Liver & intrahepatic bile ducts

• Spherical, enveloped, single stranded RNA virus
  • Genus Hepacivirus
  • Flaviviridae family
• Sequence heterogeneity with 6 major genotypes (types 1 - 6)
  • Most common subtypes in the U.S. are 1a, 1b, 2, 3 (J Clin Gastroenterol 2019;53:40, Gastroenterology 2006;131:478)
• Transmission
  • IV drug use
  • Vertical (perinatal)
  • Sexual (low compared to HBV, HIV)
  • Transfusion (low risk with donor screening)

Batts-Ludwig grading and staging of chronic hepatitis

Grading				Staging
Semiquantitative	Descriptive	Interface activity	Lobular activity	Semiquantitative	Descriptive	Criteria
0	Portal inflammation only (no activity)	None	None	0	No fibrosis	Normal connective tissue
1	Minimal	Minimal; patchy	Minimal; occasional hepatocyte apoptosis	1	Portal fibrosis	Fibrous portal expansion
2	Mild	Mild; involving some or all portal tracts	Mild; little hepatocellular damage	2	Periportal fibrosis	Periportal or rare portal - portal septae
3	Moderate	Moderate; involving all portal tracts	Moderate; with noticeable hepatocellular damage	3	Septal fibrosis	Fibrous septa with architectural distortion; no obvious cirrhosis
4	Severe	Severe; may have bridging necrosis	Severe; with prominent diffuse hepatocellular damage	4	Cirrhosis	Cirrhosis

• Batts-Ludwig grading and staging system is simpler and more routinely used in clinical practice compared to the Ishak modified hepatic activity index (HAI) (Am J Surg Pathol 1995;19:1409, Clin Exp Med 2023;23:273)

Ishak modified hepatitis activity index (HAI) grading and staging of chronic hepatitis

Necroinflammatory score	Portal inflammation	Interface hepatitis	Confluent necrosis	Focal (spotty) lytic necrosis and focal inflammation	Modified staging	Descriptive
0	None	Absent	Absent	Absent	0	No fibrosis
1	Mild (some or all portal areas)	Mild (focal, few portal areas)	Focal	1 focus or less per 10x objective	1	Fibrous expansion of some portal areas, with or without short fibrous septa
2	Moderate (some or all portal areas)	Mild to moderate (focal, most portal areas)	Zone 3 necrosis in some areas	2 - 4 foci per 10x objective	2	Fibrous expansion of most portal areas, with or without short fibrous septa
3	Moderate to marked (all portal areas)	Moderate (continuous around < 50% of tracts or septa)	Zone 3 necrosis in most areas	5 - 10 foci per 10x objective	3	Fibrous expansion of most portal areas with occasional portal - portal bridging
4	Marked (all portal areas)	Severe (continuous around > 50% of tracts or septa)	Zone 3 necrosis + occasional portal - central bridging	> 10 foci per 10x objective	4	Fibrous expansion of portal areas with marked bridging (portal - portal, portal - central)
5			Zone 3 necrosis + multiple portal - central bridging		5	Marked bridging (portal - portal or portal - central) with occasional nodules (incomplete cirrhosis)
6			Panacinar or multiacinar necrosis		6	Cirrhosis, probable or definite

• Ishak modified hepatitis activity index (HAI) was published in 1995 as a modification of the original Knodell system (1981)
• It is still commonly used in therapeutic trials as it includes semiquantitative evaluation of necroinflammatory activity and provides a numerical value
• Original system included adding both the necroinflammatory and fibrosis parameters to produce a numerical score; however, in practice, a modified HAI (mHAI) is produced by separately reporting the sum of necroinflammatory scores (0 - 18) and the fibrosis stage (J Hepatol 1995;22:696, Clin Exp Med 2023;23:273)

Images hosted on other servers:

• Acute phase rarely diagnosed (asymptomatic)
• Chronic infection (> 6 months) often diagnosed during serologic workup of elevated transaminases
• Initial screening for anti-HCV antibodies (standard or rapid immunoassay)
  • Positivity does not distinguish between current and previous infections
• HCV RNA assays
  • Real time PCR or transcription mediated amplification (TMA)
  • Detection confirms present infection
  • Quantitative and qualitative tests; quantitative tests can measure baseline viral load
• HCV core antigen test
  • Resource limited settings where nucleic acid tests not available
• Liver biopsy performed infrequently for primary diagnosis but can serve the following purposes (N Engl J Med 2017;377:756)
  • Grading (activity) and staging (fibrosis) of liver (Mod Pathol 2007;20:S3)
  • Diagnosis / exclusion of other injury etiologies (e.g., autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, metabolic dysfunction associated steatotic liver disease)
  • Evaluation of suspicious lesions / masses

• Aminotransferase levels (ALT, AST) typically elevated
• Anti-HCV antibody immunoassay and HCV RNA detection by real time PCR or TMA (see Diagnosis)
• Autoantibodies may be detected: antinuclear antibodies (ANA), anti-liver kidney microsomal antibody (anti-LKM), anti-smooth muscle, antithyroid antibodies (BMJ Open Gastroenterol 2018;5:e000203, Biomed Pharmacother 1999;53:234)

Images hosted on other servers:

• Goal is eradication of HCV RNA and achieve sustained virologic response (SVR)
  • SVR = undetectable viral level at 12 weeks following cessation of therapy
• Direct acting antiviral agents (DAAs)
  • Acute and chronic infection
  • Pangenotypic DAA regimens have high efficacy (SVR ≥ 95%)
  • Prevent recurrent (posttransplant) hepatitis C in HCV viremic donors
  • Examples of DAA regimens include sofosbuvir - velpatasvir and glecaprevir - pibrentasvir
• Historically, treatment included pegylated interferon alpha in combination with ribavirin
  • High rate of side effects
  • SVR rate ~30% (J Clin Transl Hepatol 2015;3:140)

Images hosted on other servers:

Contributed by Alexander Kikuchi, M.D., Ph.D.

Images hosted on other servers:

• See information covered under Etiology, Diagnosis and Laboratory subsections

• Liver, core biopsy:
  • Active hepatitis with mild activity and periportal fibrosis (grade 2 of 4, stage 2 of 4, Batts-Ludwig methodology), consistent with hepatitis C (see comment)
  • Comment: Sections of the biopsy contain approximately 12 portal tracts for evaluation. The portal areas show mild, predominantly lymphocytic inflammation with patchy interface activity and associated periportal hepatocellular swelling. One portal area contains a lymphoid aggregate. No significant ductular reaction is seen and interlobular bile ducts are intact. The lobular parenchyma shows mild inflammation with frequent spotty necrosis (acidophil bodies). No significant steatosis, cholestasis or viropathic changes are identified. A trichrome stain is performed and shows mild periportal fibrosis (stage 2, scale 0 - 4, Batts-Ludwig methodology). The overall findings are consistent with the provided clinical history of hepatitis C; however, other causes of hepatitis, including drug induced injury, other infectious etiologies (hepatotropic and nonhepatotropic viruses), Wilson disease and autoimmune hepatitis, should be excluded.

• Liver, core biopsy:
  • Active hepatitis with mild periportal fibrosis; mild steatosis and centrizonal pericellular fibrosis (see comment)
  • Comment: Sections of the biopsy contain approximately 18 portal tracts for evaluation. Prominent, dense lymphoid aggregates are noted within the portal tracts along with occasional plasma cells, eosinophils and histiocytes. Mild interface activity is seen as well as focal ductular reaction. The interlobular bile ducts are intact. The lobular parenchyma shows patchy inflammation with scattered spotty necrosis (acidophil bodies). Mild steatosis is present, involving approximately 30% of the sampled hepatic parenchyma. Occasional swollen hepatocytes are present but no definite ballooned hepatocytes are identified. No cholestasis or viropathic changes are identified. A trichrome stain highlights centrizonal, pericellular fibrosis as well as periportal fibrosis with septa formation. The overall findings are those of active hepatitis. Some of the histologic features, such as dense periportal lymphocytic inflammation with lymphoid aggregates and interface activity, are in keeping with the clinical history of hepatitis C. Other features, including the presence of steatosis and centrizonal pericellular fibrosis, may also raise consideration of prior steatohepatitic injury. By the Batts-Ludwig system of chronic hepatitis grading, the mild lobular and periportal inflammatory activity would be grade 2 (scale 0 - 4). The findings of centrizonal and periportal fibrosis with septal formation indicate stage 2 by either the Batts-Ludwig or modified Kleiner-Brunt methodology (scale 0 - 4).

• HBV hepatitis:
  • Serologic testing for hepatitis B markers
  • May have ground glass hepatocytes (chronic infection; not specific for hepatitis B)
• Autoimmune hepatitis:
  
  • Generally more severe hepatitis (interface activity, hepatocyte injury)
  • Prominent plasma cells
  • Serologic testing for autoantibodies
  • Caveat: autoantibodies can be expressed in HCV; false positive anti-HCV has been reported in autoimmune hepatitis (Ann Intern Med 1992;116:21)
• Drug induced hepatitis:
  • History of causative agent (drug / herbal supplement)
• Metabolic dysfunction associated steatotic liver disease (formerly nonalcoholic fatty liver disease):
  
  
  • Ballooned hepatocytes
  • Pericentral pericellular fibrosis
  • Predominantly lobular inflammation
  • Portal inflammation less pronounced (ranging from mild to focally moderate)
  • Zone 3 predominant steatosis (rather than nonzonal distribution)
• Acute cellular rejection (transplant setting):
  • Predominantly mixed portal inflammatory infiltrate (typically containing eosinophils)
  • More prevalent duct injury or presence of true endothelial injury (not just passenger lymphocytes in subendothelial space)
  • More rapid rise in liver function enzymes, negative viral load
  • Both recurrent hepatitis C and acute cellular rejection can be present in same biopsy
• Primary biliary cholangitis:
  
  • May demonstrate similar portal based inflammation with interface and lobular activity
  • More prominent duct injury, eventual duct loss
  • Florid duct lesions
  • Elevated alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), serum IgM and antimitochondrial autoantibodies

• Torbenson: Biopsy Interpretation of the Liver, 4th Edition, 2021, Burt: MacSween's Pathology of the Liver, 8th Edition, 2023, Odze: Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 4th Edition, 2022, Ferrell: Liver Pathology, 1st Edition, 2011

A 40 year old woman is found to have elevated transaminases and a liver biopsy is performed showing the above finding. What is the most likely etiology?

1. Autoimmune hepatitis
2. Chronic biliary obstruction
3. Hepatitis B
4. Hepatitis C
5. Lymphoma

D. Hepatitis C. The image shows a portal tract containing a lymphoid aggregate composed of a dense, relatively well circumscribed collection of lymphocytes. Occasionally these lymphoid aggregates may also contain a germinal center (not seen in this example). This finding is characteristic (though not pathognomonic) for chronic hepatitis C infection.

Answer A is incorrect because autoimmune hepatitis is typically characterized by prominent portal plasma cells and the presence of a relatively discrete portal lymphoid aggregate is more suggestive of hepatitis C virus. Answer B is incorrect because features suggestive of chronic biliary obstruction including ductular reaction, cholestasis, duct injury or cholangitis are not identified. Answer C is incorrect because the histologic finding of a portal lymphoid aggregate is more characteristically seen in hepatitis C, although hepatitis B is an important differential diagnosis that should be clinically excluded. Hepatocytes with glassy eosinophilic cytoplasm (so called ground glass hepatocytes, not seen in this example) can also be seen in hepatitis B. Answer E is incorrect because although chronic hepatitis C is associated with non-Hodgkin B cell lymphomas, the findings in the current biopsy tract show a polymorphic appearing lymphoid aggregate without significant cytologic atypia or monomorphic appearance.

Comment Here

Reference: Hepatitis C virus (HCV)

The liver from a 55 year old man with a known history of hepatitis C infection is shown above. If the findings in this image are representative of the remaining liver, what would be an appropriate grade and stage using Batts-Ludwig methodology for chronic hepatitis?

1. Grade 1, stage 1
2. Grade 1, stage 2
3. Grade 2, stage 3
4. Grade 2, stage 4
5. Grade 4, stage 4

D. Grade 2, stage 4. The image shows cirrhotic liver recognizable by the presence of thick, bridging fibrotic bands separating nodules of hepatocytes. Cirrhosis is stage 4 (highest available stage) using Batts-Ludwig methodology. Patchy, mild interface activity is seen without prominent, diffuse hepatocellular injury, making grade 2 (not grade 4 as listed in answer choice E) the more appropriate interpretation. Answer A is incorrect because the image shows cirrhotic liver (stage 4) and the inflammation is more appropriately categorized as mild (grade 2), not minimal (grade 1). Answers B and C are incorrect because the image shows cirrhotic liver (stage 4). Answer E is incorrect because the image shows patchy, mild interface activity without prominent diffuse hepatocellular injury, making grade 2 (not grade 4) the more appropriate interpretation.

Comment Here

Reference: Hepatitis C virus (HCV)