Jaundice PDF

Normal levels of serum gastrin in untreated ZES → extremely rare (1%) ○ Gastric acid secretory tests: suggestive of ZES Basal acid output (BAO): > 15 mEg/h Or > 5 mEg/h in patients with prior vagoto...

Normal levels of serum gastrin in untreated ZES → extremely rare (1%) ○ Gastric acid secretory tests: suggestive of ZES Basal acid output (BAO): > 15 mEg/h Or > 5 mEg/h in patients with prior vagotomy and partial gastrectomy Basal gastric secretary volume: > 140 mL in patients with no prior gastric acid-reducing surgery (ex: vagotomy) Gastric pH: < 2.0 in presence of large gastric volume (>140 mL) over 1 hour in patients without prior gastric acid-reducing surgery Complications: ○ Abdominal perforation secondary to ulceration Most common sites: duodenum and jejunum ○ Esophageal stricture with reflux ○ Obstruction ○ GI bleeding ○ Gastric carcinoids Hypergastrinemia: especially in patients with MEN I Prognosis: excellent in patients without metastatic disease Goals of treatment: ○ Medical control of gastric acid hypersecretion IV proton pump inhibitors (PPI) IV pantoprazole was approved recently by US FDA Proton pump inhibitor superior to H2 blockers for control of gastric acid hypersecretion ○ Surgical resection of the tumor ○ Chemotherapy with interferon and octreotide (in metastatic disease) ○ Liver transplantation in hepatic metastasis ○ Surgical resection or thermoablation in single confined liver metastatic lesion Lecture 15: Hyperbilirubinemias. Jaundice. Cholestatic liver diseases. Gallbladder diseases. Alcoholic and non-alcoholic fatty liver diseases. Liver Diseases: Hyperbilirubinemias (including inherited hyperbilirubinemias) and jaundice Cholestatic liver disease Acute and chronic hepatitis Liver cirrhosis Alcoholic liver disease Nonalcoholic fatty liver disease Gallbladder disease Hyperbilirubinemias / Jaundice (icterus): Normal plasma concentration of bilirubin = 17 μmol/L (1 mg/dL) Bilirubin > 30 μmol/L → sclera become yellow If the concentration rises further → skin turns yellow Prehepatic: increased bilirubin production ○ In hemolysis (hemolytic anemia, toxins) ○ Inadequate erythropoiesis (megaloblastic anemia) ○ Massive transfusion (transfused erythrocytes are short-lived) ○ Absorption of large hematomas ○ Unconjugated (indirect reacting) bilirubin in plasma is increased Intrahepatic: ○ Specific defect of bilirubin uptake in the liver cells (Gilbert syndrome) ○ Defect of bilirubin conjugation (neonatal jaundice, Criglar-Najjar syndrome) ○ Defect in secretion of bilirubin in the bile canaliculi (Dubin-Johnson or Rotor syndrome) Posthepatic: ○ Extrahepatic bile ducts are blocked by gallstones, tumors (carcinoma of the head of the pancreas) ○ Cholangitis or pancreatitis ○ Conjugated bilirubin in plasma is increased Cholestatic Liver Diseases: Bile production ○ Essential for digestion and absorption of dietary fats and fat-soluble vitamins ○ 600 - 1200 mL of yellow-green bile daily ○ Bile: water, bile salts (0.6 g/day), bilirubin, cholesterol ○ Bile salts: emulsification of dietary fats and formation of micelles ○ ~94% of bile salts is reabsorbed into the portal circulation in the distal ileum and are recycled in the liver Cholestasis: ○ Blockage of bile low due to either: Intrahepatic disorders (ex: cystic fibrosis) Granulomatosis Drug side effects (ex: allopurinol, sulfonamides) High estrogen concentration (pregnancy, contraceptive pill) Graft versus host reaction after transplantation Extrahepatic bile duct occlusion (cholelithiasis or neoplasms) ○ The bile canaliculi are enlarged Fluidity of the canalicular cell membrane is decreased Their brush border is deformed (or totally absent) Function of the cytoskeleton, including canalicular motility, is disrupted ○ One of the two ATP-driven bile salt carriers, which are meant for the canalicular membrane, is falsely incorporated in the basolateral membrane in cholestasis  ○ Retained bile salts increase the permeability of the tight junctions and reduce mitochondrial ATP synthesis ○ Consequences of cholestasis → a result of retention of bile components: Bilirubin leads to jaundice (in neonates there is a danger of kernicterus) Cholesterol deposition in skin folds and tendons, as well as in the cell membranes of liver, kidneys, an erythrocytes (echinocytes, acanthocytes) Pruritus (itching) is thought to be caused by retained bile salts in the skin The absence of bile in the the intestine results in fatty stools and malabsorption Infection of accumulated bile leads to cholangitis which has its own cholestatic effect Gallstones (Cholelithiasis): Gallstone disease: ○ 75% of patients: gallstones consist of cholesterol (F > M) ○ 25%: pigment stones with unconjugated bilirubin Both poorly soluble in water Cholesterol is normally not precipitated in bile, because it contains sufficient conjugated bile salts and phosphatidylcholine (lectin) for it to be in a micellar solution If the ratio of cholesterol / bile salts and lectin increases → cholesterol will remain in a “supersaturated” micellar solution If the relative cholesterol content increases further, multi micellar vesicles are formed (up to 1000 nm) ○ Less stable and precipitate in the aqueous environment in the form of cholesterol crystals → precursors of gallstones Important causes of an increased cholesterol / bile salts and lectin ratio: ○ Increased cholesterol secretion: Increased cholesterol synthesis (raised activity of HMG-CoA cholesterol reductase) Inhibition of cholesterol esterification (progesterone during pregnancy → inhibition of acetyl-CoA cholesterol acetyl transferase) ○ Reduced bile salts secretion: Decrease in the bile salt pool (Chron’s disease or after gut resection) Prolonged sequestration of bile salts in gallbladder (fasting or parenteral nutrition) Decreases the enterohepatic circulation of bile salts so that their secretion into the bile is reduced ○ Sedentary lifestyle and sugary / high-fat food consumption: Increased plasma concentration of cholesterol Increase in storage of cholesterol in liver and subsequently a greater release of cholesterol from liver to gallbladder ○ Cholesterol secretion is not linearly related to bile salt secretion ○ Cholesterol / bile salts and phosphatidylcholine ratio increases when bile salt secretion is low  ○ Ratio rises further under the influence of estrogens Increase in concentration ratio of cholate to chenodeoxycholate (activation of 12α-hydroxylase) → more cholesterol is secreted per mol bile salts Increased amount of unconjugated bilirubin → pigment stones ○ Consist to a large extent (~50%) of calcium bilirubinate (black or brown color) Black stones: calcium carbonate and phosphate Brown stones: stearate, palmitate, and cholesterol ○ Causes of an increased concentration of unconjugated bilirubin are: Increased liberation of hemoglobin (hemolytic anemia) Reduced conjugating capacity in the liver (liver cirrhosis) Nonenzymatic deconjugation of bilirubin in bile (especially monoglucuronide) Enzymatic deconjugation (β-glucosidase) by bacteria (mostly brown stones) Gall bladder and cholelithiasis: ○ Disorders of gallbladder emptying: Insufficient CCK being liberated (main stimulus for gallbladder contraction is weakened) After selective vagotomy the second most important contraction signal (acetylcholine) is absent ○ Gallbladder contraction is weakened in pregnancy ○ Raised mucus secretion (stimulated by prostaglandins) → increased number of nuclei of crystallization ○ Consequences: Colic: when cystic duct or common bile duct is transiently blocked by a stone, pressure rises in the bile ducts Increased peristaltic contraction in the region of the blockage causes severe visceral pain in the epigastric area, possible with radiation into the back, as well as vomiting Trauma to gallbladder epithelium caused by stones → prostaglandins are liberated from gallbladder epithelium in addition to phospholipase A2 Phospholipase A2 splits phosphatidylcholine to lysolecithin → acute cholecystitis → may lead to gallbladder perforation Bacterial cholangitis: bile flow is stopped because of cholelithiasis Results in rise in pressure with dilation of the bile ducts Posthepatic cholestasis and biliary pancreatitis may also develop Gallbladder cancer (rare) Fatty liver disease: Ethanol → alcoholic fatty liver disease Insulin resistance & metabolic syndrome → non-alcoholic fatty liver disease (NAFLD, or metabolic-associated fatty liver disease MAFLD) Characterized by:  ○ Steatosis ○ Steatohepatitis ○ Fibrosis / Cirrhosis Alcohol-related fatty liver disease: ○ 60% chronic liver disease in Western countries ○ 40-50% of deaths due to cirrhosis ○ Of patients who chronically consume excess alcohol: Steatosis: 90-100% Steatohepatitis: 10-35% Cirrhosis: 8-20% Hepatocellular carcinoma: 10% ○ Regression of some of these changes can be seen with abstinence ○ Pathogenesis of steatosis: Ethanol metabolism: Generates large amounts of NADH → impairs beta-oxidation and tricarboxylic acid cycle activity Lipid biosynthesis (instead of catabolism) → reduced oxidation of hepatic fatty acids and increased lipogenesis Ethanol impairs secretion of lipoproteins (fat retains within hepatocytes) Gross and microscopic findings: enlarged, soft, yellow, and greasy liver with micro- and macrovesicular droplets ○ Pathogenesis of steatohepatitis: Ethanol directly affects mitochondrial function and membrane fluidity Acetaldehyde: lipid peroxidation and acetaldehyde-protein adduct formation (antigenic) Impaired mitochondrial function Impaired macrophage function ROS: generated by ethanol oxidation and influx of neutrophils (IL-33 and IL-8 pathways) → protein damage Generation of acetaldehyde and ROS is maximal in centrilobular region Morphology of steatohepatitis: Hepatocytes ballooning (swelling and necrosis) Mallory hyaline bodies (filaments of keratins in degenerating hepatocytes) Neutrophils infiltration More pronounced in alcohol excess than NAFLD ○ Pathogenesis of steatofibrosis / cirrhosis: Death of large number of hepatocytes → collapse of underlying reticulin Activated perisinusoidal hepatic stellate cells: Fibrogenic myofibroblasts → fibrous septa → encircled nodules of regenerating hepatocytes → cirrhosis Cirrhosis develops in a small percentage of individuals who chronically consume excess of alcohol Abstinence is the most important part of therapy  ○ Morphology of steatofibrosis / cirrhosis: Gross findings: nodular surface, greenish Microscopic findings: central vein sclerosis, perisinusoidal scarring, central portal fibrous septa, continual subdivision of nodules (micronodular cirrhosis) With abstinence → regeneration (macronodules) ○ Clinical features of alcohol-related fatty liver disease: Steatosis: Asymptomatic if present with hepatomegaly Mild increase in serum bilirubin and alkaline phosphatase Resolves with abstinence Steatohepatitis: Weeks to months of heavy alcohol consumption Possible acute onset Malaise, anorexia, tender hepatomegaly, fever Hyperbilirubinemia, increased serum alkaline phosphatase AST & ALT < 500 U/mL AST : ALT > 2:1 Increase risk of cirrhosis and death Chronic liver failure/cirrhosis Pathogenesis of NAFLD: ○ Diabetes type II ○ Central obesity ○ Dyslipidemia (high TG & LDL, low HDL) ○ Hypertension ○ Steatosis: nonalcoholic steatohepatitis (NASH) → steatofibrosis (inflammation less prominent) ○ Insulin resistance → increased activity of lipoprotein lipase → increased release of free fatty acids ○ Decreased production of adiponectin by adipocytes Decreased oxidation of FFA by skeletal muscle Increased uptake of FFA by hepatocytes ○ Activation of inflammasome (release of IL-1) ○ Products of lipid metabolism → hepatocytes injury → stellate cell activation → fibrosis ○ Clinical features: Transaminase elevation (AST : ALT < 1) Steatosis: usually asymptomatic Steatohepatitis: asymptomatic or fatigue, malaise, discomfort in right upper quadrant Low progression to NASH / cirrhosis Lecture 16: Diabetes mellitus. Types. Complications.