Viral hepatitis

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Viral Hepatitis

A comprehensive overview based on Robbins & Kumar Basic Pathology, Goldman-Cecil Medicine, and Sleisenger & Fordtran's GI and Liver Disease.

Overview

The term "viral hepatitis" refers to liver inflammation caused by hepatotropic viruses - those with a specific tropism for hepatocytes. Five major agents are recognized: HAV, HBV, HCV, HDV, and HEV. Other viruses (EBV, CMV, HSV, SARS-CoV-2, adenovirus) can also cause hepatitis but are not primarily hepatotropic. Liver injury in all forms is immune-mediated rather than directly cytopathic - CD8+ cytotoxic T cells, pro-inflammatory cytokines, NK cells, and antibody-dependent cellular cytotoxicity all contribute to hepatocellular damage.

Robbins & Kumar Basic Pathology, p. 598

Comparative Summary Table

Feature	HAV	HBV	HCV	HDV	HEV
Genome	ssRNA	Partially dsDNA	ssRNA	Circular defective ssRNA	ssRNA
Family	Hepatovirus (Picornaviridae)	Hepadnaviridae	Flaviviridae	Deltaviridae (subviral)	Hepeviridae
Transmission	Fecal-oral	Parenteral, sexual, perinatal	Parenteral (IVDU, needlestick)	Parenteral (requires HBV)	Fecal-oral
Incubation	2-6 weeks	2-26 weeks (mean 8 wk)	4-26 weeks (mean 9 wk)	Same as HBV	4-5 weeks
Chronic disease	Never	5-10% (adults); >90% (perinatal)	>80%	10% (coinfection); 90-100% (superinfection)	Rarely (immunocompromised)
Carrier state	No	Yes	Yes	Yes (with HBV)	No
Vaccine	Yes (since 1995)	Yes	No	Prevented by HBV vaccine	Approved in China; investigational elsewhere

Individual Viruses

Hepatitis A (HAV)

HAV is a non-enveloped, positive-strand RNA picornavirus. Transmission is fecal-oral, typically via contaminated water, food, shellfish, or infected food-industry workers. It sheds in stool for 2-3 weeks before and 1 week after jaundice onset - the period of peak infectivity.

Key features:

Incubation: 2-6 weeks
Self-limited; never causes chronic hepatitis
Fulminant hepatitis in ~0.1% of cases
Does not establish a carrier state
HAV itself is not cytopathic; CD8+ T cells drive hepatocellular injury
Viremia is transient, so bloodborne transmission is very rare

Serologic diagnosis:

HAV Serology - Temporal changes in serologic markers in acute hepatitis A infection

IgM anti-HAV: appears at symptom onset - marker of acute infection
Fecal viral shedding ends as IgM titer rises
IgG anti-HAV: persists for years, confers lifelong immunity
HAV vaccine (live attenuated) has reduced US cases by >95% since 1995 (~2,800 cases/year now)
Robbins & Kumar Basic Pathology, p. 598-599

Hepatitis B (HBV)

HBV is the world's most consequential hepatitis virus. Two billion people have been infected; 250 million have chronic infection; 75% of carriers live in Asia and the Western Pacific rim.

Structure: Enveloped, partially double-stranded DNA virus (hepadnavirus). The virion (Dane particle) has:

HBsAg (surface antigen) - on the outer envelope
HBcAg (core antigen) - on the nucleocapsid (not found in serum)
HBeAg - a secreted antigen derived from pre-core protein; correlates with active viral replication and infectivity

HBV replication involves reverse transcriptase (unique among DNA viruses), so antiviral drugs targeting RT (tenofovir, entecavir) are effective.

Clinical outcomes of HBV:

Acute hepatitis with recovery and viral clearance
Nonprogressive chronic hepatitis
Progressive chronic disease → cirrhosis → hepatocellular carcinoma (HCC)
Fulminant hepatitis with massive liver necrosis
Asymptomatic "healthy" carrier state

Chronicity rates:

Adult-acquired infection: 5-10% progress to chronic
Perinatally acquired (endemic areas): >90% develop chronic infection and carrier state

Extrahepatic manifestations (immune complex-mediated):

Membranous or membranoproliferative glomerulonephritis
Polyarteritis nodosa (hepatitis B surface antigen-containing immune complexes)
Serum sickness-like prodrome (urticaria, arthralgias, fever)

Serology and markers:

Marker	Significance
HBsAg	Present in acute and chronic infection; persistence >6 months = chronic
Anti-HBs	Appears after recovery or vaccination; confers immunity
IgM anti-HBc	Acute infection (including window period when HBsAg has cleared but anti-HBs has not yet appeared)
IgG anti-HBc	Past or chronic infection
HBeAg	Active viral replication; high infectivity
Anti-HBe	Decreasing replication; seroconversion is favorable
HBV DNA (PCR)	Quantifies viral load; guides therapy

Treatment:

Tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) - first-line nucleotide analogues
Entecavir - first-line nucleoside analogue
Pegylated interferon-alpha - finite-duration therapy; suitable for selected patients
Goal: sustained suppression of HBV DNA, HBeAg seroconversion, and ideally HBsAg loss

Hepatitis C (HCV)

HCV is the leading cause of chronic liver disease and liver transplantation in the Western world.

Structure: Enveloped, single-stranded RNA flavivirus. Its genome encodes a single polyprotein processed into 10 functional proteins including:

NS3/4A protease - required for polyprotein processing (target of drugs like glecaprevir, voxilaprevir)
NS5A - essential for viral assembly (target of ledipasvir, velpatasvir)
NS5B RNA polymerase - replicates the viral genome (target of sofosbuvir)

Because the RNA polymerase has very low fidelity, HCV mutates rapidly, generating 7 major genotypes and multiple quasispecies within each infected patient. This rapid mutation previously complicated treatment, though modern pan-genotypic regimens overcome this.

Risk factors for HCV:

Intravenous drug use (IVDU) - most common route in high-income countries
Needlestick injury (risk ~1.8% per stick vs. 0.3% for HIV)
Perinatal transmission (~5-6% of infants born to HCV+ mothers)
Blood transfusion (risk now essentially zero in developed countries due to screening)
Sexual transmission is inefficient but possible

Clinical course:

Incubation: 4-26 weeks (mean 9 weeks)
85% of acute infections are asymptomatic - most patients unaware they are infected
HCV RNA detectable in blood within 1-3 weeks of exposure
Severe acute hepatitis is rare
>80% develop chronic infection - major distinguishing feature from HBV
Of those with chronic HCV: ~20% develop cirrhosis over 20-30 years
Cirrhosis is a major risk for HCC; HCV accounts for ~1/3 of liver cancers in the US

Characteristic feature of chronic HCV: episodic elevations of serum aminotransferases separated by periods of normal levels - patients may appear to improve but fibrosis still progresses.

Treatment (Direct-Acting Antivirals - DAAs):

Sofosbuvir/ledipasvir (Harvoni) - for genotype 1
Sofosbuvir/velpatasvir (Epclusa) - pan-genotypic
Glecaprevir/pibrentasvir (Mavyret) - pan-genotypic, 8 weeks for non-cirrhotic
Sustained virologic response (SVR) - undetectable HCV RNA 12 weeks after treatment completion - is equivalent to cure; achieved in >95% of patients

Hepatitis D (HDV)

HDV is a defective viroid - it can only infect individuals already infected with HBV because it uses HBsAg as its own envelope protein. HDV contains circular, defective single-stranded RNA and is classified in Deltaviridae.

Two patterns of HDV infection:

Coinfection (simultaneous HDV + HBV acquisition): usually self-limited, low risk of chronicity (~10%), but higher risk of fulminant hepatitis than HBV alone
Superinfection (HDV acquired by chronic HBV carrier): severe, rapidly progressive; 90-100% develop chronic HDV hepatitis; may cause acute-on-chronic liver failure

Prevention: HBV vaccination also prevents HDV.

Treatment: Pegylated interferon alpha (modest efficacy). Bulevirtide (a novel entry inhibitor) has received conditional approval in Europe for chronic HDV.

Hepatitis E (HEV)

HEV is a non-enveloped, single-stranded RNA virus in the Hepeviridae family. Like HAV, it is transmitted fecal-orally.

Key features:

Incubation: 4-5 weeks
Usually self-limited; does not typically cause chronic hepatitis (except in immunocompromised hosts)
Pregnant women are uniquely vulnerable - fulminant hepatic failure occurs in up to 20-25% of pregnant women infected in the 3rd trimester, especially with HEV genotype 1 (high mortality rate in endemic regions)
HEV genotype 3/4 (zoonotic) can cause chronic infection in solid organ transplant recipients and HIV patients
Waterborne epidemics in developing countries (South Asia, Sub-Saharan Africa, Mexico)
Diagnosis: serum IgM/IgG antibodies; PCR for HEV RNA
No vaccine approved outside China; ribavirin used for chronic HEV in immunocompromised patients

Pathology: Acute vs. Chronic Hepatitis

Morphologic features of acute and chronic hepatitis - Robbins & Kumar

Acute Viral Hepatitis (Microscopy)

Portal and lobular lymphocytic infiltrate (variably with plasma cells and eosinophils)
Ballooning degeneration of hepatocytes
Apoptosis (acidophil/Councilman bodies - shrunken, densely eosinophilic hepatocytes)
Necrosis: may be focal, confluent, or bridging (portal-to-central) in severe cases
Cholestasis (bile plugs in canaliculi)
Panlobular or panacinar necrosis = fulminant hepatitis (massive liver failure)
Macrophage aggregates at sites of necrotic hepatocytes

Chronic Viral Hepatitis (Microscopy)

Dense portal lymphoplasmacytic infiltration - the defining feature
Interface hepatitis (piecemeal necrosis): inflammatory cells cross the limiting plate and damage periportal hepatocytes
Portal and periportal fibrosis → bridging fibrosis (porto-portal and porto-central) → cirrhosis
Specific features by virus:
- Hepatitis B: "ground-glass" hepatocytes (HBsAg-laden ER visible on H&E) and "sanded nuclei" (HBcAg)
- Hepatitis C: fatty change (steatosis), lymphoid aggregates in portal tracts, bile duct damage
Robbins & Kumar Basic Pathology, p. 604-606

Clinicopathologic Syndromes

1. Asymptomatic Infection

Most common outcome with HCV (85% of acute infections); also common with HBV in adults

2. Acute Symptomatic Hepatitis

Phases:

Prodromal (pre-icteric): malaise, fatigue, anorexia, nausea, vomiting, right upper quadrant discomfort, low-grade fever (1-2 weeks)
Icteric (jaundice) phase: dark urine (bilirubinuria), pale stools, jaundice, tender hepatomegaly; transaminases (ALT > AST) may be 10-40x normal
Recovery phase: symptoms resolve, liver enzymes normalize

3. Fulminant Hepatitis (Acute Liver Failure)

Massive hepatic necrosis with encephalopathy within 8 weeks of onset
Rare but life-threatening; may require emergency liver transplantation
HAV: ~0.1%; HBV: ~1%; HDV coinfection: higher risk
HEV in pregnancy: up to 20-25% fulminant failure rate

4. Chronic Hepatitis

Defined as hepatic inflammation persisting beyond 6 months
May be asymptomatic or present with fatigue, RUQ discomfort, stigmata of chronic liver disease
Graded (degree of inflammation) and staged (degree of fibrosis) on biopsy

5. Carrier State

Individuals who harbor the virus without significant liver disease
HBV: >90% of perinatally infected individuals become carriers in endemic regions
Important reservoirs of transmission

Diagnosis Summary

Condition	Key Tests
Acute HAV	IgM anti-HAV
Immunity/past HAV	IgG anti-HAV
Acute HBV	HBsAg + IgM anti-HBc
Window period HBV	IgM anti-HBc (HBsAg has cleared, anti-HBs not yet appeared)
Chronic HBV	HBsAg >6 months, IgG anti-HBc, HBV DNA
Past HBV / immunity	Anti-HBs + anti-HBc
Vaccination immunity	Anti-HBs alone
Acute/chronic HCV	Anti-HCV ELISA + confirmatory HCV RNA PCR
Chronic HCV activity	HCV RNA quantification
HDV	Anti-HDV IgM/IgG; HDV RNA
Acute HEV	IgM anti-HEV; HEV RNA (PCR)

Prevention

Virus	Prevention
HAV	Inactivated vaccine (2-dose series); good sanitation
HBV	Recombinant HBsAg vaccine (3-dose series); neonatal vaccination in endemic areas; HBIG for post-exposure prophylaxis
HCV	No vaccine; harm reduction (clean needles, IVDU programs); blood screening
HDV	HBV vaccination prevents HDV
HEV	Sanitation; vaccine available in China (Hecolin); ribavirin in chronic immunocompromised cases

Complications

All forms of chronic viral hepatitis share a common pathway to:

Cirrhosis - irreversible fibrotic replacement of liver parenchyma
Portal hypertension - varices, ascites, splenomegaly
Hepatocellular carcinoma (HCC) - particularly with chronic HBV (can occur even without cirrhosis) and HCV (almost always via cirrhosis)
Hepatic encephalopathy - in decompensated cirrhosis
Extrahepatic manifestations: cryoglobulinemia (HCV), vasculitis, glomerulonephritis

A 2026 umbrella review of 15 meta-analyses (PMID 41794163) found that underlying viral hepatitis influences immunotherapy outcomes in advanced HCC - an important emerging clinical consideration.

Sources:

Robbins & Kumar Basic Pathology, pp. 598-607
Goldman-Cecil Medicine International Edition, Chapter 134 (Acute Viral Hepatitis)
Sleisenger and Fordtran's Gastrointestinal and Liver Disease
Petrelli F, et al. Viral hepatitis and immunotherapy outcome in advanced HCC. Crit Rev Oncol Hematol, 2026 May. PMID 41794163

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