Endocrine System Flashcards by Denisse Tiangco

Rapid enlargement of pituitary adenoma with hemorrhage, depression of consciousness

Pituitary apoplexy

How well did you know this?

Not at all

Perfectly

Most common cause of hyperpituitarism

Anterior lobe adenoma

How well did you know this?

Not at all

Perfectly

Pituitary adenoma classifications

Size

Hormone production

Macro >1cm
Micro <1cm

Functioning (GH+Prolactin) mc
Non functioning

How well did you know this?

Not at all

Perfectly

Best characterized molecular abnormalities in pituitary adenomas

G protein mutation
in the alpha subunit interfering with its intrinsic GTPase activity resulting in activation of Gsalpha generation of cAMP and unchecked cellular proliferation

How well did you know this?

Not at all

Perfectly

G protein mutation is a mutation the gene

found in 40% of

GNASI

GH secreting somatotroph

How well did you know this?

Not at all

Perfectly

5% of adenomas are inherited with identified mutations in the genes

MEN I (familial pituitary a)
CDKN I B
PRKARI A
AIP

How well did you know this?

Not at all

Perfectly

Gene affected in pituitary adenomas appearing before 35 years secreting GH

aryl hydrocarbon receptor interacting protein

How well did you know this?

Not at all

Perfectly

Mutation of the gene is assoc with aggressive pituitary adenoma behavior and recurrence
Mutation demonstrates brisk mitotic activity and designated atypical adenoma

TP53

How well did you know this?

Not at all

Perfectly

Well circumscribed soft lesion with uniform polygonal cells arrayed in sheets, cords or papillae
Reticulin is sparse
Cytoplasm is acidophilic, basophilic or chromophobic depending on secretory product
Cellular Monorphism and absence of significant reticulin network distinguish it from non neoplastic anterior pituitary parenchyma

Pituitary adenoma

How well did you know this?

Not at all

Perfectly

Non functioning hormone negave p adenomas tend to be

and cause

macrocytic

hypopituitarism and destroy adjacent anterior pituitary adenoma (mass effect and visual disturbances)

How well did you know this?

Not at all

Perfectly

Most common type of hyperfunctioning adenoma

Prolactinoma

How well did you know this?

Not at all

Perfectly

Hyperprolactinemia cause

and may manifest earlier in premenop than men and post menop reaching considerable size

Amenorrhea
Galactorrhea
Loss of libido
Infertility

How well did you know this?

Not at all

Perfectly

Other causes of hyperprolactinemia

Pregnancy
High estrogen t
Renal failure
Hypothyroidism
Hypothalamic lesion
Dopamine inhibiting drugs (reserpine)
Mass on suprasellar compartment disturbing normal inhibitory hypothalamic influence (stalk effect)

How well did you know this?

Not at all

Perfectly

Second most common type of functional pituitary adenoma

GH secreting

Somatotroph cell adenoma

How well did you know this?

Not at all

Perfectly

Persistent hypersecretion of GH stimulates the hepatic secretion of

causing clinical manifestation

insulin like growth factor I

somatomedin C

How well did you know this?

Not at all

Perfectly

Gen increase in body size with disproportionately long arms and legs
GH adenoma occuring before closure of epiphyses prepubertal

Gigantism

How well did you know this?

Not at all

Perfectly

Growth most conspicuous with soft tissue, skin and viscera and bones of face, hands and feet
Enlargement of jaw called
Broadening of lower face and separation of teeth
Hands and feet enlarged with broad sausage like
GH adenoma developing after epiphyses closure
Impaired glucose tolerance and DM

Acromegaly

How well did you know this?

Not at all

Perfectly

Stain + with periodic acid schiff due to inc ACTH
clinically silent or cause hypercortisolism manifested as
ACTH on adrenal cortex

Cushing syndrome

How well did you know this?

Not at all

Perfectly

Hypercortisolism caused by excess production of ACTH by PITUITARY

Cushing disease

How well did you know this?

Not at all

Perfectly

Corticotroph adenoma after removal of adrenal glands for tx of Cushing syndrome
Loss of inh effect of corticosteroids on microadenoma
No hypercortisolism but pituitary tumor mass effect and hyperpigmentation

Nelson syndrome

How well did you know this?

Not at all

Perfectly

Become detected only when they already produce mass effects
Demonstrate immunoreactivity for a subunit specific B FSH and BLH
FSH predominant secreted hormone

Gonadotroph adenoma

LH and FSH adenoma

How well did you know this?

Not at all

Perfectly

Account for 1% of all pituitary adenomas

Rare cause of hyperthy

Thyrotroph

How well did you know this?

Not at all

Perfectly

Exceedingly rare commonly metastasizes distantly

Pituitary carcinoma

How well did you know this?

Not at all

Perfectly

Hypopituitarism occurs when there is loss of function of as much as of anterior pituitary

75%

How well did you know this?

Not at all

Perfectly

Hypopituitarism with posterior pituitary disfunction in the form of diabetes insipidus is almost always

hypothalamic in origin

Post partum ischemic necrosis of anterior pituitary in setting of hemorrhage Inc bec of prolactin cell but without concomittant inc in bs Post pituitary less susceptible bec of arterial bs Also in DIC, sickle cell, inc ICP, trauma and shock

Sheehan syndrome

ADH deficiency causes | Excessive urination due to improper water reabsorption

Central Diabetes Insipidus Nephrogenic if unresponsiveness of tubular cell to ADH

Resorption of excessive amounts of free water with resultant hyponatremia Ectopic ADH by small cell lung ca Hypothalamic injury Hyponatremia, cerebral edema, neurologic dysfunction Inc TBW but N bv no periph edema

SIADH

Hypermetabolic state due to elevated circulating levels of T3 and T4 Hyperthyroidism is only one category of this

Thyrotoxicosis Hypermetabolic state by excess thyroid hormone and overactivity of SNS

Thyrotoxicos in elderly whom typical features of thyroid hormone excess are blunted Unexplained weight loss and worsening CV disease

Apathetic hyperthyroidism

Most useful single screening test for hyperthyroidism

TSH

Worldwide mc cause of hypothyroidism

Iodine deficiency

Hypothyroidism in infancy or early childhood Himalayas and Andes where iodine is endemically deficient Impaired skeletal and CNS dev’t Severe mental retardation, short stature, coarse facial, protruding tongue, umbilical hernia MR is severe if maternal thyroid deficiency

Cretinism

Hypothyroidism in older children and adults Cretinoid state in adult Generalized apathy, mental sluggishness, depression like Listless, cold intolerant, obese Edema in skin, enlargement of tongue, deepening of voice Dec bowel motility, pericardial effusion, heart enlargement and heart failure

Hypothyroidism

Most common cause of hypothyroidism in areas where iodine is sufficient Major cause of nonendemic goiter in children

Hashimoto thyroiditis

Breakdown in self tolerance to autoantigen CD8 cytotoxic cell mediated cell death thyrocyte destructi on Cytokine mediated interferon y resulting in mac activation and follicle damage Binding of antithyroid ab followed by ab dependent cell mediated toxicity Concordance in 40% of twins Most significant link is cytotoxic T lymph associated

Hashimoto’s Antigen 4 gene CTLA4 coding for negative regulator of T cell function

Diffuse sym enlarged with mononuclear inflammatory infiltrate Well developed germinal center Atrophic follicle with abundant eosinophilic granular cytoplasm called

Hashimoto’s thyroiditis Hurthle cell Oxyphil cell

Metaplastic response of normally low cuboidal epithelium to ongoing injury Numerous prominent mitochondria Inc interstitial connective tissue Small atrophic thyroid fibrosing variant but does not extend beyond capsule

Hurthle cell | Oxyphil cell of Hashimoto

Painless enlargement of thyroid assoc with degree of hypothyroidism preceded by transient thyrotoxicosis from 2 release of TH (hasitoxicosis) Often have autoimmune disease Inc risk for

Hashimoto’s B cell non Hodgkin lymphoma and predisposition to papillary thyroid

Caused by viral infection or inflammatory process Hx of URTI prior Immune response is not self perpetuating Gland is firm with intact capsule Disruption of thyroid follicle extravasation of colloid leading to PMN infiltrate Exuberant granulomatous rx with giant cells with colloid Healing by inflamm resol and fibrosis PAIN in neck with swallowing, fever, malaise enlargement of thyroid Transient hyperthy from follicle disruption Inc leukocyte and ESR Self limited, Eu in 6-8 w

Subacute Granulomatous de Quervain Thyroiditis

``` Silent or painless thyroiditis Following pregnancy Autoimmune bec circulating ab Thyrotoxicosis then euthyroid state Lymphocytic infiltration and hyperplastic germinal center ```

Subacute Lymphocytic Thyroiditis

Rare disorder unknown etiology Extensive FIBROSIS of thyroid and neck Hard fixed thyroid mass simulating neoplasm Idiopathic fibrosis also in retroperitoneum Autoimmune due to circ autoantibody

Riedel thyroiditis

Most common cause of endogenous hypothyroidism Diffuse hypertrophy and hyperplasia Colloid is pale with scalloped margins

Graves

Triad of Graves W 7x

Thyrotoxicosis Ophthalmopathy Infiltrative dermopathy (pretibial myxedema)

Graves is assoc with genetic susceptibility from

HLA DR3 CTLA-4 PTPN22

Breakdown in self tolerance to thyroid autoantigen with TSH receptor Thyroid stimulating IgG binding to TSH receptor mimicing TSH (specific) Also proliferates thyroid follicular epithelium TSH binding inh globulin prevent TSH fr binding to receptor on epithelial cell inh thyroid cell function Coexistence of stimulating and inh IgG hence spontaneous hypothy T cell mediated autoimmune phenomenon in infiltrative ophthalmopathy (inc volume of retroorbital tissue)

Grave’s disease

Most common manifestation of thyroid disease

goiter

Degree of thyroid enlargement is proportional to the

Level and duration of thyroid hormone deficiency

Endemic of

goiter is present in >10% of population

Diffuse symmetric enlargement of gland (diffuse goiter) forming enlarged, colloid rich colloig goiter then eventually producing irregular enlargement called multinodular goiter. Minority manifest with thyrotoxicosis producing autonomous nodules independent of TSH stimulation

Diffuse goiter Multinodular goiter Plummer syndrome

Solitary thyroid nodules are more likely to be

neoplastic

Nodules in young patients tend to be

neoplastic

Nodules in males tend to be

neoplastic

Hx of irradiation at head and neck is assoc with

inc risk of malig

Hot nodules or nodules that take up radioactive iodine are more likely

benign

Follicular adenomas are assoc with mutations in

TSH receptor signalling pathway Activating mutation of TSHR and alpha subunit of Gs GNAS allow follicular cells to secrete thyroid hormone (autonomy) hence hot nodule Minority: less than 20 RAS, PIK3CA or PAX8/PPARG

Solitary, well defined intact capsule with multiple nodules on cut surface no compression of adjacent thyroid parenchyma with Hurthle Cell occasionally

Follicular adenoma

Careful evaluation of this in follicular adenoma is distinguishing from a carcinoma

intact integrity of capsule

Two pathways in thyroid carcinoma generation

MAP Kinase | PI-3K/AKT

Genetic anomaly in most papillary thyroid carcinomas

MAP kinase by rearrangement of RET or NTRKI activating point mutation in BRAF

Follicular thyroid carcinomas are assoc with genetic mutations of

PI3K/AKT pathway | PAX8/PPARG in less than 10%

Highly aggressice arising from dedifferentiation from papillary or follicular Sometimes by inactivation of TP53

Anaplastic carcinoma

Arise from parafollicular C cells Occur in MEN 2 Assoc with this mutation

Medullary thyroid RET protooncogene

Major rf predisposing to thyroid cancer is

ionizing radiation in first two decades of life

Chernobyl nuclear disaster

Papillary carcinom

Deficiency of iodine

Follicular carcinoma

Diagnosis is based on nuclear features in absence of papillary architecture Contain chromatin, optically clear ground glass or Orphan annie eye nuclei Pseudoinclusion Papillary architecture Psammoma bodies Most common variant: follicular

Papillary carcinoma

Most common metastases of papillary

Cervical node | Lung (hematogenous)

Widely invasive or minimal Requires extensive histologic sampling of tumor-capsule thyroid interface to exclude: Most frequent solitary COLD nodule

Follicular carcinoma Capsular or vascular invasion

Follicular adenomas metastasize through

hematogenous (lungs, bone, and liver) | with uncommon regional mets

Aggressive mortality of 100% Bulky masses growing beyond thyroid capsule into neck structures Highly anaplastic: pleomorphic giant, spindle with sarcomatous, mixed spindle and giant

Anaplastic carcinoma

Neuroendocrine neoplasm from parafollicular cells Secrete: Sporadic in 70, MEN2A or 2B in 30 Demonstrate RET mutation Multicentricity C cell hyperplasia Polygonal spindle shaped cells forming nests with Amyloid deposit

Medullary carcinoma

95% of cases of primary hyperparathy is caused by

Adenoma Primary hyperplasia 5-10 Parathyroid 1%

Genetic defects in familial primary hyperparathyroidism

MEN1 and MEN2A CyclinD1 gene inversion chromosomal inversion MEN 1 mutation

Rare cause of hyperparathy due to inactivating mutation of calcium sensing receptor on parathyroid cell

Familial hypocalciuric hypercalcemia

Invariable confined to single glands composed predominantly of chief cells Endocrine atypia

Parathyroid adenoma

Multiglandular process Chief cell hyperplasia Water clear cell hyperplasia from accumulation of glycogen

Parathyroid hyperplasia

Circumscribed diff to distinguish from adenoma Gray white irregular masses Diagnosis based on cytologic detail is unreliable Only definitive dx is invasion of surrounding tissue and mets Skeletal and kidney changes

Parathyroid carcinoma

Bone resorption with inc osteoblastic activity and new bone trabeculae Grossly thinned cortex with marrow of inc fibrous tissue accompanied by foci of hemorrhage and cyst

osteitis fibrosa cystica

Osteoclast, reactive giant cells and hemorrhagic debris

Brown tumor

Most common manifestation of primary hyperparathyroidism is

inc serum ionized calcium

Causes of hyperkalemia with raised PTH

Hyperparathyroidism Primary adenoma>hyperplasia Tertiary Familal hypocalciuric hypercalcemia

Hypercalcemia | Decreased PTH

``` Hypercalcemia of malignancy Osteolytic metastases PTH-rP-mediated Vit D toxicity Immobilization Drugs thiazide Granulomatous disease sarcoidosis ```

Painful bones Renal stones Abdominal groans Psychic moans

Primary hyperparathyroidism

Chronic depression of serum calcium Most common cause:

Secondary hyperparathyroidism Renal failure causing hyperphosphatemia elevating PTH inc serum Ca and reduces alpha hydroxylase which converts Vit D leading to dec Ca reabsorption in intestine

Hyperplastic parathyroid glands Inc chief cell water-clear cell Bone changes Metastatic calcification

Secondary hyperparathyroidism

Metastatic calcification of blood vessels secondary to hypophosphatemia resulting with significant ischemic skin damage

calciphylaxis

Most important cause of symptomatic hypercalcemia resulting from osteolytic metastases or release of PTH related protein from nonparathyroid tumor

Malignancy

Most common cause of hypoparathy

surgical other causes Congenital absence also with thymic displasia DiGeorge and cardiac defect Autoimmune hypoparathyroidism

Hereditary polyglandular deficiency arising from antibodies to MEN Chronic fungal infection of skin and mucous Causes by mutations in the gene: Make autoantibodies against own IL17 hence inc susceptibility to Candida Inc neuromuscular irritability tingling, spasm, facial grimace carpopedal spasm or tetany

Hypoparathyroidism

Hypercortisolism typically manifests as caused by condition that produces elevation in glucocorticoid levels Mostly iatrogenic with the other 3 as primary hypo-pituitary, secretion of ACTH by non, primary adrenocortical neoplasm

Cushing’s syndrome

Accounts for 70% of spontaneous Cushing syndrome Primary hypothalamic pituitary disease assoc with hypersecretion of ACTH Pituitary containing ACTH microadenoma without mass effect or corticotroph hyperplasia Adrenal glands are charac by degree of bilateral nodular cortical hyperplasia secondary to inc ACTH

Cushing disease

Often times, secretion of ectopic ACTH is caused by

Small cell carcinoma of the lung carcinoid, medullary carcinoma or PanNET

Primary adrenal adenoma or carcinomax | Primary cortical hyperplasia is a form of Cushing’s designated as

ACTH independent Cushing Syndrome

Biochemical hallmark of adrenal cushing

elevated cortisol with low serum level of ACTH

Macronodules of primary cortical hyperplasia of the cortex

>3cm

Micronodules of primary cortical hyperplasia

1-3mm diameter

Most common pituitary alteration in Cushing syndrome resulting from high levels of endogenous or exogenous glucocorticoid is cortical atrophy, diffuse hyperplasia, macronodular or micronodular hyperplasia or adenoma

Crooke hyaline change normal granular basophilic cytoplasm replaced by homogenous lightly basophilic material due to accumulation of intermediate keratin

Supression of endogenous ACTH from exogenous glucocorticoids in Cushings result in

bilat cortical atrophy due to lack of stimulation with normal zona glomerulosa thickness

In ACTH dependent Cushing, glands are yellowish enlarged with

lipid laden, diffuse hyperplasia appearing vacuolated

In primary cortical hyperplasia the cortex is replaced by with 1-3mm darkly pigmented nodules called

Macro or micro Lipofuscin wear and tear

Yellow tumors with thin well developed capsules less than 30g in zona fasciculata

Adrenal adenoma

Larger than adenoma | 200-300g all of anaplastic characteristics

Adrenal carcinoma

Hypercortisolism causes selective atrophy of

Type II fast twitch myofiber and dec muscle mass of proximal limb

Extraadrenal cause Inc aldosterone bec of RAAS activation Inc levels of plasma renin with dec re al perfusion, arterial hypovolemia and edema, pregnancy

Secondary hyperaldosteronism

Primary autonomous production of aldosterone With supression of RAAS DEC plasma renin activity due to bilateral nodular hyperplasia pf adrenals 60%, adrenocortical neoplasm, or familial hyperald from genetic defect leading to overactivity of:

Primary Hyperaldosteronism Aldosterone synthase CYP11B2

Bilateral nodular hyperplasia | Most common UNDERLYING cause of primary hyperald 60% of cases

Bilateral idiopathic hyperaldosteronism

Solitary aldosterone secreting adenoma is called

Conn’s syndrome

Hallmarked by eosinophilic laminated cytoplasmic inclusions called Found after tx of spironolactone which is DOC for primary hyperald

Aldosterone adenoma

Diffuse or focal hyperplasia of cells resembling those of normal zona glomerulosa

Bilateral idiopathic hyperplasia

Clinical hallmark of hyperaldosteronism

hypertension

Patterns of adrenocortical insufficiency

1 primary acute adrenocortical insufficiency 2 primary chronic adrenocortical insuff/Addison 3 secondary adrenocortical insuff

Classically associated with N meningitidis septicemia, pseudomonas, h influenzae As acute crisis after stress that results in inability of the atrophic adrenal glands to produce glucocorticoid Massive adrenal hemorrhage

Waterhouse Friderichsen Syndrome

AR hereditary disease in enzyme involved in adrenal steroid biosynthesis ie cortisol Dec cortisol leads to inc ACTH due to absence of feedback Adrenal hyperplasia causes precursor steroid channeled into synthesis of androgen with virilizing activity

Congenital adrenal hyperplasia

Most common enzyme defect causing CAH is

21 hydroxylase deficiency 90% assoc with CYP21A2

CAH with bilateral hyperplasia is assoc with: esp in those with salt losing 21 hydroxylase def Charac by incomplete migration or chromaffin cell to center of gland pronounced intermingling of nests of chromaffin and cortical cell

Adrenomedullary dysplasia

Masculinization in females, clitoral hypertrophy, pseudohermaphroditism oligomen, hirsutism, acne In males enlargement of external genitalia precoc pub and oligospermia

21 hydroxylase deficiency

Form of CAH with mineralocorticoid activity Sodium retention Hypertension

11B hydroxylase

The adrenal cortex can secrete excess androgen in either two of settings

``` Adrenocortical neoplasm (virilizing) Congenital adrenal hyperplasia ```

Dec in cortisol production results in inc androgen production due to

compensatory inc in ACTH secretion

Waterhouse-Frederichsen Sudden longterm corticosteroid therapy withdrawal Stress in chronic adrenal insuff

Acute adrenal insuff

``` Autoimmune adrenalitis APS1 and APS2 TB AIDS Mets Amyloidosis Fungal infec Hemochromatosis Sarcoidosis ```

Chronic adrenal insuff

Progressive destruction of adrenal cortex | 90% attributable to 4 disorders: AIDS, TB, Autoimmune adrenalitis, mets

Chronic adrenal insuff | Addison Disease

60-70% of cases most common cause of primary adrenal insuff | Autoimmune destruction of steroid producing cells and autoantibodies to steroidogenic enzymes

Autoimmune adrenalitis

Autoimm polyendocrine syndrome APS1 is caused by mutations in Chronic mucocutaneous candidiasis, skin ab, dental enamel, nails with auto adrenalitis, hypoparathy, hypogonadism and pernicious anemia

Autoimmune regulator AIRE on ch21

Protein involved in expession of tissue antigen in thymus and T cell elimination

AIRE

Early adulthood combination of adrenal insuff and autoimmune thyroiditis or type1 DM

APS2

TB adrenalitis is assoc with infections of

lung | genitourinary tract

Any disorder of hypothalamus pituitary mets, infection infarction irradiation resulting to dec ACTH but without hyperpigmentation

Secondary adrenocortical insufficiency

Clinica manif of adrenocortical insuff only manifest when at least such as weakness, easy fatigability, GI disturbances inc ACTH and hyperpigmentation

90% | Adrenocortical insufficiency

Functional adenomas are more likely While virilizing neoplasms are

Assoc with hyperaldosteronism Cushing’s Carcinoma

Rare neoplasms occuring at any age Invasive, variegated, poorly demarcated with areas of necrosis and hemorrhage Strong tendency to invade the adrenal vein and lymphatics

Adrenocortical carcinoma

Neoplasms composed of chromaffin cells which synthesize and release catecholamine giving rise to surgically correctable hypertension

Pheochromocytoma

Pheochromocytoma rule of 10: Location Laterality Type of tumor

Extraadrenal: organ of Zuckerkandl and carotid body aka paraganglioma Bilateral inc to 50% Malignant

Familial pheochromocytoma cases are related to mutations in

25% RET type2 MEN NF1 VHL SDHB, SDHC, SDHD mitochondrial ox phos

Polygonal spindle shaped cells with finely granular appearance called Capsular and vasc invasion even in benign lesion Mere presence of mitotic lesion does not imply malig

Zellballen Pheochromocytoma

Definitive diagnosis of pheochromocytoma is clinched by

presence of metastases involving regional LN, Liver lung and bone

Most common extracranial solid tumor Infants - 5 yrs Anywhere in SNS within brain and abdomen Majority in retroperitoneal or adrenal medulla

Neuroblastoma

Group of inherited diseases resulting in proliferative lesions of multiple endocrine organs Younger age Synchronous or metachronously Multifocal Preceeded by asymptomatic stage of endocrine hyperplasia More aggressive and recur

Multiple Endocrine Neoplasia

AD Gene at 11q13 tsg Parathyroid, pancreas, pituitary

MEN 1

Most common manifestation of MEN 1 (80-95%) | Initial

Primary hyperparathyroidism Hyperplasia Adenoma

Leading cause of death in MEN1 Aggressive metastatic microadenomas functional like Zollinger Ellison Gastrinomas more likely duodenum

Endocrine tumor of pancreas

Most frequent pituitary tumor in MEN 1 is a

Prolactin secreting microadenoma | sometimes acromegaly

Two distinct group unified by activating mutations of RET

MEN 2

Medullary carcinoma Adrenal pheochromocytoma Parathyroid gland hyperplasia with Primary Hyperparathyroidism

MEN 2A

Distinct germline RET with single AA change Usually involves thyroid and adrenal medulla but WITHOUT Primary Hyperparathyroidism More EXTRAENDOCRINE manifestation like ganglioneuroma of mucosa (GI, lips, tongue) and Marfanoid habitus overly long bones of axial skeleton

MEN 2B

All persons carrying germline mutations of RET are advised to have prophylactic to prevent inevitable development of medullary carcinoma

thyroidectomy