Acute Viral Hepatitis¶
Chapter 350 | Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders · Chapter 350
Key Clinical Points¶
- HAV incubation is ~3–4 weeks; virus present in liver, bile, stools, and blood during late incubation/preicteric phase.
- HBV entry into hepatocytes is mediated by binding to the NTCP receptor.
- HCV RNA is the most sensitive indicator of infection; neutralizing antibodies are short-lived and do not indicate protection.
- HDV is a defective RNA virus requiring the helper function of HBV for replication/expression.
- HBV genotype B is associated with less rapidly progressive disease and lower risk of HCC than genotypes C, D, or F.
- HCV does not integrate into the host genome because it lacks a DNA intermediate.
- Precore mutations in HBV (e.g., G1896A) result in HBeAg-negative chronic hepatitis.
- HDV antigen is primarily in hepatocyte nuclei; only occasionally detectable in serum.
- HCV replication rate is very high (10^12 virions/day) with a half-life of 2.7 hours.
- HBsAg persists >6 months in chronic HBV, whereas it typically disappears 1–2 months after jaundice onset in acute cases.
DEFINITION & CLASSIFICATION¶
• Acute Viral Hepatitis: Systemic infection affecting the liver predominantly. • Pathogens: Primarily caused by five viral agents: ◦ HAV, HBV, HCV, HDV (HBV-associated delta agent), and HEV. • Viral Nature: ◦ All are RNA viruses except HBV (a DNA virus that replicates like a retrovirus). • Clinical Spectrum: Ranges from asymptomatic/inapparent to fulminant and fatal infections across all types. • Chronic Potential: Bloodborne types (HBV, HCV, HDV) can lead to chronic disease, cirrhosis, and hepatocellular carcinoma (HCC). • Non-Hepatotropic Viruses: Rare cases of severe hepatitis caused by CMV, EBV, other herpes viruses, or SARS-CoV-2; recently linked to adenovirus type 41 and adeno-associated virus 2.
EPIDEMIOLOGY¶
• HBV Distribution: ◦ Genotypes A and D predominate in US/Europe. ◦ Genotypes B and C predominate in Asia. • Clinical Impact of Genotype: ◦ Clinical course is independent of subtype. ◦ Genotype B: Associated with less rapidly progressive disease, lower likelihood of HCC (or delayed appearance) compared to C, D, or F. ◦ Genotype A: Higher rates of persistent infection (23.4% vs 8.6% for non-A) and higher rates of HBeAg/HBsAg loss during treatment.
ETIOLOGY & PATHOPHYSIOLOGY¶
Hepatitis A (HAV)¶
• Structure: Nonenveloped, 27-nm, heat/acid/ether-resistant, single-stranded, positive-sense RNA virus (Hepatovirus). ◦ Quasienveloped particles circulate in blood. ◦ Genome: 7500-nucleotide; produces four structural capsid polypeptides (VP1–VP4) and six nonstructural proteins. • Inactivation: Boiling (1 min), formaldehyde, chlorine, or UV irradiation.
Hepatitis B (HBV)¶
• Structure: DNA virus; compact 3200-bp circular genome; Hepadnavirus type 1. ◦ Replicates via reverse transcription of minus-strand DNA from a pregenomic RNA intermediate. ◦ Entry: Mediated by binding to the NTCP receptor. • Genomic Economy: Four overlapping genes (S, C, P, X) produce multiple products: ◦ S gene: HBsAg (major envelope protein); Pre-S1 + S = 'middle' protein; Pre-S1 + Pre-S2 + S = 'large' protein. ◦ C gene: HBcAg (core protein) and HBeAg (soluble, secreted). ◦ P gene: DNA polymerase. ◦ X gene: HBxAg (transactivates genes; may bind p53 to contribute to carcinogenesis). • Particles: ◦ 22-nm particles (HBsAg) are most numerous. ◦ 42-nm double-shelled particles = intact virions. ◦ HBsAg concentration can reach 500 μg/mL; virions up to 10 trillion/mL.
Hepatitis C (HCV)¶
• Structure: Linear, single-strand, positive-sense, 9600-nucleotide RNA virus (Hepacivirus). ◦ No DNA intermediate; does not integrate into host genome. ◦ Replication rate: 10^12 virions/day; half-life: 2.7 hours. • Genome Organization: ◦ 5' end: 500-region (IRES), Core (C), and Envelope (E1, E2). ◦ E2 contains the hypervariable region (evades immune detection). ◦ 3' end: Nonstructural (NS) regions. ◦ NS2: Cysteine protease. ◦ NS3: Serine protease and RNA helicase. ◦ NS4 & NS4B; NS5A (membrane-associated phosphoprotein); NS5B (RNA-dependent RNA polymerase). • Entry: Mediated by CD81 receptor and claudin-1.
• Nature: Defective RNA virus; requires HBV helper function for replication/expression. ◦ 35–37 nm, enveloped hybrid particle with HBsAg coat. ◦ Genome: 1700-nucleotide, circular, single-strand RNA (negative polarity). ◦ Replication: Uses host RNA polymerase II and I; involves a ribozyme structure. • Proteins: ◦ HDAg (two forms: 195-AA and 214-AA). ◦ Antigen is primarily in hepatocyte nuclei; occasionally in serum. • Dynamics: ◦ Superinfection: HDV takes the HBsAg subtype of the recipient. ◦ Duration: Limited by HBV duration; suppresses HBV replication. ◦ Serology: IgM anti-HDV predominates in acute infection (30–40 days post-symptoms).
Hepatitis E (HEV)¶
• Structure: Nonenveloped icosahedral virus; 7.6-kb RNA genome. ◦ Orthohepevirus. ◦ Enterically transmitted; rare in US; common in Asia, Mediterranean, Central America.
CLINICAL FEATURES¶
Hepatitis A (HAV) Progression¶
• Timeline: Follows a progression of clinical and laboratory features over 20 weeks post-exposure. ◦ Key marker: ALT (alanine aminotransferase) elevation.
Acute Hepatitis B Progression¶
• Sequence of Events: 1. HBsAg appears first (precedes symptoms by 2–6 weeks). 2. HBeAg and ALT peak during acute phase (coincides with Jaundice). 3. Transition: HBeAg drops, Anti-HBe appears (around week 20). 4. Resolution: HBsAg disappears (week 24), followed by Anti-HBs appearance (weeks 28–36).
Chronic Hepatitis B Phases¶
• Replicative Phase: ◦ Characterized by: HBeAg (+), high HBV DNA. ◦ Clinical status: High infectivity and liver injury. ◦ Transition: Seroconversion to nonreplicative phase occurs at ~10% per year (marked by Anti-HBe appearance). ◦ Note: Precore mutations can cause replicative disease without HBeAg. • Nonreplicative Phase: ◦ Characterized by: HBeAg (-), Anti-HBe (+), lower/undetectable HBV DNA. ◦ Clinical status: Limited infectivity and liver injury.
Acute Hepatitis C Progression¶
• Timeline (Months post-exposure): 1. Month 0: HCV RNA becomes detectable. 2. Months 2–4: Anti-HCV seroconversion; ALT peaks (months 3–6). 3. Month 6: Threshold for defining 'chronic' status.
DIFFERENTIAL DIAGNOSIS¶
• Non-Hepatotropic Viruses: ◦ Clinical presentation of acute hepatitis may be caused by CMV, EBV, other herpes viruses, or SARS-CoV-2. ◦ These are more common in immunocompromised hosts but can occur in healthy individuals.
DIAGNOSTIC APPROACH¶
- Initial Serology: Determine HBsAg status to identify HBV infection.
- Acute Hepatitis B Identification (Table 350-6): ◦ If HBsAg (+), IgM anti-HBc (+), and Anti-HCV (-) → Acute hepatitis B.
- Superimposed Infection: ◦ If HBsAg (+), IgM anti-HAV (+), and IgM anti-HBc (—) → Acute HAV superimposed on chronic HBV.
- Acute Hepatitis A Identification: ◦ If HBsAg (-), IgM anti-HAV (+), and IgM anti-HBc (—) → Acute hepatitis A.
- HBsAg-Negative Acute HBV: ◦ If HBsAg (-), IgM anti-HBc (+) → Acute HBV with HBsAg below detection threshold.
- HCV Identification: ◦ If HBsAg (-), and either HCV RNA or Anti-HCV is (+).
MANAGEMENT & TREATMENT¶
- Hepatitis A (HAV): ◦ No specific therapy. ◦ Prevention: Vaccines (Havrix, Vaqta) or HBIG/vaccine for others.
- Hepatitis B (HBV): ◦ Treatment: Interferon, Lamivudine, Adefovir, Pegylated interferon, Entecavir, Telbivudine, Tenofovir disoproxil fumarate, Tenofovir alafenamide. ◦ Post-exposure: HBIG, recombinant vaccine.
- Hepatitis C (HCV): ◦ Treatment: Pegylated interferon, ribavirin, telaprevir, boceprevir, simeprevir, sofosbuir, ledipasvir, paritaprevir/ritonavir, ombitasvir, dasabuvir, daclatasvir, velpatasvir, grazoprevir, elbasvir, glecaprevir, pibrentasib, voxilaprevir.
- Hepatitis E (HEV): ◦ Treatment: Pegylated interferon ±.
SPECIAL POPULATIONS¶
High Risk for HBV (Table 350-3)¶
• Geography: Born in regions with high (≥8%) or intermediate (≥2%) prevalence. ◦ Includes immigrants/adopted children and non-vaccinated US residents from endemic areas. ◦ Household/sexual contacts of, or needle sharing with, HBsAg+ individuals. ◦ Babies born to HBsAg-positive mothers. ◦ Users of injection drugs; multiple sexual contacts; history of STDs. ◦ Men who have sex with men (MSM). ◦ Incarcerated persons. ◦ Patients with elevated ALT/AST or HCV/HIV infection. ◦ Hemodialysis patients; healthcare workers/first responders exposed to blood.
High Risk for HCV (Table 350-4)¶
• Screening: All adults aged 18–79 should be screened. ◦ Users of injection drugs; patients with HIV infection. ◦ Hemophiliacs treated with clotting factors before 1987. ◦ Long-term hemodialysis patients. ◦ Patients with unexplained ALT elevations. ◦ Transfusion/transplantation recipients prior to July 1992. ◦ Recipients of organs from HCV+ donors. ◦ Children born to women with HCV. ◦ Healthcare/public safety personnel following needle injury or mucosal exposure. ◦ Sexual partners of HCV-infected individuals. ◦ Pregnant women.
KEY PEARLS & HIGH-YIELD POINTS¶
• HCV Sensitivity: HCV RNA is the most sensitive indicator; antibodies are short-lived and don't indicate protection. • HBV Window: IgM anti-HBc is the only serologic evidence in the 'window' period (no HBsAg/Anti-HBs). • HDV Dependency: HDV requires HBV for replication; its duration cannot outlast HBV infection. • Precore Mutation: G1896A substitution leads to HBeAg-negative chronic hepatitis. • Vaccination: Havrix (2 doses) and Vaqta (2 doses) are standard for HAV. Engerix-B/Recombivax/PreHevbrio are used for HBV.
Reference Tables¶
TABLE 350-1 Nomenclature and Features of Hepatitis Viruses¶
Harrison's 22e, p.2645
| HEPATITIS TYPE |
VIRUS PARTICLE, nm |
MORPHOLOGY | GENOMEa | CLASSIFICATION | ANTIGEN(S) | ANTIBODIES | REMARKS |
|---|---|---|---|---|---|---|---|
| HAV | 27 | Icosahedral nonenveloped |
7.5-kb RNA, linear, ss, + |
Hepatovirus | HAV | Anti-HAV | Early fecal shedding Diagnosis: IgM anti-HAV Previous infection: IgG anti-HAV |
| 42 27 22 |
Double-shelled virion (surface and core) spherical Nucleocapsid core Spherical and filamentous; represents excess virus coat material |
3.2-kb DNA, circular, ss/ds |
Hepadnavirus | HBsAg HBcAg HBeAg HBcAg HBeAg HBsAg |
Anti-HBs Anti-HBc Anti-HBe Anti-HBc Anti-HBe Anti-HBs |
||
| HCV | 55 | Enveloped | 9.4-kb RNA, linear, ss, + |
Hepacivirus | HCV core antigen |
Anti-HCV | Bloodborne agent, formerly labeled non-A, non-B hepatitis Acute diagnosis: anti-HCV, HCV RNA Chronic diagnosis: anti-HCV, HCV RNA; cytoplasmic location in hepatocytes |
| 35–37 | Enveloped hybrid particle with HBsAg coat and HDV core |
1.7-kb RNA, circular, ss, – |
Resembles viroids and plant satellite viruses (genus Deltavirus) |
HBsAg HDAg |
Anti-HBs Anti-HDV |
||
| HEV | 32–34 | Nonenveloped icosahedral |
7.6-kb RNA, linear, ss, + |
Orthohepevirus | HEV antigen | Anti-HEV | Agent of enterically transmitted hepatitis; rare in the United States; occurs in Asia, Mediterranean countries, Central America Diagnosis: IgM/IgG anti-HEV (assays not routinely available); virus in stool, bile, hepatocyte cytoplasm |
| Anti-HBe |
TABLE 350-2 Clinical and Epidemiologic Features of Viral Hepatitis FEATURE Incubation (days) Onset Age preference¶
Harrison's 22e, p.2652
| FEATURE | HAV | HBV | HCV | HDV | HEV |
|---|---|---|---|---|---|
| Incubation (days) | 15–45, mean 30 | 30–180, mean 60–90 | 15–160, mean 50 | 30–180, mean 60–90 | 14–60, mean 40 |
| Acute | Insidious or acute | Insidious or acute | Insidious or acute | ||
| Age preference | Children, young adults |
Young adults (sexual and percutaneous), babies, toddlers |
Any age, but more common in adults |
Any age (similar to HBV) | Epidemic cases: young adults (20–40 years); sporadic cases: older adults (>60) |
| +++ Unusual − ± |
− +++ +++ ++ |
− +++ ±a ±a |
− +++ + ++ |
||
| Clinical Severity Fulminant Progression to chronicity Carrier Cancer Prognosis |
Mild 0.1% None None None Excellent |
Occasionally severe 0.1–1% Occasional (1–10%) (90% of neonates) 0.1–30%f + (neonatal infection) Worse with age, debility |
Moderate 0.1% Common (85%) 1.5–3.2% + Moderate |
Occasionally severe 5–20%b Commond Variableg ± Acute, good; chronic, poor |
Mild 1–2%c Nonee None None Good |
| Ig, inactivated vaccine |
HBIG, recombinant vaccine | None | HBV vaccine (none for HBV carriers) |
||
| Therapy | None | Interferonh Lamivudineh Adefovirh Pegylated interferoni Entecaviri Telbivudinei Tenofovir disoproxil fumaratei Tenofovir alafenamidei |
Pegylated interferon ribavirin,h telaprevir,h boceprevir,h simeprevir,h sofosbuvir, ledipasvir, paritaprevir/ritonavir,h ombitasvir,h dasabuvir,h daclatasvir,h velpatasvir, grazoprevir, elbasvir, glecaprevir, pibrentasvir, voxilaprevir |
Pegylated interferon ± | Nonej |
TABLE 350-3 Populations with a High Risk for HBV Infection a Persons born in countries/regions with a high (≥8%) and…¶
Harrison's 22e, p.2653
- Persons born in countries/regions with a high (≥8%) and intermediate (≥2%)
prevalence of HBV infection including immigrants and adopted children and
including persons born in the United States who were not vaccinated as infants
and whose parents emigrated from areas of high HBV endemicity
Household and sexual contacts of, or needle sharing with, persons who have
hepatitis B
Babies born to HBsAg-positive mothers
Persons who have used injection drugs
Persons with multiple sexual contacts or a history of sexually transmitted
disease
Men who have sex with men
Persons incarcerated in a correctional facility or other detention settings
Persons with elevated alanine or aspartate aminotransferase levels
Persons with HCV or HIV infection
Hemodialysis patients
Health care and laboratory workers and first responders exposed to blood
TABLE 350-4 Populations with a High Risk for HCV Infection a All adults aged 18–79 should be screened , a…¶
Harrison's 22e, p.2655
- All adults aged 18–79 should be screened, a recommendation that supplants the
earlier focus on persons born between 1945 and 1965a
Persons who have ever used injection drugs
Persons with HIV infection
Hemophiliacs treated with clotting factor concentrates prior to 1987
Persons who have ever undergone long-term hemodialysis
Persons with unexplained elevations of aminotransferase levels
Transfusion or transplantation recipients prior to July 1992
Recipients of blood or organs from a donor found to be positive for hepatitis C
Children born to women with hepatitis C
Health care, public safety, and emergency medical personnel following needle
injury or mucosal exposure to HCV-contaminated blood
Sexual partners of persons with hepatitis C infection
Pregnant women
TABLE 350-5 Commonly Encountered Serologic Patterns of Hepatitis B Infection HBsAg + + +¶
Harrison's 22e, p.2657
| HBsAg | ANTI-HBs | ANTI-HBc | HBeAg | ANTI-HBe | INTERPRETATION |
|---|---|---|---|---|---|
| + | − | IgM | + | − | Acute hepatitis B, high infectivitya |
| − | IgG | + | − | ||
| + | − | IgG | − | + | 1. Late acute or chronic hepatitis B, low infectivity 2. HBeAg-negative (“precore-mutant”) hepatitis B (chronic or, rarely, acute) |
| + | + | +/− | +/− | ||
| − | − | IgM | +/− | +/− | 1. Acute hepatitis Ba 2. Anti-HBc “window” |
| − | IgG | − | +/− | ||
| − | + | IgG | − | +/− | Recovery from hepatitis B |
| + | − | − | − |
TABLE 350-6 Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis HBsAg + + + + − − − − Note: See…¶
Harrison's 22e, p.2658
| SEROLOGIC TESTS OF PATIENT’S SERUM | DIAGNOSTIC INTERPRETATION | |||
|---|---|---|---|---|
| HBsAg | IgM ANTI-HAV | IgM ANTI-HBc | ANTI-HCV HCV RNA | |
| + | − | + | − | Acute hepatitis B |
| − | − | − | ||
| + | + | − | − | Acute hepatitis A superimposed on chronic hepatitis B |
| + | + | − | ||
| − | + | − | − | Acute hepatitis A |
| + | + | − | ||
| − | − | + | − | Acute hepatitis B (HBsAg below detection threshold) |
| − | − | Either + |
TABLE 350-7 Hepatitis A Vaccination Schedules¶
Harrison's 22e, p.2662
| AGE, YEARS | NO. OF DOSES | DOSE | SCHEDULE, MONTHS |
|---|---|---|---|
| HAVRIX (GlaxoSmithKline)a | |||
| 1–18 ≥19 |
2 2 |
720 ELUb (0.5 mL) 1440 ELU (1 mL) |
0, 6–12 0, 6–12 |
| VAQTA (Merck) | |||
| 2 2 |
25 units (0.5 mL) 50 units (1 mL) |
TABLE 350-8 Preexposure Hepatitis B Vaccinations NAME Engerix-B (GlaxoSmithKline)¶
Harrison's 22e, p.2663
| NAME | VACCINE TYPE | AGE GROUP | NO. OF DOSES | SCHEDULE, MONTH | NOTES |
|---|---|---|---|---|---|
| Engerix-B (GlaxoSmithKline) |
Single antigen recombinant |
From birth, not on dialysis |
3 | 0, 1, 6 | 0.5-mL dose for 0–19 years 1-mL dose for ≥20 years Contraindicated with severe yeast allergy |
| Adults on dialysis | 4 | 0, 1, 2, 6 | 2-mL dose for adults | ||
| Single antigen recombinant |
From birth, not on dialysis |
3 | 0, 1, 6 | ||
| Recombivax HBV dialysis formulation (Merck) |
Single antigen recombinant |
Adults on dialysis | 3 | 0, 1, 6 | 1-mL dose for adults |
| Single antigen adjuvanted recombinant |
≥18 years | 2 | 0, 1 | ||
| PreHevbrio (VBI)* | Three antigen recombinant |
≥18 years | 3 | 0, 1, 6 | 1-mL dose Higher rates of seroprotection in adults ≥45 years Not for use in pregnant women |
| Combined single antigen recombinant hepatitis A and hepatitis B |
≥18 years | 3 | 0, 1, 6 Note: accelerated 4-dose regimen, days 0, 7, and 21–30, 12 months |