adenoma difficult combined wt ofall glands rarely exceeds 1.0gm & is often less

Microscopically: Chief Cell Hyperplasia – most common pattern w/c may involve the glands in diffuse or multinodular pattern

water-clear cell hyperplasia – less common there are islands of oxyphils, poorly developed delicate fibrous

strands may envelop the nodules stromal fat is inconspicuous w/in the foci of hyperplasiaParathyroid Carcinomas may be fairly circumscribed lesions that are difficult to distinguish

from adenomas or may be clearly invasive neoplasms these tumors enlarge one parathyroid gland & consists of gray-

white, irregular masses that sometimes exceed 10 gm cells are usually uniform & resemble normal parathyroid cells arrayed in nodular or trabecular patterns w/ a dense, fibrous

capsule enclosing the mass Diagnosis of Ca based on cytologic detail is UNRELIABLE, & invasion

of surrounding tissues & metastasis are the only reliable criteria of malignancy

local recurrence occur in 1/3 of cases; more distant dissemination occurs in other 3rd

Morphologic Changes in other organsSkeletal Changes prominence of osteoclasts w/c erode bone matrix & mobilize

calcium salts esp in metaphyses of long tubular bones bone resorption is accompanied by osteoblastic activity &

formation of new bone trabeculae in many cases, resultant bone contains widely spaced, delicate

trabeculae same as in osteoporosis in more severe cases, cortex is grossly thinned, marrow contains

increased amts of fibrous tissue accompanied by foci of hemorrhage & cyst formation OSTEITIS FIBROSA CYSTICA

aggregates of osteoclasts, reactive giant cells, & hemorrhagic debris occasionally form masses that may be mistaken for neoplasms BROWN TUMORS of HYPERPARATHYROIDISM

Renal Lesions/ Changes PTH-induced hypercalcemia favors Nephrolithiasis (formation of

urinary tract stones) and also Nephrocalcinosis – calcification of renal interstitium &

tubules metastatic calcification secondary to hypercalcemia may also be

seen in other sites such as stomach, lungs, myocardium, & blood vessels

SECONDARY HYPERPARATHYROIDISM caused by any condition assoc w/ chronic depression in the serum

calcium level since low serum calcium leads to compensatory overactivity of the parathyroid glands

Renal Failure – by far the most common cause other conditions that may cause this include: inadequate dietary

intake of calcium, steatorrhea, vit. D deficiency chronic renal insufficiency is assoc w/ phosphate excretion

hyperphosphatemia elevated serum phosphate levels directly depress calcium levels

stimulate parathyroid gland activity loss of renal substance reduces the availability of α-1-hydroxylase

necessary for the synthesis of the active form of vit D intestinal absorption of calcium

CLINICAL COURSE


usually dominated by those assoc w/ chronic renal failure bone abnormalities (renal osteodystrophy) & other changes w/ PTH

excess are less severe than those in 1º hyperparathyroidism vascular calcification assoc w/ 2º hyperparathyroidism may

occasionally result in significant ischemic damage to skin & other organs CALCIPHYLAXIS

in a minority of pts, parathyroid activity may become autuonomous & excessive resulting to hypercalcemia TERTIARY HYPERPARATHYROIDISM

parathryoidectomy may be necessary to control hyperparathyroidism in such pts

MORPHOLOGY glands are hyperplastic degree of glandular enlargement is not necessarily symmetric Microscopically: hyperplastic glands contain # of chief cells or

water-clear cells in a diffuse or multinodular distribution fat cells are bone changes similar to those in primary hyperparathyroidism may

also be present metastatic calcification may be seen in many tissues including lungs,

heart, stomach, & blood vessels

HYPOPARATHYROIDISM far less common than hyperparathyroidism

Possible Causes of Deficient PTH secretiona) SURGICALLY INDUCED HYPOPARATHYROIDISM

- occurs w/ inadvertent removal of ALL parathyroid glands during thyroidectomy; excision of parathyroids mistaken as lymph nodes during radical neck dissection for some form of malignant dse; or removal of too large a proportion of parathyroid tissue in tx of 1º hyperparathyroidism

b) CONGENITAL ABSENCE OF ALL GLANDS- certain developmental abnormalities such as Thymic Aplasia & Cardiac Defects (22q11.2 syndrome)

c) FAMILIAL HYPOPARATHYROIDISM- often assoc w/ chronic mucocutaneous candidiasis & primary adrenal insufficiency; - syndrome known as AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 1 (APS1); caused by mutations in the AUTOIMMUNE REGULATOR gene (AIRE)- syndrome typically presents in childhood w/ onset of candidicasis followed by hypoparathyroidism & then adrenal insufficiency during adolescence

d) IDIOPATHIC HYPOPARATHYROIDISM- most likely represents an autoimmune dse w/ isolated atrophy of the glands- 60% of pts have autoantibodies against CASR (calcium-sensing receptor) in the parathyroids- antibody binding to receptor may prevent PTH release

Major Clinical manifestations of Hypoparathyroidism are referable to hypocalcemia & are related to the severity & chronicity of the hypocalcemia

TETANY - hallmark of hypocalcemia- neuromuscular irritability resulting from serum ionized calcium

concentration- findings can range from circumoral numbness or paresthesias

(tingling) of the distal extremities & carpopedal spasm to life-threatening laryngospasm & generalized seizures

- Classical findings on P.E.CHVOSTEK SIGN – elicited in subclinical dse by tapping along

the course of the facial nerve w/c induces contractions of the eye muscles, mouth or nose

TROUSSEAU SIGN – occluding the circulation to the forearm & hand by inflating a BP cuff about the arm for several minutes induces CARPAL SPASM , w/c disappears as soon as the cuff is deflated

Mental status changes : emotional instability, anxiety, depression, confusional states, hallucinations, frank psychosis

Intracranial manifestations : calcifications of the basal ganglia, parkinsonian-like mov’t d/o, intracranial pressure w/ resultant papilledema

Ocular disease : results in calcification of the lens leading to cataract formation

Cardiovascular manifestations : conduction defect w/c produces characteristic prolongation of QT interval

Dental abnormalities : dental hypoplasia, failure of eruption, defective enamel & root formation, abraded carious teeth

PSEUDOHYPOPARATHYROIDISM hypoparathyroidism occurs bcoz of END-ORGAN RESISTANCE TO THE

ACTIONS OF PTH serum PTH levels are normal or increased 2 Key Concepts in PTH Resistance

G-proteins, principally Gs mediate the cellular actions of PTH on bone & kidney

GNAS1 is a selectively imprinted gene w/ tissue-specific patterns of imprinting

in most cases, Gsα the product of GNAS1 is expressed from both alleles

in pituitary & kidney, GNAS1 is expressed only from maternally inherited chromosome, owing to paternal imprinting (silencing) of the gene

results in mutation that affects the maternal allele then complete loss of Gsα expression in the kidney, while a mutation in normally expressed paternal allele has no effect on Gsα levels

mutation of both alleles 50% in Gsα in tissues other than the kidneys &pituitary since GNAS1 is expressed from both copies of the gene

2 Types of Pseudohypoparathyroidism (depends on parent of origin of mutant allele)

a) PSEUDOHYPOPARATHYROIDISM TYPE 1A - assoc w/ multihormone resistance & Albright hereditary osteodystrophy (AHO) - skeletal & developmental defects - pts often have short stature, obesity, short metacarpal & metatarsal bones, variable mental deficits


- multihormone resistance involves: PTH, TSH, LH/FSH (all activate Gsα-mediated pathways in target tissues - PTH resistance – most obvious clinical manifestation; presenting as hypocalcemia, hypophosphatemia, elevated circulating PTH

-TSH resistance – generally mild - LH/FSH resistance – hypergonadotropic hypogonadism in

females; mutation is inherited on maternal allele, severly impeding actions of PTH on the kidney in maintaining calcium homeostasis

b) PSEUDOPSEUDOHYPOPARATHYROIDISM - mutation inherited from paternal allele - characterized by AHO w/o accompanying multihormonal resistance - serum calcium, phosphate, PTH: ALL NORMAL

PANCREAS

▪ Normal Blood glucose range: 70-120 mg/dl

▪ 3 criteria for diagnosis of diabetes:o Random glucose > 200 mg/dl + classical signs and symptomso Fasting glucose > 126 mg/dl on more than one occasiono Abnormal OGTT, in w/c glucose is >200mg/dl 2 hrs after a

standard carbo load** any one of these can establish diagnosis of diabetes

▪ Indivs w/ fasting glucose < 110mg/dl, or less than 140 mg/dl following an OGTT euglycemic

▪ Fasting glucose >110, but, <126, or OGTT > 140, but < 200 impaired glucose tolerance (IGT)

Classification

▪ The vast majority of cases of diabetes fall into one of two broad classes:

o Type 1: absolute def of insulin caused by pancreatic B-cell destruction (10%)

o Type 2: combi of peripheral resistance to insulin axn and inadequate secretory response by pancreatic B-cells

▪ The long term complications in kidneys, eyes, nerves, and blood vessels are the same as are the principal causes of morbidity and death

Normal Insulin Physiology

▪ Normal glucose homeostasis is tightly regulated by three processes:

o Glucose production in livero Glucose uptake and utilization by peripheral tissueso Actions of insulin and counter-regulatory hormones,

including glucagons, on glucose▪ Insulin and glucagons: opposing effects

▪ Fasting states, low insulin, high glucagons levels hepatic gluconeogenesis and glycogenolysis while decreasing glycogen synth prevent hypoglycemia

▪ Fasting plasma glucose levels determined primarily by hepatic glucose output

▪ Meal insulin levels rise, glucagons levels fall

Regulation of Insulin Release

▪ B-cell of the pancreatic islets

▪ Preproinsulino Synth in RER and delivered to golgi apparatuso Proteolytic steps mature insulin and C-peptideo The most important stimulus that triggers insulin

synthesis and release is glucose itselfo A rise in blood glucose levels results in glucose

uptake into pancreatic Bcells, facilitated by an insulin-independent glucose-transporting protein, GLUT-2

Insulin Action and Insulin Signaling Pathways

▪ Insulin: most potent anabolic hormone

▪ Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body (striated cells and adipocytes)

▪ Glucose uptake in other peripheral tissues is insulin-independent

▪ The anabolic effects of insulin are attributable to increased synthesis and reduced degradation of glycogen, lipids and proteins

▪ Insulin also has mitogenic functions

▪ Binding of insulin cascade of protein phosphorylation and dephosphorylation

▪ MAPK pathway: responsible for mitogenic effects

▪ PI-3K: metabolic effects

Hormone production in pancreatic islet cells. Immunoperoxidase staining shows a dark reaction product for insulin in cells (A), glucagon in cells (B), and somatostatinin cells (C)

Metabolic actions of insulin in striated muscle, adipose tissue, and liver.


Pathogenesis of Type 1 DM

▪ Most commonly develops in childhood, becomes manifest at puberty, and progress with age

▪ Can develop at any age

▪ An autoimmune dse in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined B cell antigens

Mechanisms of B cell destruction:

▪ The classic manifestation of DM (hyperglycemia and ketosis) occur late in its course

▪ T lymphocytes react against B cell antigens and cause cell damage

o CD4+ T cells of the TH1 subset w/c cause tissue injuryo CD8+ cytotoxic T cells w/c directly kill B cells and secrete

cytokines that activate macrophageso Insulitis: necrosis and lymphocytic infiltration of the

islets▪ Locally produced cytokines damage B cells

o IFN-γ, TNF, and IL-1 induce B cell apoptosis

▪ Autoantibodies againt islet cells and insulin are also detected in blood of 70% to 80% of patients

o The autoantibodies are reactive with a variety of B cell antigens, including glutamic acid decarboxylase (GAD)

Genetic Susceptibility

▪ Putative susceptibility genes have been mapped to at least 20 loci▪ The most important locus is the class II MHC (HLA)

MHC Locus

▪ Chromosome 6p21 (HLA-D)

▪ DQB1*0302 allele is considered the primary determinant of susceptibility for the HLA-DR4 haplotype

▪ HLA-DQB1*0602 allele is considered “protective” against diabetes

Non-MHC Genes

▪ The first disease-associated non-MHC gene to be identified was insulin

▪ Mechanism of association is unknown

▪ Another gene has been shown to be associated with the disease, encoding the T-cell inhibitory receptor CTLA-4

▪ Pxs with type 1 diabetes show increased frequency of a splice variant that may abrogate the normal ability of this receptor to keep self-reactive T lymphocytes under control

Environmental Factors

▪ Infections

▪ Epidemiologic studies suggest a role of viruses

▪ Association of coxsackieviruses of group B and pancreatic diseases, including diabetes

▪ Mumps, measles, CMV, rubella, and infectious mononucleosis are also implicated to trigger autoimmunity

▪ Infections induce tissue damage and inflammation, leading to release of B-cell antigens and the recruitment and activation of lymphocytes and other inflammatory leukocytes in tissues

▪ Virus produce proteins that mimic self-antigens and the immune response to the viral protein cross-reacts w/ the self tissue

Insulin action on a target cell. Insulin binds to the subunit of insulin receptor, leading to activation of the kinase activity in the -subunit, and sets in motion a hosphorylation (i.e., activation) cascade of multiple downstream target proteins.

Pathogenesis of Type 2 DM

▪ Sedentary lifestyle, dietary habits play a role

▪ Genetic factors are even more important than in type 1 DM

▪ The 2 metabolic defects that characterize type 2 diabetes are:o Decreased ability of peripheral tissues to respond to

insulino B-cell dysfunction that is manifested as inadequate

insulin secretion in the face of insulin resistance and hyperglycemia

▪ In most cases, insulin resistance is the primary event

Insulin Resistance

▪ Resistance to the effects of insulin or glucose uptake, metabolism and storage

▪ Characteristic of most pxs w/ typ2 diabetes and almost universal finding in diabetic indivs who are obese

▪ Insulin resistance is often detected 10-20 yrs before the onset of diabetes in predisposed indivs

▪ In prospective studies, insulin resistance is the best predictor for subsequent progression to diabetes

▪ Functional studies in indivs w/ insulin resistance have demonstrated numerous quantitative and qualitative abnormalities of the insulin signaling pathway, including down-regulation of the insulin receptor; decreased insulin receptor phosphorylation and tyrosine kinase activity; reduced levels of active intermediates in the insulin signaling pathway; and impairment f translocation, docking, and fusion of GLUT-4-containing vesicles w/ the plasma membrane

o Genetic defects of the insulin receptor and insulin signaling pathway

o Obesity and insulin resistance – risk for diabetes increases as the BMI increases Role of free fatty acids: inverse correlation

between fasting plasma FFAs and insulin sensitivity


Role of adipokines in insulin resistance: leptin (acts on CNS for satiety; insulin-sensitizing actions) adiponectin, resistin

Role of peroxisome proliferator-activated receptor gamma (PPAR) and thiazolidinediones (TZD): TZD acts on PPAR leading to reduction of insulin resistance

B-cell Dysfunction

▪ Reflects the inability of these cells to adapt themselves to the long-term demands of peripheral insulin resistance and increased insulin secretion▪ In states of insulin resistance, insulin secretion is initially higher for each level of glucose than in controls▪ This hyperinsulinemic state is a compensation for peripheral resistance and can often maintain normal plasma glucose for years▪ Bcell dysfunction in type 2 diabetes manifests as both qualitative and quantitative defects:

o Qualitative: initially subtle, seen as a loss of normal, pulsatile, oscillating pattern of insulin secretion and attenuation of the rapid first phase of insulin secretion and attenuation of the rapid first phase of insulin secretion triggered by an elevation of in plasma glucose

o Quantitative: reflected by a decrease in B-cell mass, islet degeneration, and deposition of islet amyloid

Monogenic Forms of Diabetes (table 24-6)

▪ Maturity-Onset Diabetes of the Young (MODY)o A primary defect in B-cell dysfunction that occurs w/o B-

cell loss, affecting either B-cell mass and/or insulin production

o Autosomal-dominant inheritance as a monogenic defect, w/ high penetrance

o Early onset, usually before age 25, as opposed to after age 0 for most pxs w/ type 2 diabetes

o Absence of obesityo Lack of islet cell autoantibodies and insulin resistance

syndromeo Glucokinase: implicated in MODY2o MODY1, 3 and 5 are associated with severe B-cell insulin

secretory defects w/ the full range of diabetic complications

o MODY2 feature mild chronic hyperglycemia that typically does not worsen over time

o Up to 50% of carriers of glucokinase mutations develop gestational DM, defined as any degree of glucose intolerance with onset or first recognition during pregnancy

o Mutations or polymorphisms in the 6 known MODY genes do not appear to contribute to the dev’t of late-onset (classic) type 2 diabetes in the vast majority of pxs

▪ Mitochondrial Diabeteso Inherited maternallyo Encodes several genes in the oxidative phosphorylation

pathway, ribosomal RNAs and 22 transfer RNAso Caused by a primary defect in B-cell function

▪ Diabetes Associated with Insulin Gene or Insulin Receptor Mutations

o Rare cause of diabetes

Pathogenesis of the Complications of Diabetes

▪ Morbidity associated w/ long-standing diabetes of either type results from a number of serious complications (macrovascular and microvascular diseases)

▪ Macrovascular dse causes accelerated atherosclerosis among diabetics increased risk of MI, stroke, and lower extremity gangrene

▪ Microvascular dse: effects are most profound in the retina, kidneys, and peripheral nerves diabetic retinopathy, nephropathy and neuropathy

▪ Diabetes is the leading cause of blindness and end-stage renal dse in the western hemisphere

▪ Most of the available experimental and clinical evidence suggests that the complications of diabetes are a consequence of the metabolic derangements, mainly hyperglycemia

▪ 3 distinct metabolic pathways:o Formation of Advanced Glycation End Products

(AGEs) see table 24-7o Activation of protein kinase Co Intracellular hyperglycemia w/ Disturbances in

Polyol pathways

Morphology of Diabetes and Its Late Complications

▪ In most pxs, morphologic changes are likely to be found in arteries (macrovascular dse), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues

Pancreas

▪ Lesions are inconstant and rarely of diagnostic value

▪ Distinctive changes more common in type 1 diabetes

▪ Reduction in number and size of islets (esp in type 1)

▪ Leukocytic infiltration of the islets (insulitis): principally compsed of T lymphocytes; may be seen in type 1 diabetes; eosinophilic infiltrates may also be found esp in infants

▪ B-cell degranulation: reflects depletion of stored insulin in already damaged B cells; more common in type 1

▪ In type 2 diabetes, there may be a subtle reduction in islet cell mass

▪ Amyloid replacement of islets in type 2 diabetes appears as deposition of pink, amorphous material beginning in and around capillaries and between cells

▪ An increase in the number and size of islets is especially characteristic of nondiabetic newborns of diabetic mothers

Diabetic Macrovascular Disease

▪ The hallmark of diabetic macrovascular disease is accelerated atherosclerosis involving the aorta and large- and medium- sized arteries

▪ MI caused by atherosclerosis of the coronary arteries is the most common cause of death in diabetics

▪ Gangrene of the lower extremities as a result of advanced vascular disease , is about 100 times more common in diabetics than in the general population

Hyaline Arteriosclerosis

▪ Vascular lesion associated with HPN


▪ More prevalent and more severe in diabetes and may be seen in elderly nondiabetics w/o HPN

Diabetic Microangiopathy

▪ One of the most consistent morphologic features of diabetes is diffuse thickening of the basement membranes

▪ Thickening is most evident in capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla

▪ Diabetic capillaries are more leaky than normal to plasma proteins

▪ The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy

Diabetic Nephropathy

▪ Kidneys are prime targets of diabetes

▪ Renal failure is only second to MI as a cause of death from this dse▪ 3 lesions: • Glomerular lesions

Renal vascular lesions, principally arteriosclerosis

Pyelonephritis, including necrotizing papillitis

▪ The most important glomerular lesions are capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerusclerosis (PAS positive nodules Kimmelstiel-Wilson lesion)

▪ Renal atherosclerosis and arteriosclerosis constitute part of the macrovascular dse in diabetics

▪ Hyaline arteriosclerosis affects not only the afferent but also the efferent arteriole

▪ Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules

▪ Necrotizing papillitis or papillary necrosis (special pattern of acute pyelonephritis), is much more prevalent in diabetics than in nondiabetics

Diabetic Ocular Complications

▪ Retinopathy, cataract formation, or glaucomaDiabetic Neuropathy

▪ Central and peripheral nervous system involvement

endocrine system - part 1 (robbins)

Documents

pituitary hormones

endocrine hormones

release of hormones

overproduction of hormones

hormone msh

pituitary stalk

peptide hormones gh