Endocrine System Flashcards
Rapid enlargement of pituitary adenoma with hemorrhage, depression of consciousness
Pituitary apoplexy
Most common cause of hyperpituitarism
Anterior lobe adenoma
Pituitary adenoma classifications
Size
Hormone production
Macro >1cm
Micro <1cm
Functioning (GH+Prolactin) mc
Non functioning
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
G protein mutation is a mutation the gene
found in 40% of
GNASI
GH secreting somatotroph
5% of adenomas are inherited with identified mutations in the genes
MEN I (familial pituitary a)
CDKN I B
PRKARI A
AIP
Gene affected in pituitary adenomas appearing before 35 years secreting GH
aryl hydrocarbon receptor interacting protein
Mutation of the gene is assoc with aggressive pituitary adenoma behavior and recurrence
Mutation demonstrates brisk mitotic activity and designated atypical adenoma
TP53
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
Non functioning hormone negave p adenomas tend to be
and cause
macrocytic
hypopituitarism and destroy adjacent anterior pituitary adenoma (mass effect and visual disturbances)
Most common type of hyperfunctioning adenoma
Prolactinoma
Hyperprolactinemia cause
and may manifest earlier in premenop than men and post menop reaching considerable size
Amenorrhea
Galactorrhea
Loss of libido
Infertility
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)
Second most common type of functional pituitary adenoma
GH secreting
Somatotroph cell adenoma
Persistent hypersecretion of GH stimulates the hepatic secretion of
causing clinical manifestation
insulin like growth factor I
somatomedin C
Gen increase in body size with disproportionately long arms and legs
GH adenoma occuring before closure of epiphyses prepubertal
Gigantism
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
Stain + with periodic acid schiff due to inc ACTH
clinically silent or cause hypercortisolism manifested as
ACTH on adrenal cortex
Cushing syndrome
Hypercortisolism caused by excess production of ACTH by PITUITARY
Cushing disease
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
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
Account for 1% of all pituitary adenomas
Rare cause of hyperthy
Thyrotroph
Exceedingly rare commonly metastasizes distantly
Pituitary carcinoma
Hypopituitarism occurs when there is loss of function of as much as of anterior pituitary
75%
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
