Hepatitis

Dr. Shaswat Bhattarai

1st year JR pathology
• Hepatitis is the inflammation of liver caused by
immune response against liver parenchyma
induced by viral infections, or intracellular
pathogens that survive in Kupffer cells causing
granulomatous infections (typhoid fever,
brucellosis, Q fever, T.B).
Viral causative agents of hepatitis can be:
• Professional-hepatitis viruses: Hepatitis
A,B,C,D, and E viruses: strong tropism to
hepatocyte.
• Non-professional viruses: Viruses that cause
extra-hepatic diseases: Yellow fever viruses,
E.B virus secondary to I.M, CMV, adenoviruses,
Herpes simplex viruses, VZV…..
 Hepatitis Viruses: Hepatitis A, B, C, D, and E:
Type Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
N

Mode of Fecal-oral* Bloodborne Bloodborne Bloodborne Fecal-oral*

Transmission Sexual (depend on
Vertical HBV)
Super or co
infection

Classification Picornaviri Hepadnaviriae Flaviviridae Deltaviridae Calicivirid-

-dae. Circular Linear Circular ae. Linear
Linear SS- DS DNA SS-RNA SS RNA SS- RNA
RNA R.T enzyme

Incubation 2—6 weeks 2 –6 months 2 weeks- 6 60-180 days 21-42 days

months
Chronic NO. YES (10%) YES (60 - YES NO.
infection 80%)

Clinical NO Cirrhosis or Cirrhosis or Co-infection NO

outcomes hepatocellular hepatocellular
of Chronic carcinoma carcinoma
Infection
• Clinically defined as elevation in aspartate transaminase (AST) and
alanine transaminase (ALT) (at least 2x upper normal reference
range) for < 6 months
• Hepatotropic viruses: increase in AST / ALT > 5 times upper limit of
normal and alkaline phosphatase (ALP) < 3 times upper limit of normal
• Acute HAV: anti-HAV IgM present for 4 - 6 months
• Acute HBV: anticore IgM, hepatitis B surface antigen (HBsAg)
• Acute HCV: HCV RNA in serum; anti-HCV antibodies may not
appear for 6 weeks to 6 months
• Acute HDV: total anti-HDV (IgG and IgM)
• Acute HEV: anti-HEV antibody
• Acute alcoholic hepatitis
• Marked elevation in bilirubin; slight elevation in transaminases (<
10x upper limit of normal)
• Autoimmune hepatitis
• Increased total IgG, presence of autoantibodies (antinuclear
antibody, anti smooth muscle antibody)
 Hepatitis B virus:
Pathogenesis:
• Interferon-α production; Up-regulates MHC-I
expression and inhibits viral replication cycle.
• Kupffer cell response; release of cytokines and
inflammatory mediators; chemotaxis.
• Infection of hepatocytes activate T-cell mediated
cytotoxicity: interaction between hepatocyte-
MHC-I + HBc Ag or HBe Ag fragments and CD8.
• Enhanced natural killer cell activity; cytotoxicity.
• HBs Ag & anti-HBs Ag antibodies complexes
activate complement system; damage.
Clinical presentation of hepatitis B infection:
Incubation period: 60- 180 days.
o Acute infection period:
A- Pre-icteric phase: (days to week): mild fever,
anorexia, myalgia, and nausea.
B- Icteric acute phase:(one to two months): Jaundice
(yellowish coloration of mucous membrane,
conjunctivae, and skin), enlarged and tender liver.
C- Fulminant hepatitis: (in 1-2% of patients): severe
necrosis of liver in icteric phase; high fever, abdominal
pain, renal dysfunction, encephalopathy (lethal in 8%
of cases).
 Chronic infection:
• Chronic asymptomatic carrier
• Chronic persistent hepatitis
• Chronic active hepatitis
n

Acute Hepatitis B
infection

Virulent strain of Limited cell-mediated and Effective cell-mediated

hepatitis, Co- humoral immunity and humoral immunity
infection (HDV), (Anti HBs antibodies)
Uncontrolled
immunity and
cytokines
Chronic stage;
Asymptomatic
carrier Chronic active
Minimal chronic
hepatitis Resolution
hepatitis
(persistent,
fluctuating)

Fulminant Hepatitis Liver Cirrhosis Hepatocellular Carcinoma

 Diagnosis of Hepatitis B infection:
• In incubation period and pre-icteric phase: The
first indicator is HBs Ag and HBe Ag (envelope).
• In acute icteric phase: Elevated bilirubin (total &
direct), liver enzymes (transaminases), bilirubinuria,
elevated anti-HBc antibodies in serum.
• In convalescence phase: Anti-HBs Antibodies starts
elevation in serum (positive).
• In chronic period:
o HBs Ag: positive
o Anti-HBs Antibodies: negative.
o Anti-HBc Antibodies: positive
Ground glass appearance viral hepatitis
 Hepatitis C Virus Infection:
• 90% of cases of non-A, non-B hepatitis.
• Transmission:
o post- transfusion hepatitis.
o Intravenous drug users
o Patients on hemodialysis.
• Pathogenesis:
o Replication of virus in hepatocytes, lymphocytes,
and macrophages.
o Destruction of cells by the virus and immunity.
Clinical outcomes of acute hepatitis C infection:
N

Acute hepatitis C infection

Subclinical infection in 75% of cases Acute hepatitis C (25% of cases)

Resolution of
Chronic hepatitis C (10-15 years) disease (months)

Cirrhosis Mixed
Hepatocellular Liver Cryoglobulinemia:*
(20%) Carcinoma failure Arthritis, purpura,
glomerulonephritis
 Diagnosis of HCV:
N

• Detection of Anti-HCV recombinant viral

protein antibodies in patient serum by ELISA.
• Detection of viral nucleic acid in serum by RT-
PCR technique.
Treatment and Prevention:
o Combination therapy of interferon-α and
ribavirin provides a significant response (30-
50% for genotype 1 and 70-75% for viral
genotype 2 and 3).
o No available vaccine.
 Hepatitis A infection:
o Responsible for most cases of infectious hepatitis.
o Non-enveloped SS-RNA Virus.
o Transmission: fecal-oral or contaminated water.
o Pathogenesis:
• Enter blood from intestine; portal system; liver.
• Replicate in hepatocytes (destruction), excreted
through bile ducts into stool (a high titer =1011
virion/ml)
• Released in bloodstream (to a lesser extent);
transient viremia.
o Vaccines:
• inactivated vaccine (cell-cultured).
• post-exposure prophylaxis (Anti-HAV).
 Alcoholic hepatitis
• Definition / general
• Acute hepatitis is largely a clinical term used to
describe a sudden elevation in liver enzymes that lasts
< 6 months in duration
• Can occur de novo or as a flare of various chronic liver
diseases
• Acute liver failure is defined as an abrupt onset of
severe liver disease that leads to hepatic
encephalopathy and coagulopathy shortly after
presentation
• Essential features
• Acute hepatitis is a clinical term used to describe a
sudden elevation in liver enzymes that lasts < 6
months
• Hepatotropic viruses account for the majority of cases,
most commonly hepatitis A and B viruses
• Histologic features are fairly nonspecific displaying
lobular disarray and can include lobular inflammation,
varying degrees of parenchymal necrosis, bile
ductular reaction and bland lobular cholestasis
• Features of chronic injury are not present
• Cases of acute hepatitis can resolve spontaneously
with supportive therapy, progress to acute liver failure
or develop into chronic liver disease
• Pathophysiology
• Necrosis of minute groups of hepatocytes occurs
initially without disturbing the hepatic architecture,
usually resulting in complete recovery when the
insult resolves
• In severe disease, large groups of hepatocytes die,
which leads to necrosis and collapse of the reticulin
framework
• Etiology
• Viral hepatitis
• Hepatotropic viruses (hepatitis A, B, C, D, E)
• Account for 72% of acute hepatitis
• Majority of infections are hepatitis A virus (HAV) and
hepatitis B virus (HBV)
• Nonhepatotropic viruses
• Herpes simplex virus (HSV), cytomegalovirus (CMV),
Epstein-Barr virus (EBV), adenovirus, hemorrhagic fever
associated viruses, varicella zoster virus, yellow fever,
dengue
• Other infections
• Tick borne diseases, malaria, visceral leishmaniasis, Q fever,
leptospirosis
• Drug induced liver injury
• Direct toxins versus idiosyncratic drug reactions
• Autoimmune hepatitis, acute alcoholic hepatitis, Budd-
Chiari, Wilson disease, ischemic hepatitis
• Diagnosis
• Clinical diagnosis
• Elevated serum alanine aminotransferase and aspartate
aminotransferase (ALT, AST) tests
• Viral hepatitis
• Serum antibody tests (IgG, IgM), PCR tests for viral RNA,
enzyme linked immunoassay (ELISA) test
• Drug induced hepatitis
• Exclusion of viral hepatitis
• Clinical history is taken to investigate any temporal
relationship of drug administration and the presence of
abnormal liver tests
• Biopsies typically not performed unless there is a clinical
suspicion of a second independent hepatic insult (i.e., underlying
chronic liver disease)
Microscopic (histologic) description
•Lobular disarray
• Disruption of the sinusoidal architecture by cell injury and
inflammation
•Lobular inflammation
•Composed of mainly small T lymphocytes with variable number of
macrophages, plasma cells and occasional eosinophils
• Plasma cells may be predominant in acute hepatitis A and B
• Predominantly sinusoidal inflammation with little hepatocyte
damage, is characteristic of EBV infection
• Neutrophilic microabscesses or small sinusoidal clusters of
neutrophils can sometimes be seen in CMV infection
• Zone 3 accentuation may be seen in some drug induced liver
injury
• Granulomas
• Typically seen in infection (tick borne diseases) and
drug reactions
• Kupffer cell hyperplasia may be present in more severe
cases
• Tick borne diseases, malaria, autoimmune hepatitis
• Resolving cases of acute hepatitis
• Portal tracts have less pronounced inflammation but may
be edematous or contain variable amounts of a
mononuclear cell infiltrate
• Inflammation from portal tract may spill over, limiting
plate mimicking interface activity but hepatocytes are
not damaged
• Necroinflammation is diffuse but can be heterogenous
• Lytic or spotty necrosis: foci of inflammation surrounding
damaged hepatocytes or minute groups of hepatocytes
• Confluent necrosis: zonal death of larger groups of hepatocytes,
leading to collapse of reticulin framework, typically starts in zone
3
• Zone 1 or zone 1 - 2 necrosis can rarely be seen in acute hepatitis
A infection
• Punched out necrosis can be seen in nonhepatotropic viral
infections (adenovirus, HSV) and can have an azonal pattern
• Central hyaline necrosis can be seen in acute alcoholic liver
disease and shows central confluent necrosis with obliteration
of the central vein and accompanying neutrophilic inflammation
• Bridging necrosis
• Severe acute hepatitis is characterized by confluent necrosis,
linking terminal / central venules to portal tracts
• May mimic septa of chronic liver disease
 • Panlobular, panacinar, multilobular, multiacinar,
submassive (26 - 75% parenchymal volume),
massive necrosis (> 75% parenchymal volume)
• Parenchyma replaced by collapsed stromal
inflammatory cells and activated macrophages
Hepatocellular damage
• Apoptotic bodies are degenerated hepatocytes with
increased cytoplasmic staining and pyknotic nuclear
remnants (Councilman bodies used for yellow fever)
• Minor hepatocyte swelling characterized as rarified,
granular or finely vacuolated cytoplasm
 • Ballooning degeneration is a more severe
swelling characterized by rarified cytoplasm and
occasional Mallory hyaline
• Drug reactions, autoimmune hepatitis, acute
alcoholic hepatitis, Wilson disease
• Neutrophilic satellitosis: neutrophils
surrounding ballooned hepatocytes with
Mallory hyaline and is seen in active cases of
alcoholic steatohepatitis
• Cholestasis
• Bland lobular cholestasis may be in canaliculi or
(in more severe cases) within the hepatocytes
• Acute hepatitis A, acute hepatitis B
• Drug reactions
• Biliary changes
• Bile duct epithelial stratification, cytoplasmic
vacuolization, necrosis, altered nuclear
polarity, intraepithelial lymphocytosis
• Bile ductular proliferation, which may mimic
an obstruction
• Described in some cases symptomatic cases
of acute hepatitis C
• Drug reactions, Wilson disease
Hepatocyte damage
 Autoimmune hepatitis
• Typical morphological changes: Portal plasma cell rich
inflammation
• Interface hepatitis, formerly referred to as piecemeal
necrosis: portal inflammatory cells eroding through the
limiting plate between the portal tract and liver
parenchyma
• Emperipolesis: active penetration of lymphocytes into
and through a hepatocyte
• Hepatocyte rosettes
• Variable fibrosis (about 10% of autoimmune hepatitis
does not show any fibrosis at initial presentation)
• Lobular necroinflammatory activity: usually
accompanied by portal and periportal inflammation
Serum autoantibodies
• Antinuclear antibody: positive in 75% of type 1 autoimmune
hepatitis; not associated with disease course or outcome.
• Anti smooth muscle antibody: positive in 95% of type 1
autoimmune hepatitis; not associated with disease course or outcome
• Anti liver kidney microsomal: diagnostic for type 2 autoimmune
hepatitis; associated with younger age at presentation, fulminant
hepatic failure and partial IgA deficiency
• Anti liver cytosol type 1: diagnostic for type 2 autoimmune hepatitis;
associated with more severe inflammation and rapid progression to
cirrhosis
• Antisoluble liver antigen / liver pancreas: positive in 20 - 50% of
autoimmune hepatitis; associated with more severe disease, treatment
dependence, relapse after drug withdrawal and need for
transplantation
• Elevated liver enzymes; ALT / AST > ALP
• Serum immunoglobulin G (IgG): marker for diagnosis (> 1.1 x
upper limit of normal [ULN]) and monitoring treatment response.
Rosettes
Lymphoplasmacytic infiltrates