Viral Hepatitis

Chapter
2 VIRAL HEPATITIS
MAJOR HEPATOTROPIC VIRUSES: SYSTEMIC VIRAL INFECTIONS WITH RARE SYSTEMIC VIRAL INFECTIONS
A, B, δ, C, E, G, “NON-A THROUGH HEPATIC INVOLVEMENT 39 WITH HEPATIC INVOLVEMENT 47
NON-G” 16 Epstein-Barr Virus 39 Lassa Fever 47
Acute Viral Hepatitis 16 Cytomegalovirus 41 Yellow Fever 48
Chronic Viral Hepatitis 27 Herpes Simplex Virus 43 Echovirus (Enterovirus) 49
Human Immunodeficiency Virus OTHER VIRUSES THAT MAY CAUSE
and Acquired Immunodeficiency LIVER DAMAGE 50
Syndrome 45
MAJOR HEPATOTROPIC VIRUSES: A, B, δ, C, E, G, or interface hepatitis (“piecemeal necrosis”) is not a

“NON-A THROUGH NON-G” manifestation.
6. The portal and lobular lymphocytes, usually T cells, can
Acute Viral Hepatitis sometimes be seen attached to endothelial cells of portal
and terminal hepatic venules.
Typical Form (Spotty Necrosis) 7. Portal tracts may also exhibit variable degrees of infiltra-
tion by plasma cells, macrophages, and rarely eosinophils.
(Figs 2-1 through 2-13) 8. Although the portal inflammation commonly involves
all of the portal tracts, at times there may be some varia-
Major morphologic features tion in the degree of inflammation from one portal tract
1. All portal tracts exhibit a moderate to marked predomi- to another.
nantly lymphocytic infiltrate. 9. Bile duct and cholangiolar proliferation can be present
2. Focal necrosis and apoptosis occur in all zones of all but is generally mild.
lobules, with associated hepatocytolysis and hydropic 10. Cytologic injury to interlobular bile ducts can occur at
ballooning changes (lytic necrosis) of the liver cells. In times but is not prominent (the exception being acute
early-stage disease, these changes are more prominent in hepatitis C virus (HCV) infection; see discussion later
the perivenular zone (zone 3 of Rappaport). in this chapter).
3. Variable but often prominent lymphocytic inflammatory 11. With resolution:
infiltrates are seen within the lobules. a. Residual spotty clusters of pigment-laded (ceroid-
4. Phagocytosis of damaged liver cells by macrophages and laden) macrophages may be seen (tombstone lesions
Kupffer cells is present. that are periodic acid-Schiff (PAS)-positive after dia-
stase digestion [DiPAS]).
Other features b. Hydropic regenerative activity of liver cells occurs,
1. The basic lobular architectural pattern (portal tracts– with slight thickening of the liver cell plates (best
terminal hepatic venules–portal tracts) is maintained, appreciated on the reticulin stain) and increased
although in more severe cases there may also be peri- mitotic activity of hepatocytes. Note that in the
venular liver cell dropout and focal perivenular collapse elderly patient population there may be some degree
of the reticulin framework (confluent necrosis; refer to of impairment in liver cell regeneration; this is associ-
discussion under “Fulminant Hepatitis”). ated with a poorer prognosis.
2. Apoptotic cells (Councilman bodies, acidophil bodies) c. Eventually (months later) mild, nonspecific portal
frequently occur in all zones and consist of hepatocytes and lobular inflammatory changes can occur; these
with shrunken eosinophilic cytoplasm and small pyk- usually resolve by 1 year.
notic nuclei; these cells are seen either within the trabec- 12. All types of acute hepatitis secondary to the hepato-
ulae or phagocytized by Kupffer cells after extrusion into tropic viruses (A, B, δ, C, E, G, and “non-A through
the perisinusoidal space. Usually the late-stage apoptotic non-G”) basically exhibit similar morphologic features,
cells are devoid of nuclei. as described previously; however, the individual sub-
3. Cholestasis may be present, often with perivenular (zone types may also show the following:
3) accentuation. a. Hepatitis A virus (HAV)
4. Kupffer cell hyperplasia is present and is often prominent. i. Portal plasma cells may at times be prominent.
5. Although spillover of lymphocytes from portal tracts ii. Inflammation and necrosis may be more promi-
into the adjacent periportal zones is seen, true periportal nent in the periportal than in the perivenular zones.
16
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Chapter 2 / Viral Hepatitis 17
A B
Figure 2-1 Acute viral hepatitis. A and B. These two images from the same biopsy demonstrate prominent portal lymphocytic infiltrates with
some degree of “spillover” of the inflammatory cells into the adjacent periportal zone without true periportal interface inflammatory activity
(“piecemeal” necrosis). Interlobular bile ducts are normal in number with occasional cholangioles present.
Figure 2-2 Acute viral hepatitis. The parenchyma shows variable Figure 2-3 Acute viral hepatitis. Medium power shows mild
hydropic change of hepatocytes and diffuse necroinflammatory hydropic change, spotty liver cell necrosis, and Kupffer cell hyper-
change, the inflammatory cells chiefly lymphocytes. Kupffer cell plasia. A mild lymphocytosis can also be seen within the sinusoids.
hyperplasia is present.
iii. P
erivenular cholestasis may be striking in com- d. HCV
parison with only mild lobular inflammation, i. Portal lymphocytic infiltrates often show lym-
mimicking a drug-induced cholestatic hepa- phoid aggregate and follicle formation, occasion-
titis versus other causes of cholestasis such as ally with germinal centers.
benign recurrent intrahepatic cholestasis (refer ii. Interlobular bile ducts may be noted within the
to further discussion of this liver disorder in centers of these lymphoid aggregates, with lym-
Chapter 8). phocytes occasionally infiltrating beneath the duct
b. Hepatitis B virus (HBV) basement membrane, associated with cytologic
i. Lymphocytic lobular inflammation may show damage of the duct epithelium (epithelial hyper-
close contact with injured hepatocytes, with lym- plasia, vacuolization, nuclear irregularity).
phocytes occasionally identified within the cell cy- iii. Although rare, granulomatous-type necrosis can
toplasm (emperipolesis). be seen within the lobules, without true epithelioid
c. HBV and δ granuloma formation.
i. The degree of inflammation and necrosis is of- iv. A sinusoidal lymphocytosis may also be present.
ten more prominent than in acute HBV infection Note: The first two described features may be a sign of
alone. In approximately 1⁄3 of cases, a fulminant impending progression to chronicity.
hepatitis with confluent necrosis may occur. e. Hepatitis E virus (HEV)
ii. Microvesicular fatty change within liver cells has i. Cholangiolar (ductular) proliferation may be seen,
been described. sometimes associated with bile plugs within the
18 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
A
Figure 2-4 Acute viral hepatitis. Moderate necroinflammatory
change, the inflammatory cells chiefly lymphocytes, is seen in
the perivenular zone on high power. The liver cells show variable
hydropic change, making it difficult to visualize the hepatic sinusoi-
dal network.
B
Figure 2-6 Acute viral hepatitis, apoptosis. A, Diffuse necroinflam-
matory changes are seen, with spotty necrosis and hypertrophic
Kupffer cells. Toward the left of the field, occasional hepatocytes
show a more intense eosinophilic cytoplasm with smaller pyknotic
nuclei (apoptosis). A similar but smaller cell with a flattened degen-
erating nucleus is seen in the bottom right. B, Higher power shows
an apoptotic cell with small nuclear remnants and intensely eosino-
Figure 2-5 Acute viral hepatitis. This field demonstrates spotty philic cytoplasm. This cell has been extruded from the hepatic cord
necrosis with phagocytosis of the necrotic liver cells by the hypertro- and is now being phagocytized within a plump Kupffer cell.
phic Kupffer cells. The small eosinophilic cytoplasmic droplets seen
in the center of the field represent increase in lysosomal activity g. Other types (non-A through non-G)
within the Kupffer cells. A prominent lymphocytic infiltrate is also i. Giant cell transformation of hepatocytes has been
seen within the sinusoids and hepatic cords.
described.
ii. In some cases, paramyxovirus has been identified
dilated cholangioles that also may be surrounded within the cytoplasm by electron microscopy.
and focally infiltrated by neutrophils. iii. V iruses such as transfusion-transmitted virus
ii. Acinar changes (dilated canaliculi) often containing (TTV) and SEN virus (SEN-V), both single-
bile can sometimes be appreciated within the lobules. stranded circular DNA viruses, are postulated to
iii. The degree of lobular inflammation is generally play some part in inducing or enhancing acute
mild; however, infrequently a severe necroinflam- hepatitis in certain patient populations; however,
matory process can occur, with inflammation of there is no convincing evidence to date that these
the portal and terminal hepatic venules reported. viruses play any significant or primary role.
f. Hepatitis G virus (HGV)
i. In general, the portal and lobular inflammation Special stains
and the lobular necrosis are milder than what is 1. PAS after diastase digestion (DiPAS): Cytoplasmic intra-
seen with the other hepatotropic viruses. lysosomal granules in macrophages and Kupffer cells are
ii. There is some question whether acute HGV infec- prominent in areas of necrosis and in portal macrophages.
tion does, in fact, cause a histologically apparent 2. Reticulin: Condensation of reticulin fibers may be seen in
acute hepatitis, with many believing it is more a the perivenular zones secondary to liver cell necrosis and
passenger virus. dropout in the more severe cases.
Figure 2-7 Acute viral hepatitis. Cholestasis is seen within a dilated Figure 2-9 Acute viral hepatitis: hepatitis B virus (HBV) + δ. The
canaliculus in the center of the field. necroinflammatory change is prominent, with perivenular confluent
necrosis and liver cell dropout evident in the center of the field.
Figure 2-8 Acute viral hepatitis: hepatitis A virus (HAV). The portal Figure 2-10 Acute viral hepatitis, severe (reticulin). The perivenu-
tract shows numerous plasma cells, a feature sometimes prominent lar (zone 3) confluent necrosis that can be seen in severe cases of
with acute HAV infection. acute viral hepatitis is associated with liver cell necrosis, dropout,
and collapse of the reticulin framework, this latter feature high-
3. Perl’s iron: Hemosiderin may be seen in macrophages and lighted with this reticulin stain. When this morphologic feature is
striking, patients usually present with fulminant hepatitis.
Kupffer cells in areas of necrosis.
Immunohistochemistry both a portal and lobular inflammatory reaction may be

1. Hepatitis B surface antigen (HBsAg), hepatitis B core anti- similar to those seen in acute viral hepatitis; however, in
gen (HBcAg): Surface and core antigen staining in acute some instances the degree of portal lymphocytic infiltrates
viral hepatitis type B is always negative. Positive staining may be less prominent than in classic acute viral hepa-
for either antigen in biopsies exhibiting changes of acute titis. In addition, scattered admixed eosinophils within
hepatitis is indicative of either (1) a replicative (active) the portal tracts often favor drug-induced injury. Finally,
phase of early chronic hepatitis B, where the portal fibro- with some exceptions (e.g., the cholestatic phase of acute
sis is minimal and easily missed, or (2) an acute non-B viral hepatitis types A and E), the degree of intralobular
or drug-induced hepatitis in a patient with underlying cholestasis in drug-induced cholestatic hepatitis usually
early-stage chronic hepatitis type B. outweighs the degree of portal and lobular inflammation.
2. Delta antigen: In acute hepatitis B with acute δ infec- 2. Early stages of chronic viral hepatitis: Both early and rela-
tion, liver cell nuclei exhibit variable and often prominent tively active stages of chronic viral liver disease may resem-
degrees of positive staining. ble the morphologic features seen in acute viral hepatitis,
especially in small biopsies with few portal tracts or with
Differential diagnosis only segments of portal areas for evaluation. For hepatitis
1. Drug-induced liver cell injury (e.g., isoniazid, rifampin; type B, the presence of stainable HBV antigens (HBsAg,
refer to Table 5-4): The morphologic features secondary HBcAg) by immunohistochemical techniques in the
to hepatotoxicity by certain drugs and toxins that elicit cytoplasm and nucleus, respectively, is a useful tool in the
diagnosis of early chronic HBV infection. Similarly, the 4. Epstein-Barr virus (EBV), cytomegalovirus (CMV) hepa-
presence of HBsAg and anti-HBc immunoglobulin G titis: Both of these viruses may produce acute hepatitis
(IgG) in the absence of anti-HBc IgM in serum samples (refer to “Epstein-Barr Virus” and “Cytomegalovirus”
also points to chronic hepatitis type B. Of note is that later in this chapter), with portal lymphocytic infiltrates
the presence of distinct portal lymphoid aggregates and and diffuse lobular necroinflammatory changes. The dif-
follicles in acute viral hepatitis type C is believed to be ferences from acute viral hepatitis are as follows:
an indicator that the disease will most likely progress to a. EBV and CMV tend to cause less individual liver
chronicity. cell damage, without the characteristic ballooning
3. Early stages of autoimmune hepatitis: The degree of por- hydropic changes and apoptosis seen in typical acute
tal and lobular inflammation in the early stages of auto- viral hepatitis.
immune hepatitis may resemble that seen in acute viral b. The degree of necroinflammatory changes and eleva-
hepatitis; however, the portal and lobular plasma cell tions of the serum aminotransferases (seldom greater
component and the presence of definite periportal inter- than 500 IU/L) are considerably less in acute EBV and
face inflammatory activity are signs suggesting an autoim- CMV infections than in typical acute viral hepatitis.
mune process. In addition, most of the time, some degree c. Sinusoidal lymphocytosis, although sometimes a fea-
of portal fibrosis may also be present in early autoimmune ture present in acute viral hepatitis (particularly HCV),
liver disease. This feature is best highlighted on trichrome is usually quite prominent in EBV and CMV infection,
and Sirius red stains for collagen. with the lymphocytes frequently enlarged and atypical.
Figure 2-11 Acute viral hepatitis: hepatitis E virus (HEV). The por- Figure 2-13 Acute viral hepatitis, non-A through non-G. Syncytial
tal tract exhibits a mild lymphocytic infiltrate. Prominent ductular giant cell transformation is seen in a biopsy from an adult who clini-
(cholangiolar) proliferation and ectasia are present, and many of the cally presented with signs and symptoms of an acute hepatitis. The
ductules contain bile plugs. diagnosis rests on the exclusion of other causes of acute hepatitis.
A B
Figure 2-12 Acute viral hepatitis: hepatitis E virus (HEV). A, The parenchyma shows a mild lymphocytic infiltrate with Kupffer cell hyperpla-
sia. Cholestasis is prominent, the hepatocytes often arranged in rosettes around the bile within the dilated biliary canaliculi. B, The canaliculi
are markedly dilated and contain prominent bile plugs. In contrast to the parenchymal changes seen in the preceding figure, the hepatocytes
are hydropic without liver cell necrosis or lobular inflammation.
d. CMV often causes a granulomatous type of necrosis. from 1000 to 10,000 IU/L. The alkaline phosphatase is
The granulomas sometimes contain true epithelioid usually mildly elevated. Mild leukopenia and thrombo-
histiocytes, a feature not seen in typical acute viral hep- cytopenia are also common.
atitis. Although acute HCV infection may rarely cause 4. Children usually tend to be anicteric and asymptomatic,
some degree of “granulomatous” necrosis, true epithe- and adults, especially elderly individuals, may develop a
lioid cells are not present. more severe course.
e. In the immunocompromised patient (e.g., status post- 5. Although serum transaminases are lower in anicteric
chemotherapy or liver transplantation), the presence of and asymptomatic forms of acute hepatitis, the degree of
CMV nuclear and cytoplasmic inclusions in liver cells, transaminase elevations does not correlate with outcome
Kupffer cells, and/or duct epithelium is a useful marker or prognosis.
for CMV infection. 6. A cholestatic phase may follow acute hepatitis due to
f. A positive Epstein-Barr-encoded RNA (EBER)-1 HAV and HEV infection and is characterized by jaun-
DNA probe and demonstration of specific EBV- dice and pruritus. Pruritus is sometimes intractable and
specific proteins (Epstein-Barr nuclear-associated may last for weeks or months.
antigens) are useful markers for EBV infection in cer- 7. In acute hepatitis due to HAV, relapses may occur 30
tain settings. to 60 days after the initial illness and mimic a biphasic
5. Wilson disease: Wilson disease, an autosomal recessive hepatic disorder.
inherited disorder associated with increased hepatic cop- 8. The absence of gastrointestinal symptoms, improve-
per deposition (see Chapter 9), may present in the early ment in prothrombin time, and improved overall sense
stages with an acute hepatitis picture similar to that seen of well-being indicate recovery.
in acute viral hepatitis. Confluent necrosis may be seen 9. Chronic hepatitis generally occurs less frequently fol-
as well. The presence of Mallory bodies, glycogenated lowing acute symptomatic (icteric) hepatitis.
nuclei, increased hepatic copper (rubeanic acid and rho- 10. The hepatitis D virus (HDV, δ) requires the HBV virus
danine stains on liver biopsy, copper quantification on for both acute and chronic infection. Patients with acute
liver tissue), as well as low serum ceruloplasmin levels and HDV infection may present in two ways:
increased urinary copper excretion are helpful indicators a. In acute HBV and HDV coinfection, resolution of
pointing toward a diagnosis of Wilson disease. acute hepatitis B is followed by a second biphasic epi-
sode of hepatitis. This is due to suppression of HDV
Clinical and biologic behavior during the initial HBV infection.
(Tables 2-1 and 2-2) b. In acute HDV superinfection of chronic HBV infec-
1. Acute viral hepatitis may present clinically with jaun- tion, the ensuing hepatitis usually has a severe chronic
dice, but frequently it is not associated with hyperbiliru- accelerated course.
binemia (anicteric hepatitis). 11. The type of preexisting HBV infection may be impor-
2. Prodromal signs may include low-grade fever, arthral- tant in determining the outcome of HDV superinfec-
gias and myalgias, and anorexia. tion. Active HBV viral replication (hepatitis B e antigen
3. Significant elevations of serum transaminases occur, are [HBeAg] positive, HBV DNA positive) appears more
usually greater than 500 IU/L, and may at times range likely to be associated with a severe acute illness,
Table 2-1 Clinical and Biologic Behavior of Hepatotropic Viruses

HEPATITIS A VIRUS HEPATITIS B VIRUS HEPATITIS C HEPATITIS D VIRUS HEPATITIS E HEPATITIS G
(HAV) (HBV) VIRUS (HCV) (HDV) VIRUS (HEV) VIRUS (HGV)
Virus Type RNA picornavirus DNA hepadnavirus RNA flavivirus Defective RNA RNA calcivirus RNA flavivirus
satellite
Genome 7.5 kb 3.2 kb 9.4 kb 1.7 kb 7.6 kb 8.6 kb
Linear, ss Circular, ss/ds Linear, ss Circular, ss Linear, ss Linear, ss
Size 27 nm 42 nm 40–60 nm 34–37 nm 35–39 nm 50–100 nm
Dane particle Associated with
HBsAg
Incubation 15–45 30–150 15–160 30–180 14–60 20–140
Period (Days)
Transmission Fecal-oral* Parenteral Parenteral Parenteral Fecal-oral Parenteral
Sexual (Sexual, Sexual (Sexual,
Perinatal perinatal) (Perinatal) perinatal)
Chronicity None <2% adults 65%–85% <1% acute None High†
>90% newborns 90% with chronic
HBV
Fulminant <1% <1% Very rare 5%–30% acute δ <1%‡ None
Course with acute HBV
ds, Double stranded; ss, single stranded.
*Parenteral drug addicts have been reported to develop acute HAV, presumably from contamination of heroin, black tar heroin, amphetamines, and cocaine.
†Although the serologic marker is often positive, there is no convincing evidence that HGV alone causes acute or chronic hepatitis; 10% to 15% of patients with chronic HCV
have HGV in the serum.

‡During epidemics, mortality of pregnant women infected is 10% to 20% in certain countries only.
presumably related to high viral levels. The propensity meaning chronic infection develops in about 65%
to develop chronic HDV infection is more likely in cases to 70% of patients. Fulminant hepatitis almost never
of low-level replication (anti-HBe positive, HBV DNA occurs. Patients in whom the virus clears have strong
<105 copies/ml). virus-specific CD4+ T-cell reactivity within the first
12. Symptomatic hepatitis occurs in only about 15% of few weeks of infection. Because HCV antibody lev-
patients with acute HCV, which is usually diagnosed els are seen 12 weeks after infection, early diagnosis
in the setting of postexposure surveillance or sero- requires testing for HCV RNA by polymerase chain
conversion in high-risk populations (e.g., health care reaction (PCR).
providers, injection drug users). Elevations in serum 13. The hepatotropic viruses HBV, HCV, and HDV cause
transaminases in acute HCV can be as high as 10 times both an acute and chronic hepatitis and are discussed
the upper limit of normal. Jaundice is rare; however, in more detail in this chapter under “Chronic Viral
there is a higher likelihood of clearance of the hepa- Hepatitis”; however, the enteric hepatic viruses HAV
titis virus in symptomatic jaundiced patients. Overall, and HEV are associated with only acute infection (rare
the infection clears in about 30% to 35% of patients, examples of HEV chronicity).
Table 2-2 Serologic Diagnoses of Acute and Chronic Viral Hepatitis

TYPE A HEPATITIS (HAV)
Acute • HAV Ab IgM positive (HAV Ab IgG positive)
Immunity • HAV Ab IgG positive
TYPE C HEPATITIS*
Acute • HCV Ab positive in 80% of patients within 15 weeks of exposure; ≥97% of patients within 6 months of exposure
• HCV RNA positive within 2 weeks of exposure
Chronic • HCV Ab positive in >95% of cases (may be negative in immunosuppressed patients and those with chronic renal
failure on dialysis)
• HCV RNA positive
TYPE E HEPATITIS (HEV)
Acute • HEV Ab IgM positive (HEV Ab IgG positive)
• HEV RNA positive
Past exposure** • HEV Ab IgG positive
TYPE G HEPATITIS (HGV)
Acute and chronic • HGV RNA positive
• HGV Ab E2 positive
TYPE B HEPATITIS (HBV)
CLINICAL STATE HBsAg ANTI-HBc IgM ANTI-HBc IgG HBV DNA ANTI-HBs HBeAg ANTI-HBe
Acute + + +a − +b +c +d
Chronic (low replicative) + − + −e − − +
Chronic (high replicative) + − + +f − + −
Reactivation + + + ++ − + −
Previous infection with − − + − ++b − −
resolution
Immunization − − − − ++ − −
Precore mutantg + − + ++ − − +
TYPE B (HBV) PLUS D (δ) HEPATITIS
CLINICAL STATE HBsAg ANTI-HBc IgM HBV DNA HBeAg ANTI-HBe ANTI-δ IgM ANTI-δ IgG
Acute¶ + + − +† +‡ ++ +
Chronic + − −§ − + + ++
*In patients who are HCV Ab positive but HCV RNA negative, the HCV RIBA (recombinant immunoblot assay) test is useful in distinguishing between past infection with
clearance (when HCV RIBA is positive) or false-positive anti-HCV (when HCV RIBA is negative). The HCV RIBA assays antibodies toward several HCV peptide antigens:
5-1-1, C100, C33c, C22, NS5, and HSOD. The test is considered indeterminate or negative if two or less antigens are positive.
**Epidemics of acute HEV are known to occur in endemic areas and involve those previously infected with HEV, suggesting that past exposure may not provide an entirely
protective role.
aHBcAb is positive in all HBV infections and reflects prior exposure and not immunity; absent with immunization.
bHBsAb is positive at recovery from acute HBV infection after clearance of HBV and denotes immunity (titers >100 IU).
cHBeAg is positive in early acute infection and becomes negative when HBV is cleared.
dHBeAb becomes positive when HBV is cleared during active infection.
eHBV DNA <105 copies/ml; HBV DNA is never negative in chronic infections and can be detected using sensitive polymerase chain reaction (PCR) techniques.
fHBV DNA >105 copies/ml.
gAlso includes the core promoter mutation. The most common precore mutation, G
1896A, creates a premature stop codon in the precore region. The most common core
promotor mutation, A1762T and G1764A, decreases transcription of the core messenger RNA and production of HBeAg.
¶Hepatitis D antigen may be detected by HDV RNA polymerase chain reaction (PCR) transiently during the acute (coinfection or superinfection) phase and is positive in
chronic infection.
†HBeAg is positive in early acute infection and eventually becomes negative when HBV is cleared.
‡HBeAb becomes positive when HBV is cleared during active infection and is also present in chronic HBV and HDV infection.
§HBV DNA <105 copies/ml; HBV DNA is never negative in chronic infections and can be detected using sensitive PCR techniques.
a. V iral hepatitis type A e. Although the cytotoxic T lymphocytes are the princi-
i. The HAV is a single-stranded 7.6-kb positive sense pal determinate in destroying the infected cells, non-
nonenveloped RNA virus with three viral capsid destructive mechanisms that also eliminate the virus
proteins (VP1, VP2, and VP3). It causes acute infec- are mandatory in eventual viral eradication and liver
tion with clearance and complete immune response cell regeneration.
and has fulminant, relapsing, and cholestatic presen- f. Chronicity results when the curative response is only
tations. There are three genotypes: 1A, 1B, and 2. partial, whereby the immune mechanism does not
ii. The virus replicates in the gastrointestinal tract, entirely eliminate the virus and can occur via either
enters the portal circulation, accesses the hepa- decreased CD8+ activity (resulting in a persistent but
tocytes through the space of Disse, and replicates active chronic hepatitis) or total absence of CD8+
in the cytoplasm in membrane-bound replication activity (chronic “carrier” state).
complexes. The virus is excreted via the biliary
canalicular membrane (because of lack of a lipid Treatment and prognosis
envelope) and into feces, where shedding can oc- 1. Although resolution of acute hepatitis is the rule, the devel-
cur for 30 days, providing a source of infection opment of fulminant or submassive necrosis is associated
in person-to-person contact. Elimination of the with a poor prognosis, leading to mortality in more than 80%
infection occurs by a T-cell-medicated cytokine of patients. In these patients, liver transplantation should be
response, and immunity is established by neutral- considered, provided these patients do not have comorbid
izing antibodies. conditions that would preclude a successful outcome.
iii. Vaccination confers immunity in almost 100% of
patients.
b. V iral hepatitis type E Fulminant Hepatitis
i. The HEV is a single-stranded 7.2-kb RNA virus
with the RNA genome expressed in ORF pro- (Figs 2-14 through 2-22)
teins (ORF1, ORF2, and ORF3). There are two
genotypes (1 and 2) that occur worldwide, mostly
in the developing countries.
ii. Recently genotypes 3 and 4 have been noted in
swine and humans, and genotype 4 has been shown
to be a zoonotic source of subclinical infection in
developed countries. The infection presumably
occurs from the ingestion of infected meat.
iii. Pregnant women appear to be susceptible to in-
fection, with high mortality in India for unclear
reasons.
iv. Chronic HEV leading to cirrhosis has been re-
ported in organ transplant recipients in both de-
veloping and developed countries.
v. Two vaccines are in development using 56 kD
ORF 2 protein; their efficacy against HEV infec- A
tion is 85% to 95%.
14. Some of the basic but important pathophysiologic concepts
of viral hepatitis include the following:
a. The obligatory hepatotropic viruses initially bind to
liver cell surface molecules, whereby antibodies against
the viruses may either initiate phagocytic clearance via
opsonization or inhibit viral attachment and penetra-
tion within the cell, with eventual viral clearance.
b. The viruses that do enter the hepatocyte elicit an
immune reaction that clears the virus in two ways: (1)
by destroying the cell containing the virus and (2) by
secreting antiviral cytokines that directly inhibit viral
gene expression and replication without cell destruction.
c. The principal mechanism rests with the function of
CD8+ cytotoxic T lymphocytes, although other cells,
including CD4+ T cells, macrophages and neutro- B
phils, natural killer (NK) cells, and various lympho- Figure 2-14 Fulminant hepatitis, massive (panlobular) hepatic
kines and cytokines, also play a role in viral-related necrosis. A, The liver is slightly small (1100 g) and has a wrinkled
liver cell injury. capsule as a result of significant loss of the liver volume from severe
panlobular liver cell necrosis in this example of fulminant hepatitis
d. The eventual necrosis of infected cells is also accom- from acute hepatitis A virus (HAV) infection. B, Cut section shows
panied by antibody-associated neutralization of cir- striking hemorrhage in the lobules, which microscopically showed
culating virus and inhibition of liver cell reinfection. almost total loss of the hepatocytes.
Major morphologic features: subtypes 2. The areas of confluent necrosis contain abundant hyper-
1. Confluent (submassive) hepatic necrosis: Portal and paren- trophic Kupffer cells and macrophages that phagocytize
chymal changes are similar to those seen in acute viral the damaged liver cells; these macrophages often contain
hepatitis, but with prominent perivenular liver cell abundant ceroid (DiPAS) pigment.
necrosis, cell dropout, and collapse of the reticulin 3. Portal tracts show a predominantly lymphocytic infiltrate,
framework. Bridging necrosis may also be seen adjoin- sometimes with occasional plasma cells, with mild prolif-
ing adjacent perivenular zones or extending from the eration of interlobular bile ducts.
perivenular to the periportal zones. The term submas- 4. Prominent proliferation of cholangioles (ductules, trans-
sive is best used when the degree of confluent necrosis is formed or “metaplastic” ducts, neocholangioles) that some-
quite striking and involves dropout of most, but not all, times contain bile plugs are often seen at the edges of the
hepatocytes. portal tracts; these ectatic cholangioles represent progeni-
2. Panlobular, panacinar (massive) hepatic necrosis: Portal tor cells capable of transforming into duct epithelium or
inflammation and diffuse lobular necroinflammatory hepatocytes.
change with associated liver cell dropout and lobular col- 5. Portal tracts sometimes will appear close together due
lapse involving all liver cells in all zones occur. to the confluent necrosis and dropout of hepatocytes,
substantially decreasing the volume of liver parenchyma
Other features between portal tracts.
1. The lobular architectural pattern remains intact, with the 6. Confluent necrosis involving the periportal zones often
perivenular and midzones showing extensive liver cell demonstrates viable but damaged hepatocytes “trapped”
dropout and lobular collapse of the reticulin framework. in and among the areas of necrosis.
Figure 2-17 Fulminant hepatitis. This low-power image from a sec-

Figure 2-15 Fulminant hepatitis, submassive hepatic necrosis. tion taken from the liver in Figure 2-14 shows marked wrinkling of
The liver is small (580 g). The hepatic lobes show numerous bulg- Glisson’s capsule due to panacinar necrosis and liver cell dropout.
ing regenerative nodules representing hepatocytes that survived the The parenchyma stains a vague light blue from condensation of the
acute hepatitis and that are attempting to replace the damaged liver. reticulin framework and not from true fibrosis. (Trichrome.)
A B
Figure 2-16 Fulminant hepatitis, hepar lobatum. A, The liver shows large deep scars within both the right and left lobes, with marked bulging
as a result of liver cell regeneration (hepar lobatum) in this example of fulminant hepatitis secondary to acute hepatitis A virus (HAV) infection.
B, Cross section shows the deep fibrous scars encompassing hilar vessels. The parenchyma shows a somewhat mottled pattern. Microscopy
from this liver showed the portal tracts within the nodules to have little, if any, fibrosis.
7. Cholestasis can be present within the lobules and may be Special stains
prominent in areas where the hepatocytes are still pres- 1. PAS after diastase digestion (DiPAS): Cytoplasmic intra-
ent; however, in the areas of confluent necrosis, cholesta- lysosomal granules are quite prominent in macrophages
sis may be absent. and Kupffer cells in areas of necrosis secondary to phago-
8. In instances associated with severe confluent necrosis cytosis of necrotic liver cells.
with marked liver cell regeneration, fibrous scars repre- 2. Masson trichrome, orcein, Verhoeff ’s Van Gieson, Sirius red
senting the collapsed parenchyma can be seen adjacent to stains: The portal tracts, which normally contain the dou-
large, grossly bulging regenerative nodules, the liver then bly refractile type I mature collagen fibers, stain dark blue,
having a potato-like appearance (hepar lobatum). whereas the lobular areas of collapse, with condensation
9. Progression to chronic liver disease with fibrosis and of reticulin fibers (type III collagen), stain a light blue
cirrhosis does not usually occur with resolution of the using Masson trichrome stain. In addition, the orcein and
hepatitis; however, those biopsies showing conflu- Van Gieson stains for elastic tissue fibers, and the Sirius
ent necrosis with portal-perivenular bridging are more red stain for collagen, are usually negative in areas of con-
often associated with disease progression compared with fluent necrosis. These stains can be helpful in differen-
biopsies showing only perivenular-perivenular bridging tiating fulminant hepatitis arising in a nonfibrotic liver
necrosis. from severe fibrosis or cirrhosis that errantly is diagnosed
A B
Figure 2-18 Fulminant hepatitis. A, The basic portal-perivenular architectural pattern is intact, with the portal tracts of normal size; however,
there is prominent liver cell necrosis and dropout surrounding a terminal hepatic venule in the upper left of the field. B, Three portal tracts
can be seen closely approximating each other as a result of striking confluent necrosis and almost total liver cell dropout in the corresponding
lobules between these portal tracts. (Trichrome.)
Figure 2-19 Fulminant hepatitis. A portal tract and the adjacent

parenchyma are present. The portal tract shows prominent lym-
phocytic infiltrates and bile ductular proliferation. The parenchyma Figure 2-20 Fulminant hepatitis. A higher-power view of a portal
shows striking liver cell necrosis with dropout of all the hepato- tract shows prominent lymphocytic infiltrates similar to that seen
cytes (massive hepatic necrosis). Lobular lymphocytic infiltrates and in typical nonfatal acute viral hepatitis. Bile ductular proliferation is
Kupffer cell hyperplasia are prominent. prominent.
A
Figure 2-22 Fulminant hepatitis. Residual spared hepatocytes are
seen in this field (submassive hepatic necrosis).
3. Cytokeratins (particularly CK7, CK8, CK18, and CK19):

Staining of the proliferating cholangioles is enhanced.
Differential diagnosis
1. Drug-induced liver cell injury (e.g., isoniazid, ketoconazole;
see Table 5-5): Many drugs that cause acute hepatitis may
also be associated with fulminant hepatitis (confluent
submassive or massive hepatic necrosis). Sometimes the
degree of portal inflammation in drug-induced fulminant
hepatitis is not as prominent as that seen in acute viral
infection.
2. Wilson disease: This autosomal recessive inherited disorder
B associated with increased hepatic copper deposition may
Figure 2-21 Fulminant hepatitis. A, Medium-power view of the rarely present with jaundice, hemolysis, and renal failure
parenchyma shows total liver cell dropout with lymphocytic infil- and histologically may resemble the features of fulminant
trates and Kupffer cell hyperplasia. Proliferating ductules are seen hepatitis secondary to the hepatotropic viruses. The pres-
at the edges of the field and represent activation and proliferation of ence of Mallory bodies, prominent irregular cytoplasmic
stem cells in the reparative process. B, High-power view shows the clumps (lysosomes), glycogenated nuclei, and increase in
collapsed parenchyma to be composed of hyperplastic Kupffer cells,
macrophages, residual apoptotic hepatocytes, and lymphocytes. stainable copper (rubeanic acid stain) and often copper-
binding protein (orcein stain) in viable hepatocytes are
helpful clues in distinguishing fulminant Wilson disease
because on hematoxylin and eosin (H&E) stain, the areas from a viral etiology.
of collapse may resemble true fibrous bands. 3. Autoimmune hepatitis: Patients with this liver disease may
Note: The reticulin stain helpfully demonstrates the areas of present with an acute, rapidly progressive course, with
lobular collapse by staining the type III collagen; however, histologic changes of confluent (submassive) hepatic
reticulin fibers are also normally present to some degree necrosis and marked portal and lobular inflammation.
within portal structures, meaning portal fibrosis and even In autoimmune hepatitis, however, some degree of por-
cirrhosis rather than lobular collapse can also be highlighted tal fibrosis is usually also present. In addition, the plasma
by this stain. Therefore, the Masson trichrome and other cell infiltrates in autoimmune hepatitis are usually quite
stains listed here are more helpful in distinguishing the dif- prominent.
ference between true fibrosis and lobular collapse. 4. Chronic hepatitis with severe fibrosis, cirrhosis: Areas of
confluent bridging necrosis with regenerative activity of
Immunohistochemistry viable hepatocytes in fulminant hepatitis may mimic on
1. HBsAg, HBcAg: Surface and core antigens in fulminant H&E stain active but chronic hepatitis with bridging
acute viral hepatitis secondary to HBV infection are fibrosis. The trichrome stain showing a loose light blue
always negative. If there is any positive cytoplasmic or staining pattern and the absence of elastic tissue fibers
nuclear staining, then acute “fulminant” hepatitis arising (using orcein or Verhoeff ’s Van Gieson stains) are fea-
in a patient with underlying early-stage chronic HBV or tures of confluent necrosis and not true fibrosis. In addi-
a severe reactivation of chronic HBV hepatitis is present. tion, a Sirius red stain for collagen is usually negative in
2. Delta antigen: In cases of fulminant hepatitis secondary to areas of confluent necrosis.
HBV and acute δ infection, the δ antigen is present in the 5. Extrahepatic bile duct obstruction: The prominent pro-
nuclei of viable liver cells. liferation of cholangioles that sometimes contain bile
plugs in fulminant hepatitis can resemble, in part, the Treatment and prognosis
ductular changes associated with extrahepatic bile duct 1. The prognosis and outcome depend on the type of hepa-
obstruction; however, the interlobular bile ducts, which titis, the presence of underlying liver disease, and the
occur adjacent to hepatic arteriole segments and show patient’s age. For example, coexisting HBV and HDV
prominent proliferation, ectasia, periductal edema, and infections have a greater probability of a severe course,
sometimes acute cholangitis in bile duct obstruction, and consequently, a poorer prognosis, than seen with
are normal appearing in fulminant hepatitis. In addi- HBV infection alone.
tion, confluent necrosis is not a feature seen in bile duct 2. Older individuals tend to have a more protracted and
obstruction. severe course compared with younger patients, with mor-
tality approaching 100% in persons older than 40 years.
Clinical and biologic behavior
1. The prevalence of fulminant hepatitis from viral hep-
atitis (types A, B, C, and E) overall is less than 1%; Chronic Viral Hepatitis
however, during epidemics of acute HEV, the mor-
tality in infected pregnant women in India is 10% to (Figs 2-23 through 2-52)
20%, compared with Egypt, which has no increased
mortality. The probability of fulminant hepatitis Major morphologic features
developing in type B hepatitis with HDV coinfection 1. Portal lymphocytic infiltrates are present, with variable
is increased. Fulminant hepatitis with acute HCV is periportal inflammatory activity (periportal interface
extremely rare. hepatitis, “piecemeal” necrosis) consisting of lympho-
2. A high prevalence of HDV markers (21% to 50%) among cytes spilling over into the adjacent periportal zones and
patients with fulminant hepatitis B indicates that the surrounding individual and small groups of hepatocytes
severe hepatitis results from cumulative damage by the (“trapped” liver cells).
two viruses.
3. This severe form of acute viral hepatitis is clinically her-
alded by the persistence of gastrointestinal symptoms
(e.g., nausea, vomiting, dyspepsia), prolonged prothrom-
bin time, and features of early encephalopathy (drowsi-
ness, lethargy, and asterixis).
4. Ascites, lower extremity edema, renal failure, gastroin-
testinal bleeding, disseminated intravascular coagulation,
hypoglycemia, sepsis, hypovolemia, adult respiratory dis-
tress syndrome, and cerebral edema may complicate the
course of fulminant hepatitis.
5. In fulminant hepatitis B virus infection, significant expo-
nential elevations of α-fetoprotein are more often associ-
ated with improved survival.
6. Patients who recover do not develop any form of chronic
liver disease. Of note, during the early stages, large
regenerative nodules may irregularly form, mimick-
A
ing a cirrhotic liver on imaging and gross examination.
Upon resolution, these nodules coalesce and eventually
disappear.
7. Biopsies are generally not performed in these patients
because of low prothrombin time unless done by the
transjugular route. Overall, biopsies are usually not useful
to predict recovery.
8. A number of pathophysiologic processes play a role and
include the following:
a. Immune-mediated injury (most important with HBV
infection; fulminant hepatitis often occurs in the
absence of detectable HBV because of the low level of
viral replication)
b. Injury from activation of cytokines, tumor necrosis fac-
tor (TNF), and interleukins (IL-1 and IL-6)
c. Direct liver cell injury by lymphocytes, fibroblasts, and B
monocytes Figure 2-23 Chronic viral hepatitis, cirrhosis. A, The external sur-
d. Tissue hypoxia (decreased hepatic perfusion second- face of the liver from a patient with chronic viral hepatitis resulting
ary to disturbance in the microvasculature; capillary from hepatitis B virus (HBV) infection is coarsely nodular, the nod-
ules measuring from less than 1 to up to 2 cm in greatest dimension
obstruction from debris such as actin filaments and (macronodular). B, Cut section shows the nodules to be well demar-
collagen) cated; the largest nodule in this image measures 9 mm in diameter.
e. Endotoxin-induced damage The nodules appear green as a result of marked cholestasis.
A B
Figure 2-24 Chronic viral hepatitis, early stage, relatively inactive. A and B.These two portal tracts from the same biopsy show expansion
by lymphocytes; fibrosis is minimal or absent. No periportal interface inflammatory activity (“piecemeal” necrosis) is present.
Figure 2-25 Chronic viral hepatitis, early stage, minimally active. Figure 2-26 Chronic viral hepatitis, active. The portal tract shows
The parenchyma shows diffuse mild hydropic change with rare lymphocytes spilling out into the periportal region, surrounding indi-
spotty necrosis. vidual and small groups of hepatocytes (periportal interface inflam-
matory activity, “piecemeal” necrosis), a morphologic indicator of
active disease.
Figure 2-28 Chronic viral hepatitis, active. Lymphocytes can be

seen spilling out of the portal tracts at the edges of the field and
Figure 2-27 Chronic viral hepatitis, active. High-power view of surrounding individual and small group of hepatocytes (periportal
the periportal zone shows periportal interface inflammatory activity
interface inflammatory activity), a feature characteristic of the active
(“piecemeal” necrosis).
stage of the disease.
Figure 2-29 Chronic viral hepatitis, active. Periportal interface Figure 2-32 Chronic viral hepatitis. Variability in the same field of
inflammatory activity is present, with the hepatocytes exhibiting cell size, cytoplasmic changes, and the degree of inflammation are
cytoplasmic eosinophilia as a result of prominence of the mitochon- often characteristic of chronic viral hepatitis. The lobule to the left of
dria (oxyphilic change); these types of cells are sometimes seen in the field shows no inflammation; rather, it exhibits diffuse hydropic
chronic viral hepatitis. change of the hepatocytes secondary to liver cell regeneration. The
lobule to the right shows fatty change, prominent nuclear anisocyto-
sis of hepatocytes, and a mild lymphocytic infiltrate.
Figure 2-30 Chronic viral hepatitis. Nuclear anisocytosis and mild

fatty change are seen.
Figure 2-33 Chronic viral hepatitis: hepatitis B virus (HBV) + δ.
The degree of lobular necroinflammatory activity can sometimes be
diffuse and is often seen in chronic HBV with associated δ virus
infection, as this example demonstrates.
2. Lobular necrosis, inflammation, hydropic change, and

apoptosis away from the periportal zones occur and are
often irregularly distributed from one lobule to the next.
3. Although the portal tracts in early-stage disease may
show little, if any, fibrosis and may only appear expanded
because of the prominent inflammatory infiltrates, with
time portal fibrosis with bridging (portal-to-portal and
portal-to-perivenular) and cirrhosis (fibrous septa and
regenerative nodule formation) eventually occur.
Other features
1. The degree of portal and periportal inflammatory activ-
Figure 2-31 Chronic viral hepatitis. The periportal hepatocytes ity varies from one portal tract to the next.
show variability in the nuclear size (anisocytosis), with some of the
nuclei pleomorphic, an example of large cell dysplastic change usu-
2. Bile duct and cholangiolar proliferation may be present
ally evident in cirrhotic nodules but sometimes occurring in fibrotic but are not prominent, except in instances of severe liver
livers as well. cell injury.
A B
Figure 2-34 Chronic viral hepatitis: hepatitis B virus (HBV). Hepatocytes that have a ground-glass appearance can be seen in ½ to 2⁄3 of cases
of chronic viral hepatitis caused by HBV infection. They are usually scattered within the lobules (A), but at times may be diffuse (B).
p m
L
Figure 2-35 Chronic viral hepatitis: hepatitis B virus (HBV) + δ. The

ground-glass cells in chronic HBV infection with or without δ coinfec- m
tion may also demonstrate a clearing (“halo” effect) immediately
adjacent to the ground-glass inclusions, as seen in this image.
Figure 2-37 Chronic viral hepatitis: hepatitis B virus (HBV), elec-

tron microscopy. This ground-glass cell on electron microscopy
shows proliferation of tubular and spherical particles (22 nm) located
within the endoplasmic reticulum, representing the hepatitis B sur-
face antigen (HBsAg). The small spherical particles (27 nm) located
within the liver cell nucleus at the upper left of the field represent
hepatitis B core antigen (HBcAg). An arrow (upper field) notes hepa-
titis B core particles immediately outside a nuclear pore. The other
arrows show larger spherical double-ringed (42 nm) Dane particles
representing the complete hepatitis B virus. L, Lipid; m, mitochon-
dria; p, peroxisomes. (From Phillips MJ et al: The Liver. An Atlas
and Text of Ultrastructural Pathology. New York: Raven Press, 1987;
with permission from Lippincott Williams & Wilkins.)
3. Cholestasis may be seen in the more severe and active

stages of the disease.
4. “Reactivation” of hepatitis may occur. This is associated
with active viral replication and can be associated with
Figure 2-36 Chronic viral hepatitis: hepatitis B virus (HBV). The
ground-glass cell shown on high power is due to proliferation of the
a diffuse necroinflammatory change, sometimes with
endoplasmic reticulum synthesizing the hepatitis B surface antigen perivenular confluent necrosis, that may histologically
particles. mimic acute viral hepatitis.
A B
Figure 2-38 Chronic viral hepatitis: hepatitis B virus (HBV). The surface antigen particles may be numerous or spotty and often vary from
one lobule to another. A, Almost all the hepatocytes take up a diffuse strong cytoplasmic staining in this medium-power field. B, The cytoplas-
mic staining in this higher-power field is intense but focal, with relative sparing of the liver cell nuclei. (Immunoperoxidase stain for HBsAg.)
Figure 2-39 Chronic viral hepatitis: hepatitis B virus (HBV). The Figure 2-41 Chronic viral hepatitis: hepatitis B virus (HBV). Orcein
core antigen most characteristically is present within the hepatic stain, most often useful for staining copper-binding protein, can also
nuclei. In active disease, cytoplasmic staining can often be seen as demonstrate diffuse cytoplasmic staining of the hepatitis B surface
well. (Immunoperoxidase stain for HBcAg.) antigen.
5. The liver cells adjacent to areas of necroinflammatory

change may appear hydropic as a result of liver cell
regeneration; these groups of liver cells often have a
cobblestone pattern and form cords two to three cells
thick (best appreciated on the reticulin stain).
6. Focal nuclear anisocytosis and dysplasia of hepatocytes
can occasionally be seen and are usually more obvious in
the periportal zones.
7. Kupffer cell hyperplasia is seen to variable degrees.
8. Periportal or periseptal hepatocytes occasionally have a
prominent cytoplasmic eosinophilia (oncocytic or oxyphilic
change) secondary to proliferation of mitochondria.
9. In intravenous drug users, particulate polarizable bire-
fringent material may be seen within the portal tracts
and occasionally within Kupffer cells and represents
the injectant used (e.g., talc, silicon). These crystalline
Figure 2-40 Chronic viral hepatitis: hepatitis B virus (HBV) + δ. In inclusions seldom elicit a histiocytic response.
chronic HBV with coexisting δ infection, the δ antigen can be seen 10. In the cirrhotic stage, the regenerative nodules are often
within the liver cell nuclei. (Immunoperoxidase stain for δ antigen.) “macronodular” (>3 mm in diameter); however, both
A
Figure 2-44 Chronic viral hepatitis: hepatitis C virus (HCV). The
centrally located duct within the lymphoid aggregate shows minimal
cytologic damage.
B
Figure 2-42 Chronic viral hepatitis: hepatitis C virus (HCV). A, A
benign lymphoid aggregate is seen within the portal tract. B, This
lymphoid aggregate also contains a small reactive germinal center.
Figure 2-45 Chronic viral hepatitis: hepatitis C virus (HCV). Peri-

portal arachnoid fibrosis is seen in this field and is often present in
chronic HCV infection. (Trichrome.)
Figure 2-43 Chronic viral hepatitis: hepatitis C virus (HCV). The Figure 2-46 Chronic viral hepatitis: hepatitis C virus (HCV). Fatty
lymphoid aggregate contains an interlobular bile duct that shows change is common in chronic HCV infection, is usually mild, and is
some cytologic distortion; the duct is also infiltrated by lymphocytes. seen in this image with associated mild necroinflammatory change.
A B
Figure 2-47 Chronic viral hepatitis, intravenous (IV) drug abuser. Chronic viral hepatitis associated with IV drug abuse can sometimes dem-
onstrate in liver biopsies the injectant material, which is most concentrated within the portal tracts. A, The portal tract on low power shows
scattered lymphocytes and histiocytes. A suggestion of crystalline material is seen at this magnification. B, High power of the same portal
tract demonstrates abundant crystalline material that is predominantly free within the stroma.
A B
Figure 2-48 Chronic viral hepatitis, intravenous (IV) drug abuser. A, High power of a portal tract in a long-term IV drug abuser shows classic
extracellular crystalline material. B, The crystals in the same field are best demonstrated and confirmed by their strong birefringence under
polarized light.
A B
Figure 2-49 Chronic viral hepatitis, bridging fibrosis. A and B. These two images demonstrate portal fibrosis with portal-to-portal bridging,
without complete regenerative nodule formation. (Trichrome.)
Figure 2-50 Chronic viral hepatitis, cirrhosis. The fibrous bands Figure 2-52 Chronic viral hepatitis, cirrhosis. An increase in portal
with regenerative nodule formation can be seen from this explanted venous radicals within the fibrous septa as a result of portal hyper-
liver. The nodules are well demarcated, without appreciable perisep- tension is characteristically seen in cirrhotic livers of almost any
tal intrasinusoidal collagen deposition. (Trichrome.) cause. A diffuse lymphocytic infiltrate and scattered bile ducts and
ductules are also present.
these cells; in fact, the ground-glass cells can clus-

ter and sometimes be prominent in one regenera-
tive cirrhotic nodule but be absent in others.
ii. The liver cell nuclei can sometimes have a sand-
ed, finely granular appearance as a result of the
presence of HBcAg.
iii. Portal and lobular plasma cell infiltrates can be
prominent at times.
iv. The degree of liver cell dysplasia and oxyphilic (on-
cocytic) cellular changes are more frequently seen
when compared to the other hepatotropic viruses.
v. Development of hepatocellular carcinoma is fre-
quent over time and may occur in both fibrotic
and cirrhotic livers.
b. HBV and δ
Figure 2-51 Chronic viral hepatitis, cirrhosis. The regenerative nod-
i. The degree of periportal interface inflamma-
ules are well demarcated, with the fibrous septa exhibiting a mild tory activity is usually more prominent than with
lymphocytic infiltrate. chronic HBV infection alone.
ii. Occasional hepatocytes may exhibit microvesicu-
micronodules (≤3 mm in diameter) and “mixed” mac- lar fat.
ronodules and micronodules may also be seen. iii. Progression to hepatocellular carcinoma is un-
11. In the cirrhotic liver, enlarged regenerative nodules common.
(macronodules when >8 mm in greatest dimension) c. HCV
that show nuclear and cytoplasmic atypia (“dysplastic” i. Portal lymphoid aggregates and follicles, some-
nodules) may occur and may require further investiga- times exhibiting germinal centers, are seen in
tion for transformation to hepatocellular carcinoma (see more than ½ of the cases.
“Regenerative Lesions” in Chapter 10). ii. Interlobular bile ducts may be seen within the
12. All of the aforementioned histologic changes can be center of the lymphoid aggregates and exhibit var-
seen with any of the hepatotropic viruses associated with iable cellular atypia, with lymphocytes hugging up
chronic hepatitis (B, δ, C, G, non-A through non-G); against the duct basement membrane and some-
however, the subtypes may also show the following on times infiltrating into the duct epithelium itself.
routine stains: iii. Variable but usually mild macrovesicular fatty
a. HBV change is common.
i. “Ground-glass” cells are present in 1⁄2 to 2⁄3 of the iv. Glycogenated liver cell nuclei, intrasinusoidal col-
cases; these hepatocytes have a diffusely finely lagen deposition, and variable degrees of stainable
granular eosinophilic cytoplasm, sometimes with iron are usually present.
a thin “clear” space adjacent to the cell membrane, v. Some degree of sinusoidal lymphocytosis may
and represent proliferation of the endoplasmic re- occur.
ticulum synthesizing the 22-nm HBsAg particles. vi. Progression to hepatocellular carcinoma is common
There is no particular zonal predominance for and occurs most frequently in the cirrhotic stage.
d. HGV Table 2-3 Chronic Viral Hepatitis Histologic

i. The degree of portal and lobular inflammation is Grading and Staging Systems
usually mild.
SYSTEM* FIBROSIS ACTIVITY
ii. Fibrosis is not a feature associated with chronic
HGV infection alone; if portal fibrosis is present, Ishak K et al Portal fibrosis Portal inflammatory infiltrates
(1995) (0–6) (0–4)
then concurrent HBV or HCV infection should Periportal inflammation (0–4)
be strongly suspected. Confluent necrosis (0–6)
iii. There is some question as to whether chronic Lobular necroinflammatory
HGV infection alone, without coinfection with change (0–4)
HBV or HCV, causes histologic changes of a Batts KP, Portal fibrosis Periportal and intralobular
chronic viral hepatitis or simply represents a car- Ludwig J (1995) (0–4) inflammation (0–4)
rier state. METAVIR Portal fibrosis Piecemeal necrosis and lobular
e. Non-A through non-G Cooperative (0–4) inflammation (0–3)
Study Group
i. Giant cell transformations of hepatocytes have (1994, 1996)
been reported, similar to those also described in
the acute phase. *see Expert Consult website for references.
Note: Chronic HEV infection has been reported in immu-
nosuppressed patients after liver transplantation, with case b. In chronic δ infection, variable nuclear staining of hepa-
reports of progression to cirrhosis. tocytes with an irregular distribution from one lobule
to another is characteristic; suppression of HBcAg, not
Special stains HBsAg, commonly occurs.
1. In chronic HBV infection, cytoplasmic staining of the 4. HBeAg: Nuclear staining is seen that parallels HBcAg
HBsAg particles in ground-glass cells can be demon- nuclear staining.
strated using the following stains: 5. HCV: Cytoplasmic staining of hepatocytes using mono-
a. Orcein (brown) clonal antibodies directed against HCV core polypeptides
b. V ictoria blue (blue) is positive in up to 75% of cases; however, it is impor-
c. Aldehyde fuchsin (purple) tant to exclude background cytoplasmic staining in these
2. Masson trichrome: This stain for collagen enhances visual- cases. In addition, there does not appear to be a correla-
ization of the degree of fibrosis and can more easily help tion with staining and the presence or absence of inflam-
depict sinusoidal collagen deposition. matory activity.
3. PAS after diastase digestion (DiPAS): Increases in lyso-
somal activity and deposition of ceroid pigment in areas Histologic disease grading and staging
of necrosis are highlighted. Histologic staging (degree of fibrosis) and grading (degree
4. Reticulin stain: The liver cell plates one to two cells thick of necroinflammatory activity) has become a very useful tool
in the regenerative cirrhotic nodules can best be appre- for the clinician in deciding whether patients with chronic
ciated, and this stain is helpful in dysplastic foci to rule viral hepatitis should be treated with antiviral therapy. The
out hepatocellular carcinoma where the liver cell plates recommended histologic sign-out description first states the
are thicker and/or the reticulin stain shows decreased etiology of hepatitis (e.g., chronic hepatitis C), followed by
to absent staining (see “Hepatocellular Carcinoma” in the degree of fibrosis (e.g., portal fibrosis with bridging) and
Chapter 10). the degree of activity (e.g., mildly active), with appropriate
numerical codes using the particular classification and scor-
Immunohistochemistry ing system used. Some of the more popular grading and
1. HBsAg: The cytoplasm of ground-glass cells in chronic staging systems are listed in Table 2-3 and are described in
HBV infection shows either uniform or perinuclear stain- detail in the Appendix (Tables A through C).
ing. Cytoplasmic staining can also be seen in cells that do
not have the characteristic ground-glass appearance on Differential diagnosis
H&E stain. Less frequently, linear membrane staining can 1. Acute viral hepatitis: Portal fibrosis is not present in acute
also be present and is usually associated with active viral viral hepatitis alone, with the necroinflammatory change
replication. seen in acute viral hepatitis evenly distributed from one
2. HBcAg: Nuclear staining of hepatocytes is present and lobule to the next. In chronic viral hepatitis, usually some
often prominent in association with active viral replica- degree of portal fibrosis is present, although in the very
tion. In some instances, staining of the cytoplasm may early stages of the disease, the fibrosis may be inconspicu-
also be seen. In immunocompromised patients (e.g., ous. In addition, in chronic viral hepatitis the degree of
acquired immunodeficiency syndrome, post-transplanta- inflammation is most often milder than in acute hepati-
tion, dialysis), the vast majority of the nuclei may show tis, with the inflammatory cellular component and necro-
strong positive staining. sis unevenly distributed from one lobule to the next. In
3. Delta antigen: chronic HBV infection, ground-glass cells, seen in 1⁄2 to
a. In acute δ infection superimposed on chronic HBV 2
⁄3 of the cases, are indicative of chronic, and never acute,
infection, variable degrees of nuclear staining of hepa- hepatitis B; however, in very early and active stages of
tocytes are present with an even distribution from one chronic viral hepatitis, the fibrosis may not be apparent
lobule to the next; staining of coexisting HBsAg may on biopsy and the lobular inflammation may be diffuse,
also occur but is uncommon in acute δ infection. hence mimicking acute viral hepatitis. In these instances,
hepatitis serologies (e.g., presence of HBsAg in con- viral hepatitis. Aiding in the correct diagnosis of Wilson
junction with the absence of high-titer anti-HBc IgM disease is the presence of increased hepatic copper and
in chronic hepatitis B) and clinical history may be most copper-binding protein demonstrated by special stains
important. on biopsy material (e.g., rubeanic acid, rhodanine stains
2. Autoimmune hepatitis: Autoimmune hepatitis usually has for copper, orcein stain for copper-binding protein), the
a prominent portal and lobular plasma cell component to demonstration of increased hepatic copper by quantita-
the infiltrates and in untreated cases may also show peri- tive methods on biopsy tissue, and correlation with low
portal and/or perivenular confluent necrosis, features not serum ceruloplasmin levels and high urinary copper
typically seen in chronic viral hepatitis; however, chronic excretion.
HBV infection can, at times, show considerable numbers 8. Other causes of chronic hepatitis: A number of other liver
of plasma cells. Therefore serologic correlation with both diseases, such as α1-antitrypsin deficiency, sarcoidosis, and
viral and autoimmune serologic markers is important (see various nonviral infectious processes (e.g., salmonellosis,
“Autoimmune Hepatitis” in Chapter 12 for further dis- syphilis), may show many morphologic changes similar
cussion of the various serologic profiles of these patients). to the various stages in chronic viral hepatitis. Although
3. Primary biliary cirrhosis (PBC): Approximately 15% of many of these liver diseases have some morphologic char-
patients with PBC exhibit prominent periportal inter- acteristics distinctive from chronic viral hepatitis (e.g.,
face and intralobular inflammation, and the inflamma- granulomas in sarcoidosis), in not all instances is biopsy
tion may mimic an active stage of chronic viral hepatitis. material adequate to arrive at the correct diagnosis. In
Nonsuppurative destructive duct lesions, duct depletion these instances, appropriate serologic workup and clinical
(paucity), epithelioid granulomas, Mallory bodies, and correlations are sometimes the only methods to help the
increased stainable copper-binding protein are features physician arrive at the most likely diagnostic possibilities.
seen in various stages of PBC and are not present in
chronic viral hepatitis. In addition, these patients have Clinical and biologic behavior
a positive antimitochondrial antibody (AMA) and often 1. Chronic viral hepatitis involves the hepatotropic viruses
high-titer antinuclear antibodies (ANA) and are consid- B, D superinfection, and C; hepatitis A and E virus do
ered a PBC variant (PBC-autoimmune hepatitis overlap not cause chronic disease. Hepatitis G virus is evident in
syndrome; refer to Chapter 12 for a more detailed descrip- chronic hepatitis but has little pathologic significance.
tion). This serology is helpful in obtaining the correct 2. The diagnosis of hepatitis non-A through non-G refers
diagnosis. Of note, although chronic HCV infection can to suspected viral hepatitis not caused by the hepatotropic
show cytologic distortion of ducts within the lymphoid viruses A, B, C, D, E, or G and is determined by negative
aggregates, the degree of cytologic damage is usually con- currently available serologic and viral tests for these viruses.
siderably less than that seen in PBC. 3. Chronic infection with any of the hepatotropic viruses
4. Primary sclerosing cholangitis (PSC): In a minority of cases is, in part, dependent on various viral determinants such
of PSC, periportal interface inflammatory activity can as gene products that initiate or inhibit apoptosis, with
occur. Sometimes these patients may also have high-titer direct hepatotoxicity playing a minimal role, except in
ANA and/or smooth muscle antibody (SMA) (autoim- immunosuppressed patients in whom cytopathic effects
mune hepatitis-PSC overlap syndrome; refer to Chapter 12 are rarely seen. Abnormalities in the innate and adaptive
for a more detailed description). Periductal sclerosis and immune response play a part in persistence of virus infec-
obliteration, duct loss (ductopenia), Mallory bodies, and tion and in chronic hepatitis.
increase in stainable copper-binding protein are features 4. The liver may be enlarged, firm, and nontender, and it
seen in PSC but not present in chronic viral hepatitis. often becomes impalpable when cirrhosis occurs. Sple-
Imaging of the biliary tract that shows the characteris- nomegaly is present in about 50% of cases regardless of
tic “beading” appearance of the bile ducts also supports a the cause and is almost always present when cirrhosis and
diagnosis of PSC. portal hypertension develop.
5. Drug-induced liver injury (e.g., α-methyldopa, phenylbu- 5. Chronic HBV
tazone; see Table 5-13): The morphologic changes seen a. HBV is a 3.2-kb DNA virus with complete minus
with drug-induced chronic hepatitis may be virtually strand and incomplete positive strand that replicates
indistinguishable from chronic viral hepatitis. The pres- by reverse transcriptase; at infection peak, 109 virions
ence of ground-glass cells signals chronic HBV infection. are produced.
Serologic serum markers and a drug history are critical b. HBV genome in the hepatocyte exists in the cytoplasm
for proper histologic assessment. as covalently closed circular DNA (cccDNA), which
6. Nonspecific reactive changes: Portal lymphocytic infiltrates, serves as a template for six messenger RNAs and pre-
mild lobular fatty change, and mild focal necroinflam- genomes that maintain infection. Linear genomes
matory change may be seen in certain conditions such as recombine to produce cccDNA or recombine for inte-
intra-abdominal or systemic infections and in chronic sys- gration into host DNA.
temic inflammatory disorders (e.g., rheumatoid arthritis) c. Replication is noncytopathic. Antiviral therapy stops
and may mimic early forms of a mildly active chronic viral new cccDNA but does not eliminate existing cccDNA,
hepatitis on histologic grounds alone. Serologic testing which survives mitoses. Elimination of cccDNA occurs
and clinical correlation are necessary in these instances. with death of the hepatocytes, and clearance is seen
7. Wilson disease: This autosomal recessive inherited disor- with more than 70% loss of infected hepatocytes. At
der associated with increased hepatic copper deposition initial infection, HBV spreads to 95% of the hepato-
may show all of the histologic changes seen in chronic cytes; this declines to 30% in chronic infection.
d. An estimated 400 million persons are chronically genotypes is as follows: A, 42%; B, 28%; C, 26%; and
infected with HBV worldwide, and an estimated D, 20%. Genotype C has a high association with liver
500,000 people die annually of cirrhosis and hepato- cancer in the Far East, whereas genotype F may be
cellular carcinoma. associated with HBV-related hepatocellular carcinoma
e. HBV is transmitted by perinatal, percutaneous, sexual, in Alaskan natives.
and close person-to-person contact, the latter espe- 6. Chronic HCV
cially common in children and adolescents in high- a. HCV is a positive single-stranded RNA virus with a
endemic areas. 9.6-kb genome (~3000 amino acid polyproteins) that
f. The risk of developing chronic HBV after acute expo- has structural proteins (components of the mature
sure is approximately 2% to 4% in adults. Hepatitis virus) consisting of the core and two envelope pro-
B carriers are those individuals who are positive for teins. The nonstructural proteins are elements that
HBsAg for more than 6 months and who have inappar- permit viral replication and consist of NS2, NS3
ent infection based on normal liver tests and low-level (protease, helicase), NS4A, NS4B, NS5A, and NS5B
viral replication based on HBV DNA quantitation. (polymerase).
g. The clinical presentation in hepatitis B can vary, rang- b. V iral replication occurs by RNA-dependent RNA
ing from normal liver tests and minimal histologic polymerase (NS5B polymerase), resulting in spontane-
changes in asymptomatic individuals to fatigue, vague ous mutations and in the development of quasispecies
abdominal complaints and mildly to moderately ele- (population of related, slightly different, ever-changing
vated serum transaminases (50 to 500 IU/L) in those genomes) characteristic of HCV. This provides the
who are symptomatic. Mild hepatomegaly may be the virus the ability to evade host antiviral processes as well
only finding. HBsAg is almost always positive, and as drugs. HCV infection of hepatocytes occurs when
HBV DNA may be either mildly elevated (in low- the two envelope proteins E1 and E2 bind lipoprotein
level replication, <102 copies/ml) or markedly elevated ApoE1 and ApoC1, which attaches to the low-density
(>105 copies/ml). Serum bilirubin and hepatic syn- lipoprotein (LDL) receptor on the hepatocyte cell sur-
thetic function are usually normal. Mild decreases in face and enters by endocytosis.
serum albumin and prolongation of prothrombin time c. The persistence of infection within the hepatocyte is
may be seen in early cirrhosis. based on the ability of the virus to evade intracellu-
h. Three serovirologic patterns of chronic HBV infection lar antiviral processes. Both the clearance and persis-
have been observed: tence of chronic hepatitis C infection depend on the
i. In Asia, where perinatal transmission is common, interactions between innate immunity (complement,
positive HBeAg and elevated HBV DNA with neutrophils, dendritic cells, macrophages, NK T cells)
normal serum transaminases persist, often into and adaptive immunity (dendritic cells and T and B
adulthood, at which time seroconversion (positive cells). Although not clear, it is suggested that a vig-
HBe antibody, negative HBeAg) may occur. orous innate immune response may be responsible for
ii. In sub-Saharan Africa, where person-to-person clearing acute infection.
contact occurs at an early age, HBeAg seroconver- d. Hepatitis C is the major cause of liver disease in the
sion to positive HBe antibody occurs at puberty. United States, where it is estimated that more than 4
iii. The third pattern occurs when HBV is acquired million Americans are infected.
in adulthood, largely as a result of sexual transmis- e. The virus is commonly transmitted by the parenteral
sion, and is characterized by detectable HBeAg, el- route and less frequently (6%) through sexual and peri-
evated serum transaminases, and measurable HBV natal routes.
DNA. Most patients with positive HBe antibody f. Chronic infection develops in about 65% of patients
and low levels of HBV DNA have a benign course, following acute exposure. Infection is usually asymp-
but periodic reactivation may occur either sponta- tomatic, with fewer than 30% of patients having symp-
neously or when immunosuppression is withdrawn toms of acute hepatitis with jaundice, fatigue, and
(as occurs after chemotherapy), leading to active nausea. The risk of transfusion-acquired hepatitis C
severe hepatitis. with current hepatitis C antibody (EIA-3) tests is less
i. In approximately 0.5% to 1% of HBsAg carriers, the than 0.001% per unit transfused.
antigen will spontaneously clear every year. In addi- g. Chronic hepatitis is characterized by normal serum
tion, in about 4% of carriers, HBsAg will clear yearly; transaminase levels in about 30% of patients, mod-
in other words, over a 5-year period of follow up after est elevations in 60% to 70%, and in some patients,
antiviral therapy, serovirologic conversion (negative marked fluctuations in serum transaminase levels,
HBe antigen, positive HBe antibody, undetectable often up to 1000 IU/L in some patients. Usually the
HBV DNA) will be achieved in 20% of carriers. Most alanine transaminase (ALT) is higher than the aspar-
of these patients will develop immunity with the devel- tate transaminase (AST), except when cirrhosis is
opment of the HBs antibody. present. Serum bilirubin is rarely elevated, and hepatic
j. There are seven genotypes for hepatitis B (A through synthetic function is preserved. Cirrhosis develops in
G). Genotype A is more common in HBV infections 10% to 20% of patients over 20 to 30 years, and hepa-
in the Western world. The common genotypes in tocellular carcinoma develops in about 1% to 4% of
other geographic areas are as follows: Asia, B and C; patients per year after cirrhosis is established. Serum
West Africa, A and E; South America, A; and Central transaminases are lower and may even normalize when
America, H. Interferon responsiveness for the different cirrhosis develops, but hepatic synthetic function is
impaired. In established cirrhosis and portal hyperten- in superinfection, HDV IgG levels are higher than
sion, muscle wasting, ascites, and variceal bleeding may HDV IgM levels; however, in clinical practice, HDV
be the presenting features, and in severe cases, jaundice IgG is the only test that is commercially available.
with pruritus may be present. HDV antigen or HDV RNA may be detected early
h. Elevated levels of HCV RNA indicate active viral during acute HDV and can be measured using PCR
replication. There is no correlation between the levels techniques.
of HCV RNA and the severity of the hepatitis. Liver f. In HDV/HBV chronic hepatitis, HBeAg is usually
biopsy is necessary to stage and grade the severity of negative, HBe antibody is positive, and HBV DNA is
the disease and is useful to predict the risk of cirrhosis at low levels of replication.
developing if bridging fibrosis is present. HCV RNA g. The seroprevalence of HDV was high in East Asia,
levels using quantitative PCR are important before ini- occurring in more than 60% prior to 1978; however,
tiating therapy with combination antiviral drugs and in between 1978 and 1981 the seroprevalence was 25%,
evaluating response. which declined to 8% in 1997, likely related to the
i. There are 7 genotypes (1 to 7) and more than 15 sub- lower incidence of HBV infections and to HBV vacci-
types. Genotype 1 is the predominant (70%) genotype nation. In HBV carriers, the seroprevalence of HDV in
in North America. the Middle East is 6% to 20% and in North America,
j. Cryoglobulins are present in about 30% of patients 0% to 5%.
with chronic hepatitis C, but cryoglobulinemia and
vasculitis are observed in only about 2% of patients. Treatment and prognosis
Other extrahepatic manifestations include membra- 1. Chronic HBV
noproliferative glomerulonephritis with nephrotic a. Studies of α-interferon therapy in a large number of
syndrome and porphyria cutanea tarda. Other less HBeAg-positive patients with elevated HBV DNA
well-established associations are seronegative arthri- have demonstrated loss of serum HBV DNA in 37%
tis, Sjögren syndrome, autoimmune thyroiditis, lichen and loss of HBeAg in 33% of patients. The current rec-
planus, idiopathic pulmonary fibrosis, polyarteritis ommendation is to treat (1) patients with HBV DNA
nodosa, aplastic anemia, and B-cell lymphomas. greater than 2000 copies/ml who are HBeAg positive
7. Chronic HDV (δ) for at least 5 years and (2) those that are HBeAg nega-
a. HDV (δ agent) is an RNA defective or putative virus tive lifelong.
but is now considered a viroid. Viroids are small cir- b. The nucleoside analog lamivudine also results in loss of
cular RNA pathogens that do not code for proteins HBeAg in 17% to 32% of patients, with 47% serocon-
but contain RNA structural elements that use the host version at 4 years. The increase in resistance mutants
cellular proteins to replicate, transport, evade defense at 5 years for lamivudine (80%), adefovir (29%), and
mechanisms (high mutation rate), and alter its gene telbivudine (21%) at 2 years make these agents less
expression. desirable for long-term treatment. The newer drugs
b. HDV is a 30- to 40-nm particle, single-stranded cir- tenofovir (acyclic nucleoside phosphonate) and ente-
cular RNA genome that requires HBV for replication cavir (deoxyguanosine analog) approved for treatment
utilizing polymerase II. In the hepatocyte, HDV repli- of chronic HBV have better seroconversion rates,
cates in the nucleoplasm and not in the nucleoli. with significantly lower rates of resistance mutants
c. There are a number of genotypes with 35% variation (0% to 2%).
in the genotype sequence. G1 is seen mostly in West- c. Newer agents such as adefovir and tenofovir have
ern countries; G2 and G4, in the Far East; and G3, in been effective in the treatment of lamivudine-resistant
Africa. mutants.
d. Two modes of presentation occur: (1) coinfection d. Improvement in necroinflammatory changes and
(occurring in about 2% of all HDV infection cases), fibrosis has been observed in patients who have a sus-
where HDV and HBV produce a simultaneous infec- tained or durable response to therapy. Liver failure can
tion and present with a biphasic hepatitis, and (2) develop in patients with more advanced disease and
superinfection (occurring in >90% of HDV infections), those in whom spontaneous reactivation of hepatitis B
where HDV infection occurs in an individual previ- occurs.
ously infected with HBV who developed chronic e. In advanced cirrhosis or acute liver failure result-
hepatitis B. The outcome of coinfection with HBV and ing from reactivation of HBV, liver transplantation
HDV is frequently an acute severe hepatitis with a is an accepted treatment with good outcomes and
high mortality rate. If the patient survives, immunity low recurrence of hepatitis B when using hepatitis
from both viruses ensues. In superinfection, the likeli- B immunoglobulin prophylaxis and/or lamivudine
hood of chronic infection with both viruses is high, therapy.
with propensity to more severe histologic changes than 2. Chronic HCV
with HBV infection alone, leading to cirrhosis in 80% a. In patients with genotype 1, chronic hepatitis C com-
over 5 to 10 years. bination antiviral therapy using α-interferon and riba-
e. The diagnosis of HDV is made in patients who virin results in sustained response in about 50% of
are HBsAg positive and have positive HDV anti- patients, with relapses occurring in about 20% when
body. In acute HDV infection, such as in coinfec- therapy is discontinued.
tion, HDV IgM levels are usually higher than HDV b. In non-genotype 1 HCV infection, particularly in gen-
IgG levels. In chronic HDV infection, such as occurs otypes 2 and 3, response rates exceed 80%.
c. Liver biopsy is an important tool in selecting patients

for therapy, particularly genotype 1 patients; the pres-
ence of bridging fibrosis predicts the development of
cirrhosis over the long term.
d. Liver transplantation is recommended for patients with
advanced cirrhosis and is the most common indication
for transplantation in the United States, accounting for
approximately 20% of all adult transplants. Recurrence
of hepatitis C occurs in all patients after transplanta-
tion at variable time points, with the development of
cirrhosis in about 20% to 30% of these patients over a
5-year period.
3. Chronic HDV (δ)
a. Vaccination against HBV will prevent infection from
both viruses.
b. In HBV and HDV coinfections, therapy with
α-interferon has been tried but the response rates are
low (13% to 20%). The use of pegylated interferon has Figure 2-53 Epstein-Barr virus. The portal tract is expanded and
exhibits a prominent lymphocytic infiltrate.
improved the response at the end of treatment in about
43% of patients. Interferon treatment combined with
the nucleoside/nucleotide inhibitors in a small number
of patients suggests improved outcomes.
c. In severe or fulminant hepatitis resulting from HBV
and HDV, liver transplantation should be considered.
It can be lifesaving and is associated with a signifi-
cantly lower rate of HBV and HDV recurrence after
transplantation.
SYSTEMIC VIRAL INFECTIONS WITH HEPATIC

INVOLVEMENT
Epstein-Barr Virus
(Figs 2-53 through 2-57)
Major morphologic features

1. Portal tracts are expanded by a marked lymphocytic infil-
Figure 2-54 Epstein-Barr virus. The sinusoids show numerous cir-
trate; the majority of the lymphocytes are atypical in cell culating lymphocytes that often have a beaded back-to-back appear-
size and nuclear and cytoplasmic appearance. ance.
2. The lobular cord–sinusoid pattern is intact, without sig-
nificant liver cell ballooning or hydropic change, and is
associated with a mild and sometimes moderate degree of
focal necrosis, apoptosis, and hepatocytolysis.
3. An increase in circulating atypical lymphocytes within
the sinusoids is seen, with a tendency of these cells to line
up in a beaded back-to-back pattern.
Other features
1. Areas of parenchymal necrosis may have an ill-defined
“granulomatous” appearance without distinct epithelioid
or multinucleated giant cells; rarely, epithelioid granulo-
mas can be seen, but they are uncommon.
2. Portal eosinophils and plasma cells in some instances
may be present.
3. Kupffer cell hyperplasia is present and is often
prominent.
4. “Endothelialitis” (inflammation of the endothelial lining)
by activated lymphocytes may be demonstrated occa-
sionally and involves portal and terminal hepatic venules. Figure 2-55 Epstein-Barr virus. The circulating sinusoidal lympho-
5. Some degree of macrovesicular fatty change may occur cytes in this example are atypical, with round to irregularly shaped
but is not prominent. nuclei and scanty to moderate eosinophilic cytoplasm.
6. Cholestasis may occur but is quite uncommon. Molecular hybridization techniques

7. Lymphocytes surrounding bile ducts and infiltrating 1. In situ hybridization (PCR) on fresh frozen or fixed tissue
into the duct epithelium (“nonsuppurative cholangitis”) specimens can be used in the localization and demonstra-
may occasionally be seen. tion of the EBV genome (EBER) in portal lymphocytes.
8. EBV infection in immunocompromised patients may Note: Both immunohistochemical and in situ methodologies
rarely initiate phagocytosis of red blood cells by Kupffer are most useful in immunocompromised patients suspected
cells and macrophages. (See “Infection-Associated of having EBV infection.
[Reactive] Hemophagocytic Syndrome” in Chapter 12.)
9. Rarely, enlarged atypical lymphocytes with promi- Differential diagnosis
nent nucleoli may be seen within portal tracts and may 1. Acute viral hepatitis: Mild forms of acute viral hepati-
resemble Reed-Sternberg cells. tis caused by the hepatotropic viruses (most often acute
10. Viral inclusions are rarely identified on routine H&E HCV infection) may resemble the histologic changes
stain except in rare fatal cases. seen in acute EBV, although the degrees of portal atypi-
11. In biopsies taken from liver allografts in patients receiv- cal lymphocytes and sinusoidal lymphocytosis are more
ing low-dose immunosuppression, post-transplant pronounced in EBV.
lymphoproliferative disorders (PTLDs) may occur (see 2. Cytomegalovirus (CMV) hepatitis: Granulomatous necro-
Chapter 11 for a more detailed discussion). sis tends to be somewhat more prominent in CMV infec-
tions than in EBV infection, and the degree of atypical
Immunohistochemistry lymphocytic infiltrates is less striking in CMV than in
1. Epstein-Barr nuclear-associated antigens (EBNAs) and EBV infection. Nuclear and cytoplasmic viral inclusions
latent membrane proteins (LMPs) show positive staining may be identified in hepatocytes, biliary epithelium,
of lymphocytes containing the EBV-encoded proteins. endothelium, and Kupffer cells in immunocompromised
patients with CMV infection.
3. Drug-induced liver cell injury (e.g., phenytoin; see Table
5-4): The basic morphologic features in drug-induced
hepatitis may be similar to those seen in EBV infection;
however, the prominence of atypical lymphocytes in EBV
is not a feature seen in drug-induced hepatitis.
4. Chronic lymphocytic leukemia: Although lymphocytes
within portal tracts and sinusoids may be quite prominent
in EBV infection, the lymphocytes are atypical and poly-
morphic in type and shape, whereas in chronic lymphocytic
leukemia, the infiltrates are monomorphic (confirmed on
immunoperoxidase stains as well as flow cytometric tech-
niques). In addition, granulomatous necrosis is not a fea-
ture seen in association with leukemic infiltrates.
5. Hodgkin lymphoma: The uncommon larger atypical portal
lymphocytes seen in and among eosinophils and plasma
cells in acute EBV infection may mimic features of
Figure 2-56 Epstein-Barr virus. The necrosis and inflammation seen Hodgkin lymphoma. The presence of numerous circulat-
within the lobule can form irregularly shaped aggregates (“granulo- ing atypical lymphocytes seen in EBV infection is not a
matous” necrosis). feature of Hodgkin disease. In addition, the CD15 and
A B
Figure 2-57 Epstein-Barr virus. Inflammation of the endothelium by lymphocytes (endothelialitis) is seen involving a portal venule (A) and a
terminal hepatic vein (B).
CD30 immunoperoxidase markers for Reed-Sternberg that can eventually progress to a monoclonal (irrevers-
cells are negative in these atypical cells associated with ible) B-cell population (overt malignant lymphoma) with
EBV infection. chromosomal abnormalities and gene rearrangements.
12. Various complement receptors, such as CD21, and trig-
Clinical and biologic behavior gering mechanisms, such as CD95-mediated apoptosis,
1. EBV is a DNA lymphotropic virus of the herpesvirus also play a role.
group and is the recognized agent causing infectious
mononucleosis, with an incidence of approximately Treatment and prognosis
100,000 cases per year (twice that of acute viral hepati- 1. Treatment is supportive, although use of steroids has been
tis). It is also associated with a number of malignancies, considered by some in severe cases.
including PTLDs. 2. Antiviral therapy has a mitigating effect on the virus.
2. The incubation period is approximately 5 weeks, after
which fever, acute pharyngitis, splenomegaly, and lym-
phocytosis (atypical lymphocytes) develop; however, ½ Cytomegalovirus
to 2⁄3 of cases are subclinical.
3. The liver is involved in more than 90% of cases. Hepa- (Figs 2-58 through 2-63)
tomegaly is present in 10% to 15%, splenomegaly is seen
in 50%, and jaundice occurs only in 5% of patients. Major morphologic features
4. Recovery takes longer in patients who have infectious 1. Portal tracts exhibit a prominent lymphocytic infiltrate,
mononucleosis with liver involvement. Elevated serum with some of the lymphocytes appearing slightly atypical.
transaminases are usually less than 500 IU/L, gener- 2. The lobular cord–sinusoid pattern is intact, without sig-
ally lower than that seen in acute viral hepatitis from nificant liver cell ballooning or hydropic change, and is
the hepatotropic viruses. Alkaline phosphatase elevation associated with a mild and sometimes moderate degree of
may at times be pronounced (~1000 IU/L), associated focal necrosis, apoptosis, and hepatocytolysis.
with moderate hyperbilirubinemia. 3. An increase in circulating lymphocytes, some atypical,
5. In immunocompromised patients, chronic enzyme ele- within sinusoids is seen, with a tendency of these cells to
vations and morphologic changes may persist for years; line up in a beaded back-to-back pattern.
however, progression of the disease into a fibrotic or cir- 4. In immunocompromised patients, large intranuclear
rhotic stage has not been reported. amphophilic viral inclusions with a surrounding halo
6. Other associated conditions include Guillain-Barré syn- (“owl’s eye”) can be identified in hepatocytes, Kupffer and
drome, pulmonary infiltrates, pericarditis and myocardi- endothelial cells, and duct epithelium. Coarsely granular
tis, and splenic rupture. cytoplasmic inclusions can also be demonstrated within
7. The “monospot” test is sensitive (80%) and specific the same cells.
(99%) for EBV infection, but it may be initially negative
in 15% of patients. The diagnosis of EBV infection is Other features
confirmed by elevation of EBV-specific IgM antibody 1. Granulomas are sometimes present and are generally
and absent or low-titer antibody to EBV-associated poorly defined (granulomatous in type) without epithe-
nuclear antigen (EBNA). A single high VCA (viral cap- lioid or multinucleated giant cells; however, sometimes
sid antigen) antibody titer does not distinguish current true epithelioid granulomas without caseation may occur.
from previous infection. 2. Mild macrovesicular fatty change can sometimes be seen.
8. EBV infects B lymphocytes, with antigenic expression 3. Cholestasis may be present in severe cases but is generally
on the surface of the cell eliciting a response by T lym- uncommon.
phocytes. Their interaction produces the characteristic
“atypical” lymphocyte seen in the peripheral blood and
in liver biopsy.
9. The technique of in situ hybridization of EBER and
histochemical LMPs are methods to identify EBV in
liver biopsy specimens. These techniques can be useful
in the diagnosis of EBV in the post-transplant patient.
10. The pathophysiology of EBV infection has various
patterns:
a. Lytic (replicative) form: The EBV genome forms a
linear structure with complete gene transcription and
development of full viral particles that are shed and
readily infectious.
b. Latent (persistent) form: The genome forms a circular
plasmid with restricted gene expression, its presence
identified by the detection of EBER-1.
11. The presence of latent infection in the immunocompro-
mised patient, especially in the post-transplant setting,
may initially induce a benign polyclonal (reversible) Figure 2-58 Cytomegalovirus. The portal tract exhibits a prominent
B-cell proliferation (mononucleosis-type syndrome) lymphocytic infiltrate.
A
Figure 2-59 Cytomegalovirus. The parenchyma demonstrates
increased numbers of sinusoidal lymphocytes.
B
Figure 2-62 Cytomegalovirus (CMV). In immunocompromised
patients, CMV can often be seen as distinct viral inclusions. These
low-power (A) and high-power (B) images are from an HIV-positive
patient. Both nuclear and cytoplasmic inclusions can be seen within
this hepatocyte. Fatty change to variable degrees may also occur in
patients who have AIDS.
Figure 2-60 Cytomegalovirus. Higher power shows sinusoidal lym-

phocytosis and mild necroinflammatory change.
Figure 2-61 Cytomegalovirus. Granulomas can sometimes be seen Figure 2-63 Cytomegalovirus. The nuclear inclusion in this HIV-
within the lobules. In this example, epithelioid cells with scattered positive patient most likely involves an enlarged endothelial or
lymphocytes are present in the immediate periportal zone. Kupffer cell.
4. Lymphoid cells can occasionally be identified surround- or in those with acquired immunodeficiency syndrome
ing and infiltrating into interlobular bile duct epithelium, [AIDS]). Rarely, CMV may be acquired in adulthood
causing nonsuppurative bile duct injury. from numerous blood transfusions, such as occurs after
5. D uct destruction and depletion also may be associated open-heart surgery.
with periductal sclerosis (“sclerosing cholangitis”) in HIV 2. CMV hepatitis is clinically mild and self-limiting and
patients (HIV-associated cholangiopathy). accounts for approximately 8% of cases presenting with
6. The viral inclusions may be seen isolated, or they may an “infectious mononucleosis-like syndrome” with
elicit an inflammatory response that may be granuloma- hepatic involvement. Liver tests reveal mild to moder-
tous (mixed lymphocytes, eosinophils, macrophages, neu- ate elevations of serum transaminases (200 to 300 IU/L),
trophils) or purely neutrophilic (microabscess formation), elevation of the alkaline phosphatase values, and mild
the latter especially evident in liver allografts. hyperbilirubinemia. Atypical lymphocytes may be seen
7. Portal fibrosis does not occur in adults; however, portal on peripheral smear.
and interstitial fibrosis may be seen in neonates, often 3. The liver may be involved in congenital infection. Neo-
associated with multinucleated giant cell transformation, nates present with hepatosplenomegaly, jaundice, throm-
cholestasis, acute cholangitis, and duct destruction with bocytopenia, microcephaly, periventricular calcification,
ductopenia. chorioretinitis, and other signs of intrauterine infection.
Brain damage is often permanent.
Immunohistochemistry 4. Other associated conditions include Guillain-Barré syn-
1. CMV: Nuclear and less commonly cytoplasmic staining of drome, hemolytic anemia, meningoencephalitis, pneu-
viral inclusions may be identified in hepatocytes, bile duct monitis, myocarditis, esophagitis, and colitis presenting
epithelium, and Kupffer and endothelial cells in immu- with diarrhea and bleeding.
nocompromised patients. Most often, these inclusions 5. Rare cases of fatal massive hepatic necrosis have been
are also seen on routine H&E stain; however, CMV may reported, usually in immunocompromised patients.
infect cells without accompanying nuclear inclusions or an 6. CMV can be isolated from saliva, urine, blood, and tis-
inflammatory infiltrate, therefore making this stain clini- sues, with the virus causing cytopathic change on mono-
cally useful in early or latent infection. layer fibroblast cultures, and can be propagated in cell
culture from blood and urine samples. Antigenemia assay
Differential diagnosis is the current standard for the detection of viral DNA
1. Acute viral hepatitis: Mild forms of acute viral hepati- in infected white blood cells and is used to decide pre-
tis, more often secondary to acute HCV, may resemble emptive antiviral therapy in patients with post-transplant
the histologic changes seen in acute CMV infection, infections. By using PCR techniques, both quantita-
although the degree of sinusoidal lymphocytosis is more tive and qualitative viral DNA can be detected. Invasive
pronounced with CMV. In addition, the presence of CMV infection is best confirmed by histologic changes
granulomatous necrosis and epithelioid granulomas are on biopsies.
more often seen with CMV hepatitis. 7. CMV-specific antibody by solid-phase immunoassay
2. EBV hepatitis: Although the degree of lymphocytic infil- is useful to detect primary infection; however, approxi-
trates and numbers of atypical lymphocytes are more mately 30% of immunosuppressed patients may produce
marked in EBV infection, the granulomatous response in IgM-specific antibody with recurrent infection.
EBV is less commonly seen than with CMV. In addition,
EBV is not associated with intranuclear or intracytoplas- Treatment and prognosis
mic inclusions on routine H&E stain. 1. Supportive therapy is offered in most cases, because the
3. Drug-induced liver cell injury (e.g., phenytoin; see Table disease is almost always self-limiting in the immunocom-
5-4): Certain drugs can elicit a histologic response simi- petent patient.
lar to that seen with CMV infection, although usually 2. Acyclovir is effective for prophylaxis and ganciclovir for
a sinusoidal lymphocytosis, when present with drug- active disease in the immunocompromised patient (e.g.,
induced injury, is not prominent. status post-organ transplant, AIDS). Rarely, in ganci-
4. Chronic lymphocytic leukemia: Although numerous lym- clovir-resistant CMV infections, foscarnet has shown
phocytes within portal tracts and sinusoids may be seen in benefit. The newer agent valacyclovir may hold some
CMV infection, the lymphocytes are sometimes atypical promise for the long-term treatment of CMV infections.
and polymorphous in type and shape, whereas in chronic 3. In patients with AIDS who are receiving highly active
lymphocytic leukemia, the infiltrates are monomorphic antiretroviral therapy (HAART), the incidence of CMV
(confirmed on immunoperoxidase staining). In addition, infections appears to be declining.
granulomatous necrosis is not a feature seen in associa-
tion with leukemic infiltrates.
Herpes Simplex Virus
1. CMV is a ubiquitous DNA virus of the herpesvirus group (Figs 2-64 through 2-66)
that is the most common etiologic agent in congenital
infections. The virus commonly acquired at birth is not Major morphologic features
eradicated but becomes incorporated into the host cells 1. Coagulative-type necrosis is present, may be patchy or
as a latent infection and reactivates during immunosup- confluent with no particular zonal distribution pattern,
pressed states (e.g., after transplantation or chemotherapy and is associated with a minimal to absent inflammatory
Figure 2-64 Herpes simplex virus. Nuclear inclusions in hepato- Figure 2-65 Herpes simplex virus. Higher magnification demon-
cytes can be seen in the middle of the field in this low-power image. strates nuclear inclusions of both Cowdry type A (large and eosino-
The adjacent hepatocytes at the bottom of the field show extensive philic, with a peripherally located “clear” space or halo) and Cowdry
coagulative necrosis. type B (basophilic, filling up the entire nucleus with a peripheral rim
of finely granular chromatin). Some of the involved hepatocytes are
multinucleated.
response. This infection is most often seen in immuno-
compromised patients.
2. Two types of intranuclear inclusions are identified in liver
cells located at the interface of the necrotic and viable
regions:
a. Cowdry type A: Large and eosinophilic, with a periph-
erally located “clear” space or halo.
b. Cowdry type B: Basophilic, filling up the entire nucleus
(ground-glass appearance), with a peripheral rim of
finely granular chromatin.
Other features
1. The cytoplasm of the viable liver cells containing the nuclear
inclusions often has a more eosinophilic appearance.
2. The individual hepatocytes demonstrating the viral inclu-
sions may at times be multinucleated.
3. A prominent multinucleated giant cell transformation of
viable hepatocytes, particularly in the neonate, may be seen.
4. A variable, but generally sparse, portal lymphocytic
inflammatory infiltrate can at times be seen. Figure 2-66 Herpes simplex virus. The inclusions in this example
5. Acute hemorrhage may be present in the areas of necrosis. can be seen predominantly within the periportal liver cell nuclei, with
some degree of cytoplasmic involvement as well. (Immunoperoxi-
6. Massive hepatic necrosis has been described (in under- dase stain for herpes simplex virus.)
nourished children).
Special stains
1. Feulgen reaction: Positive nuclear staining is noted when infection may exhibit granulomatous necrosis as well as
the nucleus is filled with viral DNA (Cowdry type B), but nuclear inclusions in bile duct epithelium and Kupffer
it is negative when the virus has entered the liver cell cells, features not characteristic of herpes simplex
cytoplasm (Cowdry type A). infection.
2. Toxemia of pregnancy (eclampsia): Coagulative necrosis
Immunohistochemistry may be present in toxemia but is predominantly peripor-
1. Herpes I and II antigens: Intranuclear staining of cells tal in location and is associated with intrasinusoidal fibrin
containing the ground-glass inclusions is seen. Occasion- deposition.
ally, positive cytoplasmic staining of hepatocytes in and 3. Drug- and toxin-induced liver cell injury (e.g., acetamino-
around the necrotic areas may also be present. phen; refer to Table 5-3): Certain drugs and toxins may
be associated with coagulative-type necrosis without an
Differential diagnosis inflammatory infiltrate. In most instances a zonal distri-
1. Varicella-zoster virus infection: In rare cases, coagulative bution pattern in this type of drug-induced injury is also
confluent necrosis can be seen with chickenpox (vari- seen, although when the necrosis is severe and confluent,
cella); usually the liver injury is self-limited. Varicella the distinction with herpes virus infection may be difficult.
The absence of viral inclusions and the history and time Table 2-4 HIV-Associated Infections and
frame of drug use or toxin exposure are helpful clues in Neoplasms
diagnosis.
INFECTIOUS AGENTS NEOPLASMS
4. Various causes of vasculitis (e.g., polyarteritis nodosa, sys-
temic lupus erythematosus, rheumatoid arthritis) or severe Adenovirus Mycobacterium: Kaposi sarcoma
Aspergillus tuberculosis, High-grade (B-cell)
vascular compromise (e.g., hyperacute humoral allograft Bartonella avium-intracellulare lymphoma
rejection, heat stroke, left-sided heart failure with hypo- Candida species complex Central nervous
tension): Ischemic coagulative-type necrosis in the afore- Coccidioides Pneumocystis system lymphoma
mentioned disorders are due to impeded arterial blood Cryptococcus Toxoplasma
flow and usually involve the perivenular zones (zone 3 of Cryptosporidia Varicella-zoster
Cytomegalovirus Viral hepatitis, acute
Rappaport) first, although confluent necrosis involving Epstein-Barr virus (A, B, C, δ, E, G)
two zones or bridging necrosis involving adjacent lob- Gram-negative Viral hepatitis,
ules may occur in more severe cases. A pertinent clini- bacteria chronic (B, C, δ)
cal history and absence of viral inclusions is necessary for Herpesvirus
Histoplasma
distinction. Leishmania
Microsporidia
1. Two variants of herpes simplex hominis that may involve
the liver occur:
a. Type I: This type is present in oral secretions in 50%
of the general population and clinically manifested by
ulceration of the lip and buccal mucosa.
b. Type II: This type involves the genitalia and is spread
by sexual contact.
2. Hepatic involvement is associated with disseminated
infection and marked elevations of serum transaminases
and bilirubin. Disseminated intravascular coagulopathy
(DIC) is common.
3. Hepatic lesions are virtually never seen in healthy indi-
viduals, but they can be found in immunocompromised
patients (patients taking steroids or receiving chemother-
apy, those who are status post-transplant), malnourished
children, and rarely pregnant women.
Treatment and prognosis

A
1. In patients with symptomatic hepatic necrosis, death usu-
ally results in more than 90% of patients 1 to 2 weeks
after the beginning of symptoms.
2. Antiviral therapy with acyclovir and ganciclovir is the
standard choice for treatment; however, a number of
other agents, such as valacyclovir, penciclovir, and famci-
clovir, have been tried.
3. Liver transplantation has been offered in select patients
who were diagnosed early and treated with antiviral ther-
apy, with an overall good outcome.
Human Immunodeficiency Virus and Acquired

Immunodeficiency Syndrome
(Fig. 2-67)
Major morphologic features B

1. A marked depletion of lymphocytes within portal tracts
is seen in the majority of patients with clinically apparent Figure 2-67 Human immunodeficiency virus (HIV). Although
disease. various viral and opportunistic infections are often associated
with abnormal liver tests in HIV-positive patients (see Figs 2-62
2. Although there are no indications that a direct necroin- and 2-63), many times no microorganisms are seen on biopsy
flammatory response can occur secondary to HIV infec- material; however, in these instances, certain portal and lobular
tion, superimposed secondary opportunistic infections changes are frequent, as these two images demonstrate. A, The
are frequent; these infections include CMV and Myco- small portal tract is virtually normal, without an inflammatory infil-
trate (portal lymphocyte depletion) despite the fact that necrosis
bacterium avium-intracellulare complex (Table 2-4). The was seen in the parenchyma. B, The parenchyma from the same
morphologic changes often produce a granulomatous- biopsy shows nonspecific fatty change and mild necroinflamma-
type of inflammatory process. tory change.
Other features secondary hemolysis and/or increased numbers of blood

1. The granulomas are usually ill defined and are present transfusions.
randomly within the lobules. Multinucleated giant cells
may occasionally be seen involving the granulomas, but Immunohistochemistry
they are infrequent. The viable microorganisms that can 1. HBsAg, HBcAg: Coinfection with viral hepatitis, most
be demonstrated on special stains are often abundant. notably HBV, is sometimes seen, with serologic markers
2. Some opportunistic microorganisms such as CMV can of past and ongoing infection present in these patients
also be demonstrated within Kupffer and endothelial with HIV infection.
cells, as well as in duct epithelium. 2. Other viral markers (e.g., CMV, herpesvirus): Although var-
3. Kupffer cells may exhibit erythrophagocytosis in ious viral inclusions such as CMV can be seen on routine
approximately 10% of cases and have a foamy cytoplas- H&E stain, in some instances the inclusions can be incon-
mic appearance. spicuous, with the immunoperoxidase markers then helpful.
4. Mild to moderate predominantly macrovesicular fatty
change may be seen in 25% to 50% of cases. In rare Differential diagnosis
instances, striking macrovesicular fatty change may 1. Disorders other than AIDS that may cause portal lymphocyte
occur with fatal consequences. depletion: Portal lymphocytic infiltrates can be minimal to
5. Cholestasis occurs in less than 10% of cases. absent in various liver diseases that may otherwise dem-
6. Portal lymphocytic infiltrates, although usually sparse, onstrate lobular necroinflammatory changes. For exam-
can sometimes occur; at times the lymphocytic infil- ple, this may include patients with Hodgkin lymphoma,
trates can be prominent, particularly when associated patients who are immunocompromised secondary to che-
with a coexisting viral hepatitis (particularly HCV). motherapy or renal dialysis, and individuals with wide-
7. Damage to interlobular bile ducts may occur in some spread carcinoma. In addition, elderly patients tend to
cases, manifested by nuclear irregularity and pyknosis and have less of a portal inflammatory infiltrate in various
cytoplasmic hydropic change, and are most often second- conditions than younger patients.
ary to infiltration of the ducts by microorganisms, most 2. Disorders associated with duct loss: Ductopenia may occur in
notably CMV; however, considerable duct damage may patients with HIV-associated cholangiopathy, where the
be seen without demonstrable organisms or an accompa- portal duct depletion may resemble that seen in a number
nying inflammatory response orientated to the ducts. of disorders, such as autoimmune cholangiopathy, pri-
8. Progressive duct damage, sometimes associated with mary biliary cirrhosis, and primary sclerosing cholangitis.
portal lymphocytic and plasma cell infiltrates, periduc- All three listed conditions, however, show variable, but
tal fibrosis and sclerosis (sclerosing cholangitis), and duct often prominent, lymphocytic portal infiltrates, as well as
loss (HIV-associated cholangiopathy, vanishing bile duct other morphologic changes (e.g., plasma cell infiltrates in
syndrome) may occur. Cryptosporidia, although usually autoimmune hepatitis and primary biliary cirrhosis, Mal-
involving the extrahepatic biliary system, can also rarely lory bodies in primary biliary cirrhosis and primary scle-
be seen involving medium-sized interlobular and larger rosing cholangitis) that are not seen in HIV-associated
interlobar bile ducts and can also be associated with duct cholangiopathy.
damage. Note: In any case where unexpected opportunistic infections
9. Peliotic lesions have been described. In addition, angio- are identified in the liver, HIV infection should be consid-
proliferative processes (bacillary angiomatosis) have also ered in the differential diagnosis.
been reported secondary to infection by Bartonella
(Rochalimaea) species; these organisms are demonstrated Clinical and biologic behavior
by the Warthin-Starry reaction. 1. Approximately 34 million individuals worldwide are
10. Various neoplastic disorders such as Kaposi sarcoma, infected with HIV, the majority of whom live in sub-
B-cell non-Hodgkin lymphomas, and high-grade lym- Saharan Africa and other developing countries. In the
phoma variants may also occur, with EBV infection a United States, the number of reported new infections is
leading contributory factor in the development of the about 40,000 each year.
various lymphoproliferative processes. 2. HIV is a retrovirus (specifically lentivirus) and has a pro-
pensity for mutations. There are two main types: HIV-1
Special stains and HIV-2. HIV-1 is the infection that predominates
1. Identification of superinfection is usually enhanced by worldwide.
appropriate special stains (refer to organisms in Table 2-4): 3. HIV has a predilection for cells that express CD4 on the
a. Ziehl-Neelsen, Kinyoun’s acid-fast stain: acid- surface that acts as a receptor for the HIV gp120 glyco-
fast bacilli (Mycobacterium tuberculosis and M. protein and allows viral infection. The HIV p24 antigen
avium-intracellulare) has also been demonstrated within Kupffer and endo-
b. PAS: M. avium-intracellulare; fungi (Candida albicans, thelial cells, with HIV messenger RNA within liver cells
Cryptococcus neoformans) themselves.
c. Gomori-methenamine silver (GMS): fungi (Coccidioi- 4. The virus enters cells by fusion that binds the envelope
des immitis); protozoa (Pneumocystis carinii) protein into cell membranes, with eventual nuclear local-
d. Warthin-Starry: bacilli (Bartonella [Rochalimaea] ization. Reverse transcriptase is activated, and a DNA
henselae) copy of the virus is produced, incorporating into the host
2. Perl’s iron stain: Not infrequently, hemosiderin can be cell genome and serving as the template for replication.
seen within Kupffer cells, confirmed on iron stain, due to The DNA is translated into novel proteins and packaged
into virions, which are released into the extracellular

space to infect other cells. Active replication within cells
is highly toxic, leading to eventual cell death.
5. HIV is acquired from percutaneous and sexual trans-
mission. The risk of transfusion-acquired HIV is about
0.0001%.
6. The primary HIV infection may be asymptomatic or
present with acute retroviral syndrome (ARS) with fever,
lymphadenopathy (mononucleosis-like syndrome), rash,
hepatomegaly, postural hypotension, oral lesions, and
meningitis or radiculopathy. Rarely, ARS can present
with an AIDS-defining illness with CD4 counts of less
than 400 cells/mm3. Primary HIV infection is followed
by the development of HIV-specific antibodies, which
occur as early as 8 days and as late as 12 months after
infection. About 95% of infected persons will test positive
for HIV antibody within 6 months.
7. The most common test for HIV antibody is the enzyme- Figure 2-68 Lassa fever. The portal tract exhibits a moderate lym-
phocytic infiltrate.
linked immunosorbent assay test (ELISA) technique.
If the results are negative in suspected individuals, the
Western Blot is performed. Rarely, the specific viral p24
core protein or HIV RNA by PCR will be necessary to
confirm the diagnosis.
8. Liver disease is secondary to associated infections or
neoplasms. Chronic viral hepatitis B, HBV and HDV
(coinfection and superinfection), HCV, and CMV have
been noted in HIV-infected persons. The frequency of
HBV in HIV is unknown, and HCV is estimated to
occur in 9% to 40% of HIV-infected patients. Patients
with HIV who are coinfected with hepatitis B and C
have a more progressive liver disease and a higher risk
of developing cirrhosis and hepatocellular carcinoma.
Antiviral therapy is currently being offered to these
patients with coinfection, with the results expecting to
improve the outcomes.
9. The duct involvement (cholangiopathy) induced by HIV
is frequently secondary to CMV and/or cryptosporid-
ium infection. In addition, it is speculated that a distinct Figure 2-69 Lassa fever. The parenchyma shows focal coagulative-
human leukocyte antigen (HLA) haplotype may be asso- type necrosis with scattered lymphocytes and degenerating inflam-
ciated with duct involvement by HIV. matory cells.
Treatment and prognosis

1. HAART has changed the outcome of the disease, result- Major morphologic features
ing in longer survival and reduced frequency of AIDS- 1. Coagulative-type necrosis of liver cells is present and is
defining illnesses. A number of both nucleoside and patchy, with numerous apoptotic cells (e.g., acidophil
non-nucleoside reverse transcriptase inhibitors and pro- bodies, Councilman bodies) present.
tease inhibitors are also available; however, resistance to 2. The degree of accompanying lobular inflammation is
these drugs is becoming more frequent. The cost of the minimal.
treatment, the need for several drug combinations, and
compliance are significant limitations in the treatment Other features
strategy. 1. The necrosis shows no distinct zonal distribution pattern.
2. In patients with Kaposi sarcoma, the median survival is 2. Confluent necrosis may sometimes be seen in the more
18 to 24 months. In patients with opportunistic infec- severe cases.
tions, the survival is 6 to 8 months. 3. Mild fatty change can occasionally be present but is
uncommon.
4. The portal tracts exhibit a mild lymphocytic infiltrate
RARE SYSTEMIC VIRAL INFECTIONS WITH with normal bile ducts.
HEPATIC INVOLVEMENT
Electron microscopy
Lassa Fever 1. Although no viral inclusions are present on routine
H&E-stained sections, arenavirus can be demonstrated
(Figs 2-68 and 2-69) on electron microscopy.
Differential diagnosis
1. Acute viral hepatitis (hepatotropic viruses): Acute viral
hepatitis secondary to infection by the hepatotropic
viruses usually demonstrates variable degrees of hydropic
ballooning change with prominent lobular and por-
tal lymphocytic infiltrates. These features, however, are
not characteristic of Lassa fever, which instead shows
coagulative necrosis with only minimal or absent lobu-
lar inflammation and only mild portal inflammatory
infiltrates.
2. Other viral infections associated with numerous apoptotic
cells: Certain rare viral infections (e.g., Bolivian, Korean,
and Argentinian hemorrhagic fevers; Marburg and Ebola
virus infections; yellow fever; dengue fever) may morpho-
logically resemble Lassa fever. Epidemiology and isola-
tion of the viruses are necessary for diagnosis.
Clinical and biologic behavior Figure 2-70 Yellow fever. The portal tract demonstrates a mild lym-
phocytic infiltrate.
1. Lassa fever is a highly contagious and multisystem dis-
ease characterized by fever, pharyngitis, cough, severe
myalgia, prostration, renal failure, and the development
of diffuse hemorrhage with involvement of the skin and
subcutaneous tissue from a “leakage syndrome.”
2. The disease is caused by an arenavirus, a group of RNA
viruses responsible for hemorrhagic fevers, and is widely
present in West and Central Africa.
3. Infection is usually subclinical and transmitted by contact
with rodent (reservoir) excrement.
4. Hepatomegaly, right upper quadrant pain, and tender-
ness are common. Serum transaminases and lactate dehy-
drogenase activity are elevated, but bilirubin is usually
normal.
5. With use of real-time PCR, RNA levels can be detected.
Viremia rises steadily before death. The marked increase
in interferon-γ and tumor necrosis factor (TNF)-α
shortly before death suggests that proinflammatory cyto-
kines may play a part in the pathogenesis. Figure 2-71 Yellow fever. The parenchyma exhibits numerous apop-
6. Specific antibodies to the Lassa virus have been detected. totic cells throughout the lobule.
Antibodies appear to be directed to two proteins, 11-kDa
Z and nucleoprotein (NP), which are detected in about 2. The nuclei of surviving hepatocytes may infrequently
33% of human sera from endemic areas. demonstrate large eosinophilic inclusions (Torres bodies).
Treatment and prognosis Other features

1. About 5000 deaths annually from Lassa virus infections 1. The portal tracts exhibit a moderate lymphocytic infil-
occur in Western Africa, with the overall mortality from trate with normal bile ducts.
5% to 14%; however, mortality in pregnant women is 2. Mild microvesicular fatty change may be present, with
much higher. prominent fatty change infrequent.
2. Ribavirin appears to have some effect on the Lassa virus 3. Hepatocytes may demonstrate ballooning and rarely syn-
and may act through lethal mutagenesis. cytial giant cell transformation in some cases.
3. Immunity to Lassa virus infection appears to be cell
mediated, and currently vaccine development is in prog- Immunohistochemistry
ress using viral glycoproteins G1 and G2. 1. Yellow fever viral antigen: The viral antigen can be dem-
onstrated within scattered hepatocytes and Kupffer cells.
Yellow Fever Differential diagnosis

1. Acute viral hepatitis (hepatotropic viruses): Although both
(Figs 2-70 and 2-71) acute viral hepatitis secondary to infection by the hepa-
totropic viruses and yellow fever demonstrate portal lym-
Major morphologic features phocytic infiltrates, the lobular coagulative necrosis seen
1. Coagulative-type necrosis is prominent and is accentu- in yellow fever is quite striking and not a feature seen in
ated in the midzonal areas (zone 2 of Rappaport), with acute viral hepatitis. In addition, nuclear inclusions (Torres
numerous apoptotic cells evident. bodies), when present, are a key in diagnosing yellow fever.
2. Other viral infections associated with numerous apoptotic cells:

Certain infrequent viral infections (e.g., Bolivian, Korean,
and Argentinean hemorrhagic fevers; Marburg and Ebola
virus infections; yellow fever; dengue fever) usually are
associated with minimal lobular and portal inflammation,
whereas in yellow fever, portal and lobular inflammation
is more apparent (but not as striking as that seen in acute
viral hepatitis secondary to the hepatotropic viruses).

1. Yellow fever is the original viral hemorrhagic fever and is
caused by a member of the Flaviviridae family.
2. The disease is transmitted to humans by the Aedes aegypti
mosquito and affects 200,000 persons annually in the
tropical regions of Africa and Central and South America.
3. The incubation period ranges from 3 days to 1 week, with
the spectrum ranging from subclinical infection to a ful-
minant presentation. Figure 2-72 Echovirus. Extensive confluent coagulative necrosis is
seen involving the parenchyma. The small portal structure is rela-
4. Patients clinically present with fever, renal dysfunction tively unremarkable, with occasional cholangioles present but with
(e.g., acute tubular necrosis, hemoglobinuria), gastro- no inflammatory infiltrates.
intestinal hemorrhage, and coagulation abnormalities.
Moderate to marked elevations in serum transaminases
and bilirubin are usually present. 2. Ischemia secondary to hypotension and poor hepatic perfu-
sion: The ischemic necrosis seen in vascular compromise
Treatment and prognosis is similar to that present in enterovirus infection. Cor-
1. Vaccination using the live attenuated 17D virus routinely relation with the clinical history and virus isolation are
during childhood in endemic areas and in travelers to necessary.
these endemic areas is expected to decrease the incidence 3. Other viral infections associated with numerous apop-
of this infection. The recent reports of vaccine-related yel- totic cells: Certain rare viral infections (e.g., Bolivian,
low fever infection is a concern, although the risk is small; Korean, and Argentinean hemorrhagic fevers; Mar-
however, the risk of infection in nonvaccinated persons is burg and Ebola virus infections; yellow fever; dengue
far greater than the risk of vaccine-induced infection devel- fever), as well as enterovirus infection, are usually asso-
oping. Thus the current standard of treatment mandates ciated with minimal lobular and portal inflammation.
vaccination based on reports of endemic activity, season, In some instances hemorrhagic ischemic necrosis may
and likelihood of exposure to vector mosquitos. Research also be seen in the aforementioned conditions. Correla-
in the development of new vaccines is in progress. tion with the clinical presentation and viral serologies is
2. In nonvaccinated patients, coma and death occur in 10% essential.
to 60% of patients.
1. Echoviruses are enteroviruses that belong to the Picorna-
Echovirus (Enterovirus) viridae family. They have similarity to the poliovirus.
2. They comprise coxsackie virus A (serotypes 1 to 2 and
(Fig. 2-72) 24), coxsackie B (serotypes 1 to 6), echovirus (serotypes
1 to 9, 11 to 27, and 29 to 33), and enterovirus (serotypes
Major morphologic features 68 to 71). Both echovirus 6 and 11 are considered virulent
1. Hemorrhagic coagulative ischemic necrosis with apopto- strains. Since 1967, all newly discovered viruses in this
sis may occur, is often confluent, and is usually associated class are called enteroviruses.
with intravascular thrombosis and occlusion. 3. Echoviruses are cytopathic viruses that elicit a strong
2. Massive hepatic necrosis has been described. humoral response. In younger children the response is
homotypic (same serotype), whereas in older children
Other features and adults, the response is heterotypic (where antibodies
1. Mild portal lymphocytic infiltrates, bile duct prolifera- develop against several serotypes).
tion, and portal edema may occur. 4. Infections are spread by fecal-oral and respiratory routes,
and they present with a nonspecific exanthematous rash,
Differential diagnosis herpangina, lymphonodular pharyngitis, hemorrhagic
1. Acute viral hepatitis (hepatotropic viruses): The degree of conjunctivitis, pleurodynia, myocarditis, pericarditis,
portal inflammatory infiltrates in enterovirus infection is aseptic meningitis, encephalitis, myositis, and flaccid
relatively mild compared with the prominent portal lym- paralysis. Echovirus infections are also postulated to play
phocytic infiltrates seen in acute viral hepatitis second- a role in chronic fatigue syndrome and juvenile diabetes
ary to the hepatotropic viruses. In addition, hemorrhagic mellitus. Some recent evidence suggests that echovirus
ischemic necrosis is not a feature seen in typical acute viral (coxsackie B virus) infection may cause acute liver failure
hepatitis. in pregnancy.
5. Symptoms that generally relate to liver disease develop Treatment and prognosis
within approximately 4 days, with jaundice, hepato- 1. Treatment centers on the patient’s presenting symptoms.
megaly, elevated serum transaminase levels, coagula- 2. Mortality increases with associated myocarditis and
tion abnormalities, and decreases in serum albumin and encephalitis.
fibrinogen levels. Hemorrhagic complications occur in 3. Although no vaccines are yet available, in one study,
about 63% of patients, and intracranial bleeding occurs in therapy with pleconaril (VP63843) by nasogastric tube
about 30% of cases. resulted in recovery in 66% of neonatal infections and
6. Disseminated infections develop in neonates almost appears promising.
exclusively, with fulminant hepatic failure resulting from
hemorrhagic necrosis of the liver and adrenal glands.
7. Viral damage to the vascular and hepatic venous endo- OTHER VIRUSES THAT MAY CAUSE
thelium rather than direct damage to the hepatocytes LIVER DAMAGE
in the early viremic phase is considered the postulated
mechanism for the histologic findings. Table 2-5
8. The diagnosis is made by positive enterovirus anti-
body IgM (using radioimmunoassay or PCR-enhanced
immunoassay).
Table 2-5 Other Viruses that May Cause Liver Damage

DISEASE HISTOLOGY CLINICAL/LABORATORY PARAMETERS
Adenovirus • In immunocompromised patients, features are similar to • Adenovirus is a DNA virus related to upper and lower
those of herpes simplex virus infection, with extensive respiratory tract infections, lymphadenopathy, and
coagulative-type necrosis and little inflammation, these conjunctivitis; it may also cause gastrointestinal infections
changes sometimes oriented to the perivenular zones. and hepatitis.
• Intranuclear inclusions are prominent in viable liver cells. • The more severe infections occur in immunocompro-
mised patients and are associated with markedly elevated
serum transaminase levels.
• Mild elevations of serum transaminases may be noted
with normal bilirubin in the setting of a respiratory tract
infection in the immunocompetent patient.
Coronavirus • Prominent apoptosis is seen. • The novel coronavirus is a single-stranded RNA virus and
• Liver cell ballooning and lobular necroinflammatory the cause of severe respiratory distress syndrome (SARS).
changes can occur. • Mildly abnormal transaminase levels may be present;
severe hepatitis does not occur.
Dengue fever • Focal perivenular confluent liver cell necrosis with apop- • This arbovirus (RNA virus) is transmitted by the Aedes
tosis and dropout of hepatocytes but little inflammation is mosquito; infection is endemic in tropical countries.
present. • The disease is characterized by fever, severe myalgias
(breakbone fever), headache, malaise, and prostration.
• The liver test results are mildly abnormal, and fulminant
liver failure has not been reported.
Ebola virus • Coagulative-type necrosis without inflammation is • Outbreaks of infection by this RNA virus are associated
scattered within the lobules, with numerous acidophil with severe and often fatal hemorrhagic fever.
bodies (apoptosis) present. • Patients present with sudden onset of fever, malaise,
• The necrosis is usually patchy but in some cases may be nausea and vomiting, myalgias, maculopapular rashes, and
confluent. conjunctivitis.
• Liver dysfunction develops during the second week of
illness, although hyperbilirubinemia is uncommon.
Group B coxsackie • Mixed portal and sinusoidal inflammatory infiltrates • A member of the enteroviruses, group B coxsackie virus
(enterovirus) consisting of both mononuclear cells and neutrophils are may be associated with respiratory tract infection, myo-
seen. carditis, pericarditis, aseptic meningitis, pleurodynia, and
• Perivenular cholestasis and hydropic change of hepato- vesicular and papular rashes; in epidemic situations it can
cytes may occur. cause hepatitis.
• Hemorrhagic necrosis may occur in the neonate. • Positive specific antibodies to coxsackie B virus are
helpful in confirming the diagnosis.
Herpes zoster • Focal or confluent coagulative-type necrosis without • The predominant manifestations are the vesicular skin
inflammation (similar to that seen with herpes simplex) lesions associated with pain and neuralgia.
is present. • Liver disease is restricted to those who are immunocom-
• A variable number of intranuclear inclusions within promised, in whom liver involvement may be severe.
hepatocytes is seen.
Human herpesvirus-6 • Mild portal lymphocytic infiltrates and mild lobular • This member of the herpesvirus family is a cause of child-
(HHV) inflammation are present. hood roseola, and presents with fever, central nervous
• Bile ductular proliferation with multinucleated giant cell system disturbances, and a rash; bone marrow suppression
transformation occurs. may also occur.
• Two variants are known: HHV-6A, occurring later in
childhood or during adulthood, and HHV-6B, the cause
of roseola in childhood.
• Liver test results may be abnormal, and pancytopenia and
leukopenia may be present.
Table 2-5 Other Viruses that May Cause Liver Damage—cont’d

DISEASE HISTOLOGY CLINICAL/LABORATORY PARAMETERS
Marburg virus • Coagulative-type necrosis with minimal or absent lobular • This severe viral hemorrhagic febrile disorder presents
inflammation is present and scattered within the lobules. with the sudden onset of fever, malaise, headache, and
• Acidophil bodies (apoptosis) is common. myalgia, with shock and disseminated intravascular
• Patchy or confluent liver cell necrosis can occur. coagulation.
• The mortality is high, with the liver being a major target.
Parvovirus (B19 virus) • Hydropic change of hepatocytes is present. • Also referred to as erythrovirus, this small DNA virus is
• Portal lymphocytic infiltrates and diffuse necroinflamma- spread by infected respiratory droplets.
tory change (in children) occur. • Transmission through pregnancy can occur, with hydrops
• Nuclear inclusions within hepatocytes may be seen. fetalis being a serious complication.
• Giant cell hepatitis has been described in the neonate. • Patients develop a rash with fever and malaise; arthritis
can also develop in the adult, and aplastic anemia has
been described.
• Abnormal liver test results indicating hyperbilirubinemia
and severe coagulopathy may occur, predominantly in the
neonate; acute giant cell hepatitis has also been described.
Rubella • Features of neonatal hepatitis with multinucleated giant • This RNA virus causes a benign, self-limited infection
cell transformation of liver cells is present. in humans that is manifested by mild fever, suboccipital
• In mild cases, nonspecific focal necrosis, cholestasis, and lymphadenopathy, and skin rash.
lymphocytic infiltration are seen. • Congenital rubella syndrome from intrauterine infection
• Massive hepatic necrosis has been described but is causes growth and mental retardation, deafness, congeni-
uncommon. tal heart disease, corneal opacities, cataracts, retinopathy,
• D uct loss (ductopenia) has been described but is infre- and meningoencephalitis; late manifestations include
quent. immunodeficiency.
• Hepatic manifestations include hepatosplenomegaly,
modest increases in serum transaminase levels, and nor-
mal or mild increase in serum bilirubin.
• Serologic diagnosis is made by the presence of acute and
convalescent hemagglutination inhibition antibodies.
Rubeola • Variable degrees of portal lymphocytic infiltration occur. • This highly contagious RNA virus causes an exanthema-
• Mild lobular mononuclear inflammation and focal necro- tous infection with fever, cough, coryza, and conjunctivitis
sis are present. developing after an incubation period of 8–12 days.
• Fatty change to variable degrees may occur. • In severe hemorrhagic measles, seizures, mucosal bleed-
• Multinucleated syncytial giant cells and eosinophilic ing, and disseminated intravascular coagulation can occur.
nuclear and cytoplasmic viral inclusions are rarely seen. • Transient anicteric hepatitis characterized by mild to
moderate increases in serum transaminase levels may
develop, with hyperbilirubinemia rare.
• Serologic tests by complement fixation, hemagglutina-
tion inhibition, and enzyme immunoassays confirm the
diagnosis.
REFERENCES
The complete reference list is available online at www.

expertconsult.com.

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Viral Hepatitis

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Chapter

MAJOR HEPATOTROPIC VIRUSES: A, B, δ, C, E, G, or interface hepatitis (“piecemeal necrosis”) is not a

Immunohistochemistry both a portal and lobular inflammatory reaction may be

Table 2-1 Clinical and Biologic Behavior of Hepatotropic Viruses

have HGV in the serum.

Table 2-2 Serologic Diagnoses of Acute and Chronic Viral Hepatitis

Figure 2-17 Fulminant hepatitis. This low-power image from a sec-

Figure 2-19 Fulminant hepatitis. A portal tract and the adjacent

3. Cytokeratins (particularly CK7, CK8, CK18, and CK19):

Figure 2-28 Chronic viral hepatitis, active. Lymphocytes can be

Figure 2-30 Chronic viral hepatitis. Nuclear anisocytosis and mild

2. Lobular necrosis, inflammation, hydropic change, and

Figure 2-35 Chronic viral hepatitis: hepatitis B virus (HBV) + δ. The

Figure 2-37 Chronic viral hepatitis: hepatitis B virus (HBV), elec-

3. Cholestasis may be seen in the more severe and active

5. The liver cells adjacent to areas of necroinflammatory

Figure 2-45 Chronic viral hepatitis: hepatitis C virus (HCV). Peri-

these cells; in fact, the ground-glass cells can clus-

d. HGV Table 2-3 Chronic Viral Hepatitis Histologic

c. Liver biopsy is an important tool in selecting patients

SYSTEMIC VIRAL INFECTIONS WITH HEPATIC

Major morphologic features

6. Cholestasis may occur but is quite uncommon. Molecular hybridization techniques

Figure 2-60 Cytomegalovirus. Higher power shows sinusoidal lym-

Treatment and prognosis

Human Immunodeficiency Virus and Acquired

Major morphologic features B

Other features secondary hemolysis and/or increased numbers of blood

into virions, which are released into the extracellular

Treatment and prognosis

Treatment and prognosis Other features

Yellow Fever Differential diagnosis

2. Other viral infections associated with numerous apoptotic cells:

Clinical and biologic behavior

Table 2-5 Other Viruses that May Cause Liver Damage

Table 2-5 Other Viruses that May Cause Liver Damage—cont’d

The complete reference list is available online at www.

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3. Cytokeratins (particularly CK7, CK8, CK18, and CK19):

2. Lobular necrosis, inflammation, hydropic change, and

3. Cholestasis may be seen in the more severe and active

5. The liver cells adjacent to areas of necroinflammatory

d. HGV Table 2-3 Chronic Viral Hepatitis Histologic

c. Liver biopsy is an important tool in selecting patients

6. Cholestasis may occur but is quite uncommon. Molecular hybridization techniques

2. Other viral infections associated with numerous apoptotic cells: