Cunanan, Nicole

De Guzman, Arianne
De Mata, Victoria Mariz
Diaz, Jestoni
MD-II UNIT 4, GROUP 2

Viral Hepatitis
I. Clinical Case

A 52-year-old African-American woman with overall good health and medical history of asthma and depression
presented with right lower quadrant abdominal pain, vomiting and icterus for 3 weeks. The pain was constant and cramping,
fluctuating in intensity from 5 to 9 of 10, located mostly in the right lower quadrant and umbilical areas, and was associated
with bilious vomiting. There were no changes in her mental status and no signs of any encephalopathy. No history of any
recent blood transfusions. Her other history was unremarkable except for the occasional alcohol intake of 1–2 beers once a
week and actively snorting cocaine. She was a commercial sex worker and had multiple sexual partners. Her home
medications included albuterol and methadone.

On presentation, she was haemodynamically stable (body mass index 29), afebrile and oriented. Physical examiniation
was remarkable for only sclera icterus and mild tenderness on palpation in the right lower quadrant with no guarding or
rigidity. She had no palpable hepatomegaly.

Investigations revealed marked hyperbilirubinemia and transaminitis, with other serological and radiological studies
unremarkable and a hepatitis A, B and C panel negative 3 weeks before presentation. Repeat hepatitis panel showing
hepatitis C antibody positive with viral load 20 739 524 IU/mL. Liver biopsy supported the diagnosis of acute hepatitis C
infection that showed severe active-chronic hepatitis and hepatocytes showing ballooning degeneration and hyaline
degeneration within the hepatocytes. Prominent Kupffer cell and councilman bodies were seen with no increased iron stores.

II. Etiology

The terminology for acute and chronic viral hepatitis can be

confusing, because the same word, hepatitis, can be used for
several things; careful attention to context can clarify its meaning
in any situation. First, “hepatitis” is the name of each of the
hepatotropic viruses (hepatitis A, B, C, D, and E) that have a
specific affinity for the liver. Second, “hepatitis” stands for the
histologic patterns of hepatitic injury, both acute and chronic
(depending on the specific virus), that are seen in the livers infected
by hepatotropic viruses usually systemic viruses, such as (1) mild
Epstein-Barr virus hepatitis sometimes seen in infectious mononucleosis; (2) cytomegalovirus, herpes virus, and adenovirus
infections, particularly in the newborn or immunosuppressed patient; and (3) yellow fever (yellow fever virus), a major and
serious cause of hepatitis in tropical countries.
III. Pathogenesis

Hepatitis A Virus
Hepatitis A virus (HAV) is a usually benign, self-limited disease with an incubation period of 2 to 6 weeks. HAV
does not cause chronic hepatitis or a carrier state and only uncommonly causes acute hepatic failure, so the fatality rate
associated with HAV is only about 0.1-0.3%.

The pathogenic process of HAV can be

described in terms of the following model based
on our current understanding of the disease.
Once HAV reaches the liver, it replicates in
hepatocytes (A), blocking the production of
IFNβ and other intracellular antiviral systems
that are activated by dsRNA replication
intermediates. The virus is shed in the feces and
reaches the blood, inducing viremia (B). The
binding of HAV to HAVCR1 blocks T cell
receptor activation and causes a transitory block
of Treg function, which limits de novo HAV
immune responses while allowing the
activation of preexisting responses that are no
longer controlled by Tregs [12] (C). This
transitory shutoff of Treg function allows the
activation of antiself and preexisting responses
that overwhelm the immune system, inducing a
“shock and awe” effect that limits anti-HAV de
novo responses. Indeed, HAV disrupts the Figure 1. Model of the pathogenic process of HAV. Schematic representation of the cycle of
homeostasis of the immune system, and patients immune events leading to a typical course of HAV infection
with acute hepatitis A exhibit a transitory
elevation of autoantibodies and the production of high levels of nonspecific IgM antibodies.

The primate models of hepatitis A have contributed significantly to our understanding of the natural history and
pathogenesis of HAV. The pathogenic determinants of HAV vary in the different primate models.

Hepatitis B Virus
Hepatitis B virus (HBV) can produce (1) acute
hepatitis followed by recovery and clearance of the virus, (2)
5.1
nonprogressive chronic hepatitis, (3) progressive chronic 6 5.2
disease ending in cirrhosis, (4) acute hepatic failure with
4 7
massive liver necrosis, and (5) an asymptomatic, “healthy” 10
carrier state. HBV-induced chronic liver disease is also an 3
9
important precursor for the development of hepatocellular
carcinoma even in the absence of cirrhosis. 8
2
Entry of the (1) HBV virion from the extracellular
space into susceptible cells is a poorly defined process that is
presumably receptor-mediated and leads to uncoating and 11
transport of the capsid to the nucleus. Following (2) capsid 1
disassembly, the second strand of the open circular viral
genome is completed, and the ends of each strand are ligated. Figure 2. Hepatitis B virus (HBV) life cycle
This leads to the production of a (3) covalently closed circular
DNA (cccDNA) molecule, which is the transcriptional template of the virus.
Pol II-driven transcription results in (4) production of the viral RNAs that are transported out of the nucleus. Once
in the cytoplasm, the transcripts are translated into the corresponding proteins as shown. The (5.1) precore protein contains
a leader sequence that transports it into the endoplasmic reticulum (ER) where it is further processed and eventually secreted
as (5.2) HBeAg (as shown).
 The (6) X protein is a transcription factor that does not enter the nucleus; rather it interacts with cellular
transcription factors in the cytoplasm that enter the nucleus and activate HBV promoter activity. The (7) envelope proteins
(Env) traverse the ER membrane as integral membrane proteins (as shown). The core and polymerase proteins assemble
around the pregenomic RNA (pRNA) to form (8) HBV RNA-containing capsids, within which the RNA is reverse
transcribed to produce the first (9) single-strand viral DNA (ssDNA, as shown). ssDNA serves as the template for second-
strand DNA synthesis, thereby producing capsids containing a partially double-stranded, (10) relaxed circular DNA
molecule (rcDNA, as shown).

Although the RNA-containing capsid is maturing into a DNA-containing capsid, it migrates bidirectionally within
the cytoplasm. One pathway terminates at the ER membrane where it interacts with the envelope proteins that trigger an
internal budding reaction. This reaction results in the formation of (11) virions that are transported out of the cell by the
default secretory pathway. The second pathway (2) transports the maturing capsid to the nucleus to amplify the pool of
cccDNA.

Hepatitis C Virus
Hepatitis C Virus (HCV) is a major cause of liver disease
worldwide, with approximately 170 million people affected.
According to data from the USA Centers for Disease Control, the
most common risk factors for HCV infection are:

• Intravenous drug abuse (54%)

• Multiple sex partners (36%)
• Having had surgery within the last 6 month (16%)
• Needle stick injury (10%)
• Multiple contacts with an HCV-infected person (10%)
• Employment in medical or dental fields (1.5%)
• Unknown (32%)

Like hepatitis B virus (HBV), entry of the HCV virion

from the extracellular space into susceptible cells is a poorly
defined process that is presumably receptor-mediated and possibly
involves CD81 and SRB-1. Similar to other flaviviruses, it is
thought that following receptor binding (1) and receptor-
mediated endocytosis (2), HCV is released into the cytoplasm
(3) where uncoating of the virion (4) can occur. This is followed
by internal ribosomal entry site (IRES)-mediated translation (5)
and polyprotein processing, and RNA replication (6) in a specific
membrane alteration, the membranous web. Packaging and
assembly of new virions (7) occurs within intracellular vesicles,
where maturation (8) precedes vesicle fusion at the plasma
membrane and virion release (9).

Hepatitis D Virus
Also called “the delta agent,” hepatitis D virus (HDV) is a unique RNA virus that is dependent for its life cycle on
HBV. Infection with HDV arises in the following settings.

• Co-infection occurs following exposure to serum containing both HDV and HBV. The HBV must become
established first to provide the HBsAg necessary for development of complete HDV virions. Co-infection of
HBV and HDV results in acute hepatitis that is indistinguishable from acute hepatitis B. It is self -limited and
is usually followed by clearance of both viruses. However, there is a higher rate of acute hepatic failure, in
intravenous drug users.
• Superinfection occurs when a chronic carrier of HBV is exposed to a new inoculum of HDV. This results in
disease 30 to 50 days later presenting either as severe acute hepatitis in a previously unrecognized HBV carrier
or as an exacerbation of preexisting chronic hepatitis B infection. Chronic HDV infection occurs in almost all
of such patients. The superinfection may have two phases: an acute phase with active HDV replication and
 suppression of HBV with high transaminase levels, and a chronic phase in which HDV replication decreases,
HBV replication increases, transferase levels fluctuate, and the disease progresses to cirrhosis and sometimes
hepatocellular carcinoma.

Hepatitis E Virus
Hepatitis E virus (HEV) is an enterically transmitted, water-borne infection that occurs primarily in young to
middle-aged adults. HEV is a zoonotic disease with animal reservoirs, such as monkeys, cats, pigs, and dogs.

The pathogenesis of hepatitis E is poorly understood. Since HEV is presumably transmitted by the fecal-oral route,
it is unclear how the virus reaches the liver. Perhaps there is an extra-hepatic site of virus replication. The virus could
replicate in the intestinal tract before reaching the liver. Negative strands of HEV RNA, indicating virus replication, have
been detected in the small intestine, lymph nodes, colon, and liver of pigs, indicating extra-hepatic HEV replication. HEV
then replicates in the cytoplasm of hepatocytes and is released into both blood and bile. The liver damage induced by HEV
infection may be immune-mediated by cytotoxic T cells and natural killer (NK) cells since HEV is not cytopathic. The virus
is shed in the stool.

IV. Morphological changes

The morphologic changes in acute and chronic viral hepatitis are shared among the hepatotropic viruses and can be
mimicked by drug reactions or autoimmune hepatitis.

Acute viral hepatitis

On gross inspection, livers involved by mild acute hepatitis appear normal

or slightly mottled. At the other end of the spectrum, in massive hepatic
necrosis the liver may shrink greatly as described earlier under acute liver
failure (Fig. 18-6).

Microscopically, both acute and chronic hepatitis evoke a

lymphoplasmacytic (mononuclear) infiltrate. Portal inflammation in acute
hepatitis is minimal or absent. Most parenchymal injury is scattered
throughout the hepatic lobule as “spotty necrosis” or lobular
hepatitis.

In the former, the cytoplasm appears empty with only scattered wisps of
cytoplasmic remnants. Eventually there is rupture of cell membranes Figure 3. Chronic viral hepatitis due to HCV showing
characteristic portal tract expansion by a lymphoid follicle
leading to “dropout” of hepatocytes, leaving collapsed sinusoidal collagen
reticulin framework behind; scavenger macrophages mark sites of dropout.

With apoptosis, hepatocytes shrink, becoming intensely eosinophilic, and

their nuclei become pyknotic and fragmented; effector T cells may be
present in the immediate vicinity.
There is considerable morphologic overlap in acute hepatitis caused by
various hepatotropic viruses. However, subtle differences may be seen, for
example the mononuclear infiltrate in hepatitis A may be especially rich in
plasma cells.

Chronic viral hepatitis

The defining histologic feature of chronic viral hepatitis is

mononuclear portal infiltration. It may be mild to severe and variable from
one portal tract to the next. There is often interface hepatitis as well, in
addition to lobular hepatitis, distinguished by its location at the interface
between hepatocellular parenchyma and portal tract stroma. The hallmark Figure 4. Acute hepatitis B. clusters of macrophages
of progressive chronic liver damage is scarring. At first, only portal tracts with eosinophilic cytoplasm indicate foci where
exhibit fibrosis, but in some patients, with time, fibrous septa—bands of dense hepatocytes have undergone necrosis
scar— extend between portal tracts. In parallel with increasing
scarring there is also increasing ductular reaction, reflecting
stem cell activation. In the most severe cases, continued
scarring and nodule formation leads to the development of
cirrhosis.

A somewhat greater range of histologic features

distinguish one viral infection from another in chronic
hepatitis. In chronic hepatitis B, “ground-glass” hepatocytes—
cells with endoplasmic reticulum swollen by HBsAg—is a
diagnostic hallmark. Immunostaining can confirm the
presence of viral antigen such as depicted in Figure 4.

Chronic hepatitis C quite commonly shows lymphoid

aggregates or fully formed lymphoid follicles. Often, hepatitis Figure 5. Ground-glass hepatocytes in chronic hepatitis B infection caused by
accumulation of hepatitis B surface antigen
C, particularly genotype 3, shows fatty change of scattered
hepatocytes, although the infection may also cause systemic alterations leading to metabolic syndrome and, therefore, a
superimposed non-alcoholic fatty liver disease in the liver. Bile duct injury is also prominent in some individuals with
hepatitis C infection, potentially mimicking primary biliary cirrhosis; clinical parameters distinguish these two diseases
easily, however.

V. Functional Derangement and Clinical Manifestations

Hepatitis A
Because of its unique features within the
Picornaviridae family, HAV has been classified in a separate
Hepatovirus genus. HAV is the only species of Hepatovirus
and exists in only one serotype, with three genotypes that
circulate in humans (I–III).

Figure depicted on the right shows the Natural history

of HAV in humans. Schematic representation of biomarkers
from patients with a normal course of acute HAV infection.
HAV reaches peak viremia and is shed in stools during the
incubation period and prodromal phase. Bystander and HAV-
specific CD8+ T cells are activated at different times post
infection. Alanine aminotransferase (ALT) elevation in blood
indicates hepatocellular injury. Interleukins IL22 and TGFβ
(histograms) are produced at different times post infection.
Anti-HAV IgM and IgG antibodies appear in the blood.

Hepatitis B

The natural course of the disease can be followed by serum markers

• HBsAg appears before the onset of symptoms, peaks during overt disease, and then often declines to
undetectable levels in 12 weeks, although it may persist in some individuals for as long as 24 weeks.
• Anti-HBs antibody does not rise until the acute disease is over, concomitant with the disappearance of HBsAg
In some cases, however, Anti-HBs antibody is not detectable for a few weeks to several months after the
disappearance of HBsAg. During this window period, serologic diagnosis can be made by detection of IgM
anti-HBc antibody (see below and Fig. 18-12). Anti- HBs may persist for life, conferring protection; this is the
basis for current vaccination strategies using noninfectious HBsAg.
• HBeAg, HBV-DNA, and DNA polymerase appear in serum soon after HBsAg, and all signify active viral
replication. Persistence of HBeAg is an important indicator of continued viral replication, infectivity, and
probable progression to chronic hepatitis. The appearance of anti-HBe antibodies implies that an acute infection
has peaked and is on the wane.
• IgM anti-HBc antibody becomes detectable in serum shortly before the onset of symptoms, concurrent with
 • the onset of elevated serum aminotransferase levels (indicative of hepatocyte destruction). Over a period of
months the IgM anti-HBc antibody is replaced by IgG anti-HBc. As in the case of anti-HAV, there is no direct
assay for IgG anti-HBc; its presence is inferred from decline of IgM anti-HBc in the face of rising total anti-
HBc.

Hepatitis C

Persistent infection and chronic hepatitis are the hallmarks of HCV infection, despite the generally asymptomatic
nature of the acute illness. In more than 90% of individuals with chronic HCV infection, circulating HCV RNA persists
despite the presence of antibodies. A clinical feature that is quite characteristic of chronic HCV infection is persistent
elevations in serum aminotransferases. Their levels wax and wane but almost never become normal. Even rare patients with
normal transaminases are at risk for developing permanent liver damage. Therefore, any individual with detectable HCV
RNA in the serum needs close clinical follow-up. A feature unique to hepatitis C infection is the association with the
metabolic syndrome, in particular with HCV genotype 3. Apparently, HCV can give rise to insulin resistance and non
alcoholic fatty liver disease.
Hepatitis D

HDV RNA is detectable in the blood and liver jus before and in the early days of acute symptomatic disease. IgM
anti-HDV antibody is the most reliable indicator of recent HDV exposure, although its appearance is late and frequently
short-lived. Nevertheless, acute co-infection by HDV and HBV is best indicated by detection of IgM against both HDAg
and HBcAg (denoting new infection with hepatitis B). With chronic delta hepatitis arising from HDV superinfection,
HBsAg is present in serum, and anti-HDV antibodies (IgG and IgM) persist for months or longer. Vaccination for HBV
also prevents HDV infection.

Hepatitis E

A characteristic feature of HEV infection is the high mortality rate among pregnant women, approaching 20%. In
most cases the disease is self-limiting; HEV is not associated with chronic liver disease or persistent viremia in
immunocompetent patients. Chronic HEV infection does occur in patients with AIDS and immunosuppressed transplant
patients. The average incubation period following exposure is 4 to 5 weeks.

Before the onset of clinical illness, HEV RNA and HEV virions can be detected by PCR in stool and serum. The
onset of rising serum aminotransferases, clinical illness, and elevated IgM anti-HEV titers are virtually simultaneous.
Symptoms resolve in 2 to 4 weeks, during which time the IgM is replaced with a persistent IgG anti-HEV antibodies.

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