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

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