Pathology Exam 3

Chapter 12

Chapter 12 Diseases of the Liver, Biliary Tract, & Pancreas Bilirubin Metabolism Bilirubin tetrapyrrole pigment derived from Hb breakdown; appears yellow in body fluids Hemoglobin (Hb) iron-containing red pigment found in erythrocytes o 15g Hb/dl of blood o Composed of globin (colorless protein) + 4 heme molecules Each heme molecule has 4 pyrrole rings Each pyrrole ring = 4 carbon atoms + 1 nitrogen atom Linked by methene bridges to form a ring around a ferrous iron Ferrous iron combines reversibly w/oxygen molecule o Broken down in macrophages Hb breakdown o Heme ring opened to form tetrapyrrole chain green biliverdinglobin o Iron atoms removed to be reused by the body yellow bilirubinglobin o Globin removed 4 yellow bilirubin molecules o Bilirubin moves into ECF taken up by blood & bound to plasma proteins taken up by liver cells o Each bilirubin is conjugated to 2 molecules of glucuronic acid bilirubin diglucuronide excreted into bile o Bilirubin diglucuronide is deconjugated & reduced by bacteria urobilinogen (UBG) o UBG oxidized orange urobilin excreted as feces urobilin or urinary urobilin o Bilifuscins dark brown dipyrrole substances derived from stages of heme synthesis in bone marrow; responsible for color of feces Jaundice (AKA Icterus) Features o Yellow discoloration of skin, mucous membranes, & sclerae o Due to serum bilirubin & binding of bilirubin to tissue elements (esp. elastic fibers) Causes o Hemolytic jaundice - excessive bilirubin production o Hepatocellular jaundice injury of liver cells (associated w/hypoalbuminemia) o Obstructive jaundice obstruction of bile ducts Differentiation (Tests of Liver Function) Serum bilirubin Measured by van den Bergh rxn (normal is <1mg/dl, jaundice is >3mg/dl) Tests conjugated bilirubin (directly) & unconjugated bilirubin (indirect rxn) Bilirubinuria Significant of conjugated bilirubin in the blood Urine w/ bilirubin is dark yellow-brown & is foamy when shaken; use color tests Serum alkaline Retained bile salts (obstructive jaundice) detergent action on cell membranes of liver cells phosphatase & bile duct epithelium release of hepatic alkaline phosphatase into blood Also occurs w/ hepatocellular jaundice Serum aspartate AST levels when AST enzyme is released from dying cells (esp. liver & heart cells) aminotransferase Measure of extent of hepatocellular necrosis (hepatocellular jaundice) (AST) Slight also seen in obstructive & hemolytic jaundice Hypoalbuminemia Accompanies hepatocellular jaundice (liver synthesizes albumin)

Pathology Exam 3

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Predisposing factors Cause Mechanism

Severity Liver Function Tests

Hemolytic Jaundice Hemolytic anemia w/ anoxic injury of liver Large internal hemorrhage Augmented destruction of Hb bilirubin production Liver doesnt conjugate/excrete excessive bilirubin Unconjugated bilirubin in blood indirect reacting hyperbilirubinemia Mild No bilirubinuria serum bilirubin (indirect) slight in serum AST

Hepatocellular Jaundice

Obstructive Jaundice

Rupture of bile canaliculi hepatocyte necrosis Degeneration of some hepatocytes (dont conjugate bilirubin well) Others allow conjugated bilirubin to escape into blood

Distended bile canaliculi Conjugated bilirubin escapes into hepatic lymph & blood Bile pigments dont reach intestine in normal amounts Pale stools - fecal pyrrole pigments serum bilirubin (direct) Bilirubinuria (dark urine) Marked serum alkaline phosphatase

serum bilirubin (direct reacting) Bilirubinuria (dark urine) Marked in serum AST

Hepatic Failure Normal Liver o Large reserve of function o Cells have great regenerative capacity Hepatic failure o Injury must be severe &/or chronic to cause liver failure o Clinical features more frequent/prominent in chronic liver failure o Chronic liver failure often proceeds to cirrhosis (portal venous hypertension) Cirrhosis (portal venous hypertension) Features o Chronic liver diseases in which widespread hepatocytic necrosis results in fibrosis of liver o Liver has enormous regenerative capacity regeneration from remaining viable liver cells, return of normal hepatic function & structure o Hepatic necrosis hepatic fibrosis when injury is chronic/recurrent Regeneration still occurs as nodules of regenerating cells w/ sinusoids surrounded by septa of fibrous tissue Causes Characteristics Appearance Changes Chronic Most common cause of cirrhosis Large, soft, yellow Fatty degeneration w/ alcoholism Ethanol = hepatotoxin Hepatitis: enlarge, hepatomegaly & abnormal function yellowish green (bile Acute alcoholic hepatitis w/ Can lead to chronic/repetitive staining) coagulative necrosis, Acute attacks of acute alcoholic Mallory body = meshwork inflammation, & focal fibrosis hepatitis & micronodular of hyaline cytoplasmic cirrhosis material Viral Macronodular cirrhosis Irregular, large nodules Cryptogenic cirrhosis = hepatitis (postnecrotic, posthepatitic) asymptomatic Autoimmune Circulating Abs of unknown Inflammatory infiltrate w/ many hepatitis cause plasma cells Young-middle aged women Hyperglobulinemia Responds to immunosuppressive therapy Hepatotoxic Often an unpredictable rxn drugs & Removal of drug often prevents poisons cirrhosis

Pathology Exam 3

Chapter 12

Biliary tract obstruction

Due to carcinomas of head of pancreas or biliary tract, chronic pancreatitis, gallstones, bile duct suture, cystic fibrosis of pancreas

Relieved surgically

Pathologic Anatomy o Cirrhotic liver enlarged (fatty degeneration) or shrunken (hepatocytic necrosis, retraction of fibrous tissue); firm & nodular o Nodules bulging; plates of regenerating liver cells w/ sinusoids; 1mm-many cm; o Septa shrunken & firm; b/t nodules; gray-white fibrous tissue scar; contain small blood vessels & bile ducts o Intraportohepatic shunt small blood vessels in septa; portal venous blood can reach hepatic vein tributaries w/out traversing intralobular sinusoids; causes liver cells to become ischemic Portal Venous Hypertension o Occurs in most cases of cirrhosis o Causes: Abnormal transmission of hepatic arterial pressure to portal vein branches, due to alterations of intrahepatic vascular bed Pressure on intrahepatic veins by expanding nodules of regenerating liver tissue Fibrous obliteration of small intrahepatic blood vessels in septa o Effects Chronic passive congestion of spleen enlarged, firm; excessive function shortens lifespan of formed elements of blood Ascites due to transudation of fluid from congested capillaries in portal venous bed; causes abdominal protuberance & edema of legs Establishment of collateral circulation b/t portal vein tributaries & systemic veins Esophageal varices large, dilated, thin-walled submucosal veins; bulge into lower esophagus; rupture = massive hemorrhage into alimentary tract Hemorrhoids Caput Medusae enlarged subcutaneous paraumbilical veins Portocaval shunt - Portal blood bypasses the liver Leads to hepatic ischemia & hyperammonemia Clinical Features o Manifestations of causative condition o Manifestations of chronic hepatic failure o Manifestations of portal venous hypertension o Progressive & irreversible o Cause of death hepatic failure &/or complications of portal venous hypertension

Viral Hepatitis Features o Part of several systemic viral infections (yellow fever, congential rubella, infectious mono) o Viral infection in which hepatic lesion is dominant clinical/anatomic feature Pathologic Anatomy o Major lesion hepatocellular degeneration & necrosis w/ round cell infiltrate o Hepatocyte injury due to cytotoxic T-cells cellular immune rxn to viral Ags on cell membrane of liver cells Course o Most cases resolve spontaneously regeneration, return of normal structure & function o May become chronic hepatitis can still resolve completely o Progression to cirrhosis o Death from hepatic failure may occur w/in days-weeks due to necrosis of most hepatocytes Clinical Features

Pathology Exam 3

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o o o o o o o

Incubation period weeks-months; onset abrupt or insiduous Manifestations of acute infection fever, headache, malaise, lassitude Prominent GI symptoms anorexia, nausea, vomiting Tender hepatomegably Hepatocellular jaundice Manifestations of hypersensitivity due to circulating viral Ag-Ab complexes; rash, arthralgia Leukocyte count normal or ed; relative lymphocytosis Severity of clinical features varies by patient & different type of VH Many are mild few symptoms, no jaundice

Primary Carcinoma of Liver Features o Uncommon in US o Less common than metastatic carcinoma of liver o Liver cell carcinomas (malignant hepatomas) - Occur in cirrhotic livers, regenerative hyperplasia composed of atypical hepatocytes; associated w/ chronic hepatitis B & C o Bile duct carcinomas arise from bile duct epithelium w/ noncirrhotic liver Pathologic Anatomy o Usu. starts in right lobe of severely cirrhotic liver o Soft, bulky intrahepatic mass o Numerous satellite nodules due to extensive spread w/in intrahepatic portal & hepatic veins o Metastases lungs, regional lymph nodes (peribiliary, lower mediastinal) Clinical Features o Abdominal pain, weight loss o Fever o Weakness o Rapid swelling of abdomen o Jaundice, large fixed liver & ascites o Brief course, death w/in 6 months due to hemorrhage for esophageal varices, rupture of liver, hepatic coma, or general debility Cholelithiasis Features o Gallbladder stones o Symptomatic or asymptomatic o Twice as common in women estrogen s hepatic secretion of cholesterol & s secretion of bile salts into the bile o Other predisposing factors: American Indian women, obesity, diabetes mellitus, chronic hemolytic anemia Types of Gallstones o Components: cholesterol, bile pigments, calcium, & small amount of protein Type Composition Characteristics Associated w/: Mixed Cholesterol Most common Chronic Bile pigments (bilirubin & Otherwise normal gallbladder cholecystitis biliverdin) Multiple Calcium Smooth, faceted, green or yellow Protein matrix 2-20mm diameter Pure Cholesterol Uncommon Cholesterol Traces of other substances Otherwise normal gallbladder Solitary Large, ellipsoid, pebbled, colorlessyellow, translucent surface Pure Calcium Uncommon

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Chapter 12

Calcium

Bile pigments

Otherwise normal gallbladder Small, irregular, hard, brittle, black Multiple

Pathogenesis o Cause unknown Chronic cholecystitis is RESULT, not cause of cholelithiasis o Secretion of abnormal (lithogenic) bile amount of cholesterol or bile pigments &/or amount of bile salts or phospholipids o normal gallbladder concentrated biles bile salts & phospholipids (lecithin) prevent precipitation of cholesterol o Rarely dissolve in situ o May be related to inadequate adaptation to cholesterol-rich diet (meats) Effects o Irritation of the gallbladder Mechanical & chemical irritation of mucosa Chronic cholecytitis wall becomes thick, fibrotic w/ loss of mucosal folds o Obstruction of biliary tract Obstruction of cystic duct Distention of gallbladder pain (biliary colic) If obstruction persists, distention compresses intramural blood vessels ischemic damage hemorrhage & necrosis of gallbladder (acute cholecystitis) Obstruction of common bile duct Occurs where duct narrows to enter duodenum Pain (biliary colic) Obstructive jaundice Acute ascending cholangitis bacteria ascend bile duct bile stained abscesses in liver Acute pancreatitis If persistant, Biliary cirrhosis Clinical Features o Chronic cholecystitis or slight distention of biliary tract Belching, nausea, vomiting, constipation Nonspecific symptoms of indigestion aggravated by large meals o Biliary colic Sharp pain in upper right quadrant (right subscapular area) Begins suddenly - @ night or after heavy meal; lasts 1-several hours Constant pain, nausea, vomiting, tenderness o Treatment cholecystectomy; exploration of common bile duct & stone removal

Carcinoma of Extrahepatic Biliary Tract Features o Adenocarcinomas o Cause: unknown o Sites of predilection: Gallbladder complications of longstanding cholelithiasis & chronic cholecystitis Distal communal bile duct & duodenal papilla

Pathology Exam 3

Chapter 12

Confluence of common hepatic & cystic ducts Pathologic Anatomy o Primary adenocarcinoma hard & infiltrative OR soft & papillary o Obstructive jaundice primary tumor or metastases restrict bile ducts o Metastases occur early liver, duodenum, etc. Clinical Features o Obstructive jaundice, upper abdominal pain, hepatomegaly o Palpable primary tumor o Previous confirmation of symptomatic cholelithiasis o Most incurable death w/in months-years due to biliary obstruction

Acute Pancreatitis Features o Due to escape of large amounts of pancreatic enzymes from the pancreatic ducts autocatalytic activation of enzymes by contact w/ ISF enzymatic autodigestion of pancreas Occurs due to structural or functional duct obstruction & active pancreatic secretion occurring simultaneously (ex: after a meal) o Enzymes Enzyme Effect Results Trypsin Necrosis & digestion of pancreatic Release of more pancreatic enzymes more Chymotrypsin ducts & acini necrosis Phospholipase Elastase Digestion of blood vessel walls Hemorrhage by rhexis Lipase Splits triglycerides of fat cells Fat necrosis FFAs combine w/ cations in in/around pancreas ECF Ca-salts precipitate soapy, yellowwhite nodules Hypocalcemia Amylase Minor role in pancreatitis Hyperamylasemia (amylase in blood) Causes (Predisposing Factors:) o Chronic alcoholism Ethanol induces: Direct chemical irritation of duodenum, spasm of sphincter of Oddi, & pancreatic duct obstruction Gastrin release from stomach, secondary stimulation of pancreatic secretion o Gallstones May obstruct main pancreatic duct or small interlobular ducts or cause spasm in sphincter of Oddi (surrounds common bile & main pancreatic ducts) o Obesity Obese person eats large meals - s pancreatic secretions & duct pressure o Trauma Ex: surgery in area near pancreas Ex: blunt abdominal trauma w/ pancreatic damage Pathologic Anatomy o Pancreas is swollen peritoneal cavity contains serous/seroanguineous fluid Mushy, grayish-yellow Hemorrhage o Nodules 2-5 mm, soft, opaque yellowish-white, & soapy (fat necrosis) Scattered in adipose tissue around pancreas o Bacterial infection may occur o Necrotic tissue replaced by fibrous scar OR a cyst filled w/ opaque yellowish-brown fluid (pseudocyst)

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Clinical Features o Major features: epigastric pain, hyperamylasemia o Acute interstitial pancreatitis (mild case) spontaneous recovery in 24-48 hours o Acute pancreatic necrosis (severe case) constant epigastric pain, nausea, vomiting, tenderness, shock, marked in serum amylase & lipase o Treatment conservative o 1/3 pts die w/in 10 days of onset

Chronic Pancreatitis occurs after multiple attacks of acute interstitial pancreatitis scarring of pancreas due to recovery cause: usu. chronic alcoholism appearance: small, pale, irregular, hard (sometimes calcified), dilated ducts w/ thick gray fluid or calcium carbonate stones clinical features: early attacks of abdominal pain (1-2 days long), late pancreatic insufficiency w/ steatorrhea & secondary diabetes mellitus, cause of death: attach of acute pancreatic necrosis Carcinoma of Pancreas Features o Cause: unknown o Classification: Head of pancreas more common Body & Tail of pancreas Pathologic Anatomy o Primary lesion large infiltrative mass of hard, grayish-white tissue Often invades adjacent organs/tissues biliary tract, duodenum, retroperitoneum o Microscopic appearance adenocarcinoma; invasion of lymph vessels, veins, & perineural spaces o Metastases early; regional lymph nodes, peritoneum, lungs; more massive/frequent/widespread from body & tail of pancreas Clinical Features o carcinoma of the head of pancreas early obstruction of common bile duct obstructive jaundice, epigastric or right hypochondriac pain o carcinoma of the body & tail of pancreas constant dull epigastric or left hypochondriac pain (radiate thru back, worse at night & in supine position), depression, wt. loss ascites due to peritoneal implantation metastases o treatment surgery; often fatal death 6 months after onset Cystic Fibrosis of Pancreas (systemic mucoviscidosis) Features o Generalized disease children, adolescents, young adults o Dysfunction of exocrine glands Abnormally viscid secretion duct obstruction atrophy of secretory element & fibrosis of glands o CFP is inherited autosomal recessive trait Long arm of chromosome 7 Codes for a cell membrane protein that regulates chloride transport by epithelial cells Heterozygotes are normal o Basic metabolic abnormality defect in chloride (& water) transport by epithelium of small exocrine gland ducts Secretions of pancreas & mucous glands become scant & viscid Pathologic Anatomy

Pathology Exam 3

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Histologic lesion smallest ducts/glands of all viscera are plugged by inspissated secretory material; glandular tissue atrophy & fibrosis o Secondary bacterial infection in resp. tract o Lesions & organ dysfunction pancreas, lungs, intestine, liver, & male genital tract (aspermia & sterility) Clinical Features o Intestinal obstruction @ birth (10%) most die as neonates o Pancreatic insufficiency, failure to gain weight, chronic/recurrent infections of bronchi & lungs, chronic paranasal sinusitis o Leads to resp. failure, hypoxemia, cor pulmonale o Diagnosis trypsin in duodenal fluid & high [Cl-] in sweat o Death pulmonary infection & resp. failure in childhood/adolescence o Possible to screen early in pregnancy o