Tuesday, April 3 (ellen And Ellen)

Endocrine Pathologies – April 3rd, 2007 Adrenal Gland -paired; sit above the KI -cortex – outside -sustained stress response = glucocorticoids (steroids) -mineralocorticoids = aldosterone (increases Na retention; hypovolemia triggers aldosterone to release Na to increase water retention and therefore increase blood volume) -sex steroids (estrogens and androgens) -overexertion / adrenal fatigues and TCM KI deficiency  correlated with CVA pain -medulla – inside -catecholamines (epinephrine)  SNS, stress / acute response -cortisol  adaptive purpose, inhibit formation of bone and collagen, suppresses pituitary gland hormones (know functions for exam!) Cushing’s Syndrome -excess glucocorticoids -exogenous  most common (drugs) -endogenous  primary (adrenals showing hyperplasia), secondary (pituitary tumour), tertiary (hypothalamus tumour), LU small cell carcinoma (ectopic production) -manifestations: buffalo hump, moon face, violaceous striae on abdomen -ACTH hypersecretion at pituitary is m/c cause of endogenous Cushing’s = Cushing’s disease -striae  pink then silver, caused by breakdown of skin / collagen (it’s happening too fast b/c cortisol not allowing skin to heal and therefore decrease collagen) -stretched skin -glucose increased in bloodstream, development of DM, hyperglycemia  increase urine excretion by KIs, glucose follows water  osmotic diaphoresis -changes in metabolism of lipids, proteins and fats -store fat for later on  buffalo hump -suppression of immune sys, skews reaction, get T inflammatory state leading to manifestations of autoimmune disorders -corticosteroid drugs -person stops taking drugs abruptly can lead to adrenal failure b/c adrenals have not been working -topical and inhaled don’t have as much impact Primary Cushing’s Syndrome – Adenocortical -usually unilateral neoplasm (Adenoma or carcinoma) -increased cortisol production, has negative feedback to pituitary -causes suppression of ACTH -which causes atrophy of adjacent and contralateral adrenal cortex (b/c lack of use d/t overuse of other adrenal gland) -lab tests: increase cortisol, decrease ACTH

Secondary Cushing’s DISEASE – Hypothalamic/Pituitary -ATCH-producing adenoma; no mass effects -bilateral nodular adrenocortical hyperplasia/hypertrophy d/t increase ACTH -lab tests: increased cortisol AND ACTH Ectopic Cushing’s Syndrome -often d/t small cell carcinoma of lung secretion ACTH -gross morphology: hypertrophy and hyperplasia -labs: increased cortisol AND ACTH -to ddx Ectopic and Cushing’s disease: look into LU (X-ray  masses, nodules, LU CA) and brain (CT  enlarged pituitary, sella tursica enlarged) Hyperaldosteronism -renin-angiotensin-aldosterone system -Primary: -Angiotehnsion II – vasoconstriction and activate aldosterone, exchanges Na for KI -hypokalemia  arrhythmia, tetany, weakness in general, CHF, hypertrophy of HT -aldo secreted @ adrenals abnormally  increased BP and edema -bilateral nodular hyperplasia -familial (ACTH-induced): genetic disposition -Conn’s Syndrome  neoplasma in cortex, producing aldosterone -in adults, adenoma, not malignant, non-metastatic, unilateral, single, solitary, no invasive mass effects, well-encapsulated  just a functional problem -no atrophy of opposite gland, there’s still enough ACTH b/c there’s no feedback with aldosterone (feedback pathways are different) -bilateral  mostly children, congenital, nodular hyperplasia -secondary: aldosterone secreted b/c of other cuase -d/t hemorrhage, KI failure, nephrotic syndrome, body is just compensating Addison’s Disease = Primary Hypoadrenalism -acute or chronic -uncommon -destruction of adrenal cortex  parenchyma of cortex is broken down -75-90% autoimmune -infections: m/c TB -elderly and HIV  any immunocompromised ppl -decrease cortisol, therefore increase ACTH, therefore increase melanin -metastatic neoplasms  invades tissue and takes over -manifestations: -increased ACTH  increased melanin, increased skin pigmentation -decreased glucocorticoids  hypoglycemia, inability to respond to stressors  acute stress and can have acute adrenal failure -decreased mineralocorticoids  decrease BP therefore heart failure, shock Addison’s Disease = Secondary Hypoadrenalism

-from pituitary gland -decrease ACTH, atrophy of adrenals -looks like iatrogenic Cushing’s -can be d/t tumour eg: pituitary adenoma and mass effects push on cells so they can’t make ACTH Autoimmune Addison’s Disease -autoAb vs steroidal enzymes -lymphocytic destruction of cortex -minimal cortical cells within atrophied connective tissue Acute Adrenocortical Insufficiency -inability of adrenal cortex to produce sufficient glucocorticoids in response to stress -chronic adrenocortical insufficiency and stress -volume depletion, cardiac failure, shock, death -adrenal hemorrhage  Waterhouse Fredrichson Syndrome (infection and sepsis) Adrenal Fatigue -please see graph -in alarm phase: temp and acute response -in resistance phase: chronic long term stress -exhaustion: subclinical Addison’s b/c not actual destruction of cells MSS – maladaptive stress syndrome -may ppl are on stage 2 -stage 3 is very burnt out Adrenal Medulla -distinct tissue from adrenal cortex -more neurological function than endocrinological -chromaffin cells -secrete catecholamines: SNS to deal with acute stress -tumour here increases catecholamine and always in this state Pheochromocytoma -functioning neoplasm of chromaffin cells -“rule of 10s” -10% familial (90% sporatic) -10% extra-adrenal: “paragangliomas”  in ganglia -10% bilateral (90% unilateral) -10% malignant (90% non-malignant) -may be small and circumscribed to large and hemorrhagic -vascular and capsular invasion may occur in both benign and malignant lesions -increase catecholamine  HTN d/t increase heart contractions, increase CO, increase vasoconstriction -ddx: hypoaldosteronism  d/t water retention

Endocrine Pancreas -produce hormone -Islets of Langerhans -alpha cells (5-20%)  glucagons response to decrease blood sugar  gluconeogenesis -beta cells (70%)  insulin response to increase blood sugar, therefore store glucose as glycogen and fat -delta cells (5-10%) -pancreatic polypeptide cells (1-2%) Diabetes Mellitus -deficiency in secretion or response to insulin -impaired use of glucose  hyperglycemia -seventh leading cause to death in USA -type I (5-10%)  insulin deficiency -type II (80%)  insulin resistance -other causes (10%) Type IA – Autoimmune -genetic predisposition + environmental trigger -selective AI destruction of beta cells -association with other organ-specific AI disease, especially Grave’s and Hasimoto’s -Northern European, 40% twin concordance rate -genetic mutation marks molecules on beta-cell membrane as antigenic -see CD4 T cell infiltration  development of autoAb in intracellular antigens -environmental triggers -viruses (coxsackievirus B, mumps, measles, rubella) -“molecular mimicry” (children given cow’s milk) vs “bystander effect” (immune complexes are formed) -reduced number and size of islets and beta-cell degranulation  decreased insulin synthesis and secretion  decrease uptake of glucose, decreased storage of glycogen, increased glycogenolysis  hyperglycemia and glycosuria  osmotic diuresis  polyuria and hyperosmolarity  thirst  polydipsia -negative energy balance  weight loss and polyphagia -oxidation of free fatty acids  ketone bodies  ketonemia, ketonuria, dehydration (also increase ketone excretion in urine) -increased blood lipid levels d/t fat tissue mobilization Type 2 – Insulin Resistance -black, Hispanic, aboriginal NA, Asian -60-80% twin concordance rate -central obesity -peripheral resistance  get initial compensatory insulin increase  decreased sensitivity of beta cells to glucose with eventual loss of beta cells  hyperglycemia

-excessive production of amylin (secreted with insulin)  deposition of amyloid in islets  toxic to beta cells, and inhibit reception of glucose -adipose tissue  “adipokines” (messenger molecules) which increase insulin resistance -leptins (an adipokine)  act on CNS to increase satiety and reduce food intake -in ABSENCE causes obesity and insulin resistance -increase in blood with increase adiposity -lays adipose down in diabetics maybe d/t brain not responding -often asxs, dx by routine lab tests Advanced Glycoslyation End Products (AGEs) -irreversible, non-enzymatic attachment of glucose metabolites to proteins -effects of AGEs: -cross-linking of collagen in blood vessel walls (damage) -increased permeability of endothelium -modification of circulating plasma proteins  thrombosis -immune cell activation  fibroblastic and smooth muscle cell proliferation -glycosylated hemoblogin (HbA1C)  can use to test how well diabetes is controlled Sorbital formation -hyperglycemia of cells not requiring insulin (nerves, lens of eye, KI, blood vessel) -glucose  sorbitol (aldose reductase) and fructose  get accumulation  intracellular osmolarity shifts, causing influx of water (mechanical damage in neuropathy) -NADPH used as a co-factor for aldose reductase -needed for glutathione (powerful AO  therefore get oxidative damage if NADPH decreased) Activation of Protein Kinase C -intracellular hyperglycemia  second messenger cascade  PKC activation -elements that predispose to blood vessel damage: -proangiogenic  neovascularization -increased endothelin-1 and decrease endothelial nitric oxide synthase  vasoconstriction -profibrogenic  thickening of basement membrane -procoagulant -proinflammatory Atherosclerosis -MI m/c cause of death in diabetics -early onset, accelerated, women = men -multifactorial (AGEx, immune activation and fibroblasts, vasonconstriction, thrombosis, elevated blood lipids) Microangiopathy -thickening of basement membranes of capillaries with type IV collagen -increased permeability of capillaries

-damage to endothelial cells  vessel weakness  microaneurysms Diabetic Nephropathy -second leading cause of death in DM -glomerular lesions: capillary BM thickens  glomerulosclerosis  nephrotic syndrome + tubular ischemia (in KI) -renal vascular lesions: d/t atherosclerosis -pyelonephritis: ischemia + susceptibility to infections (ascend UB quickly) Diabetic Ocular Disease -fourth leading cause of death in DM -retinopathy: -nonproliferative: microangiopathy in retina  exudates, microhemorrhages, aneurysms, macular edema -proliferative: atherosclerosis + activation of PKCs  neovascularization and fibrosis  disruption of retinal membrane  retinal detachment -cataracts: sorbital production increases water in lens of eye therefore cataract -glaucoma Diabetic Neuropathy -uptake of glucose by nerve cells  conversion to sorbitol / fructose  influx of water  Cell damage  motor and sensory peripheral neuropathy -microangiopathy of afferent blood vessels  generalized neuronal degeneration Infection -common in skin, lung, urinary tract -impaired immune function + poor blood supply + increased risk of injury  increase risk of infection (Gangrene, candida, sepsis) -check px’s feet Functional Hypoglycemia -breakdown of normal blood glucose maintenance -possible causes: hyperinsulinism, MSS, hypothyroidism, liver disease -inability of body to respond to changes in blood glucose  work on diet and lifestyle! Dysinsulinism and Syndrome X -dysinsulinism = stage between functional hypoglycemia and type 2 DM -see reactive hypoglycemia  hyperinsulinism -increased cortisol  MSS  insulin resistance -syndrome X = insulin resistance + dyslipidemia + obesity -sedentary lifestyle, consumption of refined CHO, deficient fiber, obesity, MSS-2