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HEPATITIS - Complete Study Guide

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OVERVIEW: What is Hepatitis?

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PART 1: ACUTE HEPATITIS

Definition

Clinicopathologic Phases (applies to all hepatotropic viruses)

1. Incubation period - virus replicates silently; duration varies by virus (see table below)
2. Preicteric (prodromal) phase - malaise, anorexia, nausea, vomiting, right upper quadrant discomfort, flu-like symptoms; serum transaminases (ALT, AST) begin to rise
3. Icteric phase - jaundice appears (bilirubin rises), dark urine (conjugated bilirubin), pale stools, pruritus; ALT peaks here
4. Convalescence - symptoms resolve, jaundice fades, enzymes normalize

Possible Outcomes of Acute Hepatitis

• Acute asymptomatic infection with recovery (subclinical - only detected by serology)
• Acute symptomatic infection with recovery (most common for HAV, HBV)
• Fulminant (acute) hepatic failure - massive hepatocyte necrosis, encephalopathy, coagulopathy (rare but life-threatening)
• Chronic hepatitis - inflammation persisting > 6 months (only HBV, HCV, HDV, HEV can do this)
• Asymptomatic carrier state (mainly HBV)

Lab Findings in Acute Hepatitis

Clinical pearl: ALT > AST in viral hepatitis. AST:ALT > 2:1 suggests alcoholic hepatitis.

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PART 2: HEPATITIS A (HAV)

Virus Properties

• Small, nonenveloped, positive-strand RNA picornavirus (genus Hepatovirus)
• 27 nm icosahedral capsid
• Receptor on hepatocytes: HAVcr-1 (TIM-1)
• Not cytopathic - liver injury is caused by cytotoxic T lymphocytes and NK cells

Epidemiology

• Accounts for ~25% of clinically evident acute hepatitis worldwide
• Transmission: fecal-oral route - contaminated water, food (especially raw shellfish - oysters, mussels, clams), close personal contact
• Endemic in countries with poor hygiene and sanitation
• No chronic carrier state, no chronic hepatitis
• HAV shed in stool 2-3 weeks before and 1 week after onset of jaundice (maximum infectivity before jaundice)
• Blood-borne transmission is rare (transient viremia)
• Maternal-fetal transmission does NOT occur

Incubation Period

Clinical Features

• Nonspecific symptoms: fatigue, loss of appetite, nausea, RUQ pain
• Jaundice develops; most recover within 3 months, all by 6 months
• Acute liver failure (ALF): 0.1% to 0.3% - especially in those with underlying chronic liver disease
• Uncommon complications: prolonged cholestasis, relapse within 6 months
• Extrahepatic: rash, arthralgia, leukocytoclastic vasculitis, glomerulonephritis, cryoglobulinemia

Serology

Prevention

• HAV vaccine - highly effective
• Passive immunoglobulin for post-exposure prophylaxis

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PART 3: HEPATITIS B (HBV)

Virus Properties

• Hepadnaviridae family
• Partially double-stranded circular DNA virus (only DNA hepatitis virus)
• The mature virion (Dane particle) has:
  • Outer surface envelope: lipid + viral proteins
  • Inner core: nucleocapsid (HBcAg), viral polymerase, viral DNA

Key HBV Antigens

Epidemiology

• 254 million people living with chronic HBV globally (WHO 2022); 1.2 million new infections/year; 1.1 million deaths/year
• Highest prevalence (>8%) in Africa, Asia, Western Pacific rim
• Transmission:
  • Parenteral: blood transfusion (now rare due to screening), IV drug use
  • Sexual transmission (most common in developed countries among young adults)
  • Perinatal/vertical - dominant route in high-prevalence regions (accounts for 90% of cases in endemic areas)
  • Horizontal: minor skin breaks, close bodily contact in children

Outcomes Based on Age of Acquisition

Incubation Period

Acute Hepatitis B

• Two-thirds: asymptomatic / subclinical (never recognized)
• One-third: symptomatic acute hepatitis (mild to moderate)
• Fulminant hepatic failure: ~1%; spontaneous survival rate only ~20% (liver transplant gives 50-60%)
• HBV accounts for 7% of all ALF cases
• Rapid viral elimination may cause HBsAg to clear before presentation - in these cases, diagnose by IgM anti-HBc

Chronic Hepatitis B

1. Immune tolerant phase - high viral replication (HBeAg+, high HBV DNA), normal/near-normal ALT, minimal liver damage; common in perinatally infected persons
2. Immune active (HBeAg-positive) phase - immune system attacks infected hepatocytes; elevated ALT, active necroinflammation, progressive fibrosis
3. Inactive carrier phase - HBeAg seroconversion to anti-HBe; low HBV DNA, normal ALT, reduced inflammation; low but not zero risk of HCC
4. HBeAg-negative chronic hepatitis B - reactivation with HBeAg-negative mutants; elevated ALT, elevated HBV DNA (but often lower), ongoing liver damage

• Cirrhosis develops in 20-30% of untreated active disease
• Annual risk of decompensation in HBV cirrhosis: 5-8%
• Annual risk of HCC: 2-4% in cirrhosis
• HCC can occur even WITHOUT cirrhosis (unique to HBV)

HBV Serologic Interpretation

Window period: When HBsAg has disappeared but anti-HBs not yet detectable. The only positive marker is IgG anti-HBc. IgM anti-HBc distinguishes acute infection in this setting.

Treatment of HBV

• Goal: suppress HBV DNA, prevent progression to cirrhosis/HCC
• First-line antivirals: Tenofovir (TDF or TAF) or Entecavir - high potency, low resistance
• Pegylated interferon-alpha (Peg-IFN) - finite course but more side effects
• Indications: active disease (elevated ALT + elevated HBV DNA + significant fibrosis)
• Antiviral therapy does not eradicate cccDNA (functional cure rare; eradication currently impossible)

HBV Vaccination

• 3-dose recombinant vaccine; highly effective
• Universal infant vaccination has drastically reduced transmission

HCC Screening in Chronic HBV (Box 79.2, Sleisenger)

• African American carriers > 20 years
• Asian female carriers > 50 years
• Asian male carriers > 40 years
• Family history of HCC
• Any HBV cirrhosis
• Coinfection with HDV, HCV, or HIV
• Persistent active infection (high HBV DNA + ongoing liver injury)

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PART 4: HEPATITIS C (HCV)

Virus Properties

• Flaviviridae family
• Enveloped, positive-strand RNA virus, single-stranded
• Life cycle entirely cytoplasmic (no nuclear integration) - this is why cure is possible
• 6 major genotypes (1-6); genotype 1 most common in Western countries

Epidemiology

• ~80 million infected worldwide
• Transmitted predominantly parenterally: IV drug use (most common in developed world), blood transfusions (now screened), needlestick injuries, tattoos
• Sexual transmission possible but less efficient than HBV
• Perinatal transmission: ~5-6% (increases with HIV co-infection)
• Increasing among women of childbearing age (opioid epidemic)

Incubation

Acute Hepatitis C

• Mostly asymptomatic (60-70%)
• Symptomatic: mild jaundice, fatigue, nausea
• Spontaneous clearance occurs in 20-30% within 6 months
• The remaining 70-80% progress to chronic infection
• ALF is very rare with acute HCV

Chronic Hepatitis C

• Most patients asymptomatic until advanced fibrosis develops
• Symptoms: fatigue, vague abdominal pain, depression, arthralgias, paresthesias, myalgias
• ALT fluctuates; may be normal in ~20% at any given time
• ~20% progress to cirrhosis over 20 years (faster in men, with alcohol use, with HIV co-infection)
• HCC risk: primarily occurs in cirrhotics; 1-4% per year in HCV cirrhosis

Extrahepatic Manifestations of HCV

• Mixed cryoglobulinemia (Types 2 and 3) - most characteristic; 19-50% have cryoglobulins, 5-10% have clinical symptoms
  • Presents as: fatigue, arthralgia, purpura (palpable), Raynaud phenomenon, vasculitis, peripheral neuropathy, nephropathy
  • Low complement (C4), positive rheumatoid factor, cryoglobulins
• Glomerulonephritis - especially membranoproliferative GN, membranous nephropathy
• Lichen planus
• Porphyria cutanea tarda
• Non-Hodgkin lymphoma (B-cell)
• Sicca syndrome

Diagnosis of HCV

1. Anti-HCV antibody (ELISA) - screening test; detectable 4-10 weeks after infection
2. HCV RNA by PCR - confirmatory; appears earlier (1-2 weeks after infection); used to monitor treatment
3. HCV genotyping - guides treatment choice and duration

Treatment of HCV - Direct-Acting Antivirals (DAAs)

• Direct-Acting Antivirals (DAAs) target HCV NS3/4A protease, NS5A replication complex, NS5B polymerase
• IFN-based regimens are no longer recommended
• Sustained Virologic Response (SVR) = undetectable HCV RNA 12-24 weeks after completing treatment
• SVR rates >95% with modern IFN-free DAA regimens; >99% of SVR patients are cured
• Key regimens: Sofosbuvir/ledipasvir, Sofosbuvir/velpatasvir, Glecaprevir/pibrentasvir
• Treatment also recommended for extrahepatic manifestations (cryoglobulinemia)

Unlike HBV, HCV can be cured because it does not integrate into the host genome

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PART 5: HEPATITIS D (HDV)

Key Concept: HDV is a Satellite Virus

• HDV (the "delta agent") is a defective RNA virus that requires HBV for its life cycle
• It uses HBsAg as its own envelope protein - cannot infect without HBV
• Smallest genome of any known animal virus
• Delta antigen (HDAg) is the only viral protein produced

Epidemiology

• 5% of HBV-infected individuals are co-infected with HDV = ~15 million people worldwide
• Highest prevalence: Amazon basin, central Africa, Middle East, Mediterranean
• Rare in Southeast Asia and China
• Transmission: parenteral route (IV drug use, blood transfusions)

Clinical Patterns (Two Types)

• Presents as acute hepatitis indistinguishable from acute HBV
• Usually self-limited; both viruses clear
• Higher rate of fulminant hepatic failure in IV drug users

• Presents as severe acute hepatitis in HBsAg carrier, OR exacerbation of existing chronic HBV
• Chronic HDV infection in >80% of superinfections - much worse prognosis
• Accelerated progression to cirrhosis

Serology

• HBsAg positive (required for HDV to exist)
• IgM anti-HDV - most reliable indicator of recent HDV exposure
• HDV RNA detectable just before and during acute illness

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PART 6: HEPATITIS E (HEV)

Virus Properties

• Unenveloped, positive-stranded RNA virus
• Hepeviridae family (genus Orthohepevirus)
• Genome 7.3 kb; four open reading frames
• Zoonotic disease - animal reservoirs include pigs, monkeys, cats, dogs

Epidemiology

• Fecal-oral transmission; waterborne epidemics
• Endemic in: Asia, Indian subcontinent, sub-Saharan Africa, Middle East, China, Mexico
• In India: accounts for >30% of sporadic acute hepatitis (exceeds HAV)
• In high-income countries: associated with pig farming or consumption of undercooked organ meat
• Can occur in travelers returning from endemic regions

Incubation

Clinical Features

• Self-limited acute hepatitis in most cases; resolves in 2-4 weeks
• Immunocompetent: no chronic carrier state, no chronic hepatitis
• Most important: mortality ~20% in pregnant women (especially third trimester) - a classic exam fact
• Immunocompromised (AIDS, transplant recipients): can develop chronic HEV infection with progressive liver disease

Serology

• IgM anti-HEV and HEV RNA appear simultaneously with clinical symptoms
• IgM → replaced by persistent IgG anti-HEV during recovery
• HEV RNA detectable in stool and serum before onset of illness

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PART 7: COMPARISON TABLE - All Hepatitis Viruses

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PART 8: CHRONIC HEPATITIS - General Concept

Definition

Causes (in order of global importance)

1. HBV
2. HCV
3. Autoimmune hepatitis
4. Drug-induced (e.g., methotrexate, isoniazid, methyldopa)
5. Wilson's disease, Alpha-1 antitrypsin deficiency
6. Non-alcoholic steatohepatitis (NASH)

Histologic Grading and Staging

• Grade = degree of necroinflammatory activity (predicts current damage rate)
• Stage = degree of fibrosis (predicts prognosis and risk of cirrhosis)
• Staging systems: Metavir (F0-F4), Ishak (0-6)
• F4 = cirrhosis

Clinical Presentation

• Often asymptomatic for years (especially HCV)
• Fatigue, malaise, mild RUQ discomfort
• Hepatomegaly, splenomegaly (late)
• ALT elevated (fluctuating, especially in HCV)
• Jaundice, ascites, encephalopathy = signs of decompensation (advanced disease)

Assessment of Fibrosis (Stage)

• Liver biopsy - gold standard
• Non-invasive: FIB-4 score, APRI score, FibroScan (transient elastography)

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PART 9: PATHOLOGY OF HEPATITIS (Key Histological Findings)

Acute Hepatitis (all viral types)

• Hepatocyte swelling (ballooning degeneration)
• Councilman (acidophilic) bodies = apoptotic hepatocytes; eosinophilic, shrunken
• Lobular disarray - disruption of normal hepatic architecture
• Mononuclear cell infiltrate (lymphocytes, macrophages) in portal tracts and lobule
• Kupffer cell hyperplasia
• Cholestasis (bile plugs) in severe cases

Chronic Hepatitis

• Portal tracts expanded by lymphocytic infiltrate
• Interface hepatitis (piecemeal necrosis) = lymphocytes spill into periportal hepatocytes - hallmark of activity
• Bridging fibrosis (F3): fibrous septa connect portal tracts to central veins
• Periportal fibrosis → bridging fibrosis → cirrhosis (progression)
• "Ground glass" hepatocytes in HBV = cytoplasm stuffed with HBsAg (smooth ER hypertrophy)

Fulminant Hepatitis

• Massive hepatic necrosis - large confluent zones of hepatocyte death
• Collapsed reticulin framework
• Bile duct proliferation in portal tracts

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PART 10: CHRONIC HEPATITIS → CIRRHOSIS (The Progression Story)

• Male sex, older age at infection
• High viral load (HBV DNA, HCV RNA)
• Alcohol use (synergistic with both HBV and HCV)
• HIV co-infection
• HDV co-/super-infection
• Non-alcoholic fatty liver disease

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PART 11: HEPATITIS AND THE DOWNSTREAM GI/HEPATOLOGY COMPLICATIONS

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QUICK-REFERENCE: Exam Memory Aids

"Which hepatitis can become chronic?" → B, C, D (and E in immunocompromised)

"Which can cause HCC?" → B (even without cirrhosis) and C (mainly via cirrhosis)

"Which is fatal in pregnancy?" → E (~20% mortality in third trimester)

"Which needs HBV to replicate?" → D (delta agent, satellite virus)

"Which is curable with drugs?" → C (DAAs, >95% SVR)

"Window period serology?" → Only IgG anti-HBc positive (HBsAg gone, anti-HBs not yet appeared)

"How to diagnose acute HBV in window period?" → IgM anti-HBc

"Newborn exposed to HBsAg-positive mother?" → Give HBIG + HBV vaccine within 12 hours of birth

"ALT vs AST?" → Viral hepatitis: ALT > AST. Alcoholic hepatitis: AST:ALT > 2:1

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• Robbins & Kumar Pathologic Basis of Disease (Robbins Pathology), Ch. 18
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Chs. 79-81
• Goldman-Cecil Medicine International Edition, Vol. 2
• Yamada's Textbook of Gastroenterology, 7th ed.