Hepatitis B Virus

Slide 1 · HEPATITIS B VIRUS

Viral biology • immune-mediated injury • serology • chronic liver disease

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain HBV structure, genome, entry, and replication through an RNA intermediate.

Relate antiviral immunity to hepatocyte injury, clearance, and chronic infection.

Interpret HBsAg, anti-HBs, anti-HBc, HBeAg, and serum HBV DNA in clinical context.

Recognize major histologic patterns and long-term complications of HBV infection.

Slide 3 · HBV produces several distinct clinical outcomes

Exposure to HBV

Acute infection

With recovery

Acute liver failure

Chronic infection

Asymptomatic

Carrier state

Possible fibrosis / cirrhosis

HCC risk

Multiple outcomes depend on age at infection, host immunity and comorbidities.

Slide 4 · HBV is a DNA hepatotropic virus

HBV belongs to the family Hepadnaviridae.

The virion carries partially double-stranded circular DNA.

Replication proceeds through reverse transcription of an RNA intermediate.

Long-term liver injury depends strongly on the host antiviral immune response.

Central paradox

A DNA virus that uses reverse transcriptase during replication.

Slide 5 · Burden of chronic hepatitis B

WHO estimates reported (data year: 2022)

254 million people living with chronic HBV infection

The same source reports approximately 1.2 million new infections and 1.1 million HBV-related deaths annually.

Slide 6 · Geography and transmission are linked

HBV prevalence varies substantially across world regions.

High-prevalence settings include parts of Africa, Asia, and the Western Pacific.

Perinatal acquisition is an important driver of chronic infection in high-prevalence regions.

Prevalence and transmission patterns should not be generalized from one region to another.

Slide 7 · HBV transmission occurs through infected body fluids

Exposure category

Mechanism / examples

Parenteral

Blood exposure; Needle or syringe sharing

Sexual

Unprotected sexual contact

Perinatal

Transmission from an infected mother at birth

Horizontal in children

Minor breaks in skin or mucosa; Close bodily contact

Transfusion-related

Markedly reduced by donor screening

Slide 8 · Blood-donor screening reduces transfusion-associated HBV

Screening donated blood for HBsAg helps identify infectious donations.

Exclusion of paid blood donors is another measure described in the source.

Transfusion transmission has been sharply curtailed where these measures are implemented.

Other parenteral exposures remain important routes of HBV spread.

Slide 9 · Transmission at birth changes the natural history

Maternal HBV infection

Exposure at childbirth

Infant HBV infection

High risk of chronic persistence

The very young host has a much greater risk of persistent HBV infection than an infected adult.

Slide 10 · Childhood horizontal transmission is also possible

Transmission does not require a recognized needlestick exposure.

Minor breaks in skin or mucous membranes may permit viral entry.

Close household or childhood contact contributes in some high-prevalence settings.

Route of acquisition and age at infection both influence downstream disease burden.

Slide 11 · Age is a major determinant of HBV persistence

Perinatal infection

Approximately 90% may develop chronic infection.

Prolonged viral persistence increases lifetime complication risk.

Prevention around childbirth is therefore crucial.

Adult-acquired infection

Most cases resolve spontaneously.

Chronic infection develops in a minority.

Acute symptoms may be absent despite infection.

Figures refer to the textbook population estimates, not an individual patient’s prediction.

Slide 12 · HBV virion architecture

Viral DNA + Pol

HBsAg-bearing envelope

Host-derived lipid envelope contains viral surface glycoproteins.

HBcAg nucleocapsid

Partially double-stranded circular viral DNA and polymerase are enclosed by the core.

Slide 13 · The HBV genome encodes several functional products

Gene product

Main role

HBsAg

Envelope proteins: Large, middle, and small

HBcAg

Core/nucleocapsid protein; Virion assembly

HBeAg

Product of precore/core transcript; Replication-associated serum marker

HBV polymerase

DNA polymerase and reverse transcriptase activities

HBx

Transcriptional effects; Implicated in HBV-related HCC

Slide 14 · Three related proteins comprise HBsAg

Large HBsAg

Part of the viral envelope.

Usually associated with complete virions.

Participates in hepatocyte entry.

Middle HBsAg

Related envelope glycoprotein.

Encoded by the same viral surface region.

Contributes to the HBV surface-antigen family.

Small HBsAg

Abundantly released from infected cells.

Can be present without viral core material.

Contributes to noninfectious envelope particles.

Slide 15 · HBsAg is not synonymous with an intact virion

Infected hepatocyte

HBsAg protein production

Release of excess surface-antigen particles

Noninfectious envelope particles lack a viral core; Serum HBsAg does not directly quantify intact infectious virions.

Slide 16 · HBcAg and HBeAg are related but distinct

HBcAg

Nucleocapsid protein.

Participates in assembly of complete virions.

Can be identified by tissue immunostaining.

HBeAg

Produced from a longer precore/core transcript.

Serum marker associated with ongoing replication.

May be absent in replication-competent mutants.

Slide 17 · HBV polymerase performs reverse transcription

One enzyme complex carries two crucial enzymatic activities

DNA polymerase activity + reverse transcriptase activity

Reverse transcriptase activity enables viral DNA production from an RNA intermediate.

Slide 18 · HBx may contribute to HBV-associated carcinogenesis

HBx is not essential for the core replication process.

It may activate transcription of viral and selected host genes.

Its activity has been implicated in HBV-associated hepatocellular carcinoma.

The mechanism should not be reduced to a single HBx-driven event.

Slide 19 · HBV enters hepatocytes through NTCP

Large HBsAg

NTCP on hepatocyte surface

Viral entry

Genome delivered to nucleus

NTCP: Sodium taurocholate cotransporting polypeptide, a hepatocyte bile-salt transporter.

Slide 20 · The nuclear genome forms cccDNA

Partially double-stranded HBV DNA

Completion of plus strand

Covalently closed circular DNA

CccDNA is a nuclear viral DNA form that supports subsequent transcription.

Slide 21 · Reverse transcription makes HBV biologically distinctive

Nuclear cccDNA

Viral RNA intermediate

Reverse transcription

New viral DNA

This simplified cycle displays molecular directionality, not all steps in particle assembly.

Slide 22 · HBV replication spans nuclear and cytoplasmic events

Nuclear phase

Genome reaches the hepatocyte nucleus.

Plus strand is completed.

CccDNA is established.

RNA-mediated replication

Viral transcription yields an RNA intermediate.

Reverse transcription regenerates viral DNA.

New viral particles may be assembled and released.

Slide 23 · Viral persistence is not just continued protein secretion

The cccDNA form is established in infected hepatocyte nuclei.

HBsAg may be produced abundantly without intact viral core particles.

Measures of antigen production and HBV DNA replication provide different information.

Persistent infection may not be eliminated readily by antiviral therapy.

Slide 24 · Immune responses dominate hepatocyte injury

HBV-infected hepatocyte

Virus-specific CD8+ T-cell response

Hepatocyte injury

Hepatitis

The principal tissue damage is immunologically mediated; The source also allows cytopathic effects with very high viral replication.

Slide 25 · CD8+ T cells target HBV-infected hepatocytes

Cytotoxic CD8+ T cells are major effectors of hepatocyte damage.

Virus-specific recognition couples infection to necroinflammatory injury.

The magnitude and character of host immunity shape the clinical course.

A viral infection can therefore produce severe injury without direct viral lysis as the dominant mechanism.

Slide 26 · Effective T-cell immunity favors viral clearance

Virus-specific CD4+ and CD8+ cells

IFN-γ–associated antiviral response

Control of infection

Resolution of acute HBV

The textbook associates a strong virus-specific interferon-γ–producing response with resolution.

Slide 27 · Different immune responses lead to different outcomes

Effective antiviral response

Stronger virus-specific T-cell activity.

Greater likelihood of control and recovery.

Anti-HBs may appear after clearance.

Persistent infection

Insufficient durable elimination of infection.

HBsAg and viral DNA may persist.

Repeated immune-mediated injury may lead to fibrosis.

Slide 28 · High viral protein production can also alter cells

High-level replication and abundant viral proteins can produce cytopathic changes.

Nevertheless, most hepatocyte injury is attributed to the host immune attack.

Ground-glass change exemplifies an HBV-related intracellular protein accumulation pattern.

Distinguish intracellular antigen accumulation from mechanisms of necroinflammatory injury.

Slide 29 · HBV has a prolonged incubation period

Interval reported in the source

Approximately 4–26 weeks

HBsAg can become detectable before symptoms; Infectivity is not restricted to the icteric phase.

Slide 30 · Acute viral hepatitis has recognizable clinical phases

Incubation

Preicteric symptoms

Icteric phase (if present)

Convalescence

Not all individuals enter a clinically apparent icteric phase.

Slide 31 · Most acute adult HBV infections are mild or subclinical

Nearly two-thirds of acute adult infections are reported as mild or subclinical.

Clinical silence does not exclude viral replication or transmission.

The remaining symptomatic presentations often resemble other causes of acute hepatitis.

Serology and molecular testing establish the etiology.

Slide 32 · Acute symptoms reflect a hepatitic syndrome

Constitutional symptoms include anorexia and fever.

Jaundice may develop as liver dysfunction becomes apparent.

Right upper-quadrant pain can accompany acute hepatic inflammation.

The symptom complex is not specific for HBV versus another hepatotropic virus.

Slide 33 · HBV can produce immune-complex disease outside the liver

Circulating HBV antigens

Antigen–antibody complexes

Extrahepatic immune injury

Clinical examples include glomerulonephritis and polyarteritis nodosa.

Slide 34 · Acute liver failure is an uncommon severe outcome

Acute liver failure in approximately 0.1%–0.5% of acutely infected individuals.

Severe hepatocyte necrosis can develop over a short clinical interval.

Extensive loss of hepatocyte function may be life-threatening.

Acute liver failure is distinct from slowly progressive chronic HBV-associated cirrhosis.

Slide 35 · Most adult HBV infections resolve without treatment

A self-limited course is the usual adult outcome.

HBsAg disappears as infection resolves.

Protective anti-HBs typically becomes detectable after antigen clearance.

The proportion progressing to chronic HBV is much higher after perinatal acquisition.

Slide 36 · HBV serology measures different biological events

Marker

Principal information

HBsAg

Current HBV surface-antigen expression

Anti-HBs

Antibody linked to recovery or vaccine-induced protection

IgM anti-HBc

Recent infection; Useful during serologic window

HBeAg

Often indicates active replication

Anti-HBe

Often accompanies declining replicative activity

HBV DNA

Direct evidence of viral genomic material in serum

Slide 37 · HBsAg is an early marker of HBV infection

Infection

HBsAg detectable

Symptoms may develop

Clearance or persistence

HBsAg precedes symptomatic disease and usually disappears after recovery.

Slide 38 · Anti-HBs indicates a protective antibody response

Anti-HBs typically appears after disappearance of HBsAg during recovery.

Anti-HBs may persist long-term and confer protection.

Vaccination with HBsAg seeks to generate this protective antibody.

Absence of anti-HBs in a patient with persistent HBsAg is compatible with chronic infection.

Slide 39 · The serologic window is bridged by IgM anti-HBc

Qualitative serologic sequence — schematic; Not a quantitative concentration curve

Acute infection

HBsAg wanes

Window period

Anti-HBs present

HBsAg

IgM anti-HBc

Anti-HBs

The marker positions are schematic; Timing varies among individuals.

Slide 40 · HBeAg is associated with viral replication

HBeAg usually appears soon after HBsAg during productive infection.

Its persistence supports continued replication and infectivity.

Sustained HBeAg may indicate a higher likelihood of chronic disease.

HBeAg is an indirect marker and has an important mutational exception.

Slide 41 · HBeAg-negative HBV may still replicate

Conventional interpretation

HBeAg often accompanies HBV DNA positivity.

Persistent HBeAg is evidence of viral replication.

Seroconversion to anti-HBe may accompany waning infection.

Replication-competent variants

Mutations can prevent HBeAg expression.

HBV DNA may remain detectable despite absent HBeAg.

Do not equate HBeAg negativity with no viral activity.

Slide 42 · HBV DNA provides direct evidence of ongoing viral presence

Detectable serum HBV DNA reflects viral genomic material in circulation.

HBV DNA helps clarify the significance of HBeAg-negative infection.

Antigen expression, viral replication, and hepatocyte injury are related but distinct phenomena.

Interpret HBV DNA alongside antigen markers and aminotransferase results.

Slide 43 · Anti-HBe is not equivalent to complete virologic clearance

Anti-HBe may emerge as acute infection wanes.

During chronic HBV, anti-HBe may be absent or appear late.

HBeAg-negative replication-competent viruses complicate interpretation.

Persistent HBsAg or HBV DNA prevents a conclusion of resolved infection.

Slide 44 · How acute HBV markers change over time

Qualitative serologic sequence — schematic; Not a quantitative concentration curve

Incubation

Acute illness

Early recovery

After recovery

HBsAg

HBeAg / HBV DNA

Anti-HBs

IgM anti-HBc

Schematic natural history only; Markers need not follow an identical course in every patient.

Slide 45 · Representative HBV serologic patterns

Pattern

HBsAg

Anti-HBs

Anti-HBc

Interpretation

Resolved infection

–

+

+

Prior natural infection

Post-vaccine

–

+

–

Vaccine-type response

Recent acute infection

+

–

IgM +

Recent infection

Persistent infection

+

Usually –

Often +

Evaluate for chronic HBV

Didactic patterns only; Full laboratory interpretation depends on the complete test panel and clinical context.

Slide 46 · A single HBV marker rarely tells the whole story

Practical interpretation principle

Integrate HBsAg + antibodies + HBV DNA + clinical context

In particular, neither absent HBeAg nor isolated anti-HBc should be interpreted without the other markers.

Slide 47 · Chronic hepatitis is defined by persistence and injury

The adjacent Robbins section describes continuing or relapsing liver disease beyond 6 months and/or morphologic fibrosis.

Persistent HBsAg characterizes ongoing HBV infection.

Chronic HBV may have variable aminotransferase elevations or little clinical disturbance.

Biochemical findings alone do not fully establish disease activity or fibrosis.

Slide 48 · Chronic HBV may remain clinically quiet

Some patients have few or no symptoms despite continuing infection.

Others report fatigue, malaise, appetite loss, or intermittent mild jaundice.

Aminotransferases can fluctuate during chronic disease.

Infection and liver injury must be assessed independently.

Slide 49 · An asymptomatic carrier state has specific features

Parameter

Classical low-activity HBV carrier pattern

Symptoms

Absent

HBsAg

Present

HBeAg

Absent

Anti-HBe

Present

HBV DNA

Low or undetectable

Aminotransferases

Normal

Biopsy

No significant inflammatory injury

The historical phrase “healthy carrier”; It does not mean the patient is incapable of transmission.

Slide 50 · HBV carrier status is not synonymous with no transmission

The term “carrier” denotes harboring an organism capable of transmission.

Patients without symptoms can still act as an infection reservoir.

A low-activity pattern is distinct from a claim that the infection has been eradicated.

Activity may need reassessment over time as viral and host factors change.

Slide 51 · HBV differs from enterically transmitted hepatitis viruses

HAV

Primarily fecal–oral transmission.

Does not produce chronic hepatitis.

Often resolves after acute infection.

HBV

Blood, sexual, and perinatal transmission.

Can persist chronically.

Associated with cirrhosis and HCC.

HCV

Predominantly parenteral transmission.

A high frequency of chronic infection.

May progress to cirrhosis and HCC.

Contextual comparison from the adjacent Robbins hepatitis sections.

Slide 52 · Acute viral hepatitis shows a lobular injury pattern

Focal damaged hepatocyte

SCHEMATIC — not a histologic specimen

Acute hepatitic pattern

Portal and lobular lymphocytic inflammation.

Hepatocyte apoptosis and necrosis.

Macrophages clear injured-cell debris.

Slide 53 · Necroinflammation is a cellular immune response

Inflammatory infiltrate

SCHEMATIC — not a histologic specimen

Microscopic interpretation

T cells predominate in viral hepatitis infiltrates.

Plasma cells and eosinophils may be variable.

The inflammatory pattern is not exclusive to HBV.

Slide 54 · Apoptosis and necrosis can coexist

In acute viral hepatitis, individual damaged hepatocytes may undergo apoptosis.

Dead-cell debris can be removed by pigmented macrophages.

Necrosis may affect individual cells or larger parenchymal areas.

Severity of cell loss—not merely the presence of inflammation—matters clinically.

Slide 55 · Confluent and bridging necrosis indicate severe injury

Focal hepatocyte injury

Confluent necrosis

Bridging or panacinar necrosis

Potential acute liver failure

These are possible patterns of increasing extent of injury, not mandatory sequential stages.

Slide 56 · Chronic hepatitis is centered on portal inflammation

Inflammatory infiltrate

SCHEMATIC — not a histologic specimen

Chronic hepatitic pattern

Portal lymphocytic / lymphoplasmacytic infiltrate.

Variable accompanying lobular inflammation.

Fibrosis emerges with cumulative tissue injury.

Slide 57 · Interface hepatitis injures periportal hepatocytes

Portal tract

Limiting plate

Periportal injury

SCHEMATIC — not a histologic specimen

Interface activity

Inflammatory cells cross the limiting plate.

Periportal hepatocytes become damaged.

Activity signifies ongoing immune-mediated injury.

Slide 58 · Fibrosis bridges portal tracts as disease advances

Portal tract

Portal tract

Bridging fibrous septa

SCHEMATIC — not a histologic specimen

Fibrosis progression

Initial portal / periportal fibrosis.

Portoportal bridging fibrosis.

Advanced architectural remodeling: Cirrhosis.

Slide 59 · Ground-glass hepatocytes are a distinctive HBV clue

Ground-glass cytoplasm

SCHEMATIC — not a histologic specimen

HBV-associated change

Smooth endoplasmic reticulum expands with HBsAg.

Cytoplasm appears homogeneous or ground-glass.

It is a clue, not a stand-alone serologic diagnosis.

Slide 60 · The ground-glass appearance reflects HBsAg accumulation

HBsAg production

Endoplasmic reticulum distention

Altered hepatocyte cytoplasm

Ground-glass appearance

Mechanistic explanation from the adjacent Robbins morphology section.

Slide 61 · Immunostains can demonstrate HBV antigens in tissue

HBsAg staining

Identifies viral surface antigen in hepatocytes.

Supports the interpretation of ground-glass cells.

Must be related to tissue pattern and serology.

HBcAg staining

Detects nucleocapsid antigen in tissue.

Provides complementary evidence of HBV infection.

Does not by itself measure fibrosis severity.

Slide 62 · Morphology cannot reliably type every viral hepatitis

Acute and chronic hepatitis patterns overlap among hepatotropic viruses.

Autoimmune hepatitis, drug injury, and Wilson disease can produce similar injury.

Ground-glass change raises suspicion of HBV but is not the complete diagnostic workup.

Viral serology and molecular studies are essential for etiologic attribution.

Slide 63 · Biopsy separates inflammatory grade from fibrosis stage

Activity / grade

Extent and distribution of inflammation.

Severity of hepatocyte injury and interface activity.

Describes the current necroinflammatory process.

Fibrosis / stage

Extent of collagenous architectural change.

Bridging fibrosis and cirrhosis.

Describes cumulative structural disease.

Slide 64 · HBV-related cirrhosis arises from progressive fibrosis

Chronic immune-mediated injury

Repeated hepatocyte loss and repair

Progressive fibrous septa

Cirrhotic remodeling

Cirrhosis is a possible endpoint of chronic hepatitis, not an inevitable result.

Slide 65 · Chronic HBV increases hepatocellular carcinoma risk

The Robbins source identifies HCC as a major long-term complication.

Risk is particularly important in people infected at birth who remain chronically infected.

Cirrhosis contributes to risk, but HBV-related carcinogenesis also has viral molecular components.

HBx is implicated in altered host gene transcription associated with HCC.

Slide 66 · Perinatal infection amplifies lifetime HCC risk

Perinatal acquisition

High chronicity probability

Long duration of persistent HBV

HCC risk over the life course

This is a risk pathway, not a statement that all chronically infected individuals develop cancer.

Slide 67 · Hepatitis D depends on HBV

Important related virus

HDV requires HBV for its infectious life cycle

HBV vaccination also prevents HDV infection by preventing the required HBV infection.

Slide 68 · HDV co-infection differs from superinfection

HBV–HDV co-infection

Both viruses acquired in the same exposure.

Acute hepatitis may resemble HBV alone.

Clearance of both viruses is possible.

HDV superinfection

HDV acquired in a patient with established HBV.

May sharply exacerbate chronic hepatitis.

Persistent delta infection and progression are more likely.

Slide 69 · Vaccination induces an anti-HBs response

HBsAg-based vaccination

Anti-HBs antibody generation

Protection against HBV infection

Prevention of HBV-dependent HDV

High vaccine effectiveness in infants, children, and adolescents.

Slide 70 · Prevention targets acquisition before chronicity begins

HBV vaccination establishes protective anti-HBs immunity.

Prevention of perinatal infection is especially important because chronicity risk is greatest at birth.

Blood screening and reduction of needle-sharing exposures interrupt parenteral spread.

Reducing HBV acquisition also reduces downstream risks of cirrhosis and HCC.

Slide 71 · Antiviral therapy suppresses replication and progression

Interferon and antiviral reverse-transcriptase inhibitors among therapeutic approaches.

Examples given include entecavir and tenofovir.

Treatment can slow disease progression and reduce liver damage.

Lowering progression risk is not equivalent to guaranteed complete eradication.

Slide 72 · Antiviral treatment reduces—but does not abolish—risk

Important benefits

Reduced viral replication.

Less ongoing liver damage and slower progression.

Lower risk of cirrhosis and hepatocellular carcinoma.

Persistent challenges

Complete cure remains difficult.

Established fibrosis may not disappear immediately.

Long-term clinical assessment remains relevant.

Slide 73 · Case: Silent infection detected through screening

Clinical vignette

An adult without jaundice has a positive serum HBsAg result during health screening.

Can asymptomatic status exclude current HBV infection?

Reasoning

No. HBV may be subclinical or associated with a low-activity carrier state; Interpret HBsAg with other serologic markers, HBV DNA and liver tests.

Slide 74 · Case: Antibodies during the serologic window

Clinical vignette

A patient recovering from an acute hepatitic illness has lost detectable HBsAg, but anti-HBs is not yet detected.

Which antibody may establish recent HBV infection?

Reasoning

IgM anti-HBc is useful in the window after HBsAg loss and before the appearance of anti-HBs.

Slide 75 · Case: HBeAg-negative but HBV DNA-positive

Clinical vignette

A patient has detectable HBV DNA but no detectable HBeAg.

Does absent HBeAg rule out ongoing viral replication?

Reasoning

No. Replication-competent HBV variants may lack HBeAg expression; HBV DNA should guide evaluation of replication.

Slide 76 · Case: Hepatocyte cytoplasmic ground-glass change

Clinical vignette

Liver biopsy shows hepatocytes with unusually homogeneous, finely granular cytoplasm in a chronic hepatitis pattern.

What HBV-associated mechanism should be considered?

Reasoning

Accumulation of HBsAg in expanded endoplasmic reticulum. Serology and/or HBV antigen immunostaining are needed for confirmation.

Slide 77 · Integrating the HBV diagnostic and pathology evidence

Clinical question

Most informative evidence

Current infection?

HBsAg with appropriate clinical context

Evidence of replication?

Serum HBV DNA; HBeAg as an imperfect indirect marker

Recent acquisition?

IgM anti-HBc in appropriate setting

Immune protection?

Anti-HBs

Extent of liver injury?

Clinical/laboratory assessment; Biopsy when indicated

Fibrosis/cirrhosis?

Fibrosis assessment and histologic stage when biopsied

Slide 78 · The four essential HBV distinctions

Current antigen expression is different from evidence of active viral replication.

Immune-mediated hepatocyte injury is different from intracellular viral protein accumulation.

Inflammatory activity (grade) is different from accumulated fibrosis (stage).

Prevention of infection is different from treatment-mediated control of persistent infection.

Slide 79 · References

Primary textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026). Chapter 18: Liver and Gallbladder.

Relevant sections

Hepatitis B Virus (pp. 756–758); Clinicopathologic Syndromes of Viral Hepatitis (pp. 760–762); Hepatitis D Virus (p. 760).