Liver Pathology: Viral Hepatitis PDF

Liver Pathology: Viral Hepatitis, Alcohol Liver Dz, Non-Alcohol Fatty Liver Dz Liver Review 4 lobes: o Left o Right o Caudate o Quadrate Functional unit of liver: Hepatocytes o Located in hepatic lobules o Produce bile o Bile flows btwn hepatocyte towards bile duct (portal triad) Portal Triad: o All...

Liver Pathology: Viral Hepatitis, Alcohol Liver Dz, Non-Alcohol Fatty Liver Dz Liver Review 4 lobes: o Left o Right o Caudate o Quadrate Functional unit of liver: Hepatocytes o Located in hepatic lobules o Produce bile o Bile flows btwn hepatocyte towards bile duct (portal triad) Portal Triad: o All portions drain into central vein § Portal artery: supplies oxygen § Portal vein: supplies nutrient-rich blood from GI tract to liver § Bile duct: receives bile from hepatocytes Sinusoids o Plate-like arrangement around hepatocytes o Separated by vascular channel o Take the O2 and nutrient rich blood from portal vein to give to hepatocytes o Contain Kupffer cells: Defense immune cells that remove debris, bacteria, old RBCs Liver Anatomy BLOOD ENTERS via branches of portal vein, portal artery à emptying into sinusoids BLOOD LEAVES liver by draining through sinusoids à into the central vein Liver Histology Many portal triads but only ONE central vein Central vein is the center of lobule (liver is divided into lobules) 3 zones of hepatic acinus zones: o Zone 1 § Encircles portal triad § Oxygenated blood from hepatic artery enters here § Highest in oxygen o Zone 2 o Zone 3 § Around central vein § Lowest oxygenation Liver Diseases Classified as acute, chronic, focal, diffuse, mild, severe, reversible, irreversible Most cases of liver dz are ACUTE o Caused by viral hepatitis o Mild, never come to medical attention Hepatitis Inflammatory process that causes liver death by: o Necrosis (unprogrammed death) o Apoptosis (programmed death) Can be from exposure to toxins (alcohol, drugs) Acute hepatitis infection lasts < 6 months o Isoniazid, acetaminophen Commonly caused by 5 main viruses Chronic hepatitis infection lasts > 6 months o HAV, HBV, HCV, HDV, HEV Viral Hepatitis Variant Acute/Chronic Route of infect Symp. Incub. Virus HAV Acute No risk of chronic Feco-Oral 2-4 wks 2-4 wks No envelope ssRNA HBV Acute and chronic Sex, Blood, Perinatal 2-4 wks 4-26 wks 6-8 wks avg. Lipid Bilayer Capsid protein layer Partial dsDNA Most aggressive HCV Acute and chronic Sex, Blood, Perinatal 2-26 wks 8 wks avg. Lipid bilayer Capsid protein layer ssRNA Blood transfusion related HDV Chronic Sex, Blood, Perinatal Lipid bilayer Capsid thin protein layer ssRNA (circular) Co-infection: Needs HBV to infect Superinfection: HBV first, then HDV HEV Acute Chronic (imm.comp.) Feco-oral 2-6 wks No envelope ssRNA Virus shed in stool Fulminant Hep in pregnant women **Note: HAV and HEV are from differing viral families Perinatal: Labor, breast feeding Hepatitis Pathology Replication of HAV, HCV, HDV, HEV all with ssRNA o Attachment to receptor on hepatocyte surface o Endocytosis entrance into hepatocyte o Uncoating: virus sheds bilayer and capsid, ssRNA released into nucleus o Translation: ssRNA hijacks host ribosomes, Synthesizes proteins (translation) 1. Capsomeres 2. Antigens 3. RNA polymerase 4. DNA polymerase o Replication: RNA polymerase replicates ssRNA in nucleus o Maturation and Assembly of viral proteins and ssRNA into vesicles in the ER o Exocytosis: Once matured they will leave hepatocyte § Leftover viral protein will lyse hepatocyte § Virus goes on to infect other cells Replication of HBV with pdsDNA o Attachment to receptor on hepatocyte surface o Endocytosis entrance into hepatocyte o Uncoating: virus sheds bilayer and capsid o Nuclear import: pdsDNA released into nucleus DNA repair enzymes in nucleus finish forming pdsDNA à now dsDNA o Transcription: dsDNA uses RNA polymerase to transcribe RNA § DNA Polymerase synthesizes more DNA to allow for proper replication of dsDNA § More DNA = more RNA made to make pre-genomic RNA and viral proteins o Translation: § RNA makes viral proteins in ribosomes (Capsomeres, antigens, RNA polymerase, DNA polymerase) § RNA makes Pre-Genomic RNA (a feature of HBV- retrovirus) o Reverse Transcriptase will convert Pregenomic RNA to DNA à Forms pdsDNA o Maturation and assembly: pdsDNA + viral proteins from ribosomes are assembled into vesicles in ER o Exocytosis: Once matured they will leave hepatocyte § Leftover viral protein and DNA will lyse hepatocyte § Virus goes on to infect other cells Hepatitis Pathology (Lysis of Hepatocytes via immune activation) Lysis can occur from accumulation of viral proteins OR through activation of immune cells (MHC I) Cytotoxicity is induced through perforin and granzymes which are released from cytotoxic T cell (CD 8+) MHC 1 (antigen made in ribosome) sent to surface of hepatocyte o Activates immune response to release: § INF gamma § Macrophages § Cytotoxic T cells Cytotoxic T cells (CD8+) bind to MHC I à PERFORINS and GRANZYMES released o Perforins: Perforate hepatocyte, forming pores (these pores allow granzymes to go into cytosol) o Granzyme enters cells thru perforins and cause APOPTOSIS Phases of Viral Hepatitis Infection Flu-like symptoms associated with Phase 1 infection Phase 1: Prodromal Phase First stage when person is infected Affects brain and GI with flu-like symptoms From circulation they go to brain, PG cause hypothalamic thermostat o Fever trigger release of prostaglandins change causing fever (malaise) o Nausea PGE2, PGF2 from CNS o Vomiting Damaged liver, will secrete o Dehydration certain cytokines that go o Electrolyte imbalance into circulation o Diarrhea Activate emetic center in brain stem o Eventually, weight loss Toxins go into circulation Liver cells damaged, will secrete cytokines o IL 1 and then to chemo trigger o IL 6 zone in brain o TNF alpha Damaged liver also releases Liver cytokines enter circulation and go to brain, trigger release of prostaglandins PGE2, PGF2 from CNS hepatotoxins bc liver o PG cause fever, malaise by changing hypothalamic cannot detoxify in injured thermostat state Hepatotoxins are also released from liver, as it cannot detoxify in an injured state, Toxins go into circulation Emetic center activates GI nerves Toxins affect chemo-trigger zone in brain stem, activates emetic center (stem) causing retro peristaltic action, Emetic center activate GI innervation which will induce retro-peristaltic action o Causes nausea, vomiting, dehydration, electrolyte imbalance, diarrhea causing stomach contents to reach esophagus Increased symptoms and clinical manifestations occur in phase 2 Phase 2: Icteric Phase Old RBCs are disposed by Kupffer cells in liver (Hb breakdowns to Heme, globin = makes Ubilirubin) UB must be converted to CB in liver (this still occurs bc some hepatocytes are working) Damaged liver will increase UB + CB + bile salt in circulation Cholestasis: Reduced bile flow in liver, hence bile is retained in circulation Bilirubin deposits in the body: o Sclera of eye: Icterus o Skin of palms, soles: yellow discoloration (“jaundice-like” effect) o Kidney: Dark urine due to excess conjugated bilirubin Remember kidney only filters Cbilirubin Phase 2 cont… Intestines: decreased bile in GI causes decreased bilirubin, urobilinogen, stercobilin (pigment in stool) leads to clay/acholic stool Decreased Clotting Proteins: Increased clot time Enzyme Leak from Liver: into circulation (ALT, ALP, AST, GGT) HEPATOMEGALY and pain in UR quad due to increase blood flow Phase 3: Convalescent Phase (Recovery Phase) Body resolving infection o Flu-like symptoms diminish o Jaundice, yellow sclera, hepatomegaly, urine is clearing up o Stool color back to normal o Liver enzymes go down o Clotting factors resolved