1. Author(s): Rebecca W. Van Dyke, M.D., 2012
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3. M2 GI Sequence
Hepatocellular Disease
Rebecca W. Van Dyke, MD
Winter 2012

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. Industry Relationship
Disclosures
Industry Supported Research and
Outside Relationships
• None

6. Common Types of Liver Disease
Hepatocellular: 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. Temporal Aspect of Liver Disease
ACUTE CHRONIC
days/weeks/months months/years
Injury to: injury/repair/fibrosis
hepatocytes cirrhosis
bile duct cellsetiology may be obscure

8. Approach to Identifying Liver Disease
Disease: Cholestatic Hepatocellular
Injury: Biliary tree Hepatocytes
Predominant
test abnormality: Alkaline AST/ALT
Phosphatase
(bilirubin) (PT/albumin)

9. Hepatocellular disease
Often termed hepatitis or "liver inflammation”
Diseases predominantly attack/destroy hepatocytes
Characteristic laboratory test abnormality is increased
AST/ALT (transaminases)

10. Hepatitis Appearance: Normal Liver

11. Hepatitis – Inflammation,
usually with necrosis of liver cells
Portal tract with excess
lymphocytes
Lymphocytes
infiltrating into
parenchyma

12. Aspects of Hepatocellular Disease
Severity: Extent of hepatocyte necrosis
and liver damage
Extent of liver dysfunction
Clinical symptoms of acute hepatocellular disease
Time course: acute versus chronic
Etiology

13. How to Assess:
Extent of Liver Cell Necrosis?

14. 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

15. How to Assess:
Severity of Liver Dysfunction?

16. 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 rate
duration of disease
regeneration rate

17. How to Assess:
Impaired Liver Function?

18. 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)

19. Time Course: Acute vs Chronic Hepatitis
Acute: new liver disease
usually < 2-3 months
usually heals completely due to
hepatic regeneration
Chronic: persistent liver disease > 6 months
may evolve through fibrosis to:
cirrhosis
complications of cirrhosis
hepatocellular carcinoma

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. 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

22. Acute Hepatitis: Correlation of Clinical Symptoms to
Degree of Hepatocyte Necrosis
AST/ALT Fulminant liver
failure
5000
Moderate hepatitis
2000
Mild hepatitis
1000
400
Asymptomatic Fatigue, nausea Fatigue, nausea,
Moderate jaundice vomiting, abd pain
Normal PT Severe jaundice
Elevated PT
Coma/death
Time course

23. 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 time
hypoglycemia
encephalopathy
Caused by: >80% loss of hepatocytes
Mortality rate: 40-80%
Approach: hospitalize and consider liver transplantation

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. 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. Diseases to cover today
• Viruses
• Autoimmune hepatitis
• Fatty liver diseases
• Other diseases are covered in textbook,
and by later lectures

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. Case History: Acute Viral Hepatitis
30 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 liver
Lab 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. Acute Viral Hepatitis: inflammation, dead liver cells
Normal liver Inflammed injured liver
dead liver cell
inflammation

30. How to Identify Hepatitis Viruses?

31. Tests for Hepatitis Viruses
1. 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 infection
2. Viral proteins: rarely measurable
exception: Hepatitis B
3. Viral nucleic acid: assays result of new technology
most infections will be diagnosed this
way in future

33. 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 ~? ~??

34. Hepatitis viruses that only
cause acute, resolving,
disease
• Hepatitis A
– picornavirus
• Hepatitis E

35. Hepatitis A: RNA virus
Fecal/oral transmission
Common world-wide
Acute resolving hepatitis Liver
Good vaccine available
Portal vein
Bowel
Bile duct Risk factors for
getting this virus?

36. 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

37. Hepatitis E
• RNA virus (Hepeviridae family)
• Rare in the USA, but common elsewhere
• Clinical behavior: acute resolving hepatitis
like hepatitis A

38. Geographic Distribution
of Hepatitis E
Endemic/Epidemic Areas
What history should you get from a
patient with acute hepatitis E in Michigan?

39. Hepatitis E
• Tests:
– IgM antibody to
hepatitis E for
acute disease
– IgG antibody to
hepatitis E for
past disease or
immunity
• Vaccine under
development

40. Hepatitis viruses that may
cause both acute and chronic
disease
• Hepatitis B
• Hepatitis B + D
• Hepatitis C

41. 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.

42. T4taylor, Wikimedia Commons

43. 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

44. 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.

45. 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

46. Origin of Hepatitis B “e” Antigen
A Tale of Two Transcriptions
pre-core
signal 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

47. Acute hepatitis B that resolves
Viremia
Long-term
antibodies
anti-HBc IgG

48. 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.

49. Acute hepatitis B
that becomes chronic
anti-HBc IgG
HBeAg
HBsAg anti-HBc IgM anti-HBe
Weeks Months Years
Acute disease High Low
replication replication

50. 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.

51. 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.

52. Interpretation of Serological Markers
for HBV Infection
HBsAg HBV infection (acute or chronic)
HBeAg High viral load/infectivity
HBV DNA High viral load/infectivity
Anti-HBs Immunity
Anti-HBc IgM Acute infection
Anti-HBc IgG Past or chronic infection
Anti-HBe Past or low infectivity chronic infection
Anti-HBc IgG and HBsAg Chronic infection
Anti-HBc IgG and anti-HBs Resolved (past) infection

53. 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

54. 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

55. 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

56. Superinfection of Hepatitis D on top of chronic
Hepatitis B: hepatitis D also becomes chronic

57. 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

58. Hepatitis C Virus
GrahamColm, Wikimedia Commons

59. Hepatitis C Serology: Simple
Hepatitis 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 infection
Hepatitis C RNA (by PCR):
signifies the virus is present in liver/blood
found in acute or chronic hepatitis C

60. Hepatitis C: acute infection that becomes chronic

61. Other Viruses
• Other hepatitis viruses almost certainly
exist

62. To Review: Serologic Diagnosis of
Acute Viral Hepatitis
A: IgM anti-HAV
B: HBsAg and IgM anti-HBc
later: disappearance of HBsAg and
appearance of anti-HBs
C: HCV RNA present, no anti-HCV
eventual anti-HCV appearance
D: HBsAg and later appearance of anti-HDV s
E: IgM anti-HEV

63. 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 persist
HDV RNA persists (if available)

64. 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

65. Autoimmune Hepatitis
Portal tract
Many
plasma
cells
Lymphocytes and plasma cells
encircle hepatocytes

66. 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)

67. 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.

68. Development of Fatty Liver
Excess alcohol intake Insulin resistance/obesity
Impaired insulin signaling
Increased input of fuel:
Increased input of fat to liver:
acetate from ETOH
peripheral lipolysis
peripheral lipolysis
dietary fat/carbs
dietary intake
lipoprotein input
Increased NADH/NAD
Increased hepatic triglyceride
ratio causes:
accumulation:
decreased gluconeogenesis
increased triglyceride synthesis
decreased fatty acid oxidation
decreased fatty acid oxidation
increased triglyceride synthesis
Secreted VLDL cannot unload fat
Impaired synthesis/secretion of
peripherally
proteins like lipoproteins and VLDLs

69. 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

70. 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

71. Additional Source Information
for 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