Diseases of the liver and exocrine pancreas

1. Diseases of the liver and exocrine pancreas Lecture 31 Thursday, March 15, 2007 Refs. Basic Pathology Chapters 16 and 17 Wheater’s Basic Histopathology Chapter 14

2. Definitions of jaundice and cholestasis • Jaundice = yellow discoloration of skin and sclerae is due to hyperbilirubinemia >2 mg/dL and deposition of bile pigment in skin, mucous membranes, and sclera. • Normal serum bilirubin is <1.2 mg/dL • Icterus is another term for jaundice. • Cholestasis = stoppage or suppression of the flow of bile • Site of cholestasis: • Intrahepatic • Extrahepatic (often due to stones) • Consequences of cholestasis • Impaired fat digestion • Decreased elimination of waste products: bilirubin (jaundice), cholesterol (hypercholesterolemia), aqueous insoluble xenobiotics

3. Bilirubin metabolism and excretion3. Conjugation (glucuronidation) by hepatocytes.4. Excretion of conjugates into bile.5. Colonic bacteria deconjugate and degrade it to urobilinogens. Approx. 20% of urobilinogens are reabsorbed. Most is re-excreted into bile. Small amount is excreted in urine.BP 16-1

4. Unconjugated/conjugated bilirubinemia • Excess bilirubin in blood can be unconjugated and/or conjugated • Depends on site of blockage • Serum bilirubin tests: • Total bilirubin = unconjugated plus conjugated • Direct bilirubin = conjugated only • Delta = covalently linked to albumin

5. Viral hepatitis whp 14.1

6. Viral hepatitis • Acute • All viruses produce the same histologic lesions in the acute stage. • Chronic • Severity varies • Periportal with intact limiting plate • Piecemeal necrosis of some hepatocytes • Hepatitis E and A do not cause chronic hepatitis • Chronic hepatitis can lead to cirrhosis.

7. Schematic morphologic features of acute hepatitis PBD 19-17aBP 16-9a

8. Acute viral hepatitis whp 14.3 C = Councilman body H = swollen hepatocytes (hydropic degeneration) In = aggregates of inflammatory cells

9. Sequence in acute hepatitis A infection BP 16-4

10. Outcomes in US of hepatitis B infection BP 16-5

11. Chronic hepatitis • Symptomatic- with evidence of continuous or relapsing disease for > 6 months • Causes include: • Viruses • Genetic diseases • Alcoholism • Etiology is important in determining whether the disease will be progressive.

12. Schematic morphologic features of chronic hepatitis rob 19-17bBP 16-9B

13. Chronic hepatitis whp 14.5aLimiting plates (L) are intact.A = artery, B = bile duct, V = vein

14. Chronic hepatitis with piecemeal necrosis whp 14.5bLimiting plate (L) is disrupted with necrosis (N) of hepatocytes.Plates (P) are 2 or more cells wide.

15. Chronic hepatitis: focus of necrosis and lymphocytic infiltrate whp 14.5c

16. Chronic viral hepatitis due to hepatitis B infection (G = ground glass cytoplasm) whp 14.5d

17. Alcoholic liver disease • Leading cause of liver disease in most western countries • 3 overlapping forms: • Steatosis • Alcoholic hepatitis • Hepatocyte swelling and necrosis • Mallory bodies • Neutrophilic infiltrates • Cirrhosis

18. Mallory bodies in hepatocytes in alcoholic hepatitis PBD 19-24bBP 16-15b

19. Surface of cirrhotic liver with ~3 mm nodules (alcohol-induced cirrhosis) BP 16-16

20. Microscopic view of cirrhosis (Masson stain: CT is blue; regenerative nodules are pink) BP 16-17

21. Hemochromatosis • Hereditary form is autosomal recessive • Mutated gene HFE is a nonclassical class I MHC Excessive iron is absorbed from the GI tract. • Acquired form is due to parenteral administration of iron • Repeated transfusions • Iron accumulation is toxic for cells (heart, liver and can lead to cirrhosis • Treatment is phlebotomy

22. Hemochromatosis (early stage) Prussian blue stain: iron is blue rob 19-26

23. Iron absorption • Iron is essential for formation of hemoglobin • In normal individual, iron levels are tightly controlled. • Amount absorbed equals the amount lost • Iron can be stored in cell attached to ferritin • Iron is transported in the blood bound to transferrin

24. Absorption of iron (in duodenum) Apical DMT1 and HT receptors and basolateral ferroportin Gan 25-8

25. Pathogenesis of hereditary hemochromatosis • Normal HFE binds the transferrin receptor reducing its affinity for iron-loaded transferrin. • The uptake of iron into cells is decreased. • How the increased iron content within cells causes disease is not known.

26. Neoplasia of the liver • Most metastatic • Primary • Hepatocellular carcinoma • Predisposition - chronic hepatitis and aflatoxin • Cholangiocarcinoma • From bile duct epithelium

27. Hepatocellular carcinoma whp 14.9

28. Biliary tract • Cholagogue = a substance that causes contraction of the gall bladder • CCK • Choleretic= a substance that increases the secretion of bile. • Secretin, vagus stimulation, bile acids • Cholelithiasis = the presence of gall stones • Cholecystitis = inflammation of the gall bladder • Two types of stones • Calcium bilirubinate • Cholesterol ~85% of cases in US

29. Overview of diseases of the exocrine pancreas • Cystic fibrosis • Pancreatitis • Acute • 80% associated with biliary tract disease or alcoholism • Medical emergency can result in shock, DIC, ARDS • Chronic • Can result in loss of exocrine pancreas, malabsorption • Adenocarcinoma of the pancreas • 5th most common cause of death due to cancer in the US • Most have metastasized before diagnosis