Patho: Final Exam Review PDF

Patho: Final Exam Review GI, Endocrine, & Infectious Disease Gastrointestinal Pathophysiology Intestines The GI tract has 4 layers, and has neuronal innervation...

Patho: Final Exam Review GI, Endocrine, & Infectious Disease Gastrointestinal Pathophysiology Intestines The GI tract has 4 layers, and has neuronal innervation - Serosa (Outermost layer) - Muscularis (longitudinal layer  myenteric plexus  circular layer) - Submucosal plexus - Submucosa - Mucosa (innermost layer) The enteric plexus is made up of the myenteric and submucosal plexus - Submucosal plexus is also called Meissner’s plexus Peyer’s Patches in the mucosa are key - Myenteric plexus is also called Auerbach’s players in immune surveillance for the GI tract plexus Small Intestine 3 layers: duodenum, Jejunum, Ileum Duodenum - Tall layer of mucosa - Many villi to increase surface area for nutrient absorption - Duodenum does the most amount of absorption Jejunum - Tall villi but less than in duodenum Ileum - Short, tightly packed villi Stomach The stomach has 3 muscle layers ○ Longitudinal ○ Circular ○ Oblique  this muscle layer helps churn food to aid with digestion The LES (lower esophageal sphincter) strops gastric contents from refluxing into the esophagus The pyloric sphincter prevents movement of food into the duodenum until it’s been churned and mixed with stomach acid  Stomach Lining Gastric pits: small depressions in epithelial lining of the stomach. Each pit has a gastric gland at the bottom which contains different cell types Cell Type Product Mucous neck cells Mucin – is taken into lining of gastrin mucosa to create protective mucus layer Chief cells Pepsinogen – is cleaved into pepsin which is the enzyme that breaks down proteins in the stomach Parietal cells Hydrochloric acid and intrinsic factor G cells Gastrin – stimulates acid secretion and contraction of the intestines Endocrine cells Somatostatin and histamine GI Tract Circulation Oxygenated blood circulates to the organs of the GI tract via branches of the abdominal aorta ○ Hepatic artery  liver ○ Celiac artery  stomach, spleen, pancreas ○ Superior mesenteric artery  pancreas, small intestine, proximal colon ○ Inferior mesenteric artery  distal colon, rectum Deoxygenated blood from all GI organs drains into the portal vein, which is then carried to the liver Liver = major glycogen storage Process of Acid Secretion Gastric acid secretion is stimulated by ○ Vagal nerve stimulation – stimulation by acetylcholine causes acid secretion ○ Gastrin – a hormone from G cells in the stomach ○ Histamine – binds to H2 receptors and stimulates secretion Gastric acid secretion can be inhibited by ○ H2 antihistamines ○ Short-term use of PPIs The rate of gastric acid secretion is different when fasting vs eating ○ Fasting = very little acid secretion Low amount of Cl- and H+ in the acid Higher amounts of Na+ and K+ Gastric pH sits at 5 to 5.5 usually ○ Eating = stimulates LOTS of HCL secretion Low amounts of Na+ and K+, more H+ and Cl- in the acid Gastric pH is around 1.5 Process of HCl Production HCl is made by the parietal cell CO2 in the blood diffuses into parietal cell and combines with H2O  forms carbonic acid (H2CO3) Carbonic anhydrase cleaves carbonic acid into bicarb and a proton ion ○ Bicarb is secretes back into the blood in exchange for a Cl- ○ Proton is secretes into the stomach lumen by the H-K-ATPase pump In the stomach lumen, H+ and Cl- combine to form HCl Peptic Ulcers Peptic ulcers occur when there is an imbalance between damaging (acid) and protective (mucosal) forces Duodenal ulcers ○ Most found in first portion of duodenum ○ Caused by hypersecretion of acid, leading to injury ○ H. pylori = MCC ○ Patients feel better when they eat because food neutralizes the acidity Gastric ulcers ○ Caused by deficiency in mucin production to protect the stomach lining ○ NSAIDs = MCC ○ Patients feel worse with eating because food stimulates acid secretion Digestion Digestion and Absorption of Carbs Begins in the mouth with the secretion of salivary amylase which breaks carbohydrates into polysacchardies Pancreatic amylases travel through the pancreatic duct to the duodenum and aid in digestion Finally, enzymes in the brush border of the small intestine break polysaccharides into monosaccharides Nutrients can now be absorbed into bloodstream by a sodium- glucose cotransporter Digestion and Absorption of Proteins Pepsin and HCl in the stomach do most of the work breaking proteins into proteoses and peptones Pancreatic enzymes digest the proteoses and peptones further Enzymes in brush border of small intestine digest these protein products into amino acids Amino acids are absorbed via proton amino acid antiporter and sodium-amino acid symporter into the villi and transported to the liver Digestion and Absorption of Fats Fats are the most difficult to absorb Starts when the emulsifying agents in bile cleave fatty acids to make them more soluble Pancreatic lipase breaks the fats into monoglycerides and glycerol ○ Monoglycerides are absorbed through lacteals and are transported to the liver through lymphatic circulation ○ Glycerol and short chain fatty acids are absorbed by capillaries in the villi and go to the liver via the portal vein  Each section of the GI tract has specific nutrients it absorbs ○ Stomach absorbs alcohol ○ The duodenum absorbs most nutrients (due to tightly packed villi providing more surface area for digestion) ○ Ileum absorbs vitamin B12 Absorption and Secretion Electrolyte Transport Absorption = moving materials from the GI tracts into the ECF Secretion = moving material from the ECF into the lumen of GI tract Electrolyte transport in duodenum and jejunum ○ Sodium: proton exchanger ○ Sodium: chloride transporter ○ Sodium: glucose cotransporter  targeting this transporter with supplements such as Pedialyte is the primary way we provide oral rehydration in kids with volume deficits ○ Duodenum and jejunum are considered to have “leaky epithelium” because H2O and electrolytes move through gap junctions Electrolyte Transport Electrolyte transport in the terminal ileum and colon is primary done by ○ Chloride: bicarb exchanger ○ Sodium: chloride cotransporter ○ Diarrhea causes the loss of bicarb in the feces because of bicarb secretion in the ileum/colon Diarrhea can cause metabolic acidosis from excessive bicarb loss The terminal colon has a sodium channel for absorption Diarrhea Definition: increase in stool mass, fluidity, or frequency. Usually > 200 grams per day 4 types ○ Secretory: isotonic stool. Persistent and does not go away with fasting Ex: some bacterial infections, such as cholera ○ Osmotic: excess water is drawn into the bowels from solutes that inhibit normal water and electrolyte absorption Ex: laxatives, gallbladder removal, lactase deficiency ○ Malabsorptive: inability to absorb nutrients properly in the small intestine, but WILL IMPROVE WITH FASTING Ex: Celiac disease ○ Exudative: Purulent, bloody stool that does NOT IMPROVE with fasting Ex: Inflammatory Bowel DIsease Bacterial Causes of Diarrhea The most important things for you to know are modes of transmission and symptoms Cholera “rice water stools” Enterotoxigenic E. Coli “Traveler’s Diarrhea” Enterohemorrhagic E. coli – Bloody diarrhea and HUS in children. Do not treat with abx C. diff – Foul smelling diarrhea after a course of abx treatment Cholera -= Prototype for Secretory Diarrhea Cholera toxin has an alpha and beta subunit The cholera toxin stimulates the enzyme adenylate cyclase to convert ATP  cAMP ○ This opens the chloride channel in the intestinal lumen Chloride moves out of the intracellular environment into the intestinal lumen ○ Water follows, filling up the lumen End result: profuse watery diarrhea (rice water stools) Celiac Disease = Prototype for Malabsorptive Diarrhea Celiac disease is an autoimmune disease Ingested gluten is metabolized into gliadin Gliadin moves across mucosa and is deamidated by tTG Deamidated gliadin is taken up by APCs and presented to T cells  stimulates B cells to make anti- gliadin antibodies Antigen on T cell binds to MIC-A receptor  causes loss of height of villi and crypt elongation which causes thinning and loss of intestinal epithelium Inflammatory Bowel Disease Mechanism of IBD Cause not exactly known but likely familial Mechanism ○ Certain bacteria permeate through the epithelium more readily than others → taken up by dendritic cells, degraded, and antigens are presented to CD4 and CD8 cells ○ TH2 and TH17 → humoral B cells ○ TH1 → upregulates macrophages and cytotoxic T cells that cause damage to the epithelial cells, allowing more bacteria to cross Use immunosuppressants to inhibit the T cell response and improve inflammatory symptoms Meds bind to TNF receptor on the epithelia to stop the increase in permeability. Need to know: TNF alpha is the major component of this inflammatory process Crohn’s Disease vs Ulcerative Colitis Crohn’s Disease: skip lesions throughout the entire bowel but mostly the ileum, transmural inflammation, may form granulomas and fistulas, “cobblestone” appearance Ulcerative colitis: affects ONLY the colon (starts at anus/rectum and extend proximally), no skip lesions, higher risk of colon cancer, may form toxic megacolon, “lead pipe appearance” from loss of haustra GI Motility Step 1 - Swallowing Swallowing ○ When not swallowing: UES is contracted Epiglottis is up Glottis is open ○ When swallowing: Larynx moves up, tipping the epiglottis OVER the glottis UES relaxes and peristalsis allows food to propagate down the pharynx Peristalsis happens from contraction of longitudinal and circular muscles Step 2 – Gastric Motlity Gastric Motility is divided into 2 parts ○ Accommodation Fundus of stomach + proximal ⅓ of corpus Allows food to enter stomach ○ Emptying Remaining corpus, antrum, and pylorus Allows food to digest and pass into duodenum Step 3 – Small Intestine Motility Most of the work is done by the duodenum Duodenum serves 3 general purposes ○ Absorb extrinsic enzymes from pancreas and gallbladder, then use these enzymes to form chyme ○ Secrete enzymes and waste products once everything has been absorbed ○ Propagate remnant down the jejunum and eventually the terminal ileum Once chyme enters the duodenum, 3 movements happen ○ Propagation: wavelike muscle contraction (peristalsis) ○ Segmentation: circular muscle constricts the intestine into small segments, sloshing chyme back and forth ○ Pendular: longitudinal muscle relaxes and contracts, causing a small portion of the intestine to shorten and lengthen Step 4 – Colonic Motility The colon transports waste and absorbs water/ some nutrients The colon contracts to ○ Make stool Repetitive, non-propulsive contractions to mix waste into stool form ○ Propagate stool forward Large coordinated contractions to move stool from colon into rectum Motility Disorders Esophageal dysmotility Colonic Dysmotility ○ GERD ○ Constipation ○ Achalasia ○ Diarrhea ○ Dysphagia ○ Strictures Stomach dysmotility ○ Gastroparesis Colon Cancer Need to Know! You should memorize the driving mutations at each stage progressing to colon cancer (in the boxes) Liver, Bile, and Bilirubin Metabolism Liver Functions ○ Make bile ○ Make proteins (albumin) for blood plasma ○ Make cholesterol ○ Store glycogen ○ Clear toxins from the blood ○ Regulate clotting by making clotting factors ○ Process hemoglobin, store iron Anatomy ○ Functional unit is the hepatocyte, centered around central veins to drain filtered blood Also drain bile into bile canaliculi  goes to gallbladder for storage Bile Made in the liver and stored in the gallbladder Bile is made up of ○ Bile salts ○ Bilirubin ○ Water ○ Electrolytes ○ Phospholipids Function of Bile Salts Bile salts are the most important component of bile They have 3 functions ○ Emulsify fats Pancreatic lipases separate bile salts and lipids Lipids are absorbed in the jejunum Bile salts are absorbed in the Terminal Ileum (95% recycled) ○ Cholesterol Excretion Bile acid resins prevents reabsorption (cholestyramine, colestipol, colesevelam) ○ Antimicrobial Disrupt cell membranes Less bile=more bacteria  Bilirubin Metabolism Bilirubin is a major part of bile Bilirubin is a byproduct of red blood cell breakdown ○ RBCs develop membrane deformities as they age ○ The deformities are recognized by reticuloendothelial cells in the spleen, who mark RBCs for destruction ○ RBCs are broken down and release hemoglobin, which is broken down into heme and globin ○ Heme is converted to biliverdin, which becomes unconjugated bilirubin (unconjugated means lipid soluble, water insoluble) ○ Unconjugated bilirubin is combined with glucuronic acid in the liver to make it water soluble ○ The new conjugated (water soluble) bilirubin is excreted with bile into small intestine Conjugated bilirubin is excreted in stool Conjugated bilirubin can also be converted to urobilinogen by bacteria, which is excreted in feces and urine Splanchnic Circulation Splanchnic circulation is the blood flow to GI organs ○ Blood is supplied by celiac artery, SMA, and IMA ○ Blood is drained by portal vein, which sends blood to the liver ○ The liver drains processed deoxygenated blood via hepatic veins to the inferior vena cava Splanchnic Circulation and Portal Hypertension Cirrhosis Cirrhosis is a chronic liver disease occurring when healthy liver tissue is replaced by scar tissue (fibrosis) Inflammation and production of Il-1, TNF, and TGFB stimulate stellate cells to differentiate into myofibroblasts The myofibroblasts produce collagen  causes progressive fibrosis Kupffer cells release cytokines that promote hepatocyte death Gallstones and Cholecystitis Gallstones Acute cholecystitis ○ 90% of cases are caused by stones in ○ MC are cholesterol stones gallbladder blocking cystic duct Form when there is too much Cause distention and inflammation of fat in the bile or when there is gallbladder 10% of cases are acalculous and bile stasis from improper idiopathic gallbladder emptying ○ Clinical picture ○ Pigment stones Continuous RUQ pain radiating to right scapula Caused by conditions that Fever produce excess bilirubin N/V Black = alcohol excess Leukocytosis Brown = parasite Chronic cholecystitis ○ 95% of patients will also have gallstones infections ○ Chronic inflammation of gallbladder Gallstone (cholelithiasis) pain is ○ Patients are usually minimally symptomatic ○ “porcelain gallbladder” on Xray = increased risk known as biliary colic of gallbladder cancer ○ Intermittent RUQ pain, usually worse after a fatty meal Pancreas Pancreatic Function Endocrine function ○ Islet cells produce insulin and glucagon Exocrine function ○ Acinar cells produce enzymes to break down proteins and fat for digestion Leptin and Ghrelin Leptin, ghrelin, and adiponectin help the body balance caloric intake and caloric expenditure Leptin = increases energy consumption (catabolism) ○ Decreases weight gain and inhibits desire to eat Ghrelin and Pyy molecules = stimulate fat buildup (anabolism) ○ Encourage feeding desire Adiponectin = hormone that inhibits aging ○ Increases energy expenditure ○ A beneficial hormone Endocrinology Brief Overview ❏ Hormone: substance produced that acts on distant cells through delivery in the bloodstream ❏ 2 Modes of action ❏ Cell Membrane Receptors–Non-steroid Hormones ❏ Tyrosine kinase (insulin, EGF, PDGF, VEGF) ❏ Cytokine receptors (GH) ❏ G-Protein (PTH, Vasopressin, FSH, LH) ❏ Nuclear Receptors–Steroid Hormones ❏ Cortisol, aldosterone, calcitriol, estradiol, progesterone, testosterone ❏ Regulation ❏ Feedback loops (positive and negative) Feedback Loop ❏ Negative feedback mechanisms are the most common ❏ They work to maintain a target level (equilibrium) ❏ Good thing when it comes to homeostasis! ❏ Ex. Pancreas relies heavily on (-) feedback to regulate blood glucose levels ❏ Positive feedback mechanisms move a system AWAY from equilibrium ❏ Not very common because your body doesn’t like extreme conditions ❏ Ex. Childbirth- uterine stretch receptors are activated→brain sends signal to release oxytocin→ oxytocin causes uterine muscles to continue contracting Hypothalamic/Pituitary Axis = “Master Gland” ❏ This control center in the brain secretes hormones that have direct effects on tissues ❏ Also secretes hormones that regulate the production and secretion of hormones in other glands. ❏ The hypothalamic/pituitary axis coordinates most endocrine and nervous system messages Anterior Pituitary Posterior Pituitary Glandular tissue that secretes substance Neuronal tissue into the blood Nerve fibers No nerve fibers going here Its own portal venous system Obj. Differentiate the action of steroid and nonsteroid hormones on the target cell. ❏ Steroid and nonsteroid hormones differ in how they cause the target cells to respond. ❏ Steroid hormones enter the target cells, as they can easily pass through the cell membrane. ❏ Non-steroid hormones cannot easily pass through the cell membrane, so they attach instead to receptors on the surface of the cell Hypothalamic Pituitary Abnormalities… HYPERfunction HYPOfunction ❏ Almost always due to an ❏ Hemorrhage/Infarction adenoma (hormone-secreting ❏ Apoplexy, Sheehan mass) Syndrome ❏ Prolactinoma: loss of inhibition ❏ Inflammatory/Other by dopamine, mutations in ❏ Sarcoidosis. TB Protein kinase A and MEN-1 ❏ GH mutations of receptor or ❏ Mass Compression gain of fxn mutation of Gs protein (increase cAMP),MEN-1 ❏ ACTH: mutations of P27 protein, MEN-1 Symptoms of Pituitary Mass Effect Bitemporal hemianopia from mass effect compression on optic chiasm Headache Increased ICP specific presentations are from over/underproduction of hormone(s) Prolactinoma ❏ Clin Ft: galactorrhea, amenorrhea, infertility, menorrhagia (females), testicular atrophy and sexual dysfunction (males) ❏ Dx: measure prolactin levels and imaging (MRI pituitary) ❏ Tx: Dopaminergic agents (bromocriptine, cabergoline) or surgery (transsphenoidal hypophysectomy) Growth Hormone Abnormalities ❏ Clin Ft: ❏ Overproduction: gigantism/acromegaly ❏ Underproduction: energy loss, malaise, depression ❏ Dx: ❏ Overproduction: measure GH and imaging ❏ Underproduction: evoke GH response (insulin-induced hypoglycemia or arginine + GHRH) ❏ TX: ❏ Overproduction: surgery, radiation, octreotide ❏ Underproduction: GH Adrenal Pathophysiology Layers of the Adrenal Cortex ACTH actions on adrenals ❏ ACTH stimulates the adrenal gland and regulates glucocorticoids only ❏ Has no effect on mineralocorticoids or sex hormones Cushing’s Disease ↓CRH ↑ACTH ↑Cortisol Diagnose ○ Measure AM and PM cortisol (most in the cortisol in the AM, least amount in PM) ○ dexamethasone suppression test: ↓CRH ↓ACTH ↓cortisol Treatment ○ surgery, radiation Cushing’s Syndrome ↓CRH ↓ACTH ↑cortiso l Dx ○ AM and PM cortisol (most in the AM, least amount in PM) ○ dexamethasone suppression test: ↓CRH ↓ACTH ↑cortisol Treatment ○ surgery, radiation Addison’s Disease (Adrenal Insufficiency) ↑CRH ↑ACTH ↓cortiso Presentation l ○ Weight loss, malaise, hypotension, Addisonian crisis (injury, inf. Normally more cortisol to overcome stress) ○ D/t adrenal glands not producing enough cortisol Dx ○ Serum cortisol levels (low) ○ cortrosyn (synthetic analog of ACTH) stimulation test: ↓cortisol ** ○ methampyrone stimulation Treatment ○ Need glucocorticoid AND mineralocorticoid replacement daily ○ hydrocortisone IV if under stress conditions 1° ACTH Abnormalities ❏ Clin Ft: ❏ Overproduction: Cushing Syndrome or Disease- central obesity, proximal muscle weakness, glucose intolerance, moon facies, buffalo hump, striae, osteopenia, HTN ❏ Underproduction: Addison’s Disease-weight loss, malaise, hypoTN ❏ Dx: ❏ Overproduction: am and pm cortisol, dexamethasone suppression test ❏ Underproduction: Cortrosyn stimulation test, metyrapone stimulation ❏ Tx: ❏ Overproduction: may be ectopic-surgery, radiation ❏ Underproduction: cortisol replacement ❏ Basal 20 mg in am and 10 mg in pm ❏ Stress-hydrocortisone 100 mg q8 hours intravenous Thyroid Pathophysiology  Thyroid TPO: iodination of TSH binds to TSHR → the thyroid Stimulates production of hormone thyroglobulin in Golgi to be precursors transported to lumen  Upregulates the uptake of iodine for synthesis of thyroid hormone Pendrin: transports iodine into the lumen **you need iodine for synthesis of thyroid hormone -if iodine deficient, can’t make thyroid hormone TSH Abnormalities ❏ Clin Ft. ❏ Overproduction: RARE- thyromegaly, hyperthyroidism ❏ Underproduction: COMMON- hypothyroidism ❏ Tx: ❏ Overproduction: surgery, radiation, octreotide ❏ Underproduction: thyroid hormone replacement (levothyroxine) Hyperthyroidism - Grave’s Disease Symptoms ○ Weight loss, nervousness, palpitations, tremor, weakness, bowel frequency Signs ○ Proptosis, tachycardia, warm moist skin, myxedema, fine resting tremor, hair loss ○ Thyroid gland is more soft and squishy than normal Diagnosis ○ ↓ TSH ○ ↑ T3, T4 ○ ↑ thyroid uptake with iodine scans ○ anti-TSH receptor Ab (activates receptor → increased production of thyroglobulin and uptake of iodine) Treatment ○ Methimazole, Propylthiouracil (PTU, for pregnant), radiation, surgery Hypothyroidism Symptoms ○ Loss of energy, weight gain, cold intolerance, depression, constipation Signs ○ Delayed return phase of DTRs (most sensitive), non-pitting edema, coarse skin, bradycardia, hypothermia Diagnosis ○ ↑TSH ○ ↓ T3, T4 Treatment ○ Thyroid replacement (Levothyroxine) Pancreatic Endocrine Function 2 main endocrine functions: ○ Secrete insulin: facilitate uptake of glucose and decrease plasma glucose ○ Secrete glucagon: increases blood glucose ○ The pancreas also has exocrine functions that aid in digestion and absorption of proteins and fats Glucose Uptake in the cells ❏ There are different types of glucose transporters in each cell type ❏ Different levels of glucose sensitivity to insulin ❏ GLUT-1 in RBC - no mitochondria, produces lactate by glycolysis ❏ GLUT-3 In Brain- purely have glycolytic and mitochondrial pathways but no STORAGE capabilities ❏ Brain has limited ability to use glycogen, proteins, fats for energy ❏ GLUT-4 in Muscle, Adipose, Liver - glycogen pathways for converting glucose to glycogen for energy storage ❏ GLUT-2 in Liver- dietary intake of glucose from intestinal tract is absorbed and sent to liver for metabolism A closer look at how insulin is secreted…. ❏ Glucose taken up into the cell by GLUT-2 → metabolized and produces ATP ❏ ATP inhibits the K channel → increases intracellular K concentration and hyperpolarizes the cell → increase uptake of Ca ❏ Ca activates insulin transporter to secrete insulin A closer look at how insulin is secreted…. ❏ GLP1 receptor Activated → produces cAMP, protein kinase A → transcription factors that lead to production of PDX1 (increase Beta cell mass/differentiation for the production of more insulin on a longer term basis ❏ Wnt pathway: AKT activating other downstream second messenger for the regulation of insulin secretion ❏ PY receptors lead to insulin reactive substrate nuclear factor production A closer look at how insulin works when secreted… ❏ Insulin binds to receptor → downstream products that lead to tyrosine kinase activation → through mTOR pathway, translation initiation, translation elongation, lipid synthesis ❏ Regulating huge host of enzymes in the metabolic pathway → gluconeogenesis, uptake of glucose, glycogenolysis Know pathways of carb metabolism ❏ Plasma glucose levels are the result of a balance of these processes ❏ Gluconeogenesis takes place in liver and kidneys ❏ Glycolysis takes place in cytoplasm ❏ Glycogenesis takes place in liver and muscle cells ❏ Glycogenolysis occurs in the liver and muscle cells Diagnostic Criteria for Diabetes Pre-diabetes ○ Fasting BG 100-125 ○ Post-prandial BG 140-199 ○ Hgb A1C 5.7-6.4% ○ 40% of people with pre-DM are going to be diagnosed with DM if not controlled with diet and lifestyle Diabetes ○ Fasting BG > 125 ○ Post-prandial >200 ○ Hgb A1C>6.4% Type I Diabetes Mellitus Insulin DEFICIENCY so insulin DEPENDENT Autoimmune destruction of islet cells (not making any insulin) ○ Mumps viral infection MC viral cause Diabetic ketoacidosis (DKA) ○ Due to insulin deficiency ○ Transport of acetyl CoA into mitochondria is insulin dependent ○ If no insulin is available, Acetyl CoA is converted into ketones Type II Diabetes Mellitus 3 things: ○ Impaired glucose uptake ○ Insulin resistance *** - the body is producing insulin but is unable to use it properly ○ Defective insulin secretion Genetic mutations ○ Peroxisome proliferator-activated receptor-y ○ If family history of DM, more likely for pt to develop DM Associated with obesity- decreased adiponectin, increased leptin Diabetic Complications Most common complications ○ Retinopathy ○ Vascular Disease ○ Neuropathy ○ Nephropathy Diabetics are also more prone to infections and skin changes Diabetic Complications Macrovascular disease Accelerated atherosclerosis due to lipid dysregulation Microvascular disease Damaged by AGE (advanced glycosylated end products) Proteins bind glucose and become glycosylated → no enzyme to “deglycosylate” them, can only be removed by removing protein (deposition of polyols and AGE in intima of small vessels) Diabetic Complications Retinopathy Decreased O2 delivery through microvascular disease processes (decreased perfusion → tissue hypoxia → VEGF production → neo proliferation in retina Neuropathy Small vessel ischemia or polyol deposition on myelin sheath Causes numbness, tingling in extremities (especially the feet) Nephropathy Diabetic nephropathy occurs in patients with hyperglycemia from diabetes AND a strong genetic disposition to kidney disease Not all diabetics will get diabetic nephropathy Infectious Disease Know Mechanisms of Virulence Encounter Adherence – virus wants to stay in place long enough to propagate without being shed Evasion of Immune System (Both innate and the adaptive) ○ Most infections are cleared by the body in healthy person Multiplication and Spread ○ If localized to one area, limited damage ○ Damage to host is worse when infection spreads Cell/Tissue Damage Shedding ○ Virus will try to shed off to infect other hosts Know that most organisms need a mode of transmission ○ They cannot survive on their own and need a host to infect others ○ Exception: fungi and anthrax bacteria which form spores Spores have a hard shell to protect the organism inside for a long period of time Infection Sources Endogenous = from inside the body ○ Skin = common source of staph infections ○ Colon = FILLED with bacteria Common source of gram (-), fungi, and anaerobe infections ○ Nose and oropharynx Common source of staph, strep, and anaerobe infections Exogenous = from outside the body ○ Fomites (inanimate objects that host bacteria, like a tabletop) Listeria E. coli ○ Animal and insect vectors Viruses, malaria, typhus, parasites ○ Other humans STDs TB Viruses Air-borne illnesses Mechanisms of Adherence Viruses Bacteria ○ Adhere to and enter cells by ○ Gram (+) receptors OR proteins on viral capsids Peptidoglycans on cell wall ○ Ex stick to cell surface CD4 antigen for HIV ** ○ Gram (-) Adhere to cell wall via antigens on flagella, pili, or fimbriae Know mechanism of adherence for HIV Glycoprotein 120 (GP120) on viral capsid binds to CD4 receptors on cells This recruits chemokines by binding to CCR-5 Chemokines adhere to the virus and allow it to penetrate and fuse to the cell membrane Once virus has entered cell, viral replication can occur Know this diagram Major takeaways: - LPS: endotoxin that facilitates pathogenesis of E. coli - Fimbriae: mechanism of adherence - Glycocalyx: protection from phagocytosis - Flagella: movement - E. coli is the most common cause of bladder and renal infections Spread and Multiplication of Organisms Can occur by producing toxins, as seen in the Can occur by secretion of enzymes case of ○ Streptolysin ○ E. coli, C. diff, Staph ○ Proteases Staph creates superantigens that can spread beyond the site of infection and ○ Lipoprotein saccharide cause systemic disease These enzymes break down the ECM Gram (-) organisms produce endotoxins so that bacteria can easily enter the (lipopolysaccharides) on their outer cell walls ○ Initiates immune response with IL-1 and TNFa, cells causing Fever Permeability changes Vasodilation ○ A-B toxins can join to create further damage Clostridium tetani = AB toxins affect synaptic transmission, causing muscle spams and numbness Vibrio cholera Activate cAMP to open chloride channels and cause watery diarrhea Evasion of Host Immune Response Inhibition of chemotaxis ○ Inhibiting chemotaxis inhibits activation of complement cascade, which is an important part of initiating immune response ○ C5a Strep → surrounds compliment so it is not expressed or even degrades it Killing of phagocyte ○ Α-toxin seen in Staph kills macrophages before they can engulf/destroy staph Avoiding ingestion ○ Seen in the LPS, κ-capsule of Strep ○ K capsule prevents ingestion into endosome Evasion of Host Immune Response Avoiding complement lysis ○ Coating with IgA antibodies by our Neisseria gonorrhea prevents host immune system from killing the organism by activating the MAC to avoids complement lysis Surviving within the phagocyte → the organism is taken into endosome BUT prevents lysosome-endosome fusion Survival Within Host Phagocyte Normally, host phagocyte destroys bacteria by ○ Bacteria binds to molecules on cell surface (ex. TLRs) ○ Produces an evagination endosome of cell membrane ○ Endosome buds off → enters cytoplasm w/bacteria inside ○ Fuses w/ lysosome (contains proteases & O2 free radicals) ○ Lysosome contents destroy/degrade organisms Survival within Host Phagocyte Some organisms have created ways to evade host phagocytosis ○ Inhibition of endosome-lysosome fusion from Chlamydia ○ Inhibition of NADPH oxidase from Salmonella ○ Inhibition of H+-ATPase from tuberculosis Inhibits acidification of endosome and this is how we get the endosome to move into the cytoplasm to go fuse with the lysosome Understand Antibiotic Resistance mechanisms: - Beta-lactamase inhibitors: that are put in penicillin to prevent the enzyme from cleaving the beta-lactam structure of bacteria →targets the MOA of penicillin drugs, rendering them ineffective/less effective - Multidrug resistance transporter: Multidrug-resistant transporter = large protein structure made up of about 10 protein subunits that span the cell membrane in the host organism. It has cytoplasmic nucleotide-binding domain. This domain binds ATP and opens a channel that allows a drug to be extruded from the cell. This means that the drug can not get into the cells - Alteration of metabolic function: Genes that alter the metabolic function of the organism itself so the bacteria doesn’t require a certain substrate for energy or can use another substrate - Phage transfer: bacteria transfer certain enzymes or other component that can offer resistance to treatment/antibiotics and survival of the organism Know the mechanisms of how common GI pathogens produce disease Which of the following is an example of fomite transmission? A) Being bitten by a mosquito infected with Zika Virus B) Touching a doorknob covered with adenovirus C) Your classmate doesn’t cover their mouth when they sneeze next to you D) Drinking water containing giardia Which of the following is the best example of fomite transmission? A) Being bitten by a mosquito infected with Zika Virus- insect vector B) Touching a doorknob covered with adenovirus- fomite vector C) Your classmate doesn’t cover their mouth when they sneeze next to you- indirect airborne D) Drinking water containing giardia- indirect fecal-oral Which of the following pathogens establishes symptomatic disease by mechanism of bacterial colonization in the gut? A) S. aureus B) Salmonella C) C. diff D) Campylobacter Which of the following pathogens establishes symptomatic disease by mechanism of increased bacterial colonization in the gut? A) S. aureus- toxin production B) Salmonella- adhesion and mucosal invasion C) C. diff- bacterial colonization overpowers “good bacteria” D) Campylobacter- adhesion and mucosal invasion Which of the following pathogens uses glycoprotein p120 as a mechanism of adherence to infect host cells? A) COVID-19 B) E.coli C) Gram (-) bacteria D) Gram (+) bacteria E) HIV Which of the following pathogens uses glycoprotein p120 as a mechanism of adherence to infect host cells? A) COVID-19- COVID spikes bind to ACE2 on host B) E.coli- use fimbriae to attach to urothelium of the host C) Gram (-) bacteria - adhere primarily through antigens on flagella, fimbriae, and pili D) Gram (+) bacteria- adhere primarily through peptidoglycan in cell wall E) HIV- Glycoprotein p120 on HIV virion binds to CD4 molecule Which of the following pathogens uses opening of Cl- channels and water secretion into the GI tract as a mechanism of pathogenesis? A) Vibrio Cholera B) E. Coli C) C. tetani D) Staph a. Which of the following pathogens uses opening of Cl- channels and water secretion into the GI tract as a mechanism of pathogenesis? A) Vibrio Cholera- Uses toxin to cause opening of Cl-channels resulting in excess water into GI tract causing “rice water diarrhea” B) E. Coli- Uses LPS endotoxin to produce inflammation C) C. tetani- Uses neurotoxin to cause inhibit the release of neurotransmitter and cause paralysis D) Staph a.- Uses superantigen to initiate exaggerated immune response Which of the following pathogens utilizes an IgA antibody coating to protect from complement-induced lysis? A) Strep B) Neisseria C) Chlamydia D) TB Which of the following pathogens utilizes an IgA antibody coating to protect from complement-induced lysis? A) Strep B) Neisseria- IgA antibody protects from initiation of complement C) Chlamydia D) TB *** IgA does not activate complement → coating in IgA prevents complement lysis Which of the following HPV subtypes are most closely associated with cervical cancer? A) 6 & 11 B) 31 & 33 C) 16 & 18 D) 35 & 39 Which of the following HPV subtypes are most closely associated with cervical cancer? A) 6 & 11- most commonly associated with genital warts B) 31 & 33- associated with cervical cancer, but not as frequently C) 16 & 18- most commonly associated with cervical cancers D) 35 & 39- associated with cervical cancer, but not as frequently Which of the following mutations is associated with the development of cervical carcinomas? A) Inhibition of p53 gene B) Inhibition of PTEN gene C) Upregulation of EGFR gene D) Upregulation of RB gene Which of the following mutations is associated with the development of cervical carcinomas? A) Inhibition of p53 gene- decrease activity of this tumor suppressor gene results in increase cervical carcinoma B) Inhibition of PTEN gene- decrease activity of this tumor suppressor gene results in increase of breast and colon cancer C) Upregulation of EGFR gene- upregulation of this proto-oncogene results in increase of colon cancer D) Upregulation of RB gene- upregulation of tumor suppressor gene is protective against the development of cervical cancer *** inhibition of RB would result in an increase in in cervical cancer Know the common HIV/AIDS-related illnesses Thank you! Questions? Email me ([email protected])