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PreviousNext Clinics in Liver DiseaseVolume 14, Issue 4, Pages 555-575, November 2010

Pathology of Chronic Hepatitis B and Chronic HepatitisC
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M. Isabel Fiel, MD

Abstract

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Article Outline

I.II. Approach to the diagnosis of chronic hepatitis

A. Specimen AdequacyIII. The scoring systems for grading and staging chronic hepatitis

. Grade of Necroinflammation: Portal and Lobular ChangesA. Portal ChangesB. Lobular ChangesC. Stage of Fibrosis: Architectural ChangesD. Other Features seen in Chronic Hepatitis

IV. Chronic hepatitis BV. Clinical courseVI. Clinical diagnosis

VII. Histologic features of chronic hepatitis B. Immune-Tolerant PhaseA. Immune-Active (-Clearance) PhaseB. Immune-Inactive Phase

VIII. Immunohistochemical staining PatternsIX. HBV co-infection with HDV, HIV and HCV

. HBV-HDV Co-infectionA. HBV-Human Immunodeficiency Virus Co-infectionB. HBV-HCV Co-infection

X. Chronic hepatitis C. Diagnosis

XI. Clinical courseXII. Histopathologic features of chronic hepatitis C

. Bile Duct LesionsA. Lymphoid Follicles and Lymphoid AggregatesB. SteatosisC. Inflammation/Degree of InjuryD. Fibrosis/Architectural Changes

XIII. Other entities associated with chronic hepatitis C. Overlap Syndrome of Hepatitis C and Autoimmune HepatitisA. Hepatitis C with Autoimmune FeaturesB. Fibrosing Cholestatic Hepatitis

XIV. Practical approach to diagnosisXV. AcknowledgmentsXVI. References

XVII. Copyright

Histologic evaluation of the liver is a major component in the medical management and treatment algorithm ofpatients with chronic hepatitis B (HBV) and chronic hepatitis C (HCV). Liver biopsy in these patients remainsthe gold standard, and decisions on treatment are often predicated on the degree of damage and stage offibrosis. This article outlines the clinical course and serologic diagnosis of HBV and HCV for the clinician andthe pathologist, who together have a close working relationship in managing patients with acute and chronicliver disease. The salient histologic features are elucidated in an attempt to provide the clinician with anunderstanding of the basic histopathology underlying chronic HCV and HBV.

Keywords:Liver pathology,Chronic hepatitis C,Chronic hepatitis B,Grade,Stage of fibrosis,Inflammation
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Chronic hepatitis is defined as inflammation of the liver, often in the setting of raised aminotransferase levels

for a period of 6 months or longer.1The hepatotropic viruses responsible for chronic hepatitis are hepatitis B

virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV). Current medical practice requires stagingand evaluation of the degree of fibrosis formation in the liver, and less importantly, the degree ofnecroinflammation. Because a liver biopsy has inherent risks, with the incidence of complications requiring

hospitalization associated with percutaneous liver biopsy estimated to be 0.9%,2surrogate serum markers and

various imaging techniques have been developed to assess the severity of liver fibrosis,3,

4,

5However, these

noninvasive tests have limited ability to discriminate between the stages of fibrosis and, at best, are predictivein distinguishing minimal fibrosis from significant fibrosis.

6,

7The liver injury present in chronic hepatitis may be

variable, but the basic morphologic changes in all types of chronic viral hepatitis are similar. In this regard, the

liver biopsy remains the gold standard and is an important tool in the evaluation of patients with liver disease.8

Back to Article Outline

Approach to the diagnosis of chronic hepatitisSpecimen Adequacy

Adequate tissue for evaluation is requisite for grading and staging of liver disease, because small biopsy

specimen size can affect the accuracy of histologic interpretation.9Specimens obtained with cutting biopsy

needles are superior to those obtained with suction needles.10Larger-gauge needles (14- to 16-gauge) andbiopsy specimens at least 2 cm long are more likely to be adequate for assessing histologic changes.

9The

number of portal tracts required for an adequate liver needle biopsy is between 6 and 11, although 11 portal

tracts are generally considered an optimal specimen.9Sampling error is also a major obstacle

11regardless of

the length or width of the core, because a needle core biopsy represents only one-fifty thousandth of the entire

liver. Another pitfall is the experience of the pathologist.11

Rousselet and colleagues12

found that a pathologistwith a subspecialty in hepatopathology and practicing at an academic center has better consistency andaccuracy in interpretation of liver biopsies than pathologists in community practice.


The scoring systems for grading and staging chronic

hepatitisOver the last few decades, several grading and staging schemes for chronic hepatitis have been proposed and

developed. Before this, De Groote and colleagues13

had described 2 types: chronic persistent hepatitisconsidered to have a benign course and chronic active hepatitis considered to have a worse outcome. In 1971,

Popper and Schaffner14

added lobular hepatitis. Knodell and colleagues15

provided the first paper detailing anumerical scoring system for chronic hepatitis, the histologic activity index (HAI), which was the sum ofperiportal necrosis, intralobular necrosis, portal inflammation, and fibrosis. A higher total score indicatedgreater liver damage. Combining necroinflammation and fibrosis, which could be discordant, is a problem withthe Knodell score. A simple scoring system that separates necroinflammation from fibrosis was developed by

Scheuer.16

Scores ranging from 0 to 4 based on increasing severity were each given to degree of portalinflammation and interface hepatitis and to degree of lobular inflammation. A separate score (range 04) was

given to increasing stages of fibrosis, 4 being cirrhosis. A position paper by Desmet and colleagues17

in furthersupport of the Scheuer scheme was published. The authors placed emphasis on integrating the cause of the

chronic hepatitis into the diagnosis. In 1995, Batts and Ludwig18created the modified Scheuer system withaccompanying diagrams depicting the different grades and stages of chronic hepatitis (Table 1). In the same

year, Ishak19

and a group of hepatopathologists called the Gnomes published the modified Knodell HAI. Inthis landmark paper, grades for necroinflammation were separately categorized from the stage of fibrosis. TheIshak system contains more stages of fibrosis (06) than other systems. In recent years, the Ishak stagingsystem has become widely used in clinical trials because of its ability to more clearly differentiate milder

changes in fibrosis. Westin and colleagues20

found that the Ishak system has fair-to-good reproducibilitybetween observers. In the mid-1990s, a French group consisting of hepatologists and liver pathologists

published an algorithm for grading necroinflammation and created a staging system for fibrosis (F0F4).21

,22
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Table 1. Commonly used staging systems for fibrosis

Data fromScheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol1991;13(3):3724; Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J SurgPathol1995;19(12):140917; Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronichepatitis. J Hepatol 1995;22(6):6969; Intraobserver and interobserver variations in liver biopsy interpretationin patients with chronic hepatitis C. The French METAVIR cooperative study group.

FibrosisIshak System

Score

No fibrosis 0

Fibrous expansion of some portal areas, with or without short fibrous septa 1

Fibrous expansion of most portal areas, with or without short fibrous septa 2

Fibrous expansion of most portal areas with occasional portal-to-portal (P-P) bridging 3

Fibrous expansion of portal areas with marked P-P bridging and portal-to-central (P-C) bridging 4

Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis) 5

Cirrhosis, probable or definite 6

METAVIR System Stage

No fibrosis F0

Portal fibrosis without septa F1

Portal fibrosis with few septa F2

Numerous septa without cirrhosis F3

Cirrhosis F4

Scheuer System Stage

No fibrosis 0

Enlarged, fibrotic portal tracts 1

Periportal or portal-portal septa, but intact architecture 2

Fibrosis with architectural distortion, but no obvious cirrhosis 3

Probable or definite cirrhosis 4

Batts and Ludwig Score

No fibrosis 0

Portal fibrosis 1

Periportal fibrosis 2

Septal fibrosis 3

Cirrhosis 4
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In investigative studies, particularly those involving antiviral therapies, semiquantitative methods may beneeded. The choice of the classification scheme to be used is entirely up to the group of investigators. The

Knodell scoring system and the Ishak fibrosis scores are more commonly used in such studies.15

,19

Grade of Necroinflammation: Portal and Lobular Changes

In any of the classification and scoring schemes, grade is based on the degree of damage found in the liver forboth portal and lobular areas.

23Bridging necrosis and confluent necrosis may be present.

24In general, the

greater the degree of liver damage, the greater the elevation of the aminotransaminases.

Portal Changes

Inflammation in the portal tracts may be patchy or diffuse, involving all portal areas in the biopsy specimen.The inflammatory infiltrate consists of mature lymphocytes admixed with a sprinkling of plasma cells and,rarely, some eosinophils. Lymphoid aggregates and follicles are more commonly seen in chronic HCV but may

also be present in chronic HBV infection25

,26

,27

In its mildest form, the inflammatory infiltrate is confined to theportal tracts, and the edges of the portal areas remain smooth. In its most severe form, the portal tract is

expanded, with erosion of the limiting plate throughout its circumference.17

,24

Mild interface hepatitis andsevere interface hepatitis are illustrated inFig. 1. With spillage of inflammatory cells into the periportal area, the

hepatocytes along the limiting plate and beyond are eroded, a process termed interface hepatitis (formerlycalled piecemeal necrosis), which is an immune-mediated type of inflammation that results in hepatocyte

apoptosis.28

The result is that of a portal tract with irregular borders and a loss of periportal hepatocytes.29

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Fig. 1

Interface hepatitis. These 2 portal tracts show inflammatory cells spilling over into the periportal area,creating an irregular outline of the portal tract. (A) mild interface hepatitis with focal erosion of thelimiting plate and (B) severe interface hepatitis that results in an irregular outline of the entirecircumference of the portal tract.

Lobular Changes

Different forms and degrees of parenchymal injury may be seen in chronic hepatitis. Apart from interfacehepatitis, other types of injury include ballooning degeneration, apoptosis, and spotty, bridging, and confluentnecrosis. Ballooning degeneration is a type of injury occurring when the hepatocyte loses its normal polygonalshape and becomes swollen and rounded. Apoptosis is seen as shrunken hepatocytes, with or without nuclear

fragments, having a deeply eosinophilic cytoplasm (Fig. 2).23

Early apoptosis within intact liver cell plates

usually manifests as a single hepatocyte with eosinophilic cytoplasm surrounded by lymphocytes.23

Later on inapoptosis, the nuclear component is extruded, and all that is left is an acidophilic body with or withoutaccompanying inflammatory cells. Spotty necrosis, representing areas of hepatocyte loss, consists of smallaggregates of inflammatory cells composed mostly of lymphocytes and macrophages (seeFig. 2). Hence,these foci are often referred to as tombstones. Bridging necrosis occurs when 2 vascular structures are linkedby a row of necrotic hepatocytes, whereas confluent necrosis occurs when several lobules lose hepatocytes

and the parenchyma collapses.14
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View Large Image


Fig. 2

Lobular necroinflammation. An aggregate of inflammatory cells (arrowhead) is shown. The insetshows 2 apoptotic bodies.

Stage of Fibrosis: Architectural Changes

In the evaluation of chronic hepatitis, one has to consider that fibrosis is a dynamic process occurring over timeand that scarring results from chronic inflammation. Hepatic stellate cells and portal myofibroblasts contributeto the collagen formation. Trichrome or other connective tissue stains such as Sirius red should be used to fullycharacterize the degree of fibrosis. The initial damage consists of portal fibrosis with or without formation of

fibrous septa extending into the lobular parenchyma.25

This process constitutes the earliest forms of scarring inchronic HBV and HCV. Over time, fibrous septa extend from expanded portal tracts and link adjacent portaltracts. As fibrosis progresses, there is increasing distortion of the architecture. This is apparent when portaltracts that are linked by fibrous tissue have more pronounced fibrous bridges. Eventually, fibrous septa enclose

nodules, which constitutes cirrhosis.14

Table 1shows the different staging systems, with the descriptive termand corresponding fibrosis scores. The development of fibrosis in chronic hepatitis is illustrated inFig. 3, whichalso provides a graphic portrayal of the staging schemes for fibrosis commonly used in clinical practice andinvestigative studies.

View Large Image


Fig. 3

Fibrosis progression in chronic hepatitis. The initial damage is portal fibrosis (from left to right); aschronic injury progresses, there is gradual expansion of portal areas by fibrous tissue, with linking ofportal tracts by septa followed by creation of more bridges of fibrous tissue, which eventually results incirrhosis. The bottom panels show the corresponding fibrosis scores based on the different stagingschema.

Other Features seen in Chronic Hepatitis

Ductular reaction is a process that is also called ductular proliferation, proliferation of bile ductules, or formationof neocholangioles. Ductular reaction results when hepatic progenitor cells proliferate in response to

hepatocyte loss and because of an insufficient replicative capacity of the mature hepatocytes.30

Severeductular reaction in chronic liver injury indicates greater parenchymal damage, and the residual hepatocytesare unable to replicate through the normal pathway. The area of ductular reaction directly correlates with stage

of fibrosis.31
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Iron deposition, in Kupffer cells alone or in Kupffer cells and hepatocytes, is often seen in chronic hepatitis and

has to be reported when present.32

,33

Depletion of iron has been shown to lower transaminases and affords

better response to interferon and ribavirin therapy in chronic HCV.33

Liver cell dysplasia indicates a group of cytologic abnormalities found in specimens from patients with chronic

hepatitis and cirrhosis.34

It is more common in HBV-infected individuals. Large cell change (formerly calledlarge cell dysplasia) is identified as a focus of hepatocytes that are enlarged and display nuclear

pleomorphism, hyperchromasia, and multinucleation (Fig. 4).34,35Large cell change in chronic viral hepatitishas also been reported to depict hepatocyte senescence rather than being a precursor of hepatocellular

carcinoma.36

Small cell dysplasia is characterized by small hepatocytes with high nuclear-cytoplasmic ratio

that closely resemble hepatocellular carcinoma (HCC; seeFig. 4).37

This is considered to be the earliest

morphologically recognizable precursor lesion of HCC.38

On the other hand, in a recent study of patients with

chronic HBV, Koo and colleagues39

found that large cell dysplasia was associated with a threefold increasedrisk of developing HCC. They also found that there was no significant association between small cell dysplasiaand the development of HCC when compared with patients without small cell dysplasia.

View Large Image


Fig. 4

Liver cell dysplasia in chronic hepatitis and cirrhosis. The left portion shows large cell changes asdemonstrated by large pleomorphic nuclei; on the right is a focus of small cell dysplasia. The insetshows cytologic atypia with crowded and hyperchromatic nuclei and a high nuclear-cytoplasmic ratio.


Chronic hepatitis B

The prevalence of chronic HBV infection worldwide is estimated to be 5%, which translates to about 350 million

people.40

The prevalence differs between regions; in high-prevalence areas (8%20% of the population), suchas in southeast Asia and sub-Saharan Africa, the infection mostly occurs from HBV early antigen (HBeAg)-positive mothers transmitting the virus to their offspring perinatally (vertical transmission) or during early

childhood (horizontal transmission).41

,42

Currently in the United States, the highest incidence is seen betweenages 25 and 44 years, and the lowest among children younger than 15 years. The prevalence of hepatitis Bsurface antigen (HBsAg)-positive individuals is estimated to be 0.30%, which projects to about 800,000

Americans with HBV infection.

43

HBV is an enveloped double-stranded DNA virus of the Hepadnaviridae family and can cause acute or chronic

liver disease.44

HBV has been classified into 8 genotypes (AH) and multiple subgenotypes,45

with genotypes

C and D reported to have a greater chance of progression.46

,47

HBV infection acquired in childhood is differentfrom that acquired during adulthood. Among infants infected at birth, 90% have persistent infection. Among

infected adults, up to 90% can clear the virus, and only 1% to 5% go on to become chronically infected.48

In

acute infection, clinical hepatitis B becomes apparent after an incubation period of 45 to 180 days.49

Viralelimination begins several weeks before disease onset and is largely mediated by antiviral cytokines from cellsof the innate and adaptive immune responses. After viral DNA declines, a cytolytic immune response seen as
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hepatocyte apoptosis and necrosis ensues, coincident with clinical hepatitis.50

The main mechanism ofnecroinflammation results mainly from CD8 cytotoxic cells that recognize virus-infected hepatocytes and recruit

other inflammatory cells, which is then followed by a cascade of immunologic damage.19

,51


Clinical courseThe natural history of chronic HBV infection is complex and generally consists of 3 phases: immune-tolerant,

immune-active, and inactive hepatitis B phases.52

An infected person may pass through these phases or may

stay in one phase for a long period of time. A fourth phase, recovery, has been proposed.53

The immune-tolerant phase often occurs after perinatal infection from HBsAg/HBeAg-positive mothers. Serum alanineaminotransferase (ALT) levels are normal and HBV DNA, elevated (from 200,000 to>1 million copiesinternational unit (IU)/mL). During this phase, the HBV integrates into the hosts hepatocyte DNA. During theimmune-active phase, called the chronic hepatitis B phase or immune-clearance phase, patients may be

HBeAg-positive or HBeAg-negative52

,54

Those who are HBeAg-positive have elevated ALT levels and theHBV DNA level is greater than 20,000 IU/mL, whereas those patients who are HBeAg-negative but positive foranti-HBe usually have lower levels of HBV DNA (>2000 IU/mL) and mildly elevated ALT. The inactive hepatitisB phase is characterized by the absence of HBeAg and the presence of anti-HBe, normal ALT levels, and HBVDNA less than 2000 IU/mL. Individuals who clear HBsAg have been classified as being in the recovery phase.

The clinical outcome after clearance of HBsAg is generally better than in people who continue to be HBsAg-positive.

52,

55Liver inflammation and fibrosis improve over time.

56Undetectable serum HBsAg, however, does

not prevent HCC from developing many years later, because low-titer serum HBV DNA may still be present,despite the HBsAg being negative, from the virus becoming integrated into the host genome. Studies have

shown HBV DNA to be present in liver tissue in some of these individuals.55

,57


Clinical diagnosis

Testing for HBV markers is necessary for the detection and diagnosis of HBV. The serologic markers areHBsAg and its antibody (anti-HBs), HBeAg and its antibody (anti-HBe), and immunoglobulins G and M

antibody to hepatitis B virus core antigen (IgG anti-HBc and IgM anti-HBc). HBsAg seropositivity indicatesinfection; the presence of HBeAg indicates high HBV replication and infectivity.52

,58

Previous infection isdiagnosed by the detection of anti-HBc and anti-HBs. Persistence of serum HBsAg for more than 6 months

implies progression to chronic infection.59


Histologic features of chronic hepatitis B

Acute HBV infection resembles any type of acute hepatitis and is characterized by lobular disarray, ballooningdegeneration, apoptotic bodies, and lobular and portal inflammation. Similar histology is found in chronic HBV

with acute flares, acute superinfection with hepatitis D, and concurrent drug-induced liver injury.50

This type ofhistology is also seen in the presence of precore mutation that leads to HBeAg negativity and presents with

relapsing disease.60In severe acute fulminant cases, confluent and bridging necrosis may occur, leading tomassive or submassive hepatic necrosis.

61HBV replicates in hepatocytes but is not directly cytopathic. The

damage seems to be immune-mediated, with HBV-specific T cells playing a major role.54

,55

Inimmunocompetent people, HBV is not cytopathic, and hepatocellular damage is induced by the host immune

systems efforts to eliminate HBV.62

Ongoing inflammation is the driving force that leads to fibrosis, and increasing grade is associated with more

fibrosis.14

There is usually no correlation with inflammatory activity and clinical, biochemical, or virological

parameters, with 10% of patients with normal ALT having bridging fibrosis or even cirrhosis.63

Furthermore,30% of patients with persistently normal ALT may have significant fibrosis (stage 24). Also, no consistent
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relationship exists between serum HBV DNA levels and histology, especially in patients who are HBeAg-

positive.55

,56

A histopathologic hallmark of HBV infection is the presence of ground-glass hepatocytes (GGH) that representHBsAg-containing liver cells. The hepatocytic cytoplasm exhibits a smooth almost homogeneous appearance,with accentuation of the cell membrane and, sometimes, with an artifactual halo caused by the retraction of

the cytoplasm.64

The nucleus is often pushed to the edge of the cell. GGH are usually highlighted by

immunohistochemical staining (Fig. 5). Ultrastructurally, GGH are characterized by an abundance of smoothendoplasmic reticulum with an accumulation of HBV surface antigen.

64Similar hepatocytic characteristics are

seen in non-HBV-infected individuals and should be considered in the differential diagnoses. For example,

Lafora bodies are seen in patients with myoclonus epilepsy65

; polyglucosanlike inclusions, in patients on

polypharmacotherapy66

; GGH-like cells, in patients taking cyanamide as part of an alcohol aversion therapy;

liver glycogen bodies, in transplanted patients67

; and induction hepatocytes, in patients on certain

medications.68

View Large Image

Download to PowerPoint Fig. 5

GGH with the characteristic smooth, homogeneous, lightly eosinophilic cytoplasm with eccentricnuclei (arrowheads). Immunostain for HBsAg confirms the presence of HBV surface antigen (inset).

Immune-Tolerant Phase

The immune-tolerant phase can last from a few years to more than 30.52

,69

During this phase, liverinflammation and fibrosis are absent or minimal. Patients with chronic HBV who have remained in this phasehave mild disease, with disease progression being minimal; whereas patients who progress to the immune-

active phase often have disease progression.69

In this setting, GGH are numerous. On immunostaining, thereis a diffuse nuclear HBcAg (Fig. 6) and membranous pattern of HBsAg staining (Fig. 7). Furthermore, studies

have shown that there is an inverse relationship between the degree of diffuse membranous staining and70

inflammatory activity.55

,56

,71

View Large Image

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Fig. 6

Immunostain for HBcAg. Numerous hepatocytes have positive nuclear immunoreactivity; many ofthese demonstrate spillage of the antigen into the cytoplasm. The presence of positive cytoplasmicstaining indicates active viral replication.

View Large Image


Fig. 7

HBsAg immunostain.A group of hepatocytes with positive staining for HBsAg (clonal pattern) isdemonstrated. The staining is mainly submembranous, a finding which indicates active viralreplication.

Immune-Active (-Clearance) Phase

In this phase, lymphocytic portal inflammation with interface hepatitis and spotty lobular inflammation areprominent. Sometimes, bridging and confluent necrosis may be identified. Ongoing necroinflammatory damagemay lead to variable degrees of fibrosis or cirrhosis. On immunostaining, cytoplasmic and membranous

expression of HBcAg correlates with liver damage (seeFig. 6).70

The presence of HBcAg cytoplasmic staining

has been shown to be a strong predictor of high hepatitis B viremia.72

In both groups, inflammation is presentin the liver, with or without fibrosis. The cumulative incidence of cirrhosis developing in patients who were

HBsAg carriers positive for anti-HBe (inactive carriers) has been estimated to be 15% after 25 years follow-up.

55,

56Pure cytoplasmic staining may represent the presence of mutations that block the translocation of

HBcAg, particularly in individuals with core and precore promoter mutations.

Immune-Inactive Phase

Liver histology in this and the immune-tolerant phase is similar, inflammation being minimal.55

,56

There isusually improvement in liver fibrosis and inflammation over time. In those who remain in the inactive phase, theliver fibrosis is absent or minimal in degree and shows no evidence of progression over time. Immunostaining

shows groups of hepatocytes that are positive for HBsAg; however, staining for HBcAg has negative results.70


Immunohistochemical staining Patterns

Immunostaining using primary antibodies directed against the HBV surface and core antigens is routinely used

in clinical practice.73

Positive findings confirm HBV infection. Also, the pattern of expression may helpdetermine the phase of infection. Two major types of GGH have been identified based on morphology and

distribution.70

The 2 types have different biologic significance, each one having specific pre-S deletion

mutations.74

Type I GGH are usually scattered randomly throughout the lobules and are found throughout thereplicative phase. Type I GGH have eccentric nuclei, with ground-glass inclusions within the cytoplasm. Type IIGGH are distributed in large groups called clonal patterns and are usually seen in the late nonreplicative stage
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