Pathology - Chapter 24 (The Endocrine System)

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

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

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

Thyrotrophsproduce TSH

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

Two peptides secreted from the posterior pituitaryADH and Oxytocin

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

Synthetic oxytocincan be administered to induce labor

Function of ADHconserve water by restricting diuresis

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

Hyperpituitarismexcess secretion of trophic hormones

Hypopituitarismdeficiency of trophic hormones, usually caused by destructive processes

Local Mass Effectsradiologic 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 adenomaCushings syndrome and Nelson syndrome (ACTH and POMC)

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

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

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

Thyrotroph adenomaHyperthyroidism (TSH excess)

Gonadotroph adenomaFSH and LH excess - hypogonadism, mass effects, and hypopituitarism

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

Four Genes for Familial Pituitary AdenomasMEN1, CDKN1B, PRKAR1A, and AIP3

MEN1makes menin (tumor suppressor) -> GH, prolactin, ATCH tumors -> multiple endocrine neoplasia syndrome

CDKN1Bcheckpoint regulator - MEN1 like syndrome but no mutation of MEN1

PRKAR1Acarney complex, autosomal dominant -> tumor supressor that regulates PKA -> loss of PRKAR1A lead to constant cAMP -> cell proliferation

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

Invasive Adenomasnot grossly encapsulated and infiltrate neighboring tissues -> cavernous and sphenoid sinuses, and the dura

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

Pregnancycan cause hyperprolactinemia - must do pregnancy test

Lactotroph hyperplasiausually results from interference with normal dopamine inhibition of prolactin

Bromocriptinedopamine receptor agonist that causes prolactinoma lesions to diminish in size

Somatotroph adenoma2nd most common type, densely vs. sparsely granulated - elevated GH and IGF-1 (somatomedin C)

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

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

Cushing diseaseexcessive production of ACTH by pituitary -> hypercortisolism

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

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

Hypopituitarism w/ Diabetes Insipidusso both anterior and posterior pituitary disfunction -> almost always of HYPOTHALAMIC origin

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

Empty Sella syndromeany 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 POU1F1deficiency of GH, prolactin, and TSH

Clinical manifestations of (anterior) Hypopituitarismspecific hormone deficiency, growth failure, amenorrhea, infertility, impotence, loss of axillary hair, hypothyroidism/hypoadrenalism, lactation

Diabetes Insipidusdeficiency of ADH - inability of kidney to resorb water properly - excrete large volumes of dilute urine (low spec. gravity), serum Na+ increased

SIADHresorption 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

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

Craniopharyngiomashypothalamic 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 cellselaborate VIP -> glycogenolysis and hyperglycemia

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

Diabetes Mellitusgroup 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 Diabetesrandom glucose higher than 200, fasting glucose higher than 126, abnormal OGTT greater than 200

Type 1 diabetesautoimmune disease, -cell destruction -> absolute deficiency of insulin (5-10% of all diabetes)

Type 2 diabetescombo of peripheral resistance to insulin action and inadequate secretion, vast majority of patients are overweight, "adult-onset"

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

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

High glucoseincreased levels of insulin -> glucose storage and utilization

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

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

Glucosemost important stimulus for insulin synthesis

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

PTPN1Bdephosphorylates the insulin receptor and inhibits insulin signaling

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

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

Insulin w/ VNTRinfluence level of expression in the thymus -> alter negative selection

Viral infectionsmumps, rubella, coxsackie V, cytomegalovirus -> TYPE 1

"bystander damage"where infections cause -cell injury

Fundamental immune abnormality in Type 1Failure of self-tolerance in T cells

Two metabolic defects that characterize type 21. 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 resistancedefined 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

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

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

Pro-inflammatory cytokinesAdipose 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 TCF7L2associated with reduced insulin secretion

Monogenic Diabetes1. autosomal dominant, 2. early onset - before 25 y/o, 3. absense of obesity, 4. absense of -cell antibodies

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

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

Maternally inherited diabetes and deafnessresults from mitochondrial DNA mutations

Type A insulin resistance (insulin receptor mutation)acanthosis nigricans (velvety hyperpigmentation of the skin), polycystic ovaries, and elevated androgens

Lipoatrophic Diabeteshyperglycemia 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 pathwaysustained hyperglycemia -> depletion of intracellular NADPH -> increases oxidative stress -> diabetic neuropathy

Reduction in number/size of -cellsType 1, rapidly advancing

Leukocytic infiltration of the islet cellsType 1

Subtle reduction in -cell massType 2

Amyloid deposition in insletsType 2, advanced disease islets may be obliterated and fibrous tissue may be present

Myocardial Infarctionmost common cause of death in diabetics, caused by atherosclerosis

Gangrene of lower extremitiesresults from advanced vascular disease

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

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

Diffuse Mesangial Sclerosisdiffuse increase in mesangial matrix -> overal thickening of the GBM

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

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

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

Diabetic Ocular complicationsretinopathy, cataract formation, or glaucoma

Diabetic Neuropathycentral/peripheral NS not spared

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

-cell tumorshigh plasma somatostatin for dx, diabetes m, cholelithiasis, steatorrhea, and hypochlohydria

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

Pancreatic carcinoid tumorsrare, and produce serotonin

Polypeptide-secreting endocrine tumorsassymptomatic and rare

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

Achondroplasiamost common diease of growth plate, major cause dwarfism, FGF3 mutation, short stature, bulge forehead, depression at root of nose

Thanatophoric dwarfismmost common LETHAL form of dwarfism, gain of fx FGF3, short limbs, frontal bossing, macrocephaly, small chest cavity, bell-shaped abdomen

Increased bone masscortical 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 syndromeinactivating mutation of LPR5 -> severely osteoporotic -> fractures

Osteogenesis imperfectabrittle 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 Collagenmild disorder = reduced synthesis of type 2 collagen, severe = can be fatal

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

Osteopetrosismarble 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

Osteoporosismost 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 Diseaseskeleton 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 Osteomalaciadefect in matrix mineralization - most often related to lack of vitamin D or metabolic disturbance

Hyperparathyroidismaffects 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 Osteodystrophyskeletal 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

OsteonecrosisIchemia 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

OsteomyelitisInflammation of bone - vitually always implied infection

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

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

Skeletal Syphilissyphilis 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

OsteomaGardeners Syndrome

Osteoid OsteomaSevere nocturnal pain relieved by aspirin, less than 2cm

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

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

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

ChondromaEnchondromal 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

ChondroblastomaEpiphyses/Apophyses, CHICKEN WIRE

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

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

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

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

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

Giant Cell Tumorosteoclastoma, uncommon benign, express RANKL, giant osteoclast like cells form via the RANK-RANKL path

Aneurysmal Bone CystBLUE BONE, benign, metaphyses of long bones and posterior elements of vertebral bodies