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This Concept Map, created with IHMC CmapTools, has information related to: Pancreas Pathology, Pancreas Pathology Islet Cell Tumors -much rarer than exocrine -adults -resemble carcinoid tumors ->hormones Mets to liver, LNs HYPERINSULINEMIA-Most Common -beta cell tumor-Insulinoma ->hypoglycemia 1. Hypoglycemic attacks below 50mg/dL 2.CNS Sx: stupor, confusion, lose conscious 3.Attacks ppt'd by fasting, exercise -feeding alleviates quickly MORPH-mostly benign, solitary -carcinomas=10%-local invasion, distant mets -tumor can arise in ectopic panc tissue (duod) -benign look like giant islets -malignant look similar, deceptively encapsulated Confused w/ Diffuse Hyperplasia of the Islets -more in kids of DM moms, sometimes adults CLINICAL-Mostly mild hypoglycemia -high insulin, high insulin:glucose ratio Tx-surgical removal->reverse hypoglycemia Other causes of hypoglycemia: insulin sensitivity, inherited glycogenoses, diffuse liver dz, ectopic insulin formation (retroperit firbomas, -sarcs), Pancreas Pathology Congenital CONGENITAL CYSTS -via anomalous devel of ducts -polycystic dz w/ liver, kidney -lined by duct-like epith -clear to turbid mucoid fluid VON HIPPEL-LINDAU DZ -angiomas in retina, CBLM, br stem + cysts in panc, liver, kid, Pancreas Pathology DIABETES MELLITUS -most common are primary islet cells d/os -7th leading COD in US -Insulin mainly regs GLUT4 -GLUT2 in beta-cells, fdback TYPE II-NIDDM-80-90%; onset ᡠyo -genetics more imp't than 1 -not linked to HLA-polymorphic 1. Deranged beta-cell insulin secretion -rapid first phase of ins release diminished -later-less severe minor def of insulin -irrev beta injury, not viral or AI though 2. insulin resistance in periphery -reduced synth, translocation or GLUT4 -hyperglycemia->prolonged beta cell stim Obesity-80% of type 2 pts, esp abd obesity -wt loss can reverse glucose intolerance early Amylin--may cause inpaired glucose sensing by betas, Pancreas Pathology Islet Cell Tumors -much rarer than exocrine -adults -resemble carcinoid tumors ->hormones Mets to liver, LNs ZOLLINGER-ELLISON SYNDROME (Gastrinomas) ->hypersecretion of gastric acid ->ulcers in 95% pts (ZES) -6:1 duodenal to gastric ulcers -like all others in pop-but intractable to NL Tx -also sometime occur in jejunum MORPH-gastrinoma in panc, peripanc region, duodenal wall ᡪ% locally invasive or mets at Dx time If arising in presence of other endocrine CA: 'multiple endocrine neoplasia' Histologically bland-rare anaplasia CLINICAL-diarrhea is CC in 30%, occurs in 50% Tx-histamine receptor (H2) blockers, excise mass -resection usually cures if hep mets->liver failure w/in 10yrs, Pancreas Pathology DIABETES MELLITUS -most common are primary islet cells d/os -7th leading COD in US -Insulin mainly regs GLUT4 -GLUT2 in beta-cells, fdback Clinical BOTH-long-standing: MI, CVAs, gangrene, renal insuff -enhanced suscep to skin infx, TB, pneumo, pyeloneph -5% of DM deaths -CODs: MI, renal, CVA, AS Ht Dz, infx Type 1-by age 20 in most pts-more likely to die from DM -polyuria, -dipsia, -phagia, ketoacidosis -from unopposed catabolic hormones -no glycogen storage->glucosuria ->osmotic diuresis-lose H2O, ions ->intracell H2O depleted->thirst -catabolism of proteins, fats->polyphagia ->wt loss, muscle weakness -unstable, brittle glucose intolerance -very sensitive to insulin -can->hypoglycemic episodes, ketoacidosis -KA-via no insulin, inc'd glucagon->break down fat stores->FFAs-oxidation->ketone bodies not used by body fast enough -if dehydrated, can pee ketones->KA -protein catabolism->more ketogenic AAs -DM w/ inc'd infx risk->inc'd insulin req->KA -nausea, vomiting, resp difficulties Type 2 ᡠyo obese: -polyuria, polydipsia, sometimes wt loss, wkness -sometimes (-)Sx -less severe, easier to control meta. derangements -can decompensate->hyperosmolar nonketotic coma -via severe dehydration (polyuria losses) -often elderly, disabled and can't drink water -NO KETOACIDOSIS IN TYPE 2, Pancreas Pathology Cysts CONGENITAL CYSTS -via anomalous devel of ducts -polycystic dz w/ liver, kidney -lined by duct-like epith -clear to turbid mucoid fluid VON HIPPEL-LINDAU DZ -angiomas in retina, CBLM, br stem + cysts in panc, liver, kid, Pancreas Pathology DIABETES MELLITUS -most common are primary islet cells d/os -7th leading COD in US -Insulin mainly regs GLUT4 -GLUT2 in beta-cells, fdback Maturity-Onset Diabetes of the Young -AD genetic defects of beta-cell fcn ɝ% DM; onset ញ yo -insulin secretory defect W/OUT beta dmg -NL wt, no GAD ABs, no insulin resistance, Pancreas Pathology DIABETES MELLITUS -most common are primary islet cells d/os -7th leading COD in US -Insulin mainly regs GLUT4 -GLUT2 in beta-cells, fdback MORPHOLOGY Pancreas-inconstant lesions, more w/ Type 1 Type 1-fewer, smaller islets; w/ WBCs (Tcells) -beta cell degranulation type 2-subtle reduction in islet mass -amyloid replacement of islets fibrosis DM mom, non-DM newborn-islet hyperplasia Vascular-Accelerated atherosclerosis (lipoprotein changes via nonenz glycos) -low HDL in type 2, inc. TXA2, inc. HTN MI-MOST COMMON CAUSE OF DEATH IN DM Gangrene of lower extremities-100x > NL Hyaline arteriolosclerosis - w/ HTN Diabetic Microangiopathy-diffusely thick bsmt memb -esp skin caps, sk. mm, retina, renal glom, r.medulla -but LEAKIER than NL to plasma proteins -also periph nn, Bowman's cap, placenta, renal tubs -hyaline material-type IV collagen Diabetic Nephropathy-renal failure-2nd leading COD -glom lesions, renal vasc lesions, pyelonephritis -most impt: cap bsmt memb thickens, glom'sclerosis -diffuse glom'sclerosis in most pts w/ dzᡂyr -also in HTN, old age ->nephrotic syndrome -nodular glom'sclerosis-ball-like laminar deposits -w/in mesangial core->halos around nodule 'Kimmelstiel-Wilson Dz'; only in DM Renal Atherosclerosis-hyaline AS in aff AND eff a'ole Pyelonephritis-inflam: interstit->tubules Necrotizing papillitis-more in DM than non Ocular Complications-4th leading cause of US blindness -retinopathy, cataracts, glaucoma Neuropathy-periph, symm motor and esp sensory Immune-high glucose reduces WBC effectiveness Fungi-Zygo-/Mucormycoses loves acid (KA), Pancreas Pathology DIABETES MELLITUS -most common are primary islet cells d/os -7th leading COD in US -Insulin mainly regs GLUT4 -GLUT2 in beta-cells, fdback PATHOGENESIS Microangiopathy Retinopathy Nephropathy Neuropathy -mostly due to hyperglycemia Nonenzymatic Glycosylation: HbA1C (glyc Hb) -glucose attaches to amino protein group -related to level of blood glucose -reversible, but then rearrange->irrev adv glyc end products (AGE) AGEs -accum in vessel wall-no proteolysis -on proteins-cross link coll, trap LDL -alb can bind to glyc'd basement memb -bind receptors: monocyte emigration, release GFs from macs, inc endoth perm Intracell Hyperglycemia disturbs Polyol Pathwy -tissues not needing insulin for gluc uptake: nerves, lens, kidneys, vessels ->inc glucose->sorbitol (polyol)->fructose ->inc osmolarity->influx of water, injury (in lens->opacity) -sorbitol impairs ion pumps, injures Schwann cells pericytes of retinal caps->neuropathy, retinopathy -plus processingextra glucose distracts system -alters balance of signalling, etc., Pancreas Pathology Congenital ECTOPIC PANCREAS -in 2% postmortem exams -esp STOMACH, DUOD, jej, Meckel, ileum -in submucosa -composed of NL glands, islets of Lang. -can be sessile lesions ->pain, inflam, bleeding -make up 2% of islet cell tumors, Pancreas Pathology Tumors CYSTIC TUMORS-elderly women ɝ% of all panc neoplasms -body or tail, slow-growing -some are 'mucinous cystic tumors' -like in ovary -cystadenoma vs cystadenoCA -remove both, Dx after -RARE-microcystic adenoma-SEROUS SOLID-CYSTIC TUMOR-adoles girls, women នyo -solid AND cystic zones -solid sheets or pap projections of cells ->abd pain, cured w/ resection, Pancreas Pathology Pancreatitis ACUTE PANCREATITIS -inflam of panc, often w/ acinar cell injury via enzymes -relatively common 80% ass'd w/ bil tract dz OR alcoholism; 10-20% idio -5% of pts w/ gall stones Other causes: mumps, coxsackie, M. pneumo, acute ischemia (thrombosis, embolism, vasculitis), Drugs: thiazides, azathioprine, estrogens, sulfas, furosemide, methyldopa, pentamidine, procainamide Occlusion of ducts by Ascaris, Clonorchis MORPH-all due to leakage of enzymes microvasc leakage->edema; necrosis of fat, inflam, proteolytic destruction, vessel destruction->hemorr MILD FORM-Acute Interstit P.-interstit edema, fat nec SEVERE-A Necrotizing P-acinar, islets, ductal necrosis -hemorr, chalky fat necrosis, serous peritoneal fluid PATHOGENESIS-prophospholipase, proelastase activated -by trypsin? 1. Duct obstruction, lipase build-up->nec, acinar injury 2. Primary acinar injury-viruses, drugs, trauma, shock 3. Defective intracell xport of proenzymes w/in ac cells -activation via lysosome enzs CLINICAL-acute abd pain, mild to severe -constant pain, referred to UPPER BACK -elevated PLASMA LIPASE, AMYLASE -can have hypoCa due to Ca ppts in fat necrosis -elev WBCs, hemolysis, ARDS, DIC, shock Tx-REST the panc; no food or fluids, just supportive -usually survive, Pancreas Pathology Congenital Agenesis: incomp w/ life Pancreas Divisum-imcomplete fusion ->recurrent pancreatitis Annular Pancreas-head encircles duod ->subtotal obstruction Exocrine ducts don't fuse or anomalous -careful during surgery, Pancreas Pathology Cysts PSEUDOCYSTS -localized foci of panc secretions -walled off by fibrosis -after pancreatitis** or trauma (not panc abscesses) -lacks true epith lining ->abd pain, hemorr, infx, peritonitis -diff'ate from cancer!, Pancreas Pathology Islet Cell Tumors -much rarer than exocrine -adults -resemble carcinoid tumors ->hormones Mets to liver, LNs Other Rare Islet Tumors -alpha-cell Tumors (glucagonomas) -extremely high glucagon->mild DM -migratory, characteristic skin erythema -anemia Mostly in peri-, post-menopausal -delta-cell Tumors (somatostatinomas) ->DM, cholelithiasis, steatorrhea, hypochlorhydria -high somatostatin for Dx -VIPoma (diarrheogenic islet cell tumor) ->watery diarrhea, hypokalemia, achlorhydria -due to VIP release from tumor -ass'd w/ neural crest tumors Pancreatic Carcinoid Tumors-serotonin Pancreatic Polypeptide-Secreting Islet Cell tumor -(-)Sx, just high hormone levels Some can produce ACTH, melanocyte-stim hormone, vasopressin, serotonin, NE in addition to insulin, glucagon, gastrin -'multihormone tumors', Pancreas Pathology DIABETES MELLITUS -most common are primary islet cells d/os -7th leading COD in US -Insulin mainly regs GLUT4 -GLUT2 in beta-cells, fdback TYPE I-IDDM-10% of primary DM -islet cell destruction via: genetics, AI, environmental -viral infx/molec mimicry -AI via altered beta cells->immunogenic N. Euro descent - HLA-DR3 or 4 in 95% Hyperglycemia, ketosis after 90% betas gone Autoimmunity: insulitis w/ CTLs-lymphochytes can xfer DM to NL -aberrant CD4 via cytokines (IFN-g) -70-80% w/ anti-islet cell ABs -esp against Glu Decarboxylase (GAD) Viruses: coxsackie B, mumps, measles, CMV, rubella, mono ->molec mimicry or beta injury Drugs: pentamidine (anti-parasitic), rat poison, Pancreas Pathology Tumors CARCINOMA OF THE PANCREAS -5th most freq CA cause of death -SMOKERS**, EtOH, fatty diet -esp after chronic pancreatitis -familial relapsing pancreatitis ass'd -GENES-point mut of K-ras early, p53 MORPH-60% in head, 15% body -20% diffuse -adenoCA arising in ductal epith -rarely from acinar cells -some w/ fibrosis, some produce mucin -head->obstruct bile outflow, ulceration -body and tail CA quieter, worse prog -spread all over abd, distant to lungs, bones -mod-poorly diff'd CLINICAL-presents when affecting other stuff: -nerves in back, duod, bile duct, etc. -Trousseau sign-migratory thrombophlebitis -procoags, PAFs from this tumor Tx- % resectable at Dx, Pancreas Pathology Cystic Fibrosis One of the most significant disorders of panc.. see elsewhere, Pancreas Pathology Pancreatitis CHRONIC PANCREATITIS -MIDDLE-AGED MEN, ALCOHOLICS -repeated bouts->loss of parenchyma ->replacement by fibrous tissue ass'd w/ EtOH, hyperCa, hyperlipo -12% w/ panc divisum -fam. hered. panc-begins in kids-ADom -gene prevents trypsin inactivation Causes: 1. Ductal obstruction by concretions -hypersec from acinar cells -can become stone in EtOHics 2. Secreted proteins-LITHOSTATHINE 3. Oxidative Stress via EtOH 4. Interstit fibrosis (from acute panc) Protein-Calorie malnutrition-Tropical MORPH-smaller, fewer acini; fibrosis -islets spared -protein plugs in duct lumens' CLINICAL-recurrent or persistent pain -drugs, EtOH, overeating may ppt attack -moderate SERUM AMYLASE elev -alk phos, jaundice implicate stones can->DM, malabsorp, pseudocysts -inc panc CA risk (more from smoking, EtOH)