Hepatitis B

Published on 21/04/2017 by admin

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Last modified 22/04/2025

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 Typically transmitted vertically, parenterally, or sexually

Clinical Issues

• 10% of infected patients become chronically infected

image 400 million people worldwide have chronic HBV
• Symptoms include mild flu-like syndrome, nausea, vomiting, jaundice

image > 50% are asymptomatic
• Lifelong risk of developing cirrhosis &/or HCC
• Useful laboratory tests include serology for HBV viral antigens, anti-HBV antibodies, and HBV DNA viral load

Microscopic

• Acute hepatitis B

image Hepatocytic swelling, predominantly lobular inflammation, spotty necrosis
image Severe cases may show confluent and bridging necrosis, collapse of hepatocytic cords, hepatocytic regeneration
• Chronic hepatitis B

image Portal-based inflammation with variably present ground-glass hepatocytes, “sanded nuclei” in hepatocytes, variable fibrosis 

– Stage of fibrosis indicates disease progression and is important therapeutic and prognostic indicator
• Immunohistochemistry for HBcAG and HBsAG may be useful, but not invariably positive

Top Differential Diagnoses

• Hepatitis A, hepatitis C, autoimmune hepatitis, other viral infections (CMV, EBV)

image Histologic features may be very nonspecific, so correlation with history and serology is crucial
image
Ground-Glass Hepatocytes
Ground-glass hepatocytes image have glassy eosinophilic cytoplasm representing proliferation of smooth ER in response to HBsAg.

image
Sanded Nuclei
Hepatitis B-infected hepatocytes may have pale pink, finely granular intranuclear inclusions (sanded nuclei image ) representing nuclear accumulation of HBcAg. These may be hard to detect on routine H&E staining.
image
HBV, Acute
This case of acute HBV infection shows lobular disarray with marked hepatocyte swelling and lobular inflammation.
image
HBV, Chronic
This section shows interface hepatitis in chronic hepatitis B consisting of chronic inflammatory cells that extend beyond the limiting plate image into the periportal parenchyma.

TERMINOLOGY

Abbreviations

• Hepatitis B virus (HBV)

Synonyms

• Australia antigen: Hepatitis B surface antigen (HBsAg)

Definitions

• Infection by HBV

image Member of Hepadnaviridae family
image Genome comprises partially double-stranded DNA virus

ETIOLOGY/PATHOGENESIS

Infectious Agents

• Transmitted parenterally

image Vertical transmission: Mothers to newborn infants
image Horizontal transmission: Between young children
image Sexual contact
• Liver injury appears to be immune mediated

image HBV-specific T cells play key role in pathogenesis and viral clearance

CLINICAL ISSUES

Epidemiology

• Incidence

image 400 million people worldwide are chronically infected with HBV

Presentation

• Acute hepatitis B

image Symptoms include mild flu-like symptoms, nausea, vomiting, jaundice
– > 50% are asymptomatic
image < 1% develop fulminant liver failure leading to death or liver transplantation
image Serum HBsAg and anti-HBc virus IgM Ab positive
• Chronic hepatitis B

image Serum HBsAg positive and anti-HBc virus IgM Ab negative

Laboratory Tests

• Serology for HBV viral antigens: HBsAg, HBcAg, HBeAg
• Serology for anti-HBV antibodies: Anti-HBs, anti-HBc, anti-HBe
• Serum HBV DNA and viral load
• Elevated transaminases

Natural History

• 10% of infected individuals become chronically infected

• Life-long risk of developing cirrhosis &/or HCC in chronic hepatitis B
image Cirrhosis is not prerequisite for developing HCC
– HBV viral genome can act as oncoprotein and intergrade into host genome
• Coinfection with HIV, HCV, and hepatitis D virus (HDV) is common, as they share common transmission route

Treatment

• Drugs

image Nucleoside analogue therapy: Lamivudine, adefovir, entecavir
image Interferon

MACROSCOPIC

Cirrhosis

• Nodularity (macronodular or mixed macro- and micronodular) and scarring

MICROSCOPIC

Histologic Features

• Acute hepatitis B

image Hepatocytic swelling, lobular disarray, and predominantly lobular inflammation
– Mainly mononuclear, including lymphocytes, plasma cells, and Kupffer cells
image Apoptotic hepatocytes and spotty necrosis
image Some cases may show marked cholestasis
image Confluent and bridging necrosis in severe cases with parenchymal collapse and hepatocyte regeneration
– Collapse best demonstrated by reticulin stain
image Immunohistochemistry generally not useful in acute HBV, as virus is rapidly eliminated and thus not detectable
• Chronic hepatitis B

image Portal-based inflammation

– Mononuclear inflammatory cells infiltrates, composed predominantly of lymphocytes admixed with Kupffer cells and plasma cells
– May expand portal tracts
image Interface hepatitis (previously termed piecemeal necrosis)

– Mononuclear inflammatory cells and apoptotic hepatocytes beyond limiting plate
image Lobular hepatitis

– Aggregates of mononuclear inflammatory cells, apoptotic hepatocytes, hepatocytic debris, &/or confluent necrosis
image Fibrosis

– Begins in portal regions, extends beyond limiting plate, then forms bridging septa between portal-portal and portal-central regions and ultimately cirrhosis
image Ground-glass hepatocytes

– Finely granular cytoplasmic inclusion
– Pushes cellular contents and nucleus to side due to proliferation of smooth ER in response to abundant HBsAg
– Can be highlighted by Shikata Orcein stain, Victoria Blue stain, and anti-HBs immunohistochemical stain
– Indicates chronic hepatitis B infection
– Not specific for hepatitis B
image Sanded nuclei of hepatocytes

– Pale pink granular inclusions in hepatocytic nuclei containing HBcAg
– Can be highlighted by anti-HBc immunohistochemical stain
– Extensive nuclear staining for anti-HBc indicates active HBV viral replication and may suggest immunosuppression status
• Fibrosing cholestatic hepatitis B

image Variant of viral hepatitis B that often has more progressive course and worse outcome
image Pathogenesis is thought to be due to viral cytopathic effect
image Typically occurs following orthotopic liver transplantation, but also occurs in other immunosuppressed states

– Occurrence is currently less common due to better prevention and antiviral regimens
image Unique histopathology

– Hepatocytic swelling due to cholestasis
– Canalicular and bile ductal cholestasis
– Marked bile ductular reaction
– Extensive fibrosis extending from portal tracts, surrounding hepatocytes within sinusoidal spaces, with serpiginous pattern
• Immunohistochemistry for HBcAg and HBsAg may be useful, but not invariably positive

Semiquantitative Grading and Staging

• Grading denotes inflammatory activity while staging indicates degree of fibrosis
• Stage of fibrosis indicates disease progression and is important therapeutic and prognostic indicator
• Ishak score or Batts/Ludwig system most commonly used

DIFFERENTIAL DIAGNOSIS

Hepatitis A

• Positive hepatitis A serology (anti-HAV IgM)
• Negative HBV serology
• Often history of travel or food poisoning

Autoimmune Hepatitis

• Positive autoimmune serology (ANA, anti-SMA, LKM, SLA)
• Negative HBV serology (HBsAg, anti-core IgM, anti-core IgG)
• More prominent plasma cells
• Responds to steroids

Chronic Hepatitis C

• Positive anti-HCV antibody and HCV RNA in serum
• Negative HBV serology
• Portal lymphoid aggregates, Poulsen (bile duct) lesion, and steatosis more common in hepatitis C

Drug-Associated Hepatitis

• Medication history that corresponds to onset of liver disease

image Symptoms ideally resolve after drug withdrawal
• Negative HBV serologies
• Eosinophils may be prominent

Hepatitis E

• Positive travel history and anti-HEV serology

Other Viral Hepatitides

• CMV hepatitis

image Neutrophilic microabscesses typical
image Characteristic viral inclusions
• EBV hepatitis

image Atypical lymphocytes in lobules, especially those lining sinusoidal space in bead-like appearance
• Herpes simplex virus hepatitis

image Confluent necrosis mimicking ischemia
image Typical syncytial cell virus inclusion
• Yellow fever

image Positive travel history and virologic studies
• Dengue fever

image Positive travel history and virologic studies
• Syphilitic hepatitis

image Positive serology
image Warthin-Starry stain or immunostain for Treponema pallidum

Primary Biliary Cholangitis

• Elevated antimitochondrial antibody, alkaline phosphatase, GGT
• Alkaline phosphatase typically elevated out of proportion to transaminases
• Predominantly affecting middle-aged women
• Duct destruction not characteristic of HBV infection

Other Causes of Ground-Glass Cells

• Lafora disease

• Cyanamide toxicity
• Fibrinogen storage disease
• Glycogen pseudo-ground-glass cell change
image Commonly seen in immunosuppressed individuals and post liver transplant

DIAGNOSTIC CHECKLIST

Pathologic Interpretation Pearls

• Purpose of liver biopsy is to grade and stage HBV-induced liver disease and exclude concomitant liver diseases

• HBV coinfection with other viruses, such as HCV, HDV, and HIV, is common
image Correlation with clinical history and serology is important
• Unlike hepatitis C, recurrent hepatitis B after liver transplantation is rare due to advent of antiviral prophylaxis

image Be cautious not to overdiagnose recurrent hepatitis B in posttransplant biopsy

image
HBV, Chronic
The features of chronic hepatitis B are often nonspecific, as seen in this biopsy with portal-based mononuclear cell inflammation. HBV and HCV can appear quite similar histologically and may also coexist.
image
Lobular Inflammation
H&E section demonstrates a focus of lobular inflammation composed of lymphocytes and Kupffer cells image. Ground-glass cells and sanded nuclei are present in surrounding hepatocytes.
image
HBV, Acute
This case of acute hepatitis B shows lobular inflammation and scattered apoptotic hepatocytes image. This case also has cholestatic features, which are occasionally seen in acute HBV infection.
image
Fibrosis
Masson trichrome stain shows collagen strands that extend beyond portal tracts to reach the central region and form bridging septa in chronic hepatitis B.
image
Immunohistochemistry for Surface Antigen
Positive cytoplasmic staining for hepatitis B surface antigen often forms a perinuclear crescent image .
image
Immunohistochemistry for Core Antigen
Immunohistochemical stain for anti-HBc (core antigen) shows both cytoplasmic and nuclear staining.

SELECTED REFERENCES

1.Halegoua-De Marzio, D, et al. Then and now: the progress in hepatitis B treatment over the past 20 years. World J Gastroenterol. 2014; 20(2):401–413.

2.Trépo, C, et al. Hepatitis B virus infection. Lancet. 2014; 384(9959):2053–2063.

3.Whittaker, G, et al. Hepatitis B in pregnancy. South Med J. 2014; 107(3):195–200.

4.Pol, S. Management of HBV in immunocompromised patients. Liver Int. 2013; 33(Suppl 1):182–187.

5.Liang, TJ. Hepatitis B: the virus and disease. Hepatology. 2009; 49(5 Suppl):S13–S21.

6.Mani, H, et al. Liver biopsy findings in chronic hepatitis B. Hepatology. 2009; 49(5 Suppl):S61–S71.

7.McMahon, BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009; 49(5 Suppl):S45–S55.

8.Goodman, ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007; 47(4):598–607.

9.Harrison, TJ. Hepatitis B virus: molecular virology and common mutants. Semin Liver Dis. 2006 May; 26(2):87–96. [Review. Erratum in: Semin Liver Dis. 26(3): 304-5, 2006].

10.Wisell, J, et al. Glycogen pseudoground glass change in hepatocytes. Am J Surg Pathol. 2006; 30(9):1085–1090.

11.Harrison, RF, et al. Recurrent hepatitis B in liver allografts: a distinctive form of rapidly developing cirrhosis. Histopathology. 1993; 23(1):21–28.

12.Ishak, KG. Light microscopic morphology of viral hepatitis. Am J Clin Pathol. 1976; 65(5 Suppl):787–827.

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