02.02.12: Hepatocellular Disease


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  • Slide 79 Clinical Significance of Serological Markers for HBV Infection Presence of hepatitis B surface antigen (HBsAg) indicates acute or chronic HBV infection. In patients with acute hepatitis B, hepatitis B core IgM antibody (anti-HBc IgM) will be detectable, whereas in patients with chronic hepatitis B, anti-HBc IgG is present. Presence of hepatitis B e antigen (HBeAg) generally indicates a high level of viral replication, high serum HBV DNA level, and high infectivity. Patients who are HBeAg negative and HBe antibody (anti-HBe) positive generally have lower serum HBV DNA level and are less infectious. Individuals who have recovered from previous hepatitis B infection are anti-HBc IgG and HBs antibody (anti-HBs) positive. Presence of anti-HBs is an indicator of immunity to HBV infection. Isolated anti-HBs is likely to be acquired through vaccination. Sjogren MH. Serological diagnosis of viral hepatitis. Gastroenterol Clin North Am. 1994;23:457-77.
  • 02.02.12: Hepatocellular Disease

    1. 1. Author(s): Rebecca W. Van Dyke, M.D., 2012License: Unless otherwise noted, this material is made available under the termsof the Creative Commons Attribution – Share Alike 3.0 License:http://creativecommons.org/licenses/by-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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    3. 3. M2 GI Sequence Hepatocellular Disease Rebecca W. Van Dyke, MDWinter 2012
    4. 4. Learning Objectives• At the end of these two lectures the student should be able to:•• 1. Define cholestatic and hepatocellular liver disease, provide examples of both and be able to interpret panels of liver tests.• 2. Define the difference between intrahepatic and extrahepatic cholestasis and outline approaches to distinguishing them.• 3. Define the pathophysiology of representative cholestatic diseases, including drug-induced cholestasis, primary biliary cirrhosis, primary sclerosing cholangitis and bile duct obstruction.• 4. Outline an approach to the evaluation of the jaundiced patient.• 5. Define acute and chronic hepatocellular liver disease and provide representative examples.• 6. Provide a differential diagnosis for a patient with liver tests indicating hepatocellular disease and discuss an approach to definitive evaluation.• 7. Be able to interpret serologic tests for hepatitis A, B, C, D and E.
    5. 5. Industry Relationship Disclosures Industry Supported Research and Outside Relationships• None
    6. 6. Common Types of Liver DiseaseHepatocellular: Injury to hepatocytes (necrosis/apoptosis) Consequences: decreased synthetic/metabolic activity release of intracellular contents (AST/ALT)Cholestasis: Impaired bile formation (hepatocytes) Impaired bile flow (bile ducts/ductules) Consequences: build up in blood of substances normally excreted in bile (bilirubin, bile acids) synthesis/release of apical membrane proteins (AP)
    7. 7. Temporal Aspect of Liver DiseaseACUTE CHRONICdays/weeks/months months/yearsInjury to: injury/repair/fibrosis hepatocytes cirrhosis bile duct cellsetiology may be obscure
    8. 8. Approach to Identifying Liver DiseaseDisease: Cholestatic HepatocellularInjury: Biliary tree HepatocytesPredominant test abnormality: Alkaline AST/ALT Phosphatase (bilirubin) (PT/albumin)
    9. 9. Hepatocellular diseaseOften termed hepatitis or "liver inflammation”Diseases predominantly attack/destroy hepatocytesCharacteristic laboratory test abnormality is increased AST/ALT (transaminases)
    10. 10. Hepatitis Appearance: Normal Liver
    11. 11. Hepatitis – Inflammation,usually with necrosis of liver cells Portal tract with excess lymphocytes Lymphocytes infiltrating into parenchyma
    12. 12. Aspects of Hepatocellular DiseaseSeverity: Extent of hepatocyte necrosis and liver damage Extent of liver dysfunctionClinical symptoms of acute hepatocellular diseaseTime course: acute versus chronicEtiology
    13. 13. How to Assess:Extent of Liver Cell Necrosis?
    14. 14. Assessment of Extent of Liver Cell Necrosis AST/ALT Elevation Provides CluesAST/ALT elevation approximates the number of liver cells that were injured/died “yesterday”Variables that determine the AST/ALT level are:rate of death of hepatocyte rate of enzyme clearance
    15. 15. How to Assess:Severity of Liver Dysfunction?
    16. 16. Determinants of Liver FunctionLiver function is determined by the numberof functional hepatocytes which is thealgebraic sum of: hepatocyte dysfunction (“sick cells”) hepatocyte death rate duration of disease regeneration rate
    17. 17. How to Assess:Impaired Liver Function?
    18. 18. Measurement of Impaired Liver FunctionProtein synthetic function: increased prothrombin time low albuminOrganic anion transport: hyperbilirubinemia (less specific)Glucose production: hypoglycemia (late finding)Urea synthesis: hyperammonemia (hepatic encephalopathy)
    19. 19. Time Course: Acute vs Chronic HepatitisAcute: new liver disease usually < 2-3 months usually heals completely due to hepatic regenerationChronic: persistent liver disease > 6 months may evolve through fibrosis to: cirrhosis complications of cirrhosis hepatocellular carcinoma
    20. 20. Clinical Symptoms in Acute Hepatocellular Disease• Asymptomatic (abnormal LFTs only)• Nonspecific constitutional symptoms – Fever – Nausea/vomiting – Fatigue• Physical findings – Jaundice – Tender liver – Altered mental status/coma (hepatic encephalopathy) – Bleeding• Uncommon – Headaches, myalgias, arthritis – Rash, urticaria, arthritis
    21. 21. Origin of Symptoms in Acute Hepatocellular Disease1. Release of inflammatory mediators, cytokines, TNF fever, myalgias, fatigue, nausea2. Liver dysfunction bleeding, jaundice, coma3. Immune-complex-mediated disease rash, urticaria, arthritis
    22. 22. Acute Hepatitis: Correlation of Clinical Symptoms to Degree of Hepatocyte Necrosis AST/ALT Fulminant liver failure5000 Moderate hepatitis2000 Mild hepatitis1000 400 Asymptomatic Fatigue, nausea Fatigue, nausea, Moderate jaundice vomiting, abd pain Normal PT Severe jaundice Elevated PT Coma/death Time course
    23. 23. Fulminant Hepatic FailureOnset of liver failure within 8 weeks after onset of new liver diseaseDefined by: Evidence of impaired liver function: increased prothrombin time hypoglycemia encephalopathyCaused by: >80% loss of hepatocytesMortality rate: 40-80%Approach: hospitalize and consider liver transplantation
    24. 24. Chronic Liver Disease• Liver injury tests (AST/ALT) tend to be low to moderate but persist for months/years• Thus daily symptoms often mild or even absent• Hepatic regeneration occurs but may or may not equal injury• Long-term: new symptoms may arise due to liver dysfunction and/or as consequences of cirrhosis
    25. 25. Etiology of Hepatocellular Disease: Acute or Chronic• Infectious: Viral hepatitis A-E• Inflammatory: Autoimmune hepatitis• Drugs/toxins: Ethanol (fatty liver, alcoholic hepatitis/cirrhosis) Drugs (acetaminophen, others) or herbs• Genetic: Hemochromatosis (iron) Wilson’s disease (copper) Alpha 1 anti-trypsin deficiency• Metabolic: Non-alcoholic fatty liver disease (NAFLD) Hyperthyroidism• Vascular/ischemic: Outflow obstruction (Budd-Chiari, heart failure) Decreased perfusion (shock liver) Sinusoidal obstruction (sickle cell disease)• Infiltrating mass: Tumor/leukemia, amyloid• Bowel inflammation: Crohn’s, Ulcerative colitis, Celiac sprue
    26. 26. Diseases to cover today• Viruses• Autoimmune hepatitis• Fatty liver diseases• Other diseases are covered in textbook, and by later lectures
    27. 27. Viral Hepatitis• Most common form of acute hepatocellular disease world-wide and in the United States• Most common form of chronic hepatocellular disease world-wide• Today – review virus serologic tests• Tomorrow Dr. Lok will review the viral diseases, prevention and treatment
    28. 28. Case History: Acute Viral Hepatitis30 year old woman with a 1 week history of: increasing fatigue nausea loss of taste for meat, oily foods 1-2 days of darkening urine “yellow eyes”PE: jaundice and moderately tender liverLab tests: CBC: normal Bilirubin 5.0 mg/dl (nl <1.1) AST 955 IU/ml (nl <45) ALT 1125 IU/ml (nl<55) Alk phos 250 IU/ml (nl <140) Albumin 4.2 gm/dl (3.5<nl<4.5) PT 11.2 sec (nl <12.5)
    29. 29. Acute Viral Hepatitis: inflammation, dead liver cellsNormal liver Inflammed injured liver dead liver cell inflammation
    30. 30. How to Identify Hepatitis Viruses?
    31. 31. Tests for Hepatitis Viruses1. Antibody to viral proteins (often coat proteins) take day-weeks to develop (delay) IgM - initial response to acute infection IgG - long term response to: 1. ongoing chronic infection 2. past infection2. Viral proteins: rarely measurable exception: Hepatitis B3. Viral nucleic acid: assays result of new technology most infections will be diagnosed this way in future
    32. 32. Alphabet of Hepatitis VirusesVirus % Acute hepatitis (USA) % Chronic hepatitis A ~30 0 B ~30 ~15 C ~30 (rarely detected) ~45+ D <5 ~5 E <1 0non-A - E ~? ~??
    33. 33. Hepatitis viruses that only cause acute, resolving, disease• Hepatitis A – picornavirus• Hepatitis E
    34. 34. Hepatitis A: RNA virusFecal/oral transmissionCommon world-wideAcute resolving hepatitis LiverGood vaccine available Portal vein Bowel Bile duct Risk factors for getting this virus?
    35. 35. Hepatitis A: Only transient viremia IgM anti-HA Ab = acute disease (to VP1 capsid protein) IgG anti-HA Ab = past disease, now immune Symptoms Viremia Virus in feces ALT IgM anti-HAV IgG anti-HAV Time since infection
    36. 36. Hepatitis E• RNA virus (Hepeviridae family)• Rare in the USA, but common elsewhere• Clinical behavior: acute resolving hepatitis like hepatitis A
    37. 37. Geographic Distribution of Hepatitis EEndemic/Epidemic Areas What history should you get from apatient with acute hepatitis E in Michigan?
    38. 38. Hepatitis E• Tests: – IgM antibody to hepatitis E for acute disease – IgG antibody to hepatitis E for past disease or immunity• Vaccine under development
    39. 39. Hepatitis viruses that maycause both acute and chronic disease • Hepatitis B • Hepatitis B + D • Hepatitis C
    40. 40. Hepatitis B Virus• DNA virus (Hepadnaviridae)• Replicates through RNA intermediate (like HIV)• Blood borne• Many serologic tests have been developed leading to student information overload.
    41. 41. T4taylor, Wikimedia Commons
    42. 42. Serological Testing:Viral markers that can be measured in bloodVirus components: 1. viral DNA 2. DNA polymerase (research test) 3. s antigen (surface coat protein) 4. e antigen (version of core protein)Serum antibodies: 5. Antibody to s (surface) 6. Antibody to c (core) 7. Antibody to e T4taylor, Wikimedia Commons
    43. 43. Hepatitis B Surface Antigen• Hepatitis B is an unusual virus.• As long as the virus is present in the liver, excess coat protein (surface antigen, sAg) is manufactured.• Excess sAg is released from the liver as small spheres/rods• This excess sAg can be measured in blood.
    44. 44. Hepatitis B Core Antigen• Core antigen (cAg) or core protein is a principal component of the virus nucleocapsid.• It is released from liver only in intact virions.• Core cannot be readily measured in blood (it is inside viral particles)• Antibodies made to core early in infection and can be measured (IgM and IgG types)• eAg, an alternative product of core gene, is released free into blood where it can be measured• Antibodies made to eAg
    45. 45. Origin of Hepatitis B “e” Antigen A Tale of Two Transcriptionspre-coresignal sequence core”c” protein with DNA binding region Core gene transcribed, protein synthesized in cytosol and sent to nucleus Full length gene transcribed and sent to ER for synthesis polypeptide synthesized, clipped and this portion secreted as “e” antigen
    46. 46. Acute hepatitis B that resolves Viremia Long-term antibodies anti-HBc IgG
    47. 47. Hepatitis B: Resolved (Past) Infection Virus is gone Detectable in Blood Anti-HBs - hepatitis B surface antibody (protective) Anti-HBe - hepatitis B e antibody Anti-HBc - hepatitis B core antibody (IgG) Levels of these will fall over many years, so years later all three may not be at detectable levels, however life-long protection against reinfection remains as HBs-recognizing B cells remain and can rapidly Increase production of antibody.
    48. 48. Acute hepatitis B that becomes chronic anti-HBc IgG HBeAgHBsAg anti-HBc IgM anti-HBe Weeks Months Years Acute disease High Low replication replication
    49. 49. Hepatitis B Infection (Acute or Chronic) with High Viral Replication Rate Detectable in Blood eAg Hepatitis B DNA HBsAg - hepatitis B surface antigen (red) sAg HBeAg - hepatitis B e antigen (green) Anti-HBc - hepatitis B core antibody (IgM for acute, IgG for chronic) Complete viral particles are present in blood at high levels, however no routine tests are available to detect them.
    50. 50. Hepatitis B Infection Resolving Acute or Chronicwith Low Viral Replication Rate Detectable in Blood HBsAg - hepatitis B surface antigen (red) Anti-HBe - hepatitis B e antibody Anti-HBc - hepatitis B core antibody (IgM for acute, IgG for chronic) Complete viral particles are present in blood at low levels, however no routine tests are available to detect them.
    51. 51. Interpretation of Serological Markers for HBV InfectionHBsAg HBV infection (acute or chronic)HBeAg High viral load/infectivityHBV DNA High viral load/infectivityAnti-HBs ImmunityAnti-HBc IgM Acute infectionAnti-HBc IgG Past or chronic infectionAnti-HBe Past or low infectivity chronic infectionAnti-HBc IgG and HBsAg Chronic infectionAnti-HBc IgG and anti-HBs Resolved (past) infection
    52. 52. Nomenclature of Antibodies• Anti-HBc• HBcAB• HBcAb• These are three different ways of indicating an antibody directed against the hepatitis B core protein• Ag = antigen• AB (Ab) = antibody
    53. 53. Hepatitis D (delta) Virus (HDV):a parasite on hepatitis B (HBV) Hepatitis D Hepatitis B surface antigen constitutes the HDV coat protein HDV RNA Delta antigen
    54. 54. Acute hepatitis B and D with resolution Similar early appearance of viral genome and of IgM antibodies to: HBV cAg HDV Ag With disease resolution, loss of viral genome and conversion of both IgM antibodies to IgG
    55. 55. Superinfection of Hepatitis D on top of chronicHepatitis B: hepatitis D also becomes chronic
    56. 56. Hepatitis C• Most common cause of chronic hepatitis world-wide, including USA• Almost always asymptomatic (mild hepatitis)• Chronic infection can lead to cirrhosis/ HCC in up to 25%• Now most common reason for liver transplantation in USA
    57. 57. Hepatitis C VirusGrahamColm, Wikimedia Commons
    58. 58. Hepatitis C Serology: SimpleHepatitis C IgG antibody: appears weeks after onset of new infection signifies past resolved or chronic hepatitis C occasional false positive no IgM antibody available for acute infectionHepatitis C RNA (by PCR): signifies the virus is present in liver/blood found in acute or chronic hepatitis C
    59. 59. Hepatitis C: acute infection that becomes chronic
    60. 60. Other Viruses• Other hepatitis viruses almost certainly exist
    61. 61. To Review: Serologic Diagnosis of Acute Viral HepatitisA: IgM anti-HAVB: HBsAg and IgM anti-HBc later: disappearance of HBsAg and appearance of anti-HBsC: HCV RNA present, no anti-HCV eventual anti-HCV appearanceD: HBsAg and later appearance of anti-HDV sE: IgM anti-HEV
    62. 62. Serologic Diagnosis of Chronic Viral HepatitisB: HBsAg, IgG anti-HBc +/- HBeAg, anti-HBe +/- HBV DNAC: HCV RNA and anti-HCV both present and both persistD: HBsAg and anti-HDV both persist HDV RNA persists (if available)
    63. 63. Other Hepatocellular Diseases: Autoimmune hepatitis• Injury to normal hepatocytes by infiltrating T cells and plasma cells leading to fibrosis/cirrhosis• Lab tests: – Characteristic antibodies: • Anti-nuclear antibodies • Anti-smooth (actin) muscle antibodies – High level of polyclonal immunoglobulins (IgG)• Chronic disease but usually highly response to suppression by prednisone and azathioprine
    64. 64. Autoimmune HepatitisPortal tract Many plasma cells Lymphocytes and plasma cells encircle hepatocytes
    65. 65. Fatty Liver Diseases • Alcohol: Fatty liver Alcoholic hepatitis alcoholic steatohepatitis (ASH) Alcoholic cirrhosis • Non-alcoholic fatty liver disease (NAFLD) – Non-alcoholic fatty liver – Non-alcoholic steatohepatitis (NASH)
    66. 66. Pathophysiology• Many similarities between alcoholic fatty liver and non-alcoholic fatty liver• Both start with large globules of triglyceride in hepatocytes• Both can, in some patients, lead to inflammation, hepatocyte necrosis, fibrosis and cirrhosis.
    67. 67. Development of Fatty LiverExcess alcohol intake Insulin resistance/obesity Impaired insulin signalingIncreased input of fuel: Increased input of fat to liver: acetate from ETOH peripheral lipolysis peripheral lipolysis dietary fat/carbs dietary intake lipoprotein inputIncreased NADH/NAD Increased hepatic triglycerideratio causes: accumulation: decreased gluconeogenesis increased triglyceride synthesis decreased fatty acid oxidation decreased fatty acid oxidation increased triglyceride synthesis Secreted VLDL cannot unload fatImpaired synthesis/secretion of peripherallyproteins like lipoproteins and VLDLs
    68. 68. Fatty Liver to Steatohepatitis• Further insults must occur to cause continued and progressive damage to hepatocytes and promote inflammation/fibrosis• These likely involve: – Inflammatory effects of gut-derived endotoxin – Oxidative stress/lipid peroxidation – Genetic polymorphisms
    69. 69. Summary• Many diseases cause hepatocellular injury• Lab tests can indicate hepatocellular disease and liver function• Lab tests with history and histology may identify the specific etiology
    70. 70. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 42 & 43:T4taylor, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:HBV_Genome.svg, CC:BY-SA,http://creativecommons.org/licenses/by-sa/3.0/deed.enSlide 58: GrahamColm, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:HCV_structure.png, CC:BY-SA,http://creativecommons.org/licenses/by-sa/3.0/deed.en