Tuesday, January 9 (ellen)

Tumuors of the SI and LI – January 9, 2007 Tumours of SI and LI ~ epithelial tumours of the intestine ~ primary neoplasms – colon and rectum ~ adenocarcinomas – main colorectal CA ~ SI – uncommon site for tumours (benign or malignant) SI and LI Tumours ~ polyp – mass that protrudes into lumen of gut ~ can be pedunculated (has stalk) or sessile (no stalk) ~ form due to epithelial proliferation and dysplasia = adenomatous polyps or adenomas ~ true neoplastic lesions and precursor to carcinoma ~ oma – benign EXCEPT melanoma, meyloma, lymphoma ~ sarcoma – spread thru blood and is tissue in nature ~ carcinoma – spread thru lymph and is epithelial in nature Non-neoplastic (Benign) Polyps ~ Juvenile, Peutz Jeghers ~ most are hyperplastic polyps ~ no malignant potential ~ usually on right side of colon ~ Juvenile polyps – hamartomatous proliferations ~ if in adults, called retention polyps ~ a mass resembling a tumor that represents anomalous development of tissue natural to a part or organ rather than a true tumor ~ generally occur singly in rectum, usually no malignant potential Adenomas (Neoplastic) ~ epithelial proliferation and dysplasia ~ neoplastic polyps ~ 3 subtypes: ~ 1) tubular adenomas – confined to the mucosa (intramucosal carcinoma) or extending into submucosa (invasive carcinoma) ~ 2) villous adenomas – larger and more ominous ~ 3) tubulovillous adenomas – intermediate ~ maximum diameter is chief determinant of risk of adenoma  carcinoma Familial Polyposis Syndromes ~ uncommon autosomal dominant disorder ~ familial adenomatous polyposis ~ risk of colonic cancer is almost 100% by midlife unless colectomy ~ Peutz-Jeghers polyps – uncommon hamartomatous ~ rare autosomal dominant ~ lots of melanin in mucosal and cutaneous areas

~ Cowden syndrome – hamartomatous polyps in GIT ~ increase risk of neoplasms of thyroid, breast, uterus, and skin Colorectal Carcinoma ~ mainly adenocarcinomas ~ environmental factors, especially dietary practices ~ decreased fiber leads to decreased stool bulk, therefore increased bowel feces retention and intestinal dysbiosis ~ potentially toxic oxidative byproducts of bacterial carb degradation ~ high fat intake enhances synthesis of cholesterol and bile acids by liver which is then converted potential carcinogens by intestinal bacteria ~ potential pathogenesis: induction of apoptosis in tumour cells and inhibition of angiogenesis, maybe inhibition of cyclooxygenase-2 Adeno-Carcinoma Sequence ~ 1) increased adenoma = increased colorectal CA ~ 2) adenoma and colorectal CA have similar distribution ~ 3) in biopsy carcinoma, see adenomatous tissue ~ 4) CA risk related to # of adenoma Colorectal Carcinogenesis ~ 2 pathogenetically distinct pathways ~ 1) APC/β-catenin pathway – chromosome unstable and get accumulation of mutation of oncogene or tumour suppressor gene ~ 2) DNA mismatch repair genes – lose ability to repair DNA-mismatch and the mutation accumulates Adenoma-Carcinoma Pathway ~ 1) loss of APC tumour suppressor ~ 2) mutate K-RAS – which prevents apoptosis ~ 3) 18q21 deletion – loss of CA suppressor gene ~ 4) loss of TP54 – loss of suppressor gene SI Neoplasms ~ m/c benign tumours – stromal tumours ~ GIT stromal tumours have mutation affecting KIT (tyrosine kinase receptor) Adenocarcinoma of SI ~ most in duodenum including ampulla of Vater ~ most metastasized to LV by the time of diagnosis Carcinoid Tumours ~ cells making bioactive compounds causing overactive production of hormones ~ usually seen in older people ~ can cause a clinical syndrome ~ appendix is m/c site of gut

~ rarely metastasize, yellow tan in appearance Gastrointestinal Lymphoma ~ MALT and H. pylori (chronic gastritis)  increase T and B cells  polyclonal B cell hyperplasia  monoclonal B cell neoplasm ~ secondary involvement by systemic dissemination of non-Hodgkin lymphoma ~ gut is the most common extranodal location Acute Appendicitis ~ obstruction with fecalith ~ mucinous fluid  increase pressure  collapse veins  ischemia  exudation Tumours of the Appendix ~ carcinoids: m/c form of neoplasia in appendix ~ 1) mucocele – dilation of appendix lumen, fecalith accumulation ~ 2) mucinous neoplasms – benign mucinous cystademoa to mucinous cystadenocarcinoma (invades wall, and can lead to intraperitoneal cancer = pseudomyxoma peritonei) ~ 3) cystadenoma – like tumours in ovary, cystadenocarcinomas invade wall, tumor goes into peritoneal cavity and is filled with mucin (pseudomyxoma peritonei) Hepatic Injury: ~ 5 responses: inflammation  degeneration  cell death  fibrosis  cirrhosis ~ degeneration can be ballooning or foamy ~ can remove 75% of the liver and get minimal hepatic impairment and within a few weeks, the LV mass can regenerate itself Jaundice and Cholestasis ~ 2 reasons for bile: ~ 1) bile is an elimination pathway for ex cholesterol ~ 2) bile promotes emulsification of fats ~ Jaundice: yellos skin and sclerae ~ Cholestasis: retention of bilirubin and other solutes Bilirubin and Bile Acids ~ bilirubin = end product of heme degradation ~ usually from breakdown of erythrocytes, and premature destruction of newly formed erythrocytes in bone marrow ~ heme  biliverdin  bilirubin (by biliverdin reductase) ~ bilirubin glucuronides  colorless urobilinogens (by bacterial beta-glucuronidases) and excreted in feces ~ bile acids – steroid molecules ~ primary human bile acids – cholic acid and chenodeoxycholic acid ~ almost all conjugated and deconjugated bile acids are reabsorbed (esp ileum) and returned to liver for uptake, reconjugation, and resecretion ~ fecal loss of bile acids is remade

Pathophysiology of Jaundice ~ accumulation of unconjugated bilirubin and bilirubin glucuronides in the liver ~ icterus = yellowing of sclerae ~ 2 differences between two forms of bilirubin: ~ 1) unconjugated bilirubin is tightly bound to serum albumin and is insoluble in water at physiological pH ~ kernicterus = accumulation of unconjugated bilirubin in brain ~ 2) conjugated biliruin is water soluble and excess is excreted in urine ~ jaundice occurs when one or more of these happens: ~ xs production of bilirubin ~ reduced hepatic uptake ~ impaired conjugation ~ decreased hepatocellular excretion ~ impaired bile flow ~ m/c causes of jaundice: ~ hemolytic anemias, hepatitis, and obstruction to flow of bile ~ most newborns have neonatal jaundice ~ breast-fed may be more jaundiced because of beta-glucuronidase in maternal milk Cholestasis ~ can also present as jaundice ~ pruritus – symptom related to increased plasma bile acids ~ skin xhanthomas – local cholesterol accumulation ~ usually see elevated level of serum alkaline phosphatase ~ reduced bile flow can also be related to intestinal malabsorption ~ if it’s extrahepatic biliary obstruction it can be surgically fixed ~ if intrahepatic or hepatocellular secretory failure = intrahepatic cholestasis  can’t be fixed by surgery Hepatic Failure ~ most sever clinical consequence of liver disease ~ 3 categories: ~ 1) massive hepatic necrosis ~ 2) chronic liver disease ~ 3) hepatic dysfunction without overt necrosis Cirrhosis ~ usually alcohol abuse, and chronic hepatitis, biliary disease, and iron overload ~ end stage chronic liver disease: ~ 1) bridging fibrous septa ~ 2) parenchymal nodules ~ 3) disrupt architecture of entire liver ~ diffuse fibrosis ~ 3 major pathologic mechanisms: ~ 1) hepatocellular death

~ 2) regeneration ~ 3) progressive fibrosis ~ get extra collagen in cirrhosis from perisinusoidal stellate cells (store fat and Vit A) ~ these get activated and transform into myofibroblast-like cells ~ excess collagen synthesis and deposition d/t: ~ 1) chronic inflammation ~ 2) cytokine production ~ 3) disruption of extracellular matrix ~ 4) stimulation of stellate cells by toxins Portal HTN ~ increase resistance to portal blood flow ~ prehepatic, posthepatic, and intrahepatic causes ~ dominant intrahepatic cause – cirrhosis Ascites ~ xs fluid in peritoneal cavity ~ pathogenesis involves: ~ 1) sinusoidal HTN ~ 2) hepatic lymph  peritoneal cavity ~ 3) renal retention of sodium and water b/c of secondary hyperaldosteronism Portosystemic Shunts ~ increased portal pressure and bypasses systemic and portal circulation beds ~ common sites: rectum, cardio-esophageal junction, retroperitoneum, falciform ligament of liver ~ caput medusae – dilated subcutaneous veins extending from umbilicus towards ribs Splenomegaly ~ long-standing congestion ~ not necessarily correlated with other features of portal hypertension Inflammatory Disorders ~ liver is involved with all bloodborne infections ~ primary hepatic infections – viral ~ 1) EBV – infectious mononucleosis ~ 2) cytomegalovirus or herpes virus - immunocompromised ~ 3) yellow fever – tropical ~ but viral usually refers to hepatitis viruses