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Pathology - Chapter 24 (The Endocrine System)

Somatotrophs

produce GH, constitute 1/2 of hormone producing cells of the anterior pituitary

Lactotrophs

produce Prolactin (essential for lactation) - under constant inhibition - if hypophseal portal system severed, prolactin increase

Corticotrophs

basophilic cells, produce ACTH and POMC -> MSH, endorphins, and lipotropin

Thyrotrophs

produce TSH

Gonadotrophs

produce FSH and LH, FSH = formation of graffian follicles, LH = induces ovulation and formation of corpus lutea in ovary

Two peptides secreted from the posterior


pituitary

ADH and Oxytocin

Dilation of the cervix

results in massive oxytocin release -> contraction of the uterine smooth muscle -> partuition

Synthetic oxytocin

can be administered to induce labor

Function of ADH

conserve water by restricting diuresis

Osmoreceptors

detects changes/increases in plasma osmotic pressure -> triggers ADH secretion; hypervolemia and atrial distention = inhibit ADH

Hyperpituitarism

excess secretion of trophic hormones

Hypopituitarism

deficiency of trophic hormones, usually caused by destructive processes

Local Mass Effects

radiologic abnormalities of the sella turcica (earliest change) -> bitemporal hemianopsia, increased intracranial pressure

Adenoma of the Anterior Lobe (of Ant. Pit.)

most common cause of hyperpituitarim, can secrete 2 hormones - GH and prolactin combo is the most common

Microadenoma (of Ant. Pit)

less than 1cm in diameter

Macroadenoma (of Ant. Pit)

more than 1cm in diameter

Corticotroph adenoma

Cushings syndrome and Nelson syndrome (ACTH and POMC)

Somatotroph adenoma

Gigantism (children) and Acromegaly (adults) - 40% bear GNAS mutation

Lactotroph adenoma

Galactorrhea and amenorrhea (in females) and sexual dysfunction, infertility - (prolactin)

Mammosomatotroph adenoma

GH and prolactin combo - combined features of GH and prolactin overload

Thyrotroph adenoma

Hyperthyroidism (TSH excess)

Gonadotroph adenoma

FSH and LH excess - hypogonadism, mass effects, and hypopituitarism

GNAS gene

encodes Gs - mutation in the Gs interferes with GTPase activity -> results in activation of Gs -> constant cAMP -> unchecked cell
proliferation

Four Genes for Familial Pituitary Adenomas

MEN1, CDKN1B, PRKAR1A, and AIP3

MEN1

makes menin (tumor suppressor) -> GH, prolactin, ATCH tumors -> multiple endocrine neoplasia syndrome

CDKN1B

checkpoint regulator - MEN1 like syndrome but no mutation of MEN1

PRKAR1A

carney complex, autosomal dominant -> tumor supressor that regulates PKA -> loss of PRKAR1A lead to constant cAMP -> cell
proliferation

AIP

patients with AIP germline mutation usually present with acromegaly, patients are typically younger

Invasive Adenomas

not grossly encapsulated and infiltrate neighboring tissues -> cavernous and sphenoid sinuses, and the dura

Prolactinomas

most frequent type of hyperfunctioning pituitary tumor, undergo dystrophic calcification -> pituitary stone (symptoms - see above)

Pregnancy

can cause hyperprolactinemia - must do pregnancy test

Lactotroph hyperplasia

usually results from interference with normal dopamine inhibition of prolactin

Bromocriptine

dopamine receptor agonist that causes prolactinoma lesions to diminish in size

Somatotroph adenoma

2nd most common type, densely vs. sparsely granulated - elevated GH and IGF-1 (somatomedin C)

Corticotroph adenoma

usuall small microadenomas at time of dx, basophilic, stain positive with PAS

Cushing syndrome

excess cortisol due to adrenal cortex tumor that will feedback to the hypothalamus -> stop secretion of ACTH but hypercortisolism persists

Cushing disease

excessive production of ACTH by pituitary -> hypercortisolism

Nelson syndrome

large destructive adenoma develop, adrenals removed to treat cushings syndrome - loss of inhibitory feedback - no adrenal gland = no
hypercortisol

Pituitary carnicomas

quite rare, less than 1% - usually functional neoplasms with prolactin and ACTH secreted products -> usually metastasize and recur

Hypopituitarism w/ Diabetes Insipidus

so both anterior and posterior pituitary disfunction -> almost always of HYPOTHALAMIC origin

Pituitary apoplexy

sudden hemorrage into the pituitary gland - sudden onset excrucitating headache, diplopia (pressure on CN III), and hypopituitarism
can cause cardiovascular collapse, loss of consciousness, or death

Sheehan syndrome, Postpartum necrosis


(Ant. Pit.)

most common ischemic necrosis of ant. Pit., pregnancy it enlarges to twice its normal size, ischemic area reabsorbed, replaced by nubbin
of fibrous
because of the blood supply, the posterior pituitary usually not affected

Rathke Cleft Cyst

lined by ciliated cubiodal epithelium w/ goblet cells and ant pit cells -> expand -> compromise gland

Empty Sella syndrome

any condition that destroys part of the pituitary gland


primary empty sella: defect in diaphragma sella that allows arachoid mater and CSF to herniate into sella -> expand
secondary: mass enlarges the sella -> necrosis or surgical removal -> loss of pituitary function

Mutation of POU1F1

deficiency of GH, prolactin, and TSH

Clinical manifestations of (anterior)


Hypopituitarism

specific hormone deficiency, growth failure, amenorrhea, infertility, impotence, loss of axillary hair, hypothyroidism/hypoadrenalism,
lactation
deficiency of ADH - inability of kidney to resorb water properly - excrete large volumes of dilute urine (low spec. gravity), serum Na+
increased

Diabetes Insipidus
SIADH

resorption of excessive amounts of free water -> hyponatremia, caused by secretion of ectopic ADH by malignant neoplasms
total body water is increased but blood volume remains normal - NO peripheral edema

Gliomas

hypothalamic suprasellar tumor, slow growing -> headaches, visual disturbances, growth retardation

Craniopharyngiomas

hypothalamic suprasellar tumor, slow growing -> headaches, visual disturbances, growth retardation, WNT signal pathway + -catenin
mutations
adamantinomous: children, radiologically demonstrable calcifications
papillary: calcifies very rarely, lack keratin

Pathology - Chapter 24 (The Endocrine System)

D1 cells

elaborate VIP -> glycogenolysis and hyperglycemia

Enterocromaffin cells

synthesize serotonin and are the source of pancreatic tumors that cause carcinoid syndrome

Diabetes Mellitus

group of underlying metabolic disorders sharing the common feature of hyperglycemia


hyperglycemia results from defects in insulin secretion, insulin action, or both
leading cause of end-stage renal disese, adult onset blindness, lower extremity amputations

Diagnosis of Diabetes

random glucose higher than 200, fasting glucose higher than 126, abnormal OGTT greater than 200

Type 1 diabetes

autoimmune disease, -cell destruction -> absolute deficiency of insulin (5-10% of all diabetes)

Type 2 diabetes

combo of peripheral resistance to insulin action and inadequate secretion, vast majority of patients are overweight, "adult-onset"

Glucose homeostasis

regulated by: glucose production in liver, glucose uptake and use by peripheral tissue and actions of insulin and counter-reg hormones

Low glucose

increased levels of glucagon -> gluconeogenesis, glycogenolysis and decrease glycogen synthesis (prevent hypoglycemia)

High glucose

increased levels of insulin -> glucose storage and utilization

Preproinsulin

synthesized in the rER from insulin mRNA -> delivered to golgi

C-peptide

in the golgi, series of cleavage steps -> mature insulin and c-peptide (serve as a marker or surrogate for insulin)

Glucose

most important stimulus for insulin synthesis

Insulin

most potent anabolic hormone known


increase rate of glucose transport into cells
increase source of energy
inhibits lipid degradation in adipocytes
promotes amino acid uptake and protein synthesis
inhibits protein degradation

Insulin receptor

tetrameric protein composed of 2 and 2 subunits -> tyrosine kinase -> autoP -> IRS -> activate PI3K and MAP kinase -> dock GLUT4

PTPN1B

dephosphorylates the insulin receptor and inhibits insulin signaling

Phosphatase PTEN

can weaken insulin signal via blocking of AKT activation by the PI3K path

HLA Locus

contributes to as much as 50% of cases of type 1 - highest inherited risk is HLA haplotype w/ DR3 or DR4 + DQ8 haplotype

Insulin w/ VNTR

influence level of expression in the thymus -> alter negative selection

Viral infections

mumps, rubella, coxsackie V, cytomegalovirus -> TYPE 1

"bystander damage"

where infections cause -cell injury

Fundamental immune abnormality in Type 1

Failure of self-tolerance in T cells

Two metabolic defects that characterize


type 2

1. decreased response of peripheral tissues to insulin


2. -cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia

Insulin resistance

defined as failure of target tissues to respond normally to insulin


loss of insulin sensitivity in hepatocytes is likely to be the largest contributor to the pathogenesis
obesity is the largest factor in the development of insulin resistance

NEFAs

markedly increased in muscle and liver of obese patients, overwhelm fatty acid oxidation pathways, attenuate insulin signalling responses

Adipokines

Adiponectin levels are reduced in obesity -> insulin resistance; adiponectin and leptin increase insulin sensitivity

Pro-inflammatory cytokines

Adipose tissue secretes pro-inflam cytokines -> insulin resistance; lack of pro-inflam cytokines = increased insulin sensitivity

PPAR-

antagonize the PPARG's -> decrease sensitivity to insulin -> insulin resistance

Diabetogenic Gene TCF7L2

associated with reduced insulin secretion

Monogenic Diabetes

1. autosomal dominant, 2. early onset - before 25 y/o, 3. absense of obesity, 4. absense of -cell antibodies

MODY

loss of function mutation -> example: MODY2 -> loss of GCK (RLS for glycolysis) -> superficial resemblance to type 2

Permanent Neonatal Diabetes

gain of function mutations in KCNJ11 or ABCC8 -> activate K+ channel -> membrane hyperpolarized -> hypoinsulinemic diabetes

Maternally inherited diabetes and deafness

results from mitochondrial DNA mutations

Type A insulin resistance (insulin receptor


mutation)

acanthosis nigricans (velvety hyperpigmentation of the skin), polycystic ovaries, and elevated androgens

Lipoatrophic Diabetes

hyperglycemia w/ loss of adipose tissue

AGEs

formation is accelerated in the presense of hyperglycemia, bind to RAGE -> accelerates large vessel injury and microangiopathy
antagonists of RAGE have emerged as a therapeutic treatment in diabetes
AGEs can cross link fibers in collagen type 1 -> decrease elasticity -> trap LDL

Activation of PKC

contributes to the long-term complications of diabetic microangiopathy

Disturbances in Polyol pathway

sustained hyperglycemia -> depletion of intracellular NADPH -> increases oxidative stress -> diabetic neuropathy

Reduction in number/size of -cells

Type 1, rapidly advancing

Leukocytic infiltration of the islet cells

Type 1

Subtle reduction in -cell mass

Type 2

Amyloid deposition in inslets

Type 2, advanced disease islets may be obliterated and fibrous tissue may be present

Myocardial Infarction

most common cause of death in diabetics, caused by atherosclerosis

Gangrene of lower extremities

results from advanced vascular disease

Diabetic Microangiopathy

diffuse thickening of the basement membrane, depsite thickening - diabetic capillaries are more leaky to plasma proteins - underlies
neuropathy

Nephropathy

renal failure is second to MI - glomerula and renal vascular lesions are common, plus pyelonephritis (necrotizing paptillitis).

Diffuse Mesangial Sclerosis

diffuse increase in mesangial matrix -> overal thickening of the GBM

Nodular Glomerulosclerosis

aka Kimmelstiel-Wilson disease -> lesions (oval or spherical) -> fibrin caps -> ischemia/tubular atrophy/interstitial fibrosis -> overall
contract in size

Hyaline Arteriolosclerosis

affects not only the afferent but the efferent arteriole (rarely see efferent sclerosis in anyone other than diabetics)

Pyelonephritis

acute/chronic inflammation of kidneys -> spreads to affect the tubules

Diabetic Ocular complications

retinopathy, cataract formation, or glaucoma

Diabetic Neuropathy

central/peripheral NS not spared

Hyperinsulinoma

most common pancreatic endocrine neoplasm


1. glucose less than 50, 2. CNS manifestations of confusion, stupor, loss of consciousness, 3. fasting or exercise - relieved by
feeding/glucose
usually w/in the pancreas and benign, deposition of amyloid in extracellular tissue is characteristic feature
can be caused by focal or diffuse hyperplasia of the islets

ZE syndrome

pancreatic islet lesions, hypersecretion of gastric acid, and severe peptic ulcer disease -> over 1/2 of gastrin tumors are locally invasive
1/2 have metastasized by the time of dx -> usually associated with peptic ulceration

-cell tumors

glucagonomas - increase serum glucagon, mild diabetes mellitus, skin rash, and anemia - usually peri/postmenopausal

-cell tumors

high plasma somatostatin for dx, diabetes m, cholelithiasis, steatorrhea, and hypochlohydria

VIPoma

endocrine tumor -> VIP -> severe secretory diarrhea, can lead to NC tumors and pheochromocytomas

Pancreatic carcinoid tumors

rare, and produce serotonin

Polypeptide-secreting endocrine tumors

assymptomatic and rare

Pathology - Chapter 26 (Bones, Joints and Soft Tissue)

Achondroplasia
Thanatophoric dwarfism
Increased bone mass

most common diease of growth plate, major cause dwarfism, FGF3 mutation, short stature, bulge forehead, depression at root of nose
most common LETHAL form of dwarfism, gain of fx FGF3, short limbs, frontal bossing, macrocephaly, small chest cavity, bell-shaped
abdomen
cortical thickening, enlarged/enlongated mandible, may develop torus palantinus, variety of diseases, LPR5 mutation -> WNT/-catenin
path for OB
disease names: endosteal hyperostosis, Van Buchem, osteopetrosis type 1

Osteoporosis pseudoglioma syndrome

inactivating mutation of LPR5 -> severely osteoporotic -> fractures

Osteogenesis imperfecta

brittle bone disease, type 1 collagen disorder, bone fragility, hearing loss, BLUE SCLERA, dentinogenesis imperfecta
type 1: normal life span but experience childhood fractures that decrease into puberty, type 2: uniformly fatal in utero (intrauterine
fractures)

Mutated Type 2, 9, 10, 11 Collagen

mild disorder = reduced synthesis of type 2 collagen, severe = can be fatal

Mucopolysaccharidoses

lysosomal storage diseases, result from abnormalities in hyaline cartilage -> short stature, chest wall deform, and malformed bones

Osteopetrosis

marble bone or Albers-Schonberg, rare, impaired resportion of bone or mature OC, stone bones but brittle (chalk), CA2=carbonic
anhydrase
lack of medullary cavity, ERLENMEYER FLASK DEFORMITY, CN defects, and can be treated with bone marrow transplant

Osteoporosis

most common forms, senile and postmenopausal - skeleton vulnerable to fracture, deficit in bone formation occurs with each resorption
senile=low turnover rate, reduced physcial activity, calcium deficiency
loss of height, lumbar lordosis and kyphoscoliosis, BMD of -2.5 or greater

Paget Disease

skeleton may produce leontiasis ossea and a cranium so heavy that it can barely be held up, mosaic pattern of lamellar bone = jigsaw
puzzle
three phases: 1. osteolytic stage, 2. mixed OC-OB stage, 3. burnt-out quiescent osteosclerotic stage, NET EFFECT = gain in bone mass
new bone formed in disordered and architecturally unsound

Rickets and Osteomalacia

defect in matrix mineralization - most often related to lack of vitamin D or metabolic disturbance

Hyperparathyroidism

affects cortical bone more than cancellous bone, X-ray = radiolucency that is DIAGNOSTIC of hyperPTH, RAILROAD TRACKS (dissecting
osteitis)
hallmark of severe hyperPTH: increase bone cell activity, peritrabecular fibrosis, and cystic brown tumors

Renal Osteodystrophy

skeletal changes from renal disease - 1. increased OC bone resorb, 2. delayed matrix mineralization, 3. osteosclerosis, 4. growth
retardation, 5. osteoporosis
hyperphophatemia -> 2ndary hyperPTH -> increased OC activity -> metabolic acidosis also increases OC -> hyperphosphatemia

Osteonecrosis

Ichemia underlies all forms of bone necrosis, cortex not usually affected due to collateral blood flow, CREEPING SUBSTITUTION
subcondral infarcts cause chronic pain associates w/ activity; medually infarcts are clinically silent except for large ones seen in Gaucher's,
sickle cell

Osteomyelitis

Inflammation of bone - vitually always implied infection

Pyogenic osteomyelitis

caused by bacteria = staph a, e. coli, psuedomonas, klebsiella - infection resides in osseous vascular circulation
actue systemic illness, fever, chills, etc. - radiographic finding of lytic focus of bone destruction surrounded by zone of sclerosis
in children, subperiosteal abscesses may form that can track for long distance
sequestrum - dead piece of bone
draning sinus - rupture of the periosteum -> soft tissue abscess -> formation of draining sinus
Involucrum - newly deposited bone forms sleeve of tissue around segment of devitalized infected bone
brodie abscess - small intraosseus abscess, freq. involves the cortex, walled off by reactive bone

Sclerosing osteomyelitis of Garre

develops in the jaw, associated with extensive new bone formation that obscures much of the underlying osseous structure

Tuberculous Osteomyelitis

immunosuppressed people, pain on motion, localized tenderness, 1-3% of pulmomary or extrapulmonary infected people have osseus
infection

Skeletal Syphilis

syphilis and yaws can both infect bone, syphilis is experiencing a resurgence, spirochetes at areas of active enchondral ossification
spirochetes in inflam tissue with silver stain, "saber shin" is produced massive reactive perioisteal bone deposition

Osteoma

Gardeners Syndrome

Osteoid Osteoma

Severe nocturnal pain relieved by aspirin, less than 2cm

Osteoblastoma

Dull achy pain not releived by aspirin, greater than 2cm

Osteosarcoma

Malignant - most common primary malignant tumor of bone, codman's triangle, Li-Fraumeni syndrome (p53 mutation), 50% in knee

Osteochondroma

Multiple hereditary exostosis syndrome, EXT1/2 gene mutations (loss of fx), most common benign bone tumor, MUSHROOM shaped

Chondroma

Enchondromal origin, oval lunecies surronded by thin rim of radiodense bone "C" or "O"
Ollier disease: multiple enchondromas or enchondromatosis
Maffuci syndrome: soft-tissue hemangiomas -> can develop other malignancies

Chondroblastoma

Epiphyses/Apophyses, CHICKEN WIRE

Chondromyxoid Fibroma

rarest of cartilage tumors, metaphyses of long bones, can be mistaken for chondrosarcoma

Chondrosarcoma

Malignant - 2nd most common malignant matrix producing tumor of bone, age = 40s, rarely involve the distal extremities,
painful/progressively enlarging

Fibrous Corticol Defect and Non-ossifying


Fibroma

extremely common, defects rather than neoplasms. Size matters, large ones are non-ossifying and have a pinwheel or storiform pattern

Fibrous Dysplasia

ground glass appearance; polystotic w/ caf-au-lait skin pigmentation McCune-Albright syndrome, coastline of maine, GNAS, trabeculae
mimic chinese letters

Fibrosarcoma

herringbone-storiform pattern, enlarging and painful masses, poor prognosis, mostly pelvic flat bones

Ewing Sarcoma/PNET

Ewing: undifferentiated, PNET: neuronally differentiated; onionskin appearance, homer-wright rosettes

Giant Cell Tumor

osteoclastoma, uncommon benign, express RANKL, giant osteoclast like cells form via the RANK-RANKL path

Aneurysmal Bone Cyst

BLUE BONE, benign, metaphyses of long bones and posterior elements of vertebral bodies