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🏥 HEPATITIS — A Complete Medical Teaching Module

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1. DEFINITION

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2. CAUSES & RISK FACTORS

Causes - the "VITAMINS" framework

Risk Factors for Viral Hepatitis

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3. CLASSIFICATION / TYPES

By Duration

By Etiology - The 5 Viral Hepatitis Types

HAV, HEV = "A and E come from tEa and watEr" (fecal-oral)
HBV, HCV, HDV = "B, C, D come from BlooD" (parenteral/sexual)

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4. RELEVANT ANATOMY & PHYSIOLOGY

Liver Anatomy

• Hepatocytes - the main functional cells (~80% of liver volume); produce bile, albumin, clotting factors, and metabolize drugs/toxins
• Portal triad - contains portal venule, hepatic arteriole, and bile ductule; the liver receives dual blood supply (portal vein 75% + hepatic artery 25%)
• Kupffer cells - liver macrophages; first line of immune defense
• Sinusoids - special capillaries between hepatocyte plates; blood flows from portal tract to central vein
• Space of Disse - between hepatocytes and sinusoids; hepatic stellate cells (Ito cells) reside here
• Bile canaliculi - tiny channels between hepatocytes that carry bile toward bile ducts

Key Liver Functions (What is lost in hepatitis)

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5. PATHOPHYSIOLOGY

Step-by-Step Disease Process

VIRUS enters the body
        ↓
Reaches hepatocytes via bloodstream or portal circulation
        ↓
Viral replication inside hepatocytes
        ↓
Viral antigens displayed on hepatocyte surface (MHC Class I)
        ↓
IMMUNE RESPONSE (CD8+ cytotoxic T cells attack infected hepatocytes)
        ↓
HEPATOCYTE INJURY & NECROSIS
        ↓
Liver enzymes (ALT, AST) leak into blood → elevated LFTs
Bilirubin processing fails → conjugated hyperbilirubinemia
Bile cannot flow → cholestasis
        ↓
CLINICAL FEATURES:
Jaundice + dark urine + pale stools
Nausea, vomiting (GI effects of bilirubin + cytokines)
RUQ pain (liver capsule stretching)
Fever (cytokine release - IL-1, IL-6, TNF-α)
Fatigue (metabolic disruption + cytokines)

Why does the immune system cause MORE damage?

• Immunocompromised patients (HIV, post-transplant) may have less inflammation but more viral replication
• Immunologically vigorous people (healthy young adults) often clear the virus but have more symptoms

Bilirubin Metabolism (Why Jaundice Occurs)

RBC breakdown → Unconjugated (indirect) bilirubin
                        ↓ (hepatocyte uptake + conjugation)
              Conjugated (direct) bilirubin
                        ↓ (secreted into bile)
              Bile → gut → stercobilinogen → stool (brown colour)
              Some reabsorbed → urobilinogen → urine (yellow)

In HEPATITIS:
- Conjugation impaired → unconjugated bilirubin rises
- Canalicular secretion impaired → conjugated bilirubin backs up into blood
- Result: MIXED hyperbilirubinemia (both fractions elevated)
- Less bile in gut → PALE/CLAY-COLOURED STOOLS
- Conjugated bilirubin (water-soluble) spills into urine → DARK URINE (tea-coloured)

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6. CLINICAL FEATURES

Phases of Acute Viral Hepatitis

Phase 1: INCUBATION
• No symptoms; virus replicating silently
• Duration varies by virus (see table above)

Phase 2: PRODROMAL (Pre-icteric) Phase (3-10 days)
• Constitutional symptoms come BEFORE jaundice
• Anorexia, nausea, vomiting (most prominent early)
• Fatigue and malaise
• Low-grade fever (38-39°C) - more in HAV and HEV
• Arthralgias, myalgias, headache
• Altered taste/smell (hallmark - aversion to smoking, alcohol, food)
• Right upper quadrant discomfort

Phase 3: ICTERIC Phase (jaundice appears)
• Most constitutional symptoms IMPROVE as jaundice appears
• Jaundice (yellowing of skin/sclera)
• Dark urine (tea/cola-coloured)
• Pale/clay-coloured stools
• Pruritus (itching) from bile salt deposition in skin
• RUQ tenderness continues

Phase 4: RECOVERY Phase (weeks to months)
• Jaundice fades, appetite returns
• Malaise may persist for weeks
• LFTs normalize last

Symptoms (Why Each Occurs)

Signs on Examination

Extra-hepatic Manifestations (especially HBV)

• Polyarteritis nodosa (PAN) - medium vessel vasculitis
• Membranous nephropathy / MPGN - immune complex deposition
• Serum sickness-like syndrome (urticaria, arthralgias, fever before jaundice) - HBV
• Essential mixed cryoglobulinemia - HCV (classic association!)
• Porphyria cutanea tarda - HCV
• Sjögren's-like syndrome, lichen planus - HCV
• Aplastic anemia - rare, HAV/HBV

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7. HISTORY TAKING

Key Questions and Why They Matter

• "When did you first notice yellowing of the skin/eyes?" → onset of icteric phase
• "Did you have fever, nausea, loss of appetite BEFORE the jaundice?" → prodrome (strongly suggests viral hepatitis)
• "Have you noticed dark urine or pale stools?" → confirms cholestasis
• "Any itching?" → cholestatic component
• "Any confusion, unusual drowsiness?" → critical - hepatic encephalopathy

• "Have you recently eaten shellfish (oysters, clams), or food from a restaurant/street food?" → HAV (raw shellfish concentrate the virus)
• "Any recent travel to developing countries?" → HAV, HEV
• "Do you use intravenous drugs or have you ever shared needles?" → HBV, HCV
• "What is your sexual history? Multiple partners? Men who have sex with men?" → HBV
• "Have you received blood transfusions, organ transplants?" → HBV, HCV
• "Any new tattoos, piercings?" → HBV, HCV
• "Any occupational exposure to blood? Are you a healthcare worker?" → HBV, HCV
• "Have you been immunized against hepatitis A or B?" → Establishes baseline immunity
• "Alcohol use? How much, how long?" → Alcoholic hepatitis
• "What medications, herbal remedies, or supplements do you take?" → DILI (drug-induced liver injury)

• "Are you pregnant?" → HEV in pregnancy has 20-25% mortality; crucial management point

• "Any family member with hepatitis or liver disease?" → HBV vertical transmission; Wilson's; hemochromatosis

• Prior episodes of jaundice? → Recurrent suggests chronic hepatitis
• History of autoimmune disease? → AIH

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8. DIFFERENTIAL DIAGNOSIS

Conditions That Mimic Hepatitis

Clinical Rule of Thumb

ALT:AST > 1 → Usually viral/toxic (hepatocellular)
AST:ALT > 2:1 → Alcoholic hepatitis
ALP >> ALT/AST → Cholestatic/obstructive disease
ALT > 1000 IU/L → Viral hepatitis, ischemic hepatitis, or acetaminophen toxicity

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9. INVESTIGATIONS

Basic Investigations

Specific Serological Tests

Hepatitis A

Hepatitis B - The Most Complex Serology

Hepatitis C

Hepatitis D & E

Additional Specific Tests

Imaging

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10. DIAGNOSIS

Diagnostic Criteria

• Encephalopathy + coagulopathy (PT >15s or INR >1.5) within 8-26 weeks of onset of liver disease in a patient WITHOUT prior liver disease

Diagnostic Approach - Practical Flow

Patient presents with JAUNDICE + elevated transaminases
                    ↓
Step 1: History + Examination
(Prodrome? Drug/alcohol exposure? Sexual/travel/blood exposure?)
                    ↓
Step 2: Basic LFTs
ALT, AST, ALP, GGT, Bilirubin, PT/INR, Albumin, CBC
                    ↓
Step 3: USS Abdomen
(Rule out biliary obstruction first!)
                    ↓
Step 4: Viral Serology Panel
IgM anti-HAV | HBsAg + IgM anti-HBc + HBeAg | Anti-HCV + HCV RNA | Anti-HEV IgM
                    ↓
Step 5: If all viral markers negative → Consider:
• Drug history (DILI)
• Alcohol (AST:ALT, GGT)
• Autoimmune (ANA, SMA, IgG)
• Wilson's / Hemochromatosis (if young)
• Ischemic (cardiac, LDH)
• EBV/CMV (atypical lymphocytes, heterophile)
                    ↓
Step 6: Assess Severity
PT/INR, Bilirubin, Albumin, Creatinine, Grade of encephalopathy
(MELD score, King's College Criteria for transplant referral)

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11. COMPLICATIONS

Complications of Acute Hepatitis

Complications of Chronic Hepatitis (HBV, HCV)

Chronic Hepatitis
    ↓ (years-decades of inflammation → fibrosis)
CIRRHOSIS
    ↓
Portal hypertension
    ├── Esophageal varices → VARICEAL BLEEDING (life-threatening)
    ├── Ascites → Spontaneous Bacterial Peritonitis (SBP)
    ├── Hepatic encephalopathy (asterixis → coma)
    ├── Hepatorenal syndrome (HRS)
    └── Splenomegaly → hypersplenism (thrombocytopenia, leukopenia)
                        ↓
        HEPATOCELLULAR CARCINOMA (HCC)
        - HBV: can occur WITHOUT cirrhosis!
        - HCV: almost always requires cirrhosis
        - Annual risk in HBV cirrhosis: 2-6% per year

• pH <7.30 (regardless of encephalopathy grade)
• OR all 3 of: PT >100s + Creatinine >300 μmol/L + Grade III-IV encephalopathy

• PT >100s (regardless of encephalopathy)
• OR any 3 of: Age <10 or >40, etiology (non-A non-B, DILI), duration of jaundice >7 days before encephalopathy, PT >50s, bilirubin >300 μmol/L

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12. RED FLAGS & EMERGENCIES

Dangerous Signs - Admit Immediately!

Admission Criteria

• Encephalopathy (any grade)
• INR >1.5
• Bilirubin >200 μmol/L (rising)
• Creatinine rising (hepatorenal syndrome)
• Severe vomiting/inability to tolerate oral fluids
• Hypoglycemia
• Comorbidities + hepatitis (elderly, HIV, cirrhosis)
• Suspected fulminant hepatic failure

Referral Criteria (to Hepatologist / Transplant Centre)

• Acute liver failure (any cause)
• Chronic HBV or HCV requiring antiviral therapy
• Cirrhosis
• HCC screening indication
• Diagnostic uncertainty (autoimmune, metabolic)

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13. MANAGEMENT

Treatment Goals

1. Prevent liver failure and death
2. Prevent transmission to others
3. Eradicate or suppress viral infection
4. Prevent progression to cirrhosis and HCC
5. Manage complications

Non-Drug Treatment

Drug Treatment - Overview

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14. PHARMACOLOGY OF IMPORTANT DRUGS

14A. Tenofovir (HBV)

14B. Entecavir (HBV)

14C. Pegylated Interferon Alpha-2a (HBV and HDV)

14D. Direct-Acting Antivirals (DAAs) for HCV - The Revolution

• Contraindicated with certain drugs due to P-gp/CYP3A interactions (rifampicin, carbamazepine - avoid!)
• Protease inhibitors contraindicated in decompensated cirrhosis (Child-Pugh B/C) - use Sofosbuvir/Velpatasvir instead
• Ribavirin still sometimes added for genotype 3 with cirrhosis
• Check drug-drug interactions carefully, especially with HIV antiretrovirals

14E. N-Acetylcysteine (NAC) - for Fulminant Hepatic Failure

14F. Corticosteroids - for Severe Alcoholic Hepatitis & AIH

• MDF ≥ 32 = severe alcoholic hepatitis → use Prednisolone 40 mg/day × 28 days
• Check GAHS or Lille score at day 7 to assess response

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15. TREATMENT ALGORITHM

Acute Viral Hepatitis - Severity-Based Management

ACUTE HEPATITIS DIAGNOSED
         ↓
    Assess Severity
         ↓
┌────────────────────────────────────────────────────────────────────┐
│ MILD-MODERATE                │  SEVERE              │  FULMINANT  │
│ (No encephalopathy;          │  (INR >1.5,          │  (Encephalo-│
│  INR normal; tolerating      │   Bilirubin >200,    │   pathy +   │
│  orally; bilirubin <100)     │   vomiting ++,       │   coagulo-  │
│                              │   not tolerating oral│   pathy)    │
├──────────────────────────────┼──────────────────────┼─────────────┤
│ OUTPATIENT/OPD MANAGEMENT    │  ADMISSION           │  ICU + liver│
│ • Rest + nutrition           │  • IV fluids         │  transplant │
│ • Avoid hepatotoxins         │  • IV dextrose       │  team NOW   │
│ • Antiemetics PRN            │  • Monitor LFTs,     │  • NAC IV   │
│ • Treat cause (if drug/EtOH) │    PT/INR daily      │  • Lactulose│
│ • LFT monitoring weekly      │  • Antiviral (HBV    │  • Mannitol │
│ • Notify contacts (HAV)      │    if severe)        │  • Plasmapheresis│
│ • Education + isolation      │  • Specialist review │             │
└──────────────────────────────┴──────────────────────┴─────────────┘

Chronic HBV Treatment Algorithm

CHRONIC HBV CONFIRMED
         ↓
Assess: HBeAg status | HBV DNA | ALT | Fibrosis stage (Fibroscan/biopsy)
         ↓
HBeAg+ patients:                    HBeAg- patients:
HBV DNA >20,000 IU/mL               HBV DNA >2,000 IU/mL
+ ALT elevated x2 ULN               + ALT elevated
         ↓                                   ↓
TREAT if:                           TREAT if:
- HBV DNA >2,000 IU/mL + significant fibrosis (F2+)
- Any level if cirrhosis
- HCC prophylaxis criteria
- Immunosuppression planned
         ↓
FIRST LINE TREATMENT:
• Tenofovir TAF 25 mg OD (preferred - better renal/bone safety)
• OR Tenofovir TDF 300 mg OD
• OR Entecavir 0.5 mg OD (if no renal issues)
         ↓
Monitor every 3-6 months:
HBV DNA, ALT, HBeAg/anti-HBe, HBsAg (annually), renal function
         ↓
Goal: HBV DNA undetectable → HBeAg seroconversion → HBsAg loss (rare)

Chronic HCV Treatment Algorithm

CHRONIC HCV CONFIRMED (anti-HCV + HCV RNA positive)
         ↓
Check: Genotype | Viral load | Fibrosis staging | Prior treatment
         ↓
Treatment-naive, no cirrhosis:
• Glecaprevir/Pibrentasvir (Mavyret) 3 tabs once daily × 8 weeks (all genotypes)
• OR Sofosbuvir/Velpatasvir (Epclusa) once daily × 12 weeks (all genotypes)
         ↓
With compensated cirrhosis:
• Sofosbuvir/Velpatasvir × 12 weeks
• OR Glecaprevir/Pibrentasvir × 12 weeks
         ↓
Decompensated cirrhosis:
• Sofosbuvir/Velpatasvir × 12 weeks + Ribavirin
• NO protease inhibitors!
         ↓
Check SVR at 12 weeks post-treatment
SVR12 = CURE

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16. REAL-WORLD CLINICAL APPROACH

OPD Approach

1. Don't panic - start history systematically (prodrome? exposure? drugs? alcohol?)
2. Examine - scleral icterus, hepatomegaly, splenomegaly, signs of chronic liver disease
3. Always do USS first - cheaply and quickly rules out obstructive jaundice
4. Order a viral hepatitis panel simultaneously - don't wait for USS result
5. Assess severity immediately - PT/INR is your best friend
6. Decide: admit or manage outpatient? based on severity criteria above

Emergency Approach

1. This is ACUTE LIVER FAILURE until proven otherwise
2. Secure IV access, blood glucose immediately (hypoglycemia kills)
3. INR, LFTs, FBC, renal function, blood cultures
4. Do NOT give sedatives or opioids (worsen encephalopathy)
5. Give lactulose via NG if needed
6. Call the liver transplant team early - do not wait for full deterioration
7. Avoid nephrotoxic drugs (NSAIDs, aminoglycosides)

Common Mistakes to Avoid

Clinical Pearls

• Pearl 1: In acute HBV, jaundice is a GOOD prognostic sign - it means the immune system is mounting a response. The quiet, anicteric HBV infections are more likely to become chronic.
• Pearl 2: Anti-HCV positive ≠ active infection. Always confirm with HCV RNA. Patient may have cleared infection spontaneously.
• Pearl 3: A normal ALT does NOT exclude cirrhosis in chronic HCV - burned-out cirrhosis can have near-normal enzymes.
• Pearl 4: HCV is curable! Remind patients that modern DAA therapy cures >95% in 8-12 weeks - this dramatically changes the counseling conversation.
• Pearl 5: HBV surface antigen loss ("functional cure") occurs in only 1-3% per year even with treatment. Manage expectations.
• Pearl 6: In pregnant women with jaundice from endemic area = HEV until proven otherwise. This is a medical emergency with 20-25% mortality.

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17. PRESCRIPTION EXAMPLES

Example 1: Mild Acute HAV - Outpatient

Rx:
1. Ondansetron 4 mg PO TDS × 5 days (for nausea)
2. Tab Ranitidine 150 mg BD × 7 days (for gastric symptoms)
3. Oral rehydration salts as needed
4. Multivitamin + B-complex once daily

Advice:
• Rest; light diet (high carbohydrate, low fat)
• STRICTLY NO ALCOHOL
• AVOID paracetamol, NSAIDs, herbal remedies
• Review in 1 week with LFTs + INR
• Household contacts to receive HAV vaccine/IG within 2 weeks

IMPORTANT: Return immediately if confusion, reduced urine output, severe vomiting, inability to eat.

Example 2: Chronic HBV - Starting Treatment

Patient: HBeAg+, HBV DNA 2×10^6 IU/mL, ALT 3×ULN, Fibroscan F2

Rx:
1. Tab Tenofovir Alafenamide (TAF) 25 mg OD (with or without food)
   Duration: Long-term (indefinite until HBsAg loss + 6-12 months beyond)

Monitoring plan:
• LFTs, HBV DNA, HBeAg/anti-HBe at 3 months, then 6-monthly
• Renal function, bone density baseline
• HBsAg annually
• USS liver + AFP every 6 months (HCC surveillance)

Counsel: No alcohol; vaccinate family; safe sex practices.

Example 3: Chronic HCV (Genotype 3, no cirrhosis, treatment-naive)

Rx:
1. Glecaprevir 100mg/Pibrentasvir 40mg (3 tablets once daily with food)
   Duration: 8 weeks

OR:
1. Tab Sofosbuvir 400 mg / Velpatasvir 100 mg (1 tablet once daily with food)
   Duration: 12 weeks

Check SVR12 (HCV RNA) at 12 weeks post-treatment.

Avoid: Rifampicin, St John's Wort, carbamazepine, phenytoin (reduce DAA levels dramatically)

Common Prescribing Errors

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18. PREVENTION

Primary Prevention

HBV Vaccination Schedule

• Infants: 3 doses at 0, 1-2, 6 months
• Adults (catch-up): 3 doses at 0, 1, 6 months; or accelerated schedule
• High-risk adults: 2-dose Heplisav-B (0 and 1 month) - produces faster, stronger immune response
• Post-exposure prophylaxis (unvaccinated): HBIG + vaccine within 24 hours of exposure

Post-Exposure Prophylaxis (PEP)

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19. PROGNOSIS

• King's College Criteria (see Section 11)
• MELD score (Model for End-Stage Liver Disease) - used for transplant prioritization
• Lille score (alcoholic hepatitis - response to steroids at day 7)

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20. PATIENT COUNSELING

For Acute Viral Hepatitis

"Your liver is inflamed due to a virus [or other cause]. This is causing your yellow skin, dark urine, and tiredness. Most people get better on their own in 4-8 weeks, but we need to monitor you closely."

1. Rest - your body needs energy to fight the infection
2. Eat small, frequent meals - high-carbohydrate, low-fat; avoid heavy or greasy food
3. Stay hydrated - plenty of fluids (water, soups, juices)
4. No alcohol whatsoever - not even small amounts; this can make things much worse
5. No over-the-counter painkillers without asking your doctor first - many drugs harm the liver
6. Do not donate blood until confirmed cleared

• Confusion or unusual drowsiness (you or your family notices you are "not yourself")
• Unable to eat or drink
• Severe abdominal pain
• Swelling of the abdomen
• No urine for >8 hours
• Vomiting blood or black stools

For Chronic HBV

"Hepatitis B can become a long-term liver infection in some people. The good news is that we have excellent medications that can control the virus and prevent liver damage, cirrhosis, and liver cancer. You will need to take medication every day, possibly lifelong, and come for regular monitoring every 6 months."

• No alcohol
• Regular exercise and healthy weight (reduces fatty liver)
• Vaccinate family members and sexual partners

• Safe sex (condoms until partners are vaccinated)
• Do not share needles, razors, toothbrushes
• Inform your doctor before dental/surgical procedures

For Chronic HCV

"The great news about hepatitis C in 2026 is that it is now completely curable with a short course of tablets - just 8-12 weeks of medication. The cure rate is over 95%. You will need regular blood tests to confirm the cure, and then follow-up to check your liver."

• HCV is transmitted by blood-to-blood contact
• Sexual transmission is rare but possible (especially with HIV co-infection or rougher sex)
• Do not share any personal items that may contact blood

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Summary Mnemonic - HEPATITIS

H - History (prodrome, exposure, alcohol, drugs)
E - Enzymes (ALT, AST - degree of hepatocyte damage)
P - PT/INR (most important severity marker)
A - Aetiology (viral panel - HAV/HBV/HCV/HDV/HEV serology)
T - Treatment (supportive for most; antivirals for HBV/HCV)
I - Imaging (USS to exclude obstruction)
T - Transmission prevention (vaccinate contacts)
I - Indications for admission (encephalopathy, INR>1.5, vomiting)
S - Surveillance (HCC screen in chronic disease: USS + AFP 6-monthly)

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Key Clinical Equations

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What You Just Learned - Module Summary