02.02.12: Hepatocellular Disease
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Transcript of 02.02.12: Hepatocellular Disease
Author(s): Rebecca W. Van Dyke, M.D., 2012
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M2 GI Sequence
Hepatocellular Disease
Rebecca W. Van Dyke, MD
Winter 2012
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.
Industry Relationship Disclosures
Industry Supported Research and Outside Relationships
• None
Common Types of Liver Disease
Hepatocellular: Injury to hepatocytes (necrosis/apoptosis) Consequences:
decreased synthetic/metabolic activityrelease 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)
Temporal Aspect of Liver Disease
ACUTE CHRONIC
days/weeks/months months/yearsInjury to: injury/repair/fibrosis
hepatocytes cirrhosisbile duct cellsetiology may be obscure
Approach to Identifying Liver Disease
Disease: Cholestatic Hepatocellular
Injury: Biliary tree Hepatocytes
Predominant test abnormality: Alkaline AST/ALT
Phosphatase(bilirubin) (PT/albumin)
Hepatocellular disease
Often termed hepatitis or "liver inflammation”
Diseases predominantly attack/destroy hepatocytes
Characteristic laboratory test abnormality is increased AST/ALT (transaminases)
Hepatitis Appearance: Normal Liver
Hepatitis – Inflammation, usually with necrosis of liver cells
Lymphocytesinfiltrating intoparenchyma
Portal tract with excesslymphocytes
Aspects of Hepatocellular Disease
Severity: Extent of hepatocyte necrosisand liver damage
Extent of liver dysfunction
Clinical symptoms of acute hepatocellular disease
Time course: acute versus chronic
Etiology
How to Assess:
Extent of Liver Cell Necrosis?
Assessment of Extent of Liver Cell Necrosis
AST/ALT Elevation Provides Clues
AST/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
How to Assess:
Severity of Liver Dysfunction?
Determinants of Liver Function
Liver function is determined by the number of functional hepatocytes which is the algebraic sum of:
hepatocyte dysfunction (“sick cells”)hepatocyte death rateduration of diseaseregeneration rate
How to Assess:
Impaired Liver Function?
Measurement of Impaired Liver Function
Protein synthetic function: increased prothrombin time low albumin
Organic anion transport: hyperbilirubinemia(less specific)
Glucose production: hypoglycemia (late finding)
Urea synthesis: hyperammonemia (hepatic encephalopathy)
Time Course: Acute vs Chronic Hepatitis
Acute: new liver diseaseusually < 2-3 monthsusually heals completely due to hepatic regeneration
Chronic: persistent liver disease > 6 monthsmay evolve through fibrosis to:
cirrhosiscomplications of cirrhosishepatocellular carcinoma
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
Origin of Symptoms in Acute Hepatocellular Disease
1. Release of inflammatory mediators, cytokines, TNF
fever, myalgias, fatigue, nausea
2. Liver dysfunction bleeding, jaundice, coma
3. Immune-complex-mediated disease rash, urticaria, arthritis
Acute Hepatitis: Correlation of Clinical Symptoms to Degree of Hepatocyte Necrosis
AST/ALT
400
1000
2000
5000
Mild hepatitis
Moderate hepatitis
Fulminant liver failure
Asymptomatic Fatigue, nausea Moderate jaundice Normal PT
Fatigue, nausea, vomiting, abd pain Severe jaundice Elevated PT Coma/death
Time course
Fulminant Hepatic Failure
Onset of liver failure within 8 weeks after onset of new liver disease
Defined by: Evidence of impaired liver function:increased prothrombin timehypoglycemiaencephalopathy
Caused by: >80% loss of hepatocytes
Mortality rate: 40-80%
Approach: hospitalize and consider liver transplantation
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
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
Diseases to cover today
• Viruses
• Autoimmune hepatitis
• Fatty liver diseases
• Other diseases are covered in textbook, and by later lectures
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
Case History: Acute Viral Hepatitis
30 year old woman with a 1 week history of:increasing fatigue
nausealoss of taste for meat, oily foods1-2 days of darkening urine“yellow eyes”
PE: jaundice and moderately tender liver
Lab tests: CBC: normalBilirubin 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)
Acute Viral Hepatitis: inflammation, dead liver cells
dead liver cell
inflammation
Normal liver Inflammed injured liver
How to Identify Hepatitis Viruses?
Tests for Hepatitis Viruses
1. Antibody to viral proteins (often coat proteins)take day-weeks to develop (delay)
IgM - initial response to acute infectionIgG - long term response to:
1. ongoing chronic infection 2. past infection
2. Viral proteins: rarely measurableexception: Hepatitis B
3. Viral nucleic acid: assays result of new technology most infections will be diagnosed this way in future
Alphabet of Hepatitis Viruses
Virus % Acute hepatitis (USA) % Chronic hepatitis
A ~30 0
B ~30 ~15
C ~30 (rarely detected) ~45+
D <5 ~5
E <1 0
non-A - E ~? ~??
Hepatitis viruses that only cause acute, resolving,
disease
• Hepatitis A– picornavirus
• Hepatitis E
Hepatitis A: RNA virusFecal/oral transmissionCommon world-wideAcute resolving hepatitisGood vaccine available
Risk factors forgetting this virus?
Portal vein
Bile duct
Bowel
Liver
Hepatitis A: Only transient viremia IgM anti-HA Ab = acute disease (to VP1 capsid protein) IgG anti-HA Ab = past disease, now immune
Time since infection
ViremiaSymptoms
Virus in feces
ALT
IgM anti-HAV IgG anti-HAV
Hepatitis E
• RNA virus (Hepeviridae family)
• Rare in the USA, but common elsewhere
• Clinical behavior: acute resolving hepatitis
like hepatitis A
Geographic Distribution of Hepatitis E
Endemic/Epidemic Areas
Geographic Distribution of Hepatitis E
Endemic/Epidemic Areas
What history should you get from a patient with acute hepatitis E in Michigan?
Hepatitis E
• Tests:– IgM antibody to
hepatitis E for acute disease
– IgG antibody to hepatitis E for past disease or immunity
• Vaccine under development
Hepatitis viruses that may cause both acute and chronic
disease
• Hepatitis B
• Hepatitis B + D
• Hepatitis C
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.
T4taylor, Wikimedia Commons
Serological Testing: Viral markers that can be measured in blood
Virus 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
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.
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
Origin of Hepatitis B “e” AntigenA Tale of Two Transcriptions
core”c” protein with DNA binding regionpre-core signal sequence
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
anti-HBc IgG
Long-termantibodies
Acute hepatitis B that resolvesViremia
Hepatitis B: Resolved (Past) Infection
Detectable in Blood
Anti-HBs - hepatitis B surface antibody (protective)
Anti-HBe - hepatitis B e
antibody Anti-HBc - hepatitis B core
antibody (IgG)
Virus is gone
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.
Acute hepatitis B that becomes chronic
Weeks Months Years
Acute disease High Low replication replication
anti-HBc IgG
HBeAg
HBsAg anti-HBc IgM anti-HBe
Hepatitis B Infection (Acute or Chronic) with High Viral Replication Rate
Detectable in Blood
Hepatitis B DNA
HBsAg - hepatitis B surface
antigen (red)
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.
eAg
sAg
Hepatitis B Infection Resolving Acute or Chronic
with 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.
Interpretation of Serological Markers for HBV Infection
HBsAg HBV infection (acute or chronic)HBeAg High viral load/infectivityHBV DNA High viral load/infectivity
Anti-HBs ImmunityAnti-HBc IgM Acute infectionAnti-HBc IgG Past or chronic infectionAnti-HBe Past or low infectivity chronic infection
Anti-HBc IgG and HBsAg Chronic infectionAnti-HBc IgG and anti-HBs Resolved (past) infection
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
Hepatitis D (delta) Virus (HDV):a parasite on hepatitis B (HBV)
Hepatitis B surface antigen constitutes the HDV coat protein
HDV RNA
Hepatitis D
Delta antigen
Acute hepatitis B and D with resolutionSimilar early appearance of viralgenome and of IgM antibodies to: HBV cAg HDV AgWith disease resolution, lossof viral genome and conversion of both IgM antibodies to IgG
Superinfection of Hepatitis D on top of chronic Hepatitis B: hepatitis D also becomes chronic
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
Hepatitis C Virus
GrahamColm, Wikimedia Commons
Hepatitis C Serology: Simple
Hepatitis C IgG antibody:appears weeks after onset of new infectionsignifies past resolved or chronic hepatitis Coccasional false positive no IgM antibody available for acute infection
Hepatitis C RNA (by PCR):signifies the virus is present in liver/bloodfound in acute or chronic hepatitis C
Hepatitis C: acute infection that becomes chronic
Other Viruses
• Other hepatitis viruses almost certainly exist
To Review: Serologic Diagnosis of Acute Viral Hepatitis
A: IgM anti-HAV
B: HBsAg and IgM anti-HBclater: disappearance of HBsAg and
appearance of anti-HBs
C: HCV RNA present, no anti-HCVeventual anti-HCV appearance
D: HBsAg and later appearance of anti-HDV s
E: IgM anti-HEV
Serologic Diagnosis of Chronic Viral Hepatitis
B: HBsAg, IgG anti-HBc+/- HBeAg, anti-HBe+/- HBV DNA
C: HCV RNA and anti-HCV both present and both persist
D: HBsAg and anti-HDV both persistHDV RNA persists (if available)
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
Autoimmune Hepatitis
Portal tract
Lymphocytes and plasma cellsencircle hepatocytes
Many plasmacells
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)
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.
Development of Fatty Liver
Excess alcohol intake Insulin resistance/obesityImpaired insulin signaling
Increased input of fuel: acetate from ETOH peripheral lipolysis dietary intake
Increased NADH/NADratio causes: decreased gluconeogenesis decreased fatty acid oxidation increased triglyceride synthesis
Impaired synthesis/secretion ofproteins like lipoproteins and VLDLs
Increased input of fat to liver:peripheral lipolysisdietary fat/carbs
lipoprotein input Increased hepatic triglyceride accumulation: increased triglyceride synthesis decreased fatty acid oxidation
Secreted VLDL cannot unload fat peripherally
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
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
Additional Source Informationfor more information see: http://open.umich.edu/wiki/CitationPolicy
Slide 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.en
Slide 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