Pathology Pearls Post 5: Chronic Viral Hepatitis

Brief Case Presentation

A 40-year-old immigrant male with a distant history of “hepatitis,” presents to his primary care provider with a 2-month history of nausea, abdominal pain, anorexia, and weight loss. He denies use of herbal medications, alcohol, and illicit drugs. Initial laboratory results are seen below:

Lab ValueResult
AST373
ALT904
ALP64
Total Bilirubin1.9
Direct Bilirubin0.4
Albumin4.7

Given the patient’s elevated liver function tests, his primary care provider refers him to a hepatologist for further workup. Additional serologic testing is performed, the results of which are seen below:

Lab ValueResult
ANANegative
A1 Antitrypsin152
Mitochondrial M2 Ab< 0.1
Smooth Muscle AbNegative
HAV Ab, IgGPositive
HAV Ab, IgMNegative
HBV Core Ab(s)Positive
HBVe AbNegative
HBV Surface AbNegative
HBV DNA>1.7 x 10^7
HEV Ab, IgMNegative
CMV Ab, IgMNegative
EBV VCA IgMNegative
HIV-1/2 Ab/AgNon-reactive

Liver Biopsy

The patient is sent for a liver biopsy, which is shown below. The liver architecture is intact and there is a mild mononuclear cell infiltrate, with occasional eosinophils, involving the portal tracts (Figure 1A and 1B).

Figure 1A. Low power image of the liver biopsy, demonstrating inflammation around the portal tracts.
Figure 1B. Medium power reveals the inflammation is predominantly lymphocytic.

The interlobular bile ducts are intact and there is mild interface activity (older term “piecemeal necrosis”) recognized by lymphocytes in the periportal parenchyma, in association with hepatocellular damage (Figure 2A and 2B). 

Figure 2A. Medium power image showing mild interface and lobular activity.
Figure 2B. Higher power image revealing interface activity, which is seen as lymphocytes surrounding periportal hepatocytes.

The lobular parenchyma shows mild to moderate activity (recognized by lymphocytes in the sinusoids and lymphocytic aggregates associated with hepatocyte loss in the liver parenchyma) . There is no significant steatosis or cholestasis (Figure 3).

Figure 3. Area of lobular activity with a lymphocytic aggregate.

Given the clinical history, hepatitis B core (HBcA) and surface antigen (HBSA) immunostains are performed.  The HBcA stain is positive, showing nuclear and cytoplasmic staining (Figure 4). The HBSA stain is also positive, demonstrating strong cytoplasmic staining (Figure 5).

Figure 4. HBcA immunostain demonstrating nuclear and cytoplasmic positivity (red-pink hue), supporting the diagnosis of hepatitis B.
Figure 5. HBSA immunostain demonstrating cytoplasmic positivity (diffuse red-pink hue), supporting the diagnosis of hepatitis B.

Trichrome demonstrates patchy portal and periportal fibrosis with no areas of bridging (stage 2 of 4) (Figure 6).

Figure 6. Trichrome stain showing portal and periportal fibrosis (stage 2 of 4).

These findings, in conjunction with the clinical history, are consistent with chronic hepatitis B infection with grade 2 necroinflammatory activity and stage 2 fibrosis.

The patient was started on entecavir with marked improvement in HBV DNA and liver function tests.

What are the characteristic histologic features of chronic hepatitis?

The overall pattern seen in chronic hepatitis is a mild to moderate mononuclear (predominantly lymphocytic) infiltrate involving the portal tracts, as well as mild to moderate lobular activity. Interface activity is usually present.

There are many possible causes for chronic hepatitis, including viral infection (hepatotropic viruses), autoimmune hepatitis, and drug-induced liver injury. A few other conditions produce similar histologic changes (namely portal inflammation, +/- interface activity), such as Wilson’s disease, alpha-1-antitrypsin deficiency, and primary biliary disorders (primary biliary cholangitis, primary sclerosing cholangitis) etc.

In contrast to other hepatotropic viruses, liver biopsies with hepatitis B may show “ground glass” hepatocytes, which contain abundant finely granular eosinophilic cytoplasm (Figure 7).

Figure 7. Hepatitis B demonstrating “ground glass” hepatocytes, characterized by finely granular eosinophilic cytoplasm.

As mentioned above, due to the histologic overlap between many of the causes of chronic hepatitis, the diagnosis relies heavily upon clinical correlation, especially with serologic studies and medication history.

What are the pathologic scoring systems used to evaluate chronic liver disease?

Regarding chronic liver disease, liver biopsies are taken to evaluate the extent and progression of disease, which guides therapy. There are several histologic scoring systems used to evaluate chronic hepatitis. The scoring systems used to evaluate chronic liver disease specific to ASH/NASH are discussed in LFN Post 4. Similarly, the scoring systems used to evaluate chronic liver disease secondary to other causes, such as viral infection, are also based upon the degree of necroinflammatory activity (grade) and fibrosis (stage).          

The most common scoring systems for chronic hepatitis include Batts-Ludwig [3] and Ishak (modified Knodell) [4] systems.

BATTS-LUDWIG

In the Batts-Ludwig scoring system [3], the grade is given on a scale of 0-4 based on the degree of interface activity, and lobular inflammation, and necrosis (see Table 1). The fibrosis is also scored on a scale of 0-4 (see Table 2). Representative diagrams of the degree of necroinflammatory activity and fibrosis from Theise et al. are seen in Figures 9 and 10 [5].

Table 1. Batts & Ludwig: Grading of Disease Activity in Chronic Hepatitis [3]

Terminology
Semiquantitativ
e
Terminology
Descriptive
Lymphocytic Piecemeal NecrosisLobular inflammation and necrosis
0Portal inflammation only, no activityNoneNone
1MinimalMinimal, patchyMinimal, occasional spotty necrosis
2MildMild, involving some or all portal tractsMild, little hepatocellular damage
3ModerateModerate, involving all portal tractsModerate, with noticeable hepatocellular change
4SevereSevere, may have bridging fibrosisSevere, with prominent diffuse hepatocellular damage

Figure 9. Batts & Ludwig : Diagram of Necroinflammatory Activity (adapted by Theise) [3,5]

Portal tracts in chronic hepatitis (inflammation denoted by blue dots; portal tracts denoted by the red-brown well circumscribed regions) (a) grade 1: minimal interface activity, may have some lobular activity (b) grade 2: mild interface and lobular activity (c) grade 3: moderate interface and lobular activity (d) grade 4: severe and confluent interface and lobular activity

Table 2. Batts & Ludwig: Staging of Chronic Hepatitis [3]

SemiquantitativeDescriptiveCriteria
0No fibrosisNormal connective tissue
1Portal fibrosisFibrous portal expansion
2Periportal fibrosisPeriportal or rare portal-portal septa
3Septal fibrosisFibrous septa with architectural distortion; no obvious cirrhosis
4CirrhosisCirrhosis

Figure 10. Batts and Ludwig: Progression of Scarring in Chronic Hepatitis (adapted by Theise) [3,5]

(a) portal tract scarring, (b) fibrotic septa extending from portal tracts and focally linking them, (c) a transition to cirrhosis where some of the tissue shows regenerating nodularity completely bounded by scar, and (d) fully established cirrhosis.

ISHAK (modified Knodell)

The Ishak scoring system is based off of the Knodell system, which originally designated a histologic activity index (HAI) [6]. The HAI combined the grade (necrosis and inflammation) and stage (fibrosis). The Ishak score generates the scores for grade and fibrosis separately (Tables 3 and 4) [4].

Table 3. ISHAK: Modified HAI Grading – Necroinflammatory Scores [4]

Periportal or Periseptal Interface Hepatitis (Piecemeal Necrosis)Score
Absent0
Mild (focal, few portal areas)1
Mild/moderate (focal, most portal areas)2
Moderate (continuous around <50% of tracts or septa)3
Severe (continuous around >50% of tracts or septa)4
Confluent NecrosisScore
Absent0
Focal1
Zone 3 necrosis in some areas2
Zone 3 necrosis in most areas3
Zone 3 necrosis and occasional portal-central bridging4
Zone 3 necrosis and multiple portal-central bridging5
Panacinar or multiacinar necrosis6
Focal (spotty) lytic necrosis, apoptosis, and focal inflammationScore
Absent0
One focus or less per 10x objective1
Two to four foci per 10x objective2
Five to ten foci per 10x objective3
More than ten foci per 10x objective4
Portal InflammationScore
None0
Mild, some or all portal areas1
Moderate, some or all portal areas2
Moderate/marked, all portal areas3
Marked, all portal areas4


Table 4. ISHAK: Modified Staging – Architectural changes, fibrosis, and cirrhosis [4]

Degree of FibrosisScore
No fibrosis0
Fibrous expansion of some portal areas, with or without short fibrous septa1
Fibrous expansion of most portal areas, with or without short fibrous septa2
Fibrous expansion or most portal areas with occasional portal to portal bridging3
Fibrous expansion or most portal areas with marked bridging (portal to portal as well as portal to central)4
Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis)5
Cirrhosis, probably or definite6

References

[1] R. Saxena, Practical Hepatic Pathology: A Diagnostic Approach: Second Edition. 2017.

[2] Torbenson, Atlas of Liver Pathology: A Pattern-Based Approach. 2020.

[3] Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995 Dec;19(12):1409-17. doi: 10.1097/00000478-199512000-00007. PMID: 7503362.

 [4] Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995 Jun;22(6):696-9. doi: 10.1016/0168-8278(95)80226-6. PMID: 7560864.

[5] Theise ND. Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach. Mod Pathol. 2007 Feb;20 Suppl 1:S3-14. doi: 10.1038/modpathol.3800693. PMID: 17486049.

[6] Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981 Sep-Oct;1(5):431-5. doi: 10.1002/hep.1840010511. PMID: 7308988.

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