Hepatitis Viruses

• Definition: Viral hepatitis is hepatocyte inflammation and necrosis caused by the five hepatotropic viruses A, B, C, D, and E. HAV and HEV are non-enveloped RNA viruses shed in stool; HBV is a partially double-stranded DNA hepadnavirus; HCV is an enveloped RNA flavivirus; HDV is a defective RNA satellite virus that borrows the HBV surface envelope.
• Why it matters: Acute infection can progress to fulminant hepatic failure, and chronic HBV/HCV are among the leading causes of cirrhosis, portal hypertension, liver transplantation, and hepatocellular carcinoma worldwide. Both chronic infections are largely silent for decades, so detection depends on screening rather than symptoms.

Epidemiology worth recalling

• HBV: Hundreds of millions chronically infected globally, with highest prevalence in sub-Saharan Africa and East/Southeast Asia where perinatal transmission predominates. In the US, chronic HBV is concentrated among persons born in endemic regions, people who inject drugs, and men who have sex with men. CDC now recommends screening all adults for HBV at least once with a triple panel (HBsAg, anti-HBs, total anti-HBc).
• HCV: The most common chronic bloodborne infection in the US. Two epidemiologic peaks are tested: older adults exposed through pre-1992 transfusions or remote injection use, and young adults in the ongoing opioid epidemic. CDC and USPSTF both endorse one-time screening of all adults (USPSTF ages 18–79) and screening in every pregnancy.
• HAV: Now largely an outbreak disease in the US among persons experiencing homelessness, people who use drugs, and international travelers; childhood vaccination (ACIP) has markedly reduced incidence.
• HEV: The dominant cause of sporadic acute hepatitis in South/Southeast Asia; in high-income countries it appears as a zoonotic genotype 3 infection from undercooked pork or game, and as chronic infection in transplant recipients.

Enteric (fecal–oral) mechanism — HAV, HEV

• Contaminated food and water: Raw or undercooked shellfish (HAV), untreated water in endemic regions (HEV genotypes 1/2), undercooked pork, boar, or deer (HEV genotype 3, zoonotic).
• Person-to-person spread: Daycare centers and diapered children, household contacts, congregate settings, men who have sex with men, and travel to high-endemicity regions. HAV is non-enveloped and therefore resistant to acid, drying, and detergents.

Parenteral/percutaneous mechanism — HBV, HCV, HDV

• Injection drug use with shared equipment: The dominant modifiable risk factor for HCV in the US and a major route for HBV and HDV.
• Healthcare and occupational exposure: Needlestick injury transmits HBV far more efficiently than HCV, and HCV more efficiently than HIV. Hemodialysis, unregulated tattooing, and transfusion before donor screening (pre-1992 for HCV) are classic stem details.

Sexual and perinatal mechanism

• Sexual transmission: Efficient for HBV; low but non-zero for HCV, rising with HIV coinfection and receptive anal intercourse.
• Vertical transmission: The main global route for HBV; risk correlates with maternal HBV DNA level and HBeAg positivity. ACOG recommends HBsAg testing in every pregnancy and HCV screening in each pregnancy.

Non-modifiable risk factors

• Age at acquisition: The single strongest determinant of chronicity — the great majority of perinatally infected neonates become chronic carriers, versus only a small minority of immunocompetent adults.
• Birth in an endemic country, male sex (higher HCC risk), and host genetics (IL28B/IFNL3 polymorphisms influence spontaneous HCV clearance).

Modifiable cofactors accelerating fibrosis

• Alcohol use, obesity/metabolic dysfunction–associated steatotic liver disease, HIV coinfection, and HBV–HCV or HBV–HDV coinfection each speed progression to cirrhosis and are the levers clinicians actually change.
• Immunosuppression: Rituximab, high-dose corticosteroids, and chemotherapy risk HBV reactivation and chronic HEV.

• Immune-mediated injury, not direct cytopathy: Hepatitis viruses are largely non-cytopathic. Hepatocyte death comes from CD8+ cytotoxic T cells recognizing viral peptides on MHC I, releasing perforin/granzyme and Fas ligand. This explains the paradox that a vigorous immune response produces symptomatic acute hepatitis with high aminotransferases but clears virus, whereas a weak neonatal response produces minimal ALT elevation and chronic carriage.
• Aminotransferase release: Necrotic hepatocytes spill cytosolic ALT and AST; ALT predominates because it is more liver-specific and cytosolic.
• Jaundice and cholestasis: Damaged hepatocytes fail to excrete conjugated bilirubin into canaliculi, so conjugated (direct) bilirubin refluxes into blood — hence dark urine (water-soluble conjugated bilirubin is renally filtered) and acholic stools when bile flow is impaired. Pruritus reflects retained bile acids.
• Synthetic failure: Loss of hepatocyte mass reduces factor II, VII, IX, X synthesis; factor VII's short half-life makes a rising INR the earliest and most ominous marker of failing synthetic function, more reliable than albumin.
• HBV persistence: Covalently closed circular DNA (cccDNA) forms a stable nuclear minichromosome that current nucleos(t)ide analogues suppress but do not eradicate — the reason therapy is often lifelong and why immunosuppression permits reactivation. HBV DNA integration into host chromosomes plus chronic regenerative turnover allows HCC even without cirrhosis.
• HCV persistence: An error-prone RNA-dependent RNA polymerase lacking proofreading generates quasispecies with hypervariable envelope regions, defeating neutralizing antibody and explaining the absence of a vaccine and the possibility of reinfection after cure.
• Extrahepatic disease: Circulating immune complexes drive HBV-associated polyarteritis nodosa and membranous nephropathy, and HCV-associated mixed cryoglobulinemia with membranoproliferative glomerulonephritis.
• Fibrogenesis: Persistent inflammation activates hepatic stellate cells into myofibroblasts that deposit collagen, producing bridging fibrosis, regenerative nodules, increased sinusoidal resistance, portal hypertension, and eventually decompensation.

Acute icteric hepatitis (classic HAV, symptomatic HBV)

• Prodrome: Fever, malaise, anorexia, nausea, and a characteristic aversion to cigarettes and to fatty food, reflecting systemic cytokine release before hepatocyte necrosis peaks.
• Icteric phase: Scleral icterus and jaundice with dark urine and pale stools from conjugated hyperbilirubinemia, plus pruritus from retained bile salts. Fever typically defervesces as jaundice appears.
• Examination: Tender hepatomegaly with right upper quadrant pain from stretch of Glisson capsule; splenomegaly and posterior cervical lymphadenopathy in a minority.
• Immune-complex prodrome (HBV): A serum sickness–like syndrome of urticaria, symmetric polyarthralgias, and occasionally papular acrodermatitis (Gianotti–Crosti syndrome) in children, preceding jaundice.

Chronic infection — usually silent

• Asymptomatic or nonspecific fatigue is the rule for chronic HBV and HCV; the stem often names an incidental transaminase elevation, a blocked blood donation, or a routine screening test rather than symptoms.
• Stigmata of cirrhosis when advanced: spider angiomata, palmar erythema, gynecomastia and testicular atrophy (impaired estrogen clearance), caput medusae, ascites, and asterixis with encephalopathy.
• Extrahepatic clues: Palpable purpura, arthralgias, and neuropathy of mixed cryoglobulinemia, blistering photosensitive dorsal-hand lesions of porphyria cutanea tarda, oral lichen planus, and proteinuria of membranoproliferative glomerulonephritis point to HCV; abdominal pain, hypertension, and mononeuritis multiplex from polyarteritis nodosa point to HBV.

Exposures the stem names

• Recent travel to an endemic country, a daycare outbreak, or a shellfish meal (HAV); injection drug use, incarceration, hemodialysis, or a pre-1992 transfusion (HCV); unvaccinated immigrant from an endemic region or a needlestick (HBV); a pregnant woman in the third trimester from South Asia (HEV).

Red flags for acute liver failure

• Confusion, asterixis, or somnolence with a rising INR and shrinking liver span signal fulminant failure and are an emergency.

Initial biochemical assessment

• Hepatocellular pattern: ALT and AST elevated out of proportion to alkaline phosphatase, with ALT typically exceeding AST in viral hepatitis. Values in the thousands suggest acute viral hepatitis, ischemia, or toxin. An AST:ALT ratio above 2 should redirect you toward alcohol-related liver disease.
• Assess severity, not just injury: Bilirubin, INR, albumin, platelet count, and mental status determine disposition. INR and encephalopathy — not the transaminase peak — define acute liver failure.

Serologic sequence

• Acute hepatitis panel: anti-HAV IgM, HBsAg, anti-HBc IgM, and anti-HCV with reflex HCV RNA.
• HBV interpretation: HBsAg marks infection; anti-HBc IgM identifies acute infection and covers the window period when HBsAg has cleared and anti-HBs has not yet appeared; isolated anti-HBs indicates vaccination; anti-HBs plus anti-HBc indicates resolved natural infection. HBeAg and quantitative HBV DNA define replicative phase and treatment eligibility.
• HCV interpretation: Anti-HCV antibody is the screen and persists after cure, so a positive antibody must always be reflexed to HCV RNA to distinguish current from past infection — the approach endorsed by CDC and AASLD-IDSA.
• HDV: Test anti-HDV with confirmatory HDV RNA in every HBsAg-positive patient at least once.
• HEV: anti-HEV IgM, with HEV RNA in immunocompromised patients in whom antibody may be absent.

Staging fibrosis (drives surveillance and urgency)

• Noninvasive first: FIB-4 and APRI from routine labs, then vibration-controlled transient elastography or serum fibrosis panels. Biopsy is reserved for discordant or confounded cases.
• Prognostic scores: Child–Turcotte–Pugh and MELD (MELD 3.0 for US transplant allocation) grade cirrhosis; the King's College criteria identify acute liver failure patients needing urgent transplant evaluation.

Immediate priorities in acute hepatitis

• Supportive care and risk stratification: Hydration, antiemetics, avoidance of alcohol and hepatotoxins, and serial INR/mental status checks. Any encephalopathy with coagulopathy mandates urgent transfer to a transplant center per AASLD acute liver failure guidance; monitor glucose, watch for cerebral edema, and avoid sedatives.
• Post-exposure prophylaxis: Hepatitis A vaccine (with immune globulin for infants, older or immunocompromised contacts) per ACIP; hepatitis B vaccine plus HBIG for susceptible percutaneous or perinatal exposures, given to the newborn of an HBsAg-positive mother within 12 hours of birth.

Chronic HBV (AASLD guidance)

• First line: High-barrier nucleos(t)ide analogues — entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide — for immune-active disease (elevated ALT with significant viremia) and for all patients with cirrhosis and detectable HBV DNA. Peginterferon alfa is an alternative finite-duration option in selected patients.
• Special situations: Tenofovir in the third trimester for high maternal viral load to reduce vertical transmission; antiviral prophylaxis before rituximab or other immunosuppression to prevent reactivation.
• Avoid: Lamivudine and adefovir as initial therapy (low genetic barrier); interferon in decompensated cirrhosis or autoimmune disease.

Chronic HCV (AASLD-IDSA guidance)

• First line: Pangenotypic direct-acting antiviral regimens such as sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, treating essentially all patients regardless of fibrosis stage; sustained virologic response at 12 weeks defines cure.
• Escalation: Ribavirin-containing or extended regimens for prior DAA failure or decompensated cirrhosis, ideally with specialist input.
• Contraindicated: NS3/4A protease inhibitors (the -previr agents) in Child–Pugh B/C cirrhosis; amiodarone with sofosbuvir (severe bradycardia); ribavirin in pregnancy (teratogen).

Definitive management

• Liver transplantation for acute liver failure meeting King's College criteria and for decompensated cirrhosis or HCC within accepted criteria; post-transplant HBV recurrence is prevented with HBIG plus a nucleos(t)ide analogue.

Emergencies

• Fulminant hepatic failure: Massive hepatocyte necrosis producing encephalopathy plus coagulopathy within weeks of onset; highest risk with HBV–HDV coinfection or HDV superinfection, HEV in pregnancy, and HAV superimposed on chronic liver disease. Signals include rising INR with falling transaminases and a shrinking liver span (loss of hepatocyte mass, not recovery). Cerebral edema and intracranial hypertension are the leading causes of death.
• Variceal hemorrhage: Portal hypertension from cirrhosis; presents as hematemesis or melena and requires resuscitation, octreotide, prophylactic antibiotics, and urgent endoscopy.
• Spontaneous bacterial peritonitis: Ascitic fluid PMN count at or above 250/mm³ in a cirrhotic with fever, abdominal pain, or unexplained encephalopathy — treat empirically with a third-generation cephalosporin.

Chronic hepatic complications

• Cirrhosis and decompensation: Ascites, hepatic encephalopathy from failed ammonia clearance and portosystemic shunting, hepatorenal and hepatopulmonary syndromes.
• Hepatocellular carcinoma: Arises in cirrhosis of any viral cause and, distinctively, in chronic HBV without cirrhosis because of viral DNA integration. AASLD recommends ultrasound with or without alpha-fetoprotein every 6 months in at-risk patients; a rising AFP or a new arterially enhancing nodule with washout is the signal.

Extrahepatic complications

• HBV: Polyarteritis nodosa, membranous nephropathy (children), and reactivation during immunosuppression presenting as an abrupt ALT flare with reappearing HBsAg/HBV DNA — potentially fatal and fully preventable by pre-treatment screening.
• HCV: Mixed cryoglobulinemia with palpable purpura and low C4, membranoproliferative glomerulonephritis, porphyria cutanea tarda, B-cell non-Hodgkin lymphoma, and insulin resistance.

Treatment-related

• Tenofovir disoproxil fumarate: Proximal tubulopathy and reduced bone mineral density; TAF has a more favorable renal/bone profile.
• Stopping nucleos(t)ide analogues abruptly: Severe hepatitis flare from viral rebound.
• Ribavirin: Hemolytic anemia and teratogenicity. Peginterferon: Cytopenias, depression, and autoimmune thyroiditis.

• A positive anti-HCV antibody is never the endpoint: The single best next step is HCV RNA by PCR, because antibody persists for life after spontaneous clearance or DAA cure. Testing "anti-HCV IgM" is a distractor — it is not a clinically used assay.
• The window period belongs to anti-HBc IgM: A jaundiced patient with negative HBsAg and negative anti-HBs but positive anti-HBc IgM has acute HBV. Isolated anti-HBs equals vaccination; anti-HBs plus anti-HBc equals resolved natural infection.
• Age at infection determines chronicity: Perinatal HBV becomes chronic in the great majority of infants (immature T-cell response), while immunocompetent adults clear it in most cases — the mirror image of what students assume about "stronger immunity in adults."
• HBV can cause HCC without cirrhosis: Viral DNA integrates into the host genome, so surveillance is indicated in high-risk chronic HBV carriers even with a non-cirrhotic liver (AASLD). HCV essentially requires cirrhosis first.
• Coinfection versus superinfection: HDV acquired simultaneously with HBV usually resolves; HDV superinfection of an established chronic HBV carrier causes abrupt decompensation and a much higher rate of fulminant failure and cirrhosis.
• HEV in the third trimester carries a strikingly high maternal mortality; in the transplant recipient, genotype 3 HEV can become chronic — reduce immunosuppression before reaching for ribavirin.
• Rising INR with falling AST/ALT is deterioration, not recovery — it means hepatocyte mass has been lost. Prothrombin time/INR is the best early marker of synthetic failure because factor VII has the shortest half-life.
• Screen before you immunosuppress: Check HBsAg and total anti-HBc before rituximab or chemotherapy and give a nucleos(t)ide analogue prophylactically; reactivation hepatitis is a classic preventable board death.

• HAV & HEV: Fecal-oral transmission, acute only, good prognosis
• HBV & HCV: Bloodborne transmission, can cause chronic infection and cirrhosis
• HDV: Defective virus requiring HBV co-infection
• Serology patterns: HAV (anti-HAV IgM = acute), HBV (HBsAg + anti-HBc = infection), HCV (anti-HCV antibody, confirm with HCV RNA)
• Vaccination available: HAV and HBV only

• HAV: Acute hepatitis with fever, jaundice, RUQ pain in returning traveler or daycare setting; cholestatic pattern (↑ALT/AST >> ↑ALP)
• HBV: Insidious jaundice + arthralgias in IV drug user or healthcare worker; "ground glass hepatocytes" on biopsy
• HCV: Often asymptomatic at acute stage; discovered incidentally on screening; cryoglobulinemia/glomerulonephritis
• HDV: Severe acute hepatitis only with concurrent HBsAg+
• HEV: Acute hepatitis in pregnancy (especially 3rd trimester) with high mortality risk

1. 1.Confusing HBsAg with anti-HBs: HBsAg = active infection (acute or chronic); anti-HBs = immunity/recovery; both can coexist during seroconversion window
2. 2.Assuming HCV always causes jaundice: Most HCV patients are asymptomatic carriers at acute stage; diagnosed by screening in blood donors or risk populations
3. 3.Missing HDV: Must check for anti-HDV and HDV RNA in HBsAg+ patients presenting with unusually severe hepatitis or rapid decompensation

• HAV: Supportive care only; vaccine for prophylaxis (post-exposure within 2 weeks)
• HBV (chronic): Nucleos(t)ide reverse transcriptase inhibitors (entecavir, tenofovir); consider interferon-α
• HCV (modern): Direct-acting antivirals (DAAs) - sofosbuvir/ledipasvir/velpatasvir (cure rates >95%); no longer interferon-based
• HDV: Interferon-α (limited efficacy); tenofovir may help; hepatitis B vaccination prevents acquisition
• HEV: Supportive care; ribavirin in immunocompromised; vaccine available (limited use)