Endocrine Pathology

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09 January 08 09 January 08

--A pea-sized gland, weighs 0.5 gm & measures 1cm,A pea-sized gland, weighs 0.5 gm & measures 1cm,

attached to the hypothalamus by a stalk attached to the hypothalamus by a stalk

- Two lobes: anteroir & posterior Two lobes: anteroir & posterior

- Anterior lobe (adenohypophysis) Anterior lobe (adenohypophysis)

--derived from Rathke’s pouchderived from Rathke’s pouch

--contains cells that contains cells that secretsecrete trophic hormonese trophic hormones that activate peripheral endocrine glands that activate peripheral endocrine glands

--hypothalamic releasing hormones are deliveredhypothalamic releasing hormones are delivered via a portal venous system

via a portal venous system

-- Posterior lobe (neurohypophysis)Posterior lobe (neurohypophysis)

-- derived from outpouching from floor of 3rdderived from outpouching from floor of 3rd

ventricle ventricle

-- has a separate blood supplyhas a separate blood supply

-- consists of modified glial cells & consists of modified glial cells & axonsaxons extending from the supraoptic &

extending from the supraoptic & paraventr

paraventricular nuclei in icular nuclei in the hypothalamusthe hypothalamus

-- neurons in the supraoptic & paraventricularneurons in the supraoptic & paraventricular

nuclei pr

nuclei produce oduce ADH ADH & & oxytocinoxytocin

-- ADH & oxytocin are stored in axon terminalsADH & oxytocin are stored in axon terminals in

in the the post. post. LobeLobe

THE ADENOHYPOPHYSIS THE ADENOHYPOPHYSIS

-- FFive ive celcell tyl types pes in in the the adeadenohnohypoypophyphysis sis byby immunostaining:

immunostaining:

1-1- Lactotrophs (Mammotrophs):Lactotrophs (Mammotrophs): Prolactin (Prl) -Prolactin (Prl) -acidophils.

acidophils. 2

2- Somatotrophs- Somatotrophs: growth hormone (GH) -: growth hormone (GH) -acidophils.

acidophils.

3-3- Corticotrophs:Corticotrophs: proopiomelanproopiomelanocortin ocortin (POMC)(POMC) precurs

precursor or for for adrenocoradrenocorticotropic hormoneticotropic hormone

(ACTH), melanocyte stimulating hormone (MSH), (ACTH), melanocyte stimulating hormone (MSH),

ββ

-endorphin, and-endorphin, and

ββ

-lipotropin - basophils.-lipotropin - basophils. 4

4-- ThyrotrophsThyrotrophs:: thyroid stimulating hormone (TSH)thyroid stimulating hormone (TSH) - basophils.

- basophils.

5-5- Gonadotrophs:Gonadotrophs: follicle stimulating hormonefollicle stimulating hormone (FSH) & luteinizing hormone (LH) -

(FSH) & luteinizing hormone (LH) - basophils.basophils. Hypothalamic Releasing Hypothalamic Releasing Hormone Hormone Corresponding Anterior Corresponding Anterior Pituitary Hormone(s) Pituitary Hormone(s) Gonadotropin Gonadotropin Releasing Hormone Releasing Hormone (GnRH) * (GnRH) * Luteinizing Hormone Luteinizing Hormone (LH) (LH) Follicular Stimulating Follicular Stimulating Hormone (FSH) Hormone (FSH) Growth Hormone Growth Hormone Releasing Hormone Releasing Hormone (GRH) * (GRH) * Growth Hormone (GH) Growth Hormone (GH) Corticotropin Corticotropin Releasing Hormone Releasing Hormone (CRH) * (CRH) * Adrenocorticotropic Adrenocorticotropic Hormone (ACTH) Hormone (ACTH) Thyrotropin Releasing Thyrotropin Releasing Hormone (TRH) * Hormone (TRH) * Thyroid Stimulating Thyroid Stimulating Hormone (TSH) Hormone (TSH) Dopamine **

Dopamine ** Prolactin (PRL)Prolactin (PRL) * stimulatory

* stimulatory ** inhibitory ** inhibitory

DISEASES OF THE ADENOHYPOPHYSIS DISEASES OF THE ADENOHYPOPHYSIS

--

⇑

function:function: HyperpituitarismHyperpituitarism

--

⇓

function:function: HypopituitarismHypopituitarism

--nonfunctional adenomanonfunctional adenoma

--inflammatory lesionsinflammatory lesions

--ischemic injuryischemic injury

--mass effectsmass effects

--enlargement of sella turcicaenlargement of sella turcica

--visual field defects visual field defects (classica(classically bitemporallly bitemporal hemianopsia)

hemianopsia)

--

⇑

intracranial pressureintracranial pressure

--headache, blurrinheadache, blurring of g of visionvision

--nausea and vomitingnausea and vomiting

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P w e t s 1 of 131 of 13

PITUITARY GLAND

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CAUSES

OF HYPERPITUITARISMOF HYPERPITUITARISM 1 - Primary hypothalamic disorders (rare) 1 - Primary hypothalamic disorders (rare) 2 - Primary Pituitary Hyperplasia (rare) 2 - Primary Pituitary Hyperplasia (rare) 3 - Functioning carcinomas (extremely rare) 3 - Functioning carcinomas (extremely rare) 4 - Functioning Adenomas (MCC). Classified as: 4 - Functioning Adenomas (MCC). Classified as:

1. Prolactinomas (Prl) 1. Prolactinomas (Prl)

2. Somatotroph (GH) adenomas 2. Somatotroph (GH) adenomas 3. Corticotroph (ACTH) adenomas 3. Corticotroph (ACTH) adenomas 4. Gonadotroph (FSH/LH) adenomas 4. Gonadotroph (FSH/LH) adenomas 5. Thyrotroph (TSH) adenomas 5. Thyrotroph (TSH) adenomas 6. Pleurihormonal adenomas (GH+Prl). 6. Pleurihormonal adenomas (GH+Prl). Monoclonal but Monoclonal but

polyhormonal, or mixed-cell adenomas. polyhormonal, or mixed-cell adenomas.

HYPERPROLACTINEMIA HYPERPROLACTINEMIA (amenorrhea-galactorrhea syndrome)

galactorrhea syndrome) The MC

The MC pituitary hyperfunction syndrome. Causedpituitary hyperfunction syndrome. Caused by

by::

1- Prolactinomas; 1- Prolactinomas;

--Prl secreting adenoma (sparsely granulated,Prl secreting adenoma (sparsely granulated, chromophobic)

chromophobic)

--F/M >1, peak incidence 20-30 yrs. of ageF/M >1, peak incidence 20-30 yrs. of age

--serum prolactin levelserum prolactin level

>>

300 ug/L is diagnostic300 ug/L is diagnostic

--Rx: surgery Rx: surgery (transsphenoida(transsphenoidal)l) bromocripti

bromocriptine ne (dopamine receptor agonist)(dopamine receptor agonist) radiation

radiation

2- Hypothalamic diseases. Hypothalamus normally 2- Hypothalamic diseases. Hypothalamus normally

produces dopamine (Prl-inhibitory factor). produces dopamine (Prl-inhibitory factor).

--head trauma, etc.head trauma, etc.

--stalk effectstalk effect

3- Anti-dopaminergic drugs

3- Anti-dopaminergic drugs (phenothiazines(phenothiazines,, haloperidol)

haloperidol)

4- Estrogen therapy 4- Estrogen therapy 5- P

5- Primary rimary HypothyroidiHypothyroidism sm ((

⇑

TRHTRH

⇒

⇒ ⇑

⇑

Prl)Prl) Signs & Symptoms:

Signs & Symptoms:

-- women: galactorrhea, amenorrhea,women: galactorrhea, amenorrhea, infertility,

infertility,

⇓

libidolibido

-- men:men:

⇓

libido, impotence & libido, impotence & rarelyrarely galactorrhea &

galactorrhea & gynecomastia gynecomastia SOMA

SOMATOTROPH TOTROPH ADENOMASADENOMAS Acromegaly

Acromegaly;;

--adult onset excess growth hormone (GH)adult onset excess growth hormone (GH)

⇒

enlarge

enlargement of the skullment of the skull, facial bones, j, facial bones, jaw, aw, hands,hands, feet, soft tissues & organs.

feet, soft tissues & organs.

--diabetes, hypertension, muscle diabetes, hypertension, muscle weakness, arthritis,weakness, arthritis,

gonadal dysfunction,

gonadal dysfunction, cardiovascardiovascular diseasecular disease Gigantism

Gigantism;;

--GH excess occurs in children (before closure of GH excess occurs in children (before closure of

epiphyses). epiphyses).

--generalized increase in body sizegeneralized increase in body size

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*

* MorphologyMorphology: : macroadenomamacroadenomas, s, composed composed of of densely or

densely or sparsely granulated “acidophilic” cells,sparsely granulated “acidophilic” cells, strongly positive for GH by

strongly positive for GH by immunostains.immunostains.

-- 30% elaborate both GH and Prl (a mixed cell30% elaborate both GH and Prl (a mixed cell

adenoma or

adenoma or a single cell-type pleurihormonala single cell-type pleurihormonal adenoma).

adenoma).

-- 40% express the gsp oncogene40% express the gsp oncogene

-- GH acts indirectly byGH acts indirectly by

⇑

hepatic secretion of hepatic secretion of insulin-like growth factor-1 (IGF-1)

insulin-like growth factor-1 (IGF-1)

-- Diagnosis:Diagnosis:

--

⇑

serum GH & IGF-1serum GH & IGF-1

-- serum prolactin may be serum prolactin may be elevatedelevated

-- glucose suppression testglucose suppression test

-- imaging scans (MRI better than CAT scan)imaging scans (MRI better than CAT scan)

-- Treatment:Treatment:

-- transsphenoidatranssphenoidal l surgery, octreotidesurgery, octreotide

acetate, radiation acetate, radiation

CORTICOTROPH ADENOMAS CORTICOTROPH ADENOMAS

- MC small basophilic microadenomas that secrete - MC small basophilic microadenomas that secrete

ACTH ACTH

Cushing’s disease Cushing’s disease

--

⇑

ACTHACTH

⇒

⇒ ⇑

⇑

secretion of cortisol from the secretion of cortisol from the adrenaadrenall

glands glands

-- moon face, buffalo hump, truncal obesity,moon face, buffalo hump, truncal obesity,

abdominal striae abdominal striae

--diabetes mellitus, hirsutism and amenorrhea (ACTHdiabetes mellitus, hirsutism and amenorrhea (ACTH

stimulates

stimulates androgen androgen secretion)secretion)

--increaincreased skin sed skin pigmentation (MSH is pigmentation (MSH is secreted withsecreted with

pituitary ACTH) pituitary ACTH)

--hypertension, muscle weaknesshypertension, muscle weakness

-- Diagnosis:Diagnosis:

--24 hr urine for free cortisol & 17-24 hr urine for free cortisol &

17-hydroxycorticosteroids hydroxycorticosteroids

--plasma ACTH levelplasma ACTH level

--dexamethasone suppression testdexamethasone suppression test

--MRI scanMRI scan

Dexamethasone Suppression Dexamethasone Suppression TTestest

Pathologic Entity

Pathologic Entity LowLow Dose Dose High High Dose Dose ACTH Secreting ACTH Secreting Pituitary Adenoma Pituitary Adenoma – – ++ Cortisol Secreting Cortisol Secreting Adrenocortical Adrenocortical Neoplasm Neoplasm – – –– ACTH Secreting ACTH Secreting Nonendocrine Nonendocrine Neoplasm Neoplasm – – ––

OTHER FUNCTIONING ADENOMAS OTHER FUNCTIONING ADENOMAS Gonadotroph adenomas:

Gonadotroph adenomas:

--majority produce FSH, some FSH & LH, rarely onlymajority produce FSH, some FSH & LH, rarely only LH

LH

--MC occur in middle-aged men & womenMC occur in middle-aged men & women

--usually are macroadenomasusually are macroadenomas

--symptoms MC related only to local mass effectssymptoms MC related only to local mass effects

--may cause amenorrhea or galactorrhea,may cause amenorrhea or galactorrhea,

⇓

libido inlibido in men

men

Thyrotroph adenomas Thyrotroph adenomas

--produce TSHproduce TSH

⇒

hyperthyroidismhyperthyroidism

HYPOPITUITARISM HYPOPITUITARISM

••

Caused by either hypothalamic or pituitaryCaused by either hypothalamic or pituitary lesions:

lesions:

••

HypothalamHypothalamic lesions ic lesions : craniop: craniopharyngiomharyngioma,a, gliomas &

gliomas & teratomas; metastatic carcinoma,teratomas; metastatic carcinoma, infections

infections

••

PituiPituitary tary lesiolesions ns ::

o

o _{MCCs are: nonsecretory adenomas, Sheehan’s}_{MCCs are: nonsecretory adenomas, Sheehan’s}

syndrome, radiation or surgical ablation (of syndrome, radiation or surgical ablation (of

≥≥

75% of the gland)

o

o LCCs are: metastatic carcinoma, inflammatoryLCCs are: metastatic carcinoma, inflammatory

disorders

disorders, , infections, ginfections, genetic defects enetic defects (pit-1)(pit-1)

••

Effects:Effects:

--Isolated hormone deficiencieIsolated hormone deficiencies (e.g. GH s (e.g. GH or LH)or LH)

--Panhypopituitarism:Panhypopituitarism: in childrenin children

⇒

dwarfism &dwarfism &

infantilism (retarded physical & sexual infantilism (retarded physical & sexual development) &

development) & in adultsin adults

⇒

hypogonadism,hypogonadism, hypothyroidis

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HYPOTHALAMIC

HYPOTHALAMIC (SUPRASELLAR) (SUPRASELLAR) NEOPLASMSNEOPLASMS 1- Craniopharyngioma (MC)

1- Craniopharyngioma (MC) 2- Gliomas

2- Gliomas

3- Germ cell tumors 3- Germ cell tumors

⇒

mass effectmass effect

⇒

hypopituitarism &/orhypopituitarism &/or diabetes insipidus.

diabetes insipidus. Craniopharyngioma: Craniopharyngioma:

--Accounts for 3- 5% of intracranial tumorsAccounts for 3- 5% of intracranial tumors

--MC in the 2nd & MC in the 2nd & 3rd decades3rd decades

--derived from vestigial remnants of Rathke’s pouchderived from vestigial remnants of Rathke’s pouch

--arise in hypothalamus, may encroach on opticarise in hypothalamus, may encroach on optic

chiasm chiasm

--benign, contain epithelial elements, often cysticbenign, contain epithelial elements, often cystic

with

with calcificaticalcificationon

--rupture of cystic tumorsrupture of cystic tumors

⇒

inflammatory reactioninflammatory reaction

NON-SECRETORY ADENOMAS NON-SECRETORY ADENOMAS -

- 20% 20% of of pituitary pituitary adenomasadenomas

--MC in 4th decade of lifeMC in 4th decade of life

-

- May grMay grow to ow to a a large large size (macroadenomas = size (macroadenomas = >1>1 cm).

cm).

--

⇒

local mass effect (headache & visuallocal mass effect (headache & visual disturbances

disturbances), ), and and panhypopituitarpanhypopituitarismism (hypogonadism, hypothyroidism & (hypogonadism, hypothyroidism & hypoadrenalism).

hypoadrenalism). Histologically:

Histologically:

--most consist of cmost consist of chromophobic chromophobic cells ells or intenselyor intensely

eosinophilic cells (oncocytomas) eosinophilic cells (oncocytomas)

--usually are sparsely granularusually are sparsely granular

--

often stain negative for hormones with

immunostains

SHEEHAN’S SYNDROME SHEEHAN’S SYNDROME =

= Post-parPost-partum ischemic necrtum ischemic necrosis of the anteriorosis of the anterior pituitary.

pituitary.

Precipitated by obstetric hemorrhage or shock Precipitated by obstetric hemorrhage or shock

⇒

destruction of

≥≥

75% of the gland.75% of the gland. Pedisposing factors:

Pedisposing factors:

--Anterior pituitary doubles in size duringAnterior pituitary doubles in size during

pregnancy pregnancy

--low pressure portal system unable tolow pressure portal system unable to

⇑

bloodblood

supply supply

--abrupt onset of hypotensionabrupt onset of hypotension

⇒

hypoperfusionhypoperfusion

⇒

infarction. infarction. Morphology: Morphology:

Early: gland is swollen, soft & hemorrhagic. Early: gland is swollen, soft & hemorrhagic. Later: replaced by a shrunken fibrous scar. Later: replaced by a shrunken fibrous scar. Effects:

Effects:

Failure of lactation, amenorrhea, hypothyroidism, Failure of lactation, amenorrhea, hypothyroidism, hypoadrenalism & decreased skin pigmentation. hypoadrenalism & decreased skin pigmentation. Poster

Posterior lobe: usually is ior lobe: usually is not affectednot affected POSTERIOR PITUITARY SYNDROMES POSTERIOR PITUITARY SYNDROMES ADH Deficiency (Diabetes Insipidus): ADH Deficiency (Diabetes Insipidus):

--

⇓

ADHADH

⇒

decreased reabsorption of free waterdecreased reabsorption of free water

--urine of low specific gravity, with inability tourine of low specific gravity, with inability to

concentrate it concentrate it

--polyuria, polydypsia and hypernatremiapolyuria, polydypsia and hypernatremia

--caused by hycaused by hypothalamic or pothalamic or pituitary lepituitary lesions;sions;

idiopathic idiopathic

--corrected readily by ADH administration.corrected readily by ADH administration.

Inappropriate ADH Secretion (SIADH) Inappropriate ADH Secretion (SIADH)::

--

⇑

ADHADH

⇒

excessive reabsorption of free waterexcessive reabsorption of free water

--oliguria, urine of high oliguria, urine of high specific gravity, withspecific gravity, with

inability

inability to to dilute dilute it, it, and and hyponatremhyponatremiaia

--due to a compensatorydue to a compensatory

⇑

in ANPin ANP

⇒

nono

hypervolemia, no

⇑

BP and no peripheral edemaBP and no peripheral edema

--neurologic dysfunction: most likely 2neurologic dysfunction: most likely 200toto

hyponatremia hyponatremia

--MCC is ectopic ADH secretion by a small cellMCC is ectopic ADH secretion by a small cell

carcinoma

of

the lungthe lung

--Rx: fluid Rx: fluid restrictirestrictionon

Embryology: Embryology:

--the thyroid develops from the primitive pharynxthe thyroid develops from the primitive pharynx THYROID GLAND

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--the developing thyroid is attached to the base of the developing thyroid is attached to the base of the tongue by the

the tongue by the thyroglossathyroglossal ductl duct

--the thyroid descends in the midline & assumes itsthe thyroid descends in the midline & assumes its final position in the anterior neck below the larynx final position in the anterior neck below the larynx

--excessive descent gives rise to a substernalexcessive descent gives rise to a substernal thyroid & incomplete descent

thyroid & incomplete descent

⇒

ectopic thyroidectopic thyroid higher in the neck or tongue

higher in the neck or tongue

--persistencpersistence of e of remnants of the thyroglossal ductremnants of the thyroglossal duct can

can

⇒

thyroglossathyroglossal duct l duct cystcyst

HYPERTHYROIDISM HYPERTHYROIDISM

=

= a a hypermetabohypermetabolic lic state, caused state, caused by increasedby increased levels of circulating T3 & T4.

levels of circulating T3 & T4.

Effects: nervousness, warm moist skin, fine Effects: nervousness, warm moist skin, fine

tremors, palpitations, rapid pulse, exophthalmos, tremors, palpitations, rapid pulse, exophthalmos, weight loss, heat intolerance, muscle atrophy & weight loss, heat intolerance, muscle atrophy & weakness, osteoporosis

weakness, osteoporosis Most Common

Most Common Causes: Graves’ disease, toxicCauses: Graves’ disease, toxic multinodular goiter, toxic adenoma

multinodular goiter, toxic adenoma Less Common Causes:

Less Common Causes:

--thyroiditthyroiditis, struma is, struma ovarii, toxic carcinomaovarii, toxic carcinoma

- TSH-secr

TSH-secreting eting pituitary adenomapituitary adenoma

--overtreatment with thyroid hormone tabletsovertreatment with thyroid hormone tablets

(factitious

(factitious hyperthyroihyperthyroidism)dism) HYPOTHYROIDISM

HYPOTHYROIDISM =

= a hypometabolic a hypometabolic state causstate caused by deficieed by deficiency of T3ncy of T3 & T4.

& T4.

Cretinism

Cretinism (congenital (congenital hypothyroidihypothyroidism)sm)

--Clinical: Clinical: severe severe mental mental retardation; retardation; shortshort

stature

stature; coarse ; coarse facial features, protruding tonguefacial features, protruding tongue - Causes:

- Causes:

--Endemic - due to dietary iodine deficiencyEndemic - due to dietary iodine deficiency

--SporadicSporadic

--thyroid dysgenesisthyroid dysgenesis

--inherited defects in thyroid hormoneinherited defects in thyroid hormone synthesis

synthesis

--inherited peripheral tissue resistance toinherited peripheral tissue resistance to thyroid hormone

thyroid hormone Myxedema

Myxedema (hypothyroidi(hypothyroidism in sm in adults)adults)

-- fatigue, lethargy, slowed speech, mentalfatigue, lethargy, slowed speech, mental

sluggishness sluggishness

-- cold intolerance, weight gain, constipationcold intolerance, weight gain, constipation

--

⇓

sweating, bradycardiasweating, bradycardia

-- accumulation accumulation of of ECM subsECM substancestances

(glycosaminoglycans) (glycosaminoglycans)

-- coarsening of facial features, nonpittingcoarsening of facial features, nonpitting

edema edema Causes: Causes:

-- MCC is MCC is Hashimoto’s thyroiditisHashimoto’s thyroiditis..

-- surgicasurgical ablation l ablation or radiationor radiation

-- iodine deficiencyiodine deficiency

-- drugs (e.g. propylthiouracil, lithium)drugs (e.g. propylthiouracil, lithium)

-- idiopathic primary idiopathic primary hypothyroidishypothyroidismm

-- hypothalamic hypothalamic & pituita& pituitary ry disordersdisorders

HASHIMOTO’S THYROIDITIS HASHIMOTO’S THYROIDITIS -

- MCC MCC of of hypothhypothyroidism yroidism in in areas areas where where iodineiodine intake is adequate

intake is adequate Clinically:

Clinically:

--seen predominately in middle-aged womenseen predominately in middle-aged women

--hypothyroidishypothyroidism with m with painless enlargempainless enlargement of ent of thethe

gland gland

--may have transient thyrotoxicosis early onmay have transient thyrotoxicosis early on

Physiologi

Physiologic Effects c Effects of of Thyroid Hormones Thyroid Hormones • • gluconeogenesis,gluconeogenesis, glycogenolysis, glycogenolysis,

lipolysis & ATPase’s lipolysis & ATPase’s

•

• basal metabolic rabasal metabolic rate &te &

heat heat

production production

•

• protein catabolismprotein catabolism •

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--familial predispositifamilial predisposition, associated on, associated with HLA-DR3with HLA-DR3

or HLA-DR5 or HLA-DR5 Pathogenesis: Pathogenesis:

--defective function of defective function of thyroid-specthyroid-specific suppressorific suppressor

T cells

⇒

emergence of helper T cells reactiveemergence of helper T cells reactive with thyroid antigens

with thyroid antigens

--helper T cells stimulate B cells to secretehelper T cells stimulate B cells to secrete

antithyr

antithyroid oid antibodies, directed against: thyroidantibodies, directed against: thyroid peroxidase, TSH-receptors, iodine transporter, & peroxidase, TSH-receptors, iodine transporter, & thyroglobulin

thyroglobulin, , etc.etc.

--thyroid injury is mediated by complement thyroid injury is mediated by complement fixingfixing cytotoxic

cytotoxic

antibodies, ADCC & CD8+ cytotoxic cells antibodies, ADCC & CD8+ cytotoxic cells

GRA

GRAVES’ DIVES’ DISEASESEASE Clinical:

Clinical:

--MCC of hyperthyroidism, peak incidence 20-40MCC of hyperthyroidism, peak incidence 20-40

y/o y/o

--a disease of females (F/M 10:1), affects 1-2% of a disease of females (F/M 10:1), affects 1-2% of

women in US women in US

--hyperthyrhyperthyroidism, oidism, symmetrical thyroidsymmetrical thyroid

enlargement enlargement

--opthalmopathy and dermopathy opthalmopathy and dermopathy (pretibia(pretibiall

myxedema) myxedema)

--familial predisposition, associated with HLA-B8 &familial predisposition, associated with HLA-B8 &

HLA-DR3 HLA-DR3

--Laboratory values:Laboratory values:

⇑

T3 & T4,T3 & T4,

⇓

TSH andTSH and

⇑

radioactive iodine uptake radioactive iodine uptake Pathogenesis:

Pathogenesis:

--An abnormality in T-suppressor cellsAn abnormality in T-suppressor cells

⇒

T-helperT-helper

cells that react to thyroid Ag’s

⇒

elaboration of B-elaboration of B-cell clones capable of

cell clones capable of producing autoantibodiesproducing autoantibodies reactive with TSH receptors.

reactive with TSH receptors.

--IgG antibodies directed against TSH IgG antibodies directed against TSH receptorreceptors,s,

act as agonists

⇒

⇒ ⇑

⇑

thyroid hormone secretion.thyroid hormone secretion. -

- The autoaThe autoantibodies ntibodies were were originally originally called called longlong acting thyroid stimulator (LATS), because the acting thyroid stimulator (LATS), because the peak secretion of thyroid hormone occurs 16 peak secretion of thyroid hormone occurs 16 hours after the exposure of thyroid tissue to hours after the exposure of thyroid tissue to antibody, compare

antibody, compared with 2 hod with 2 hours for TSH.urs for TSH.

Therapy:

ββ

-blockers, propylthiouracil, potassium-blockers, propylthiouracil, potassium iodide, radioiodine ablation, surgery

iodide, radioiodine ablation, surgery

GOITER GOITER

= enlargement of the thyroid, MC

= enlargement of the thyroid, MC manifestation of manifestation of thyroid disease

thyroid disease

--

⇓

hormone synthesishormone synthesis

⇒

⇒ ⇑

⇑

TSHTSH

⇒

hyperplasia &hyperplasia & hypertrophy of follicular cells

hypertrophy of follicular cells

⇒

gross enlargementgross enlargement Diffuse nontoxic goiter:

Diffuse nontoxic goiter:

--endemicendemic

--iodine deficiencyiodine deficiency

--goitrogens (e.g. cabbage, goitrogens (e.g. cabbage, cauliflower,cauliflower, turnips, cassava root)

turnips, cassava root)

--sporadicsporadic

--goitrogensgoitrogens

--hereditary defect in thyroid hormonehereditary defect in thyroid hormone synthesis

synthesis

--Clinical:Clinical: most patients are euthyroidmost patients are euthyroid

MULTINODULAR GOITER MULTINODULAR GOITER =

= nodular enlarnodular enlargement, derivgement, derived from diffuse goiteed from diffuse goiterr

--both monoclonal & polyclonal nodulesboth monoclonal & polyclonal nodules

(adenomatous goiter) (adenomatous goiter) Clinical:

Clinical:

--most patients are euthyroidmost patients are euthyroid

--mass effects: compression of trachea, vessels &mass effects: compression of trachea, vessels &

nerves, & dysphagia nerves, & dysphagia

--hyperthyrhyperthyroidism oidism (toxic (toxic multinodular multinodular goiter)goiter)

--due to a hyperfunctioning noduledue to a hyperfunctioning nodule

--not accompanied by opthalmopathy ornot accompanied by opthalmopathy or dermopathy

dermopathy

* Morphology: massive enlar

* Morphology: massive enlargement (up to gement (up to >2000>2000 gm), nodules, with a

gm), nodules, with a mixture of hyperplastic &mixture of hyperplastic & dilated follicles, involutional

dilated follicles, involutional changes: hemorrhage,changes: hemorrhage, fibrosis,

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THYROID NEOPLASMS THYROID NEOPLASMS -

- Solitary nodules Solitary nodules are are more more likely likely to be to be neoplastic.neoplastic. -

- Nodules Nodules in younger in younger patients patients (< 40 (< 40 years) years) & in& in males are more likely to be neoplastic.

males are more likely to be neoplastic. -

- Most Most neoplasms neoplasms (>90%) (>90%) are are benign benign (adenomas).(adenomas). -

- FunctiFunctioning (hot) oning (hot) nodules nodules on scion scintiscans ntiscans areare usually benign

usually benign

--Up to 10% oUp to 10% of cold nodules are malignantf cold nodules are malignant -

- Diagnosis Diagnosis can be can be made by made by fine neefine needle asdle aspirationpiration biopsy, or else by surgical excision biopsy.

biopsy, or else by surgical excision biopsy. THYROID ADENOMA

THYROID ADENOMA -

- adenomas accadenomas account for > 90% of ount for > 90% of thyroid tumorsthyroid tumors

--thyroid adenomas are not premalignantthyroid adenomas are not premalignant

Gross: a sharply demarcated solitary nodule Gross: a sharply demarcated solitary nodule Histology: a fibrous capsule separates the Histology: a fibrous capsule separates the neoplastic tissue from the surrounding neoplastic tissue from the surrounding

compressed gland. Patterns may be: trabecular compressed gland. Patterns may be: trabecular (embryonal), microfollicular (fetal)

(embryonal), microfollicular (fetal) macrofollimacrofollicularcular and Hurthle cell (oncocytic) adenomas

and Hurthle cell (oncocytic) adenomas -

- most most commonly commonly cold cold (nonfunctioning) (nonfunctioning) on on RI-scanRI-scan

--rarelrarely hot y hot (functioning) & may cause(functioning) & may cause

hyperthyroidism hyperthyroidism

THYROID CARCINOMA THYROID CARCINOMA -

- uncommon in uncommon in the US the US (~ 1.5% (~ 1.5% of all of all cancers).cancers). -

- major risk major risk facrtor is facrtor is exposure to exposure to radiationradiation Variants include:

Variants include: 1-

1- papillary papillary carcinoma carcinoma 80%80% 2-

2- follicular follicular carcinoma carcinoma 15%15% 3-

3- medullary medullary carcinoma carcinoma 5%5% 4-

4- anaplastic anaplastic carcinoma carcinoma rarerare PAPILLARY CARCINOMA

PAPILLARY CARCINOMA

--MC form of thyroid CaMC form of thyroid Ca

--Peak incidence: 3rd-5th decades, F > M.Peak incidence: 3rd-5th decades, F > M.

--Gene rearrangement on chromosome 10Gene rearrangement on chromosome 10

⇒

constitutive expre

constitutive expression of ssion of tyrosine kinase domain of tyrosine kinase domain of RET protooncogene

RET protooncogene

⇒

papillary thyroid carcinomapapillary thyroid carcinoma oncogene (RET/PTC)

oncogene (RET/PTC) -

- Often Often multifocal, multifocal, spreads spreads to lymph to lymph nodes nodes in 50%in 50% of cases, but distant spread in only 5%.

of cases, but distant spread in only 5%. *

* Gross: unencapsulated,iGross: unencapsulated,infiltrative, often cysticnfiltrative, often cystic with foci of

with foci of fibrosis & calcification.fibrosis & calcification.

* Histology: papillary fronds, empty looking nuclei * Histology: papillary fronds, empty looking nuclei

“Orphan Annie eye”, nuclear grooves & “Orphan Annie eye”, nuclear grooves & psammoma bodies.

psammoma bodies.

* Variants: encapsulated, follicular, tall cell * Variants: encapsulated, follicular, tall cell * Prognosis: 90% survival at 20 years. * Prognosis: 90% survival at 20 years.

FOLLICULAR CARCINOMA FOLLICULAR CARCINOMA -

- peak peak incidence: incidence: 5th-6th 5th-6th decades, decades, F F > M.> M.

--incidence isincidence is

⇑

in areas of dietary iodine deficiencyin areas of dietary iodine deficiency

* Gross: varies from well circumscribed to * Gross: varies from well circumscribed to

extensively invasive extensively invasive

* Histology: MC small uniform

* Histology: MC small uniform follicles containingfollicles containing colloid

colloid

with capsular and vascular invasion (sure sign of with capsular and vascular invasion (sure sign of malignancy).

malignancy).

* Variants: trabecular, Hurthle cell * Variants: trabecular, Hurthle cell

-

- spreads widely spreads widely to distant organs: to distant organs: bones, lungs,bones, lungs, liver, etc.

liver, etc.

- tumor tissue may

- tumor tissue may take up radioactive iodinetake up radioactive iodine

--patients often Rx’ed postop with patients often Rx’ed postop with thyroidthyroid

hormones to

⇓

TSHTSH

* Prognosis: depends on tumor stage, 25 to 45% * Prognosis: depends on tumor stage, 25 to 45%

10-yr survival rate for widely invasive tumors yr survival rate for widely invasive tumors

(8)

MEDULLARY CARCINOMA MEDULLARY CARCINOMA

-- NeurNeuroendoendocrinocrine tumor e tumor of C ceof C cells, lls, secrsecreteete calcitonin

calcitonin

--May May also secralso secrete: CEA, serete: CEA, serotoin, somatostatin, otoin, somatostatin, VIP,VIP,

ACTH, etc. ACTH, etc.

-- SporaSporadic or fadic or familimilial (aal (associssociated wated with MEith MEN IIa & IIbN IIa & IIb,, etc., in

etc., in

20% of cases) 20% of cases) -

- FFamilial cases are amilial cases are associated with germ lineassociated with germ line mutations in RET

mutations in RET * Gross:

* Gross: sporadic casessporadic cases: discrete tumor in one lobe,: discrete tumor in one lobe, peak incidence 5th-6th decades.

peak incidence 5th-6th decades. MEN-associated MEN-associated :: multicentric & bilateral , peak 3rd-4th decades multicentric & bilateral , peak 3rd-4th decades * Histology: cell nests or trabeculae, amyloid * Histology: cell nests or trabeculae, amyloid

deposits in the stroma, C cell

deposits in the stroma, C cell hyperplasihyperplasia, + a, + forfor calcitonin, chromograni

calcitonin, chromogranin, - n, - for thyroglobulinfor thyroglobulin * Prognosis: overall 5-yr survival rate is 60 to 80%, * Prognosis: overall 5-yr survival rate is 60 to 80%, survival rates are better in familial cases due to survival rates are better in familial cases due to screening programs, serum calcitonin & CEA screening programs, serum calcitonin & CEA levels are monitored post-op

levels are monitored post-op

-- TherThere are are usuae usually flly four glour glands (ands (they cthey can be aan be ass many as 12), weighting 30 to

many as 12), weighting 30 to 40 mg each,40 mg each,

situated in close proximity to the

situated in close proximity to the upper and lowerupper and lower poles of each thyroid lobe

poles of each thyroid lobe

-- HistHistologyology: compose: composed of chief ced of chief cells (thlls (the majore majority)ity) and fat cells. The chief cells may undergo

and fat cells. The chief cells may undergo transition to oxyphil cells (mitochondria), and transition to oxyphil cells (mitochondria), and water clear cells (glycogen).

water clear cells (glycogen). -- chichief cef cellells ss secrecrete ete PTHPTH

--secretisecretion of PTH on of PTH is regulated by the level of freeis regulated by the level of free

Ca Ca++++

--

⇑

PTH secretionPTH secretion

⇒

⇒ ⇑

⇑

serum Ca++ by:serum Ca++ by:

1. increasing synthesis of 1,25-(OH)2D, thus 1. increasing synthesis of 1,25-(OH)2D, thus enhancing

enhancing

absorption of calcium from GIT. absorption of calcium from GIT. 2. activating

2. activating osteoclastsosteoclasts

⇒

mobilizingmobilizing calcium from bone

calcium from bone

3. increasing renal tubular reabsorption of 3. increasing renal tubular reabsorption of calcium

calcium while while increasing increasing urinary urinary phosphatphosphatee excretion

excretion

--Causes of hypercalcemiaCauses of hypercalcemia::

--autonomous PTH autonomous PTH hypersecrhypersecretionetion

--osteolytic metastasesosteolytic metastases

--PTH-related protein (PTHrP)PTH-related protein (PTHrP)

PRIMARY HYPERPARATHYROIDISM PRIMARY HYPERPARATHYROIDISM =

= autonomous hypautonomous hypersecrersecretion of etion of PTH.PTH. -- AcAccoucounts fnts for up tor up to 90% oo 90% of casf cases of es of

hypercalcemia. hypercalcemia.

-- PePeak inak incidecidence 6tnce 6th decah decade & olde & older, der, F > M.F > M. -- Most cMost cases ases are are sporsporadicadic, but fe, but few casw cases ares aree

familial (associated with MEN I & MEN IIA) familial (associated with MEN I & MEN IIA) Causes: Causes: 1- Parathyroid adenoma (80%), 1- Parathyroid adenoma (80%), 2- Primary hyperplasia (15%), 2- Primary hyperplasia (15%), 3- Carcinoma (<5%) 3- Carcinoma (<5%) * Morphology: * Morphology:

••

Adenoma Adenoma

--solitary & encapsulated, may consist of any of solitary & encapsulated, may consist of any of the 3 cell types

the 3 cell types

--remaining glands are normal toremaining glands are normal to

⇓

in sizein size PARATHYROID GLANDS

(9)

--may be in an ectopic locationmay be in an ectopic location

••

HyperplasiaHyperplasia

--classically all 4 glands are involvedclassically all 4 glands are involved

--may be nodular or diffusemay be nodular or diffuse

••

CarcinomaCarcinoma

--solitary, dense capsule, may exceed 10 gmsolitary, dense capsule, may exceed 10 gm

--cytologic features are not reliable, presence of cytologic features are not reliable, presence of invasion

invasion

or metastases required to make Dx or metastases required to make Dx * Clinical Features:

* Clinical Features: - asymptomatic - asymptomatic

-- 90% are asymptomatic & discovered on90% are asymptomatic & discovered on

routine

routine blood blood teststests

-- Ca++ & PTH levels areCa++ & PTH levels are

⇑

-- symptomaticsymptomatic

-- 10% are symptomatic10% are symptomatic

-- osteitis fibrosa cysticaosteitis fibrosa cystica

-- bone pain, pathologic Fx’sbone pain, pathologic Fx’s

--

⇑

bone resorption with bone resorption with expansilexpansilee areas (brown tumors)

areas (brown tumors)

-- nephrolithiasisnephrolithiasis

-- metastatic metastatic calcificatcalcificationion

-- GI Sx’s: constipaton, nausea, peptic ulcers,GI Sx’s: constipaton, nausea, peptic ulcers,

pancreatitis pancreatitis

-- CNS Sx’s: depression, lethargy, seizuresCNS Sx’s: depression, lethargy, seizures

-- NM Sx’s: weakness, fatigueNM Sx’s: weakness, fatigue

SECONDARY HYPERPARATHYROIDISM SECONDARY HYPERPARATHYROIDISM =

= Compensatory hypCompensatory hypersecreersecretion of PTH due ttion of PTH due too hypocalcemia

hypocalcemia

--renal failurerenal failure

--vit. D deficiencyvit. D deficiency

* Morphology: * Morphology:

--hyperplasia of all (4) parathyroid glandshyperplasia of all (4) parathyroid glands

--skeletal skeletal changes of changes of “renal “renal osteodystosteodystrophy”rophy”

--metastatic calcificationmetastatic calcification

* Clinical: few

* Clinical: few cases develop “tertiary”cases develop “tertiary” hyperparathy

hyperparathyroidism, looks identical to roidism, looks identical to primaryprimary hyperplasia

hyperplasia

HYPOPARATHYROIDISM HYPOPARATHYROIDISM =

= PTH deficPTH deficiency & iency & hypocalcemiahypocalcemia

--neuromusculneuromuscular ar irritabiirritability lity (tetany): carpopedal(tetany): carpopedal

spasm, laryngospasm, mental status changes, spasm, laryngospasm, mental status changes, convulsions

convulsions

--cardiacardiac c conduction abnormalitiesconduction abnormalities

--calcificacalcification of tion of the eye lens (cataract)the eye lens (cataract)

--calcification of the basal ganglia (Parkinsonism),calcification of the basal ganglia (Parkinsonism),

⇑

ICP (headache & papilledema). ICP (headache & papilledema).

--MCC: surgical excisMCC: surgical excision of ion of all glands (during totalall glands (during total

thyroidectomy). thyroidectomy).

--LCC: congenital LCC: congenital parathyroiparathyroid d agenesis (DiGeorge’sagenesis (DiGeorge’s

syndrome), primary (idiopathic) atrophy syndrome), primary (idiopathic) atrophy -autoimmune damage

autoimmune damage

--Lab. data:Lab. data:

⇓

serum Caserum Ca++++&&

⇓

serum PTH level.serum PTH level.

PSEUDOHYPOPARA

PSEUDOHYPOPARATHYROIDISM

THYROIDISM (PHP)

(PHP)

=

= Hypocalcemia Hypocalcemia and hyperphand hyperphosphatemia, osphatemia, with:with:

--

⇑

serum levels of PTH with hyperplasia of theserum levels of PTH with hyperplasia of the

parathyr

parathyroid oid glandsglands

--no osteitis fibrosa cysticano osteitis fibrosa cystica

--no vitamin D deficiency or renal failure.no vitamin D deficiency or renal failure.

* Pathogenesis: end-organ resistance to PTH, i.e. * Pathogenesis: end-organ resistance to PTH, i.e.

kidneys & bone do not respond to PTH kidneys & bone do not respond to PTH stimulation.

stimulation.

* Clinical Features: similar to hypoparathyroidism * Clinical Features: similar to hypoparathyroidism

(tetany, etc.) (tetany, etc.)

o

o _{PHP type 1 -}_{PHP type 1 -}

⇓

_{cyclic AMP response to PTH}_{cyclic AMP response to PTH}

(deficiency

(deficiency of of GGssαα ) short stature, round) short stature, round

face, short neck, short metacarpals & face, short neck, short metacarpals & metatarsals (Albright hereditary metatarsals (Albright hereditary osteodystrophy).

osteodystrophy).

o

o PHP type PHP type 2 - 2 - normal cyclic AMP normal cyclic AMP response toresponse to

PTH, but with

⇓

response to cyclic AMP,response to cyclic AMP, phenotypicall

(10)

PSEUDOPSEUDOHYPOPARATHYROIDISM PSEUDOPSEUDOHYPOPARATHYROIDISM -

- In PHP In PHP type 1, type 1, other familother family members y members may emay exhibitxhibit the physical features of

the physical features of Albright hereditaryAlbright hereditary osteodystrophy (short stature, round face, short osteodystrophy (short stature, round face, short neck, short metacarpals & metatarsals) but are neck, short metacarpals & metatarsals) but are metabolically normal, with normal serum calcium metabolically normal, with normal serum calcium & normal PTH, i.e. false (pseudo)

& normal PTH, i.e. false (pseudo) pseudohypoparathyroidism. pseudohypoparathyroidism.

-- CompoComposed of twsed of two distio distinct uninct units: stets: steroid sroid secrecretingeting cortex

cortex & catech& catecholamine prolamine producing medullaoducing medulla -- In the In the adultadult, the n, the normaormal adrl adrenal enal weigweighs 4 gmhs 4 gm.. -- The coThe cortex crtex consisonsists of thrts of three funcee functionational zonesl zones::

1 - zona glomerulosa 1 - zona glomerulosa

2 - zona fasciculata (75% of the

2 - zona fasciculata (75% of the cortex)cortex) 3 -

3 - zona reticulariszona reticularis

-- The coThe cortex srtex secrecretes tetes threhree types oe types of sterf steroidoid hormones:

hormones: 1 -

1 - mineralocortimineralocorticoids (aldosterone) - zonacoids (aldosterone) - zona glomerulosa.

glomerulosa.

2 - glucocorticoids (cortisol) - zona 2 - glucocorticoids (cortisol) - zona fasciculata

fasciculata mainlymainly..

3 - sex steroids (testosterone) - zona 3 - sex steroids (testosterone) - zona reticularis

reticularis mainlymainly..

Cortisol Cortisol::

--regulateregulated by d by ACTH (& hypothalamic CRH)ACTH (& hypothalamic CRH)

--inhibits release of CRH & ACTHinhibits release of CRH & ACTH

--circulacirculates in the tes in the blood bound blood bound to plasma proteinsto plasma proteins

--free unbound cortisol is physiologically active &free unbound cortisol is physiologically active &

enters target cells by diffusion enters target cells by diffusion

--binds to binds to cytoplasmic receptorscytoplasmic receptors, then , then translocatedtranslocated

into the nucleus where it binds to into the nucleus where it binds to hormone-responsive elements

responsive elements altering expraltering expression of ession of specificspecific genes.

genes.

* Biologic effects: * Biologic effects:

--

⇑

gluconeogenesis &gluconeogenesis &

⇓

uptake of glucose by fat &uptake of glucose by fat & muscle

muscle

--

⇓

protein synthesis &protein synthesis &

⇑

protein degradationprotein degradation

--

⇑

vascular tone & vascular tone & some mineralocorticoidsome mineralocorticoid activity

activity

--anti-inflammatanti-inflammatory ory & immunosuppressive effects& immunosuppressive effects Aldosterone

Aldosterone:: -

- Accounts for Accounts for 95% 95% of of mineralocormineralocorticoid activityticoid activity..

--regulateregulated by d by renin-angrenin-angiotensin & iotensin & potassium levels.potassium levels.

--aldosteraldosterone promotes reabsorption of one promotes reabsorption of sodium andsodium and

excretion of potassium. excretion of potassium.

--excess aldosteroneexcess aldosterone

⇒

hypernatremia &hypernatremia &

hypokalemia

⇒

hyper-volemiahyper-volemia

⇒

hypertension.hypertension. Testosterone

Testosterone::

--Excess testosterone in females causesExcess testosterone in females causes

defemenization & virilization; (hirsutism, acne, defemenization & virilization; (hirsutism, acne, amenorrhea, clitoral enlargement, atrophy of the amenorrhea, clitoral enlargement, atrophy of the breasts & uterus, deepening of the

breasts & uterus, deepening of the voice & frontalvoice & frontal balding).

balding).

ADRENAL GLAND

(11)

--In boys, excess testosterone leads to precociousIn boys, excess testosterone leads to precocious

puberty. puberty.

DISEASES OF ADRENAL CORTEX DISEASES OF ADRENAL CORTEX Hyperfunction

Hyperfunction (hyperadrena(hyperadrenalism):lism): -- CCuusshhiinngg’’s s ssyynnddrroommee -- HHyyppeerraallddoosstteerroonniissmm -- AAddrreennooggeenniittaal l ssyynnddrroommeess Hypofunction

Hypofunction (hypoadren(hypoadrenalism):alism):

-- AcAcute (e.g. ute (e.g. WWatatererhouhouse-se-FFririderderichichsesenn Syndrome)

Syndrome) -- CChhrroonniicc::

--primary (due to primary (due to adrenal corticaladrenal cortical insufficiency

insufficiency, , e.g. Addison’s e.g. Addison’s disease)disease)

--secondary (due to ACTH deficiency)secondary (due to ACTH deficiency)

--tertiary (rarely - due to hypothalamic CRHtertiary (rarely - due to hypothalamic CRH deficiency). deficiency). CUSHING’S SYNDROME CUSHING’S SYNDROME Etiology: Etiology:

1- Exogenous: high dose cortisone therapy (MCC). 1- Exogenous: high dose cortisone therapy (MCC). 2- Pituitary hypersecreti

2- Pituitary hypersecretion of on of ACTH (Cushing’sACTH (Cushing’s disease), accounts for 70% of

disease), accounts for 70% of endogenousendogenous hypercorti

hypercortisolism. solism. Associated Associated withwith hyperpigmentat

hyperpigmentation of the ion of the skin (skin (

↑

MSH).MSH). 3- Autonomous hypersecretion of cortisol by 3- Autonomous hypersecretion of cortisol by anan

adrenal adenoma, carcinoma or primary adrenal adenoma, carcinoma or primary hyperplasia (i.e. ACTH independent). hyperplasia (i.e. ACTH independent). 4- Ectopic production of ACTH or CRH by 4- Ectopic production of ACTH or CRH by

nonendocrine neoplasms (bronchogenic small cell nonendocrine neoplasms (bronchogenic small cell carcinoma).

carcinoma).

* Clinical features: truncal obesity, moon face, * Clinical features: truncal obesity, moon face, hirsutism, cutaneous striae, muscle

hirsutism, cutaneous striae, muscle weakness,weakness, osteoporosis, hypertension & hyperglycemia; osteoporosis, hypertension & hyperglycemia; Changes are reversible if the cause is corrected. Changes are reversible if the cause is corrected. * Morphology:

* Morphology:

•

•Cushing’s disease: ACTH is elevatedCushing’s disease: ACTH is elevated

⇒

adrenalsadrenals

are bilaterally hyperplastic. Changes are the are bilaterally hyperplastic. Changes are the same with ectopic ACTH or CRH.

same with ectopic ACTH or CRH.

•

•Adrenocortical neoplasms: uninvolved adrenalAdrenocortical neoplasms: uninvolved adrenal

cortex is usually atrophic due to

cortex is usually atrophic due to ACTHACTH suppression.

suppression. •

•Adenomas are small & cytologically blandAdenomas are small & cytologically bland appearing

appearing •

•Carcinomas are large & often anaplasticCarcinomas are large & often anaplastic

* Diagnosis: 24 hr

* Diagnosis: 24 hr urine free cortisol, plasma ACTH,urine free cortisol, plasma ACTH, Dexamethasone Suppression Test

Dexamethasone Suppression Test PRIMARY HYPERALDOSTERONISM PRIMARY HYPERALDOSTERONISM =

= excessive excessive secretion of secretion of aldosterone independentaldosterone independent of

of renin-angirenin-angiotensin system.otensin system.

* Features: hypervolemia, hypokalemia, * Features: hypervolemia, hypokalemia,

hypertension, low renin hypertension, low renin * Causes:

* Causes:

--MCC is MCC is aldosterone-aldosterone-secretinsecreting adenoma g adenoma (Conn’s(Conn’s

syndrome) in 80% of

syndrome) in 80% of casescases

--Bilateral idiopathic hyperplasia (? due to anBilateral idiopathic hyperplasia (? due to an

abnormal secretagogue) abnormal secretagogue)

--Glucorticoid-suppressible hyperaldosteronism:Glucorticoid-suppressible hyperaldosteronism:

hybrid cells produce both cortisol &

hybrid cells produce both cortisol & aldosterone,aldosterone,

⇑

aldosterone under influence of ACTH,aldosterone under influence of ACTH, suppressible by administration of suppressible by administration of dexamethasone

dexamethasone

* Prognosis: adenomas are curable by surgery. * Prognosis: adenomas are curable by surgery. ADRENOGENIT

ADRENOGENITAL SAL SYNDROMESYNDROMES

Adrenogenital syndromes (ambiguous genitalia & Adrenogenital syndromes (ambiguous genitalia & virilism in females, and precocious puberty in virilism in females, and precocious puberty in males) can be caused by:

males) can be caused by:

1- Androgen-secreting adrenal cortical neoplasms. 1- Androgen-secreting adrenal cortical neoplasms. 2- Congenital Adrenal Hyperplasia (CAH):

2- Congenital Adrenal Hyperplasia (CAH):

--corticostercorticosteroid oid biosynthetic defectbiosynthetic defect

--MC 21-hydroxylase deficiency (90% of cases;MC 21-hydroxylase deficiency (90% of cases;

autosomal recessive)

⇒

⇒ ⇓

⇓

cortisolcortisol

⇒

⇒ ⇓

⇓

feedback inhibition of ACTH

⇒

⇒ ⇑

⇑

ACTH levelsACTH levels

⇒

bilateral adrenocortical hyperplasiabilateral adrenocortical hyperplasia

--aldosteraldosterone synthesis is MCly affected as one synthesis is MCly affected as wellwell

⇒

salt wasting salt wasting adrenogenadrenogenitalism (italism (

⇓

NaNa++_,,

_⇑

_K_K++_,,

hypovolemia) hypovolemia)

(12)

ACUTE

ACUTE ADRENOCORTICAL ADRENOCORTICAL INSUFFICIENCY INSUFFICIENCY MCC is sudden withdrawal of

MCC is sudden withdrawal of corticostercorticosteroids inoids in cases of long-ter

cases of long-term steroid therm steroid therapy, or apy, or destructiondestruction of adrenals by massive hemorrhage

of adrenals by massive hemorrhage

Waterhouse-Friderichsen syndrome:

--overwhelming meningococcal septicemiaoverwhelming meningococcal septicemia

--DIC with widespread purpura (esp. skin)DIC with widespread purpura (esp. skin)

--rapidly progressive hypotensionrapidly progressive hypotension

⇒

shockshock

--massive bilat. adrenal hemorrhagemassive bilat. adrenal hemorrhage

⇒

acuteacute

adrenocorti

adrenocortical cal insufficiencyinsufficiency

--? causes of adrenal hemorrhage: DIC, endotoxin-? causes of adrenal hemorrhage: DIC,

endotoxin-induced vasculitis, bacterial seeding of induced vasculitis, bacterial seeding of smallsmall vessels

vessels

--high mortality ratehigh mortality rate

CHRONIC

CHRONIC ADRENOCORTICAL ADRENOCORTICAL INSUFFICIENCY INSUFFICIENCY * Primary (adrenal) or secondary

* Primary (adrenal) or secondary (hypothalamic/pituitary):

(hypothalamic/pituitary):

Primary (Addison’s disease):

Primary (Addison’s disease): MCC:MCC: autoimmune adrenalitis; tuberculosis, autoimmune adrenalitis; tuberculosis, metastatic cancers (

metastatic cancers (

⇒

destruction of destruction of

≥≥

90% of 90% of the cortex)

the cortex)

⇒

decreased cortisol & aldosterone,decreased cortisol & aldosterone, with feed-back elevation of ACTH (+

with feed-back elevation of ACTH (+ MSH)MSH)

⇒

hyperpigmentat

hyperpigmentation of ion of skin,skin,

⇑

K K ++_,,

_⇓

_Na+,_Na+,

_⇓

_BP,_BP,

weakness, anorexia, N&V, hypoglycemia weakness, anorexia, N&V, hypoglycemia Secondary:

Secondary: to hypothalamic or pituitary lesionsto hypothalamic or pituitary lesions associated with decreased ACTH

associated with decreased ACTH

⇒

bilateralbilateral adrenal cortical atrophy, sparing the zona adrenal cortical atrophy, sparing the zona glomerulosa (skin color is pale and

glomerulosa (skin color is pale and aldosteronealdosterone is normal, i.e. no sodium or potassium

is normal, i.e. no sodium or potassium abnormalities).

abnormalities). ADRENAL MEDULLA ADRENAL MEDULLA

--Composed of Composed of specializespecialized d neuroendocrneuroendocrineine

(chromaffin) cells, and is the major source of (chromaffin) cells, and is the major source of catecholamines: epinephrine & norepinephrine. catecholamines: epinephrine & norepinephrine.

--Chromaffin cells secrete catecholamines inChromaffin cells secrete catecholamines in

response to signals from preganglionic sympathetic response to signals from preganglionic sympathetic nerve fibers.

nerve fibers.

- These cells can also secrete a wide variety of These cells can also secrete a wide variety of bioactive amines and peptides, such as: histamine, bioactive amines and peptides, such as: histamine, serotonin, & neuropeptide hormones.

serotonin, & neuropeptide hormones.

--Clusters of similar neuroendocrine cells form theClusters of similar neuroendocrine cells form the

extra-adrenal paraganglia - closely associated with extra-adrenal paraganglia - closely associated with the autonomic nervous system.

the autonomic nervous system.

- The branchiomeric (carotid bodies) &

The branchiomeric (carotid bodies) & intravagalintravagal paraganglia are parasympathetic, and the

paraganglia are parasympathetic, and the aorticosympathetic (organs of Zuckerkandl) are aorticosympathetic (organs of Zuckerkandl) are sympathetic.

sympathetic.

PHEOCHROMOCYTOMA PHEOCHROMOCYTOMA =

= neoplasm composeneoplasm composed of chromaffid of chromaffin cells thatn cells that secretes catecholamines

secretes catecholamines (0.1 - (0.1 - 0.3 % 0.3 % of all of all cases of cases of hypertension) hypertension) * The “10 %” tumor: * The “10 %” tumor: • •10 % extra-adrenal10 % extra-adrenal • •10 % familial10 % familial • •10 % in children10 % in children •

•10 % bilateral in sporadic cases, but 70%10 % bilateral in sporadic cases, but 70% bilat.in familial cases

bilat.in familial cases •

•10 % malignant in adrenal cases, but up to 40%10 % malignant in adrenal cases, but up to 40% malignant in extra-adrenal cases

malignant in extra-adrenal cases * Clinical effects:

* Clinical effects: hypertension (paroxyshypertension (paroxysmal),mal), tachycardia,

tachycardia,

arrhythmias, tremors, sweating, sense of arrhythmias, tremors, sweating, sense of apprehension,

apprehension,

attacks can be fatal attacks can be fatal

* Diagnosis: 24 hour urine for catecholamines; or * Diagnosis: 24 hour urine for catecholamines; or

metanephrine

(13)

MUL

MULTIPLE ETIPLE ENDOCRINE NEOPLASIANDOCRINE NEOPLASIA:: MEN I (Wermer’s Syndrome

MEN I (Wermer’s Syndrome)) - heritable disorder cause

- heritable disorder caused by loss of d by loss of a tumora tumor suppres

suppressor gene on sor gene on chromosome 11.chromosome 11. 1.

1. Parathyroid Parathyroid hyperplasihyperplasia or a or adenoma (95%)adenoma (95%)

⇒

⇒ ⇑

⇑

Ca

Ca++++

2.

2. PancreaticPancreatic Islet Cell tumors (75%)Islet Cell tumors (75%)

⇒

excessiveexcessive secretion of:

secretion of: - gastrin

- gastrin

⇒

peptic ulcers (Zollinger-Ellisonpeptic ulcers (Zollinger-Ellison syndrome)

syndrome) - insulin

- insulin

⇒

hypoglycemiahypoglycemia - serotonin

- serotonin

⇒

carcinoid syndromecarcinoid syndrome - VIP

- VIP

⇒

watery diarrheawatery diarrhea 3.

3. Pituitary Pituitary adenoma (66%); MC adenoma (66%); MC prolactinomaprolactinoma,, also GH &

also GH & ACTH producing adenomasACTH producing adenomas MEN IIA (Sipple’s Syndrome)

MEN IIA (Sipple’s Syndrome)

-- inherited mutation iinherited mutation in the RET protooncogene n the RET protooncogene onon chromosome 10.

chromosome 10.

1. C cell hyperplasia or Medullary thyroid 1. C cell hyperplasia or Medullary thyroid

carcinoma (100%) carcinoma (100%)

2. Pheochromocytoma (50%), often bilateral and 2. Pheochromocytoma (50%), often bilateral and

may arise in the extra-adrenal paraganglia may arise in the extra-adrenal paraganglia 3. Parathyroid hyperplasia or adenoma (25%) 3. Parathyroid hyperplasia or adenoma (25%) MEN IIB (Gorlin’s Syndrome)

MEN IIB (Gorlin’s Syndrome)

--inherited mutation in the RET protooncogene oninherited mutation in the RET protooncogene on

chromosome 10, different from that seen in

chromosome 10, different from that seen in MEN IIAMEN IIA

--neoplasms are as in MEN IIA:neoplasms are as in MEN IIA:

1- C cell

1- C cell hyperplasia or Medullary thyroidhyperplasia or Medullary thyroid carcinoma (100 %)

carcinoma (100 %)

2- Pheochromocytoma (34%) 2- Pheochromocytoma (34%)

3- Parathyroid hyperplasia or adenoma (4%) 3- Parathyroid hyperplasia or adenoma (4%)

plus plus

4- Ganglioneuromas of the skin, eyes and 4- Ganglioneuromas of the skin, eyes and

mucous membranes of the mouth, GI tract, mucous membranes of the mouth, GI tract, respir

respiratory tract & atory tract & bladder (100%)bladder (100%) 5- Marfanoid body habitus (65%) 5- Marfanoid body habitus (65%)

---

-- Aanhin pa ang damo, Aanhin pa ang damo,

Kung sayo plang, may tama na ako? Kung sayo plang, may tama na ako? I list my number…. Can I

I list my number…. Can I have yours?have yours? Nagpapacute kba? Kc umeepekto eh! Nagpapacute kba? Kc umeepekto eh! Kulangot kba? Kasi I wanna take you Kulangot kba? Kasi I wanna take you out.out.

Hi, I’m yours, can I call you

Hi, I’m yours, can I call you mine?mine? --- galing sa old trans ng acute abdomen! just to --- galing sa old trans ng acute abdomen! just to have some good memories to remember about the have some good memories to remember about the exam. hehehe

exam. hehehe

LOVE is just a word until someone you meet gives it LOVE is just a word until someone you meet gives it a proper meaning