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Microbiology and Immunology of Viral Hepatitis

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Overview Comparison Table

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1. Hepatitis A Virus (HAV)

Microbiology

Immunology and Pathogenesis

• IgM anti-HAV appears at the onset of symptoms and is the reliable marker of acute infection (positive up to 4-6 months post-infection). Fecal virus shedding ends as IgM rises.
• IgG anti-HAV follows, persisting for years and conferring lifelong immunity.
• HAV viremia is transient, making bloodborne transmission very rare.

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2. Hepatitis B Virus (HBV)

Microbiology and Structure

1. 22 nm spherical particles - the most numerous; composed exclusively of HBsAg; represent excess surface antigen
2. Tubular/filamentous forms - same 22 nm diameter but up to 200 nm long; also HBsAg only
3. 42 nm spherical Dane particles - the complete, infectious virion; the outer envelope carries HBsAg surrounding a 27 nm nucleocapsid core containing HBcAg and the viral DNA polymerase

Immunology and Pathogenesis of HBV

• CD8+ cytotoxic T cells (CTLs) recognize HBcAg/HBeAg epitopes on infected hepatocytes and kill them
• CD4+ T helper cells coordinate the response
• Neutralizing anti-HBs antibodies clear circulating virions
• This leads to acute, self-limited hepatitis with complete viral clearance

• Neonatal infection leads to tolerance to HBV antigens - the immature immune system fails to mount a CTL response
• 95% of neonates infected perinatally become chronic carriers vs. only 5-10% of adult-infected individuals
• HBV persists as covalently closed circular DNA (cccDNA) in the nucleus, which serves as a template for transcription and is resistant to current antivirals

1. Immune tolerant phase - high viral replication, normal ALT, minimal hepatic inflammation
2. Immune active/clearance phase - active CTL attack, elevated ALT, hepatic necroinflammation
3. Inactive carrier phase - HBeAg seroconversion to anti-HBe, low HBV DNA, near-normal ALT
4. HBeAg-negative chronic hepatitis - reactivation with pre-core/basal core promoter mutant virus

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3. Hepatitis C Virus (HCV)

Microbiology

• NS3/4A protease - processes the polyprotein (target of protease inhibitors: simeprevir, grazoprevir)
• NS5A protein - essential for viral assembly (target of NS5A inhibitors: ledipasvir, daclatasvir)
• NS5B RNA-dependent RNA polymerase - replicates the genome (target of polymerase inhibitors: sofosbuvir)

Immunology and Pathogenesis of HCV

1. Quasispecies variation - constant antigenic drift outpaces B and T cell responses
2. NS3/4A protease cleaves TRIF and MAVS - two critical intracellular signaling adaptors for innate antiviral interferon responses, blocking IFN-β production
3. Impaired NK cell and dendritic cell function in chronic infection
4. T cell exhaustion - chronic antigen stimulation leads to upregulation of inhibitory receptors (PD-1, Tim-3, CTLA-4) on HCV-specific CD8+ T cells, impairing their function
5. Regulatory T cells (Tregs) suppress anti-HCV immune responses

• HCV RNA is detectable in blood 1-3 weeks after exposure
• Serum transaminases (ALT) rise concurrently
• Anti-HCV antibodies (detected by ELISA) appear later (weeks to months) and are not protective
• In ~85% of cases, acute infection is asymptomatic
• Chronic infection (defined as HCV RNA persisting >6 months) occurs in 80-90% of individuals
• In chronic infection, HCV RNA persists in 90% of patients despite circulating neutralizing antibodies

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4. Hepatitis D Virus (HDV)

Microbiology

• Small HDAg (p24) - promotes viral RNA replication
• Large HDAg (p27) - inhibits replication and is required for virion assembly

Immunology and Clinical Patterns

1. Co-infection (HDV + HBV simultaneously): Usually self-limited, resembles acute hepatitis B. Both viruses typically cleared together. Higher risk of fulminant hepatitis (especially in IV drug users).
2. Superinfection (HDV infecting a chronic HBV carrier): More severe - causes acute exacerbation or severe chronic hepatitis. Chronic HDV infection follows in >80% of superinfections. Accelerates progression to cirrhosis and HCC.

• HDAg detectable in serum during early acute infection
• IgM anti-HDV - reliable marker of recent HDV exposure; short-lived in co-infection, persistent in superinfection
• In superinfection: high, persistent IgG and IgM anti-HDV, persistent HBsAg and HDV RNA
• Coinfection is confirmed by the simultaneous presence of IgM anti-HDAg and IgM anti-HBcAg

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5. Hepatitis E Virus (HEV)

Microbiology

Immunology

• IgM anti-HEV and IgG anti-HEV, plus PCR for HEV RNA, are the diagnostic tools
• Infection is usually self-limiting - no chronic disease in immunocompetent hosts
• In immunocompromised patients (solid-organ transplant recipients, HIV-infected), chronic HEV infection can occur
• Pregnant women (especially in 3rd trimester) are at greatly increased risk of fulminant hepatic failure: mortality approaches 20% - the mechanism involves hormonal modulation of immune responses (elevated estrogen/progesterone impairs T cell and innate immune control)
• No specific antiviral treatment; ribavirin is used in chronic/severe cases

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Summary: Key Immunological Mechanisms

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Pathological Features of Chronic Viral Hepatitis

• Lobular hepatitis - hepatocyte necrosis/apoptosis (acidophil/Councilman bodies)
• Interface hepatitis (piecemeal necrosis) - periportal hepatocyte destruction by lymphocytes
• Portal tract infiltration - predominantly lymphocytes, plasma cells
• Bridging necrosis - portoportal or portocentral necrosis (marks severe activity)
• Fibrosis → cirrhosis - stellate cell activation by inflammatory cytokines (TGF-β)

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🎓 Microbiology and Immunology of Viral Hepatitis — Exam-Focused Complete Guide

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❗ HIGH-YIELD EXAM MNEMONIC: "ABC DE — Hepatitis 5"

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SECTION 1: MASTER COMPARISON TABLE (Must Memorize for Exams)

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SECTION 2: HEPATITIS A VIRUS (HAV)

2.1 Microbiology / Virology

Exam Trigger: "Smallest hepatitis virus," "Picornavirus," "No envelope," "One serotype"

• Classification: Picornaviridae family, genus Hepatovirus
• Structure: 27-32 nm, non-enveloped, icosahedral capsid, positive-sense ssRNA (7.5 kb)
• Single serotype exists (clinically important - one vaccine covers all strains)
• Seven genotypes based on the 1D/2A gene junction; no cross-reactivity with other hepatitis viruses
• Stability - Exam important:
  • Stable to: 20% ether, acid (pH 1.0 for 2 hrs), heat 60°C for 1 hour
  • Destroyed by: Autoclaving (121°C/20 min), boiling 5 min, UV light, formalin 1:4000, chlorine 10-15 ppm
  • Food must be heated >85°C for 1 minute to inactivate
• Cell culture: grows in primate cell lines; no cytopathic effect usually seen
• Detected originally in stool by immune electron microscopy

2.2 Transmission and Epidemiology

• Route: Fecal-oral (contaminated water, food, shellfish, infected food handlers)
• Maximum infectivity: Virus shed in stool 2-3 weeks BEFORE and 1 week AFTER jaundice onset
• Viremia is transient - bloodborne transmission extremely rare; blood not specifically screened
• Endemic in countries with poor sanitation infrastructure

2.3 Immunology and Pathogenesis

Key Exam Concept: HAV is NOT directly cytopathic - damage is IMMUNE-MEDIATED

• HAV infects hepatocytes after fecal-oral entry
• CD8+ cytotoxic T lymphocytes (CTLs) are the principal effectors of hepatocyte destruction
• CTLs recognize viral antigens presented on MHC class I of infected hepatocytes and lyse them
• This immune-mediated lysis causes the transaminase elevation and jaundice

2.4 Disease Outcomes

• Disease is more severe in adults than children
• Relapses can occur 1-4 months after initial resolution
• Vaccine (available since 1995) has reduced US cases by >95%

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SECTION 3: HEPATITIS B VIRUS (HBV)

3.1 Microbiology / Virology

Exam Trigger: "Only DNA hepatitis virus," "Dane particle," "Reverse transcriptase," "cccDNA"

3.2 Structure - Three Morphological Forms in Serum (EXAM FAVORITE)

Exam Note: Small spheres and tubules represent excess HBsAg overproduction - important diagnostic and immunological targets. Antibody against HBsAg (anti-HBs) is the only NEUTRALIZING/PROTECTIVE antibody.

3.3 Genome Organization (3.2 kb, Circular Partial dsDNA)

3.4 Replication Cycle (EXAM HIGH YIELD)

The unique feature of HBV replication: DNA → RNA → DNA (uses reverse transcriptase - like a retrovirus!)

1. Virion attaches to hepatocyte; NTCP (sodium taurocholate cotransporting polypeptide) is the receptor
2. Uncoating; partial dsDNA genome enters nucleus
3. In nucleus: converted to cccDNA (covalently closed circular DNA) - the "persistence reservoir" - not eliminated by antivirals
4. cccDNA transcribed → pregenomic RNA (pgRNA, 3.5 kb) + mRNAs
5. pgRNA encapsidated with HBcAg and viral polymerase
6. Within capsid: reverse transcription of pgRNA → minus-strand DNA; then plus-strand DNA synthesis begins (incomplete)
7. Immature cores bud from pre-Golgi membranes, acquiring HBsAg envelope
8. Released as virions OR recycled back to nucleus to maintain cccDNA pool

Key Point: cccDNA in hepatocyte nucleus is the reason HBV cannot be cured by current antivirals - it serves as a transcriptional template even during treatment.

3.5 Viral Antigens and Antibodies - COMPLETE SEROLOGY (MOST TESTED TOPIC)

3.6 HBV Immunology and Pathogenesis

Key Exam Concept: HBV is NOT directly cytopathic - liver damage is entirely immune-mediated

• IFN-α and IFN-β produced by infected hepatocytes and dendritic cells
• NK cells recruited
• These limit but cannot eradicate HBV

• CD4+ T helper cells recognize HBcAg/HBeAg peptides on MHC class II of APCs → produce IFN-γ, IL-2
• CD8+ cytotoxic T cells (CTLs) recognize HBcAg, HBsAg on MHC class I of infected hepatocytes → direct killing + IFN-γ secretion
• B cells → anti-HBs (neutralizing), anti-HBe, anti-HBc

Mnemonic: "The younger, the worse" - immature immunity = chronic disease; mature immunity = resolution

• Polyarteritis nodosa - HBsAg-anti-HBs immune complexes deposit in vessel walls
• Membranous glomerulonephritis - immune complex deposition in glomeruli
• Cryoglobulinemia, serum sickness-like prodrome in acute infection

• HBx protein transactivates host oncogenes
• HBV DNA integration into host genome → chromosomal instability
• Cyclin A activation, tumor suppressor gene disruption
• Chronic inflammation → regenerative hyperplasia → cirrhosis → HCC
• Risk is independent of cirrhosis (HBV can cause HCC directly)

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SECTION 4: HEPATITIS C VIRUS (HCV)

4.1 Microbiology / Virology

Exam Trigger: "Most common cause of chronic viral hepatitis worldwide," "Quasispecies," "No protective vaccine," "NS5B polymerase"

• Classification: Flaviviridae family, genus Hepacivirus
• Structure: Enveloped, positive-sense ssRNA, 9.4 kb genome
• Single large polyprotein (~3000 aa) cleaved into 10 proteins by host and viral proteases

• NS5B polymerase has very low fidelity (no proofreading)
• Thousands of genetic variants accumulate in a single patient
• Each patient harbors a quasispecies - a cloud of related variants
• This is the key reason why HCV evades immune control and why no vaccine is possible

4.2 HCV Life Cycle

4.3 HCV Immunology - Why Chronicity Dominates

Exam Concept: HCV has MULTIPLE sophisticated immune evasion strategies

• ELISA for anti-HCV: screening (but can't distinguish acute from chronic or resolved)
• PCR for HCV RNA: confirms active infection; used to monitor treatment
• Genotyping: important for treatment decisions

4.4 Clinical Outcomes

• 85% of acute infections are asymptomatic
• 80-90% progress to chronic hepatitis (highest chronicity of all hepatitis viruses)
• Of chronics: ~20% develop cirrhosis over 20-30 years
• Cirrhosis → HCC risk (HCV accounts for ~1/3 of US liver cancer cases)
• Unlike HBV: HCV-related HCC occurs almost exclusively in setting of cirrhosis

• Sofosbuvir (NS5B) + Ledipasvir/Velpatasvir (NS5A) ± Glecaprevir/Pibrentasvir (NS3)
• >95% SVR (cure) rates in 8-12 weeks; pan-genotypic regimens available

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SECTION 5: HEPATITIS D VIRUS (HDV)

5.1 Microbiology

Exam Trigger: "Defective/satellite virus," "Requires HBsAg," "Delta antigen," "Worst acute hepatitis"

• Unique: HDV is a defective, satellite virus - it can only replicate in cells ALSO infected with HBV, because it BORROWS HBsAg to form its envelope
• Genome: 1.7 kb circular, negative-sense ssRNA - smallest human viral genome
• Inner core: HDV RNA + Hepatitis D antigen (HDAg)
• Outer coat: Borrowed HBsAg from HBV

5.2 Two Clinical Patterns - EXAM ESSENTIAL

• Acute HDV (co-infection): Anti-HDAg develops late, may be low titer; IgM anti-HDV detectable
• HDV superinfection: High, persistent IgM and IgG anti-HD; HBsAg positive; HDV RNA + HDAg persist
• All HDV markers disappear in recovered co-infection
• Anti-HBc IgM differentiates: POSITIVE in co-infection; NEGATIVE in superinfection

PREVENTION PEARL: HBV vaccination completely prevents HDV infection (no HBV = no HDV)

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SECTION 6: HEPATITIS E VIRUS (HEV)

6.1 Microbiology

Exam Trigger: "20% mortality in pregnancy," "Zoonosis," "Waterborne epidemic," "Fecal-oral like HAV"

• Classification: Hepeviridae family, genus Hepevirus
• Structure: 30-32 nm, non-enveloped, icosahedral, positive-sense ssRNA (7.2 kb)
• Four genotypes:
  • Genotypes 1 & 2: Human only; cause large waterborne epidemics
  • Genotypes 3 & 4: Zoonotic (pigs, deer, rabbits, wild boar); cause sporadic cases in developed countries
• Animal reservoirs: Pigs, monkeys, cats, dogs, deer

6.2 Epidemiology

• Endemic regions: Asia (India - HEV = 30-60% of sporadic acute hepatitis!), Indian subcontinent, sub-Saharan Africa, Mexico, Central America
• Sporadic cases: Europe (pig farming), North America (travelers, pork consumption)
• Fecal-oral route; large waterborne outbreaks in resource-poor settings
• Incubation: 4-5 weeks (similar to HAV)

6.3 Immunology

• Self-limiting in immunocompetent hosts - no chronic disease
• Chronic HEV in immunocompromised patients (transplant recipients, HIV): genotype 3 responsible
• Pregnant women - HIGH YIELD:
  • Mortality approaches 20% (especially 3rd trimester)
  • Mechanism: estrogen/progesterone alter T regulatory cell function and innate immunity → impaired viral clearance → fulminant hepatitis
  • Fulminant hepatic failure risk is unique to pregnancy (contrast with HAV, where pregnancy is not a major risk factor)
• Diagnosis: IgM and IgG anti-HEV + PCR for HEV RNA
• Treatment: Ribavirin for chronic/severe cases; no approved vaccine globally (one approved in China only)

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SECTION 7: IMMUNOLOGICAL MECHANISMS - COMPARATIVE SUMMARY

7.1 Mechanism of Liver Damage in All Viral Hepatitides

Universal Exam Concept: NONE of the five classical hepatitis viruses are directly cytopathic (or only minimally so). Liver damage = immune-mediated.

INFECTED HEPATOCYTE
        ↓
   Presents viral peptides
   on MHC class I
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   CD8+ Cytotoxic T Lymphocytes (CTLs)
   recognize and KILL hepatocyte
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   Hepatocyte necrosis → ↑ALT/AST
        ↓
   CD4+ T helper cells → IFN-γ, TNF-α
        ↓
   Macrophage activation → more inflammation
        ↓
   B cells → antiviral antibodies (some protective)

7.2 Why Different Viruses Lead to Different Outcomes

7.3 Innate Immunity

• Interferons (IFN-α, IFN-β): First line of defense; upregulate ISGs (interferon-stimulated genes) in hepatocytes; limit early replication
• NK cells: Kill infected cells without prior sensitization; produce IFN-γ
• Pattern recognition: RIG-I and MDA5 detect viral RNA → IRF3/7 → IFN-β production
• HCV specifically BLOCKS this: NS3/4A cleaves MAVS (RIG-I adaptor) and TRIF (TLR3 adaptor) → no IFN-β

7.4 Adaptive Immunity

• CD4+ T cells: Coordinate response; produce IFN-γ (activates macrophages), IL-2 (expands CTLs), IL-4/IL-5 (helps B cells)
• CD8+ CTLs: Primary killers of infected hepatocytes via perforin/granzyme pathway and Fas-FasL
• B cells/Antibodies: Most important for HAV and HBV; anti-HBs is the ONLY protective antibody in hepatitis; anti-HCV is NOT protective

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SECTION 8: HISTOPATHOLOGY OF VIRAL HEPATITIS (EXAM POINTS)

8.1 Acute Viral Hepatitis (All Types)

• Hepatocyte swelling (ballooning degeneration)
• Acidophil/Councilman bodies - apoptotic hepatocytes (eosinophilic, shrunken)
• Lobular disarray with hepatocyte dropout
• Inflammatory infiltrate - predominantly lymphocytes
• Cholestasis - bile in canaliculi

8.2 Chronic Viral Hepatitis (Grading & Staging)

• Grade = activity (necroinflammation) | Stage = fibrosis extent
• Interface hepatitis (piecemeal necrosis) - lymphocytes erode hepatocytes at portal-parenchymal junction; hallmark of chronic hepatitis
• Bridging necrosis - connects portal tracts or extends to central veins = severe activity
• Portal tract expansion with lymphocytic infiltrate
• Progressive fibrosis → cirrhosis

8.3 Virus-Specific Histological Clues

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SECTION 9: LABORATORY DIAGNOSIS - QUICK REFERENCE

Exam trap: Anti-HCV positive alone does NOT confirm current infection - must confirm with HCV RNA PCR (may be past/resolved infection)

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SECTION 10: VACCINES AND PREVENTION

HBV vaccine mechanism: Recombinant HBsAg induces anti-HBs production → neutralizes virus at point of entry. Anti-HBs ≥10 IU/mL = protective.

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SECTION 11: HIGH-YIELD EXAM MEMORY AIDS

"Window Period" in HBV - MUST KNOW

Patient had HBV exposure → HBsAg has CLEARED but anti-HBs NOT YET appeared. ONLY IgM anti-HBc is detectable. Window period: anti-HBc IgM is the SOLE marker.

Fulminant Hepatitis by Virus

• Most common overall cause: HBV (but rare)
• Highest risk in pregnancy: HEV (20% mortality)
• Coinfection doubles risk: HDV + HBV
• HAV fulminant: Very rare (0.1%)

"Superinfection is worse than Co-infection" (HDV Rule)

• Co-infection (HDV+HBV simultaneous): usually self-limited
• Superinfection (HDV into chronic HBV): >80% chronic, high fulminant risk

Chronicity Memory Aid:

HAV → 0%
HEV → 0% (but rare in immunocompromised)
HBV → 5-10% adults | 90-95% neonates
HDV → 10% (co-inf) | >80% (superinfection)
HCV → >80% (highest overall)

"Which antibody is protective?"

• Only anti-HBs (hepatitis B) and anti-HAV IgG confer immunity
• Anti-HCV = NOT protective
• Anti-HDV = NOT protective (still need HBsAg presence)
• Anti-HEV IgG = some protection

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🎓 Aetiology of Upper and Lower GI Bleeding — Complete Exam Guide

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PART 1: DEFINITIONS AND ANATOMICAL LANDMARK

The Ligament of Treitz (Suspensory ligament of duodenum) is the DIVIDING LINE

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PART 2: CLINICAL PRESENTATION TERMINOLOGY (EXAM MUST-KNOW)

Exam Trap: Haematochezia does NOT always mean LGIB. Severe, brisk UGIB causes haematochezia in ~15% of cases. Always exclude upper source first if haemodynamically unstable!

Biochemical Clue: Digested blood is a protein load → raises BUN (blood urea nitrogen) → elevated BUN:Creatinine ratio (>20:1) is a clue to UGIB.

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PART 3: CLASSIFICATION FRAMEWORK

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SECTION A: UPPER GASTROINTESTINAL BLEEDING (UGIB)

Epidemiology and Frequency Data (Direct Exam Numbers)

• Incidence: ~50 cases per 100,000 persons per year
• Mortality: 5-10% (unchanged since 1970s despite advances)
• 80% of UGIB is self-limited without specific therapy
• Of the 20% that rebleed: mortality is 30-40%
• Endoscopy identifies the source in 90% of cases

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A1: OESOPHAGEAL CAUSES

1. Oesophageal Varices ⭐⭐⭐ (Most Dangerous Oesophageal Cause)

Portal hypertension (cirrhosis most common cause)
         ↓
Increased portal venous pressure
         ↓
Blood diverted to portosystemic collaterals
         ↓
Oesophageal veins dilate → VARICES form
         ↓
Rupture when pressure too high (>12 mmHg threshold)
         ↓
MASSIVE haematemesis

• Pre-hepatic: Portal vein thrombosis, splenic vein thrombosis
• Intrahepatic (most common): Cirrhosis (alcohol, HBV, HCV, NASH), schistosomiasis
• Post-hepatic: Budd-Chiari syndrome, right heart failure, constrictive pericarditis

• Massive, sudden haematemesis in a known cirrhotic
• Associated signs of liver disease: jaundice, spider naevi, palmar erythema, splenomegaly
• Life-threatening - mortality 15-20% per variceal bleed episode; 30% die in 6 weeks if untreated

• Variceal bleeding accounts for the VAST MAJORITY of GI bleeding in cirrhotics
• Gastric varices also occur: Type 1 (fundic), Type 2 (distal - more dangerous)
• Treatment: Octreotide (vasoconstrictor) + endoscopic band ligation + prophylactic antibiotics (ceftriaxone)
• If uncontrolled: TIPS (Transjugular Intrahepatic Portosystemic Shunt)
• Primary prophylaxis: Non-selective beta-blockers (propranolol, nadolol)

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2. Mallory-Weiss Tear ⭐⭐

Forceful retching/vomiting (most common)
         ↓
Sudden rise in intragastric pressure
         ↓
Mucosal tear at oesophago-gastric junction
         ↓
Submucosal arterial bleeding

• Severe vomiting (alcoholism most common, pregnancy, bulimia)
• Severe coughing, hiccupping, straining
• Blunt abdominal trauma
• Cardiopulmonary resuscitation

• Accounts for up to 15% of UGIB
• Most episodes stop SPONTANEOUSLY (>90% self-limited)
• Rebleeding rate: up to 10%
• Treatment: Endoscopic haemostasis (bipolar electrocoagulation, epinephrine injection, clips, band ligation)
• Contrast with Boerhaave syndrome = full-thickness oesophageal perforation (surgical emergency)

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3. Oesophagitis ⭐

• Gastro-oesophageal reflux disease (GERD) - most common
• Infections: Candida (immunocompromised), CMV, Herpes simplex
• Pill-induced oesophagitis (bisphosphonates, tetracyclines, NSAIDs, iron tablets)
• Eosinophilic oesophagitis
• Radiation oesophagitis

• Haematemesis; less haemodynamic instability than other UGIB causes
• Prognosis excellent - low rebleeding risk
• Accounts for ~10% of UGIB

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4. Oesophageal Cancer ⭐

• Usually presents with progressive dysphagia and weight loss
• GI bleeding is usually occult (iron-deficiency anaemia)
• Overt bleeding uncommon; occurs when tumour erodes into adjacent vascular structures (aorta)
• Risk factors: smoking, alcohol (squamous cell), GERD/Barrett's (adenocarcinoma)

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A2: GASTRIC CAUSES

5. Peptic Ulcer Disease (PUD) ⭐⭐⭐ (MOST COMMON CAUSE OF UGIB OVERALL - 35-40%)

Imbalance between AGGRESSIVE and DEFENSIVE factors
         ↓
Aggressive: H. pylori, NSAIDs, acid, pepsin, bile
Defensive: mucus, bicarbonate, prostaglandins, mucosal blood flow
         ↓
Mucosal ulceration
         ↓
Erosion into submucosal blood vessel
         ↓
BLEEDING

• Gastric ulcers on the lesser curvature or posterior wall are most common
• Duodenal ulcers: 90% on the anterior wall of the first part (perforate); posterior wall (bleed)
• H. pylori + NSAIDs are the two strongest independent risk factors
• Duodenal ulcers bleed more than gastric ulcers (proximity to gastroduodenal artery)
• Treatment: IV PPI immediately; endoscopic haemostasis within 24 hours; eradicate H. pylori

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6. Gastritis and Gastropathy ⭐

• H. pylori (Type B gastritis - most common)
• Autoimmune (Type A - affects fundus/body; pernicious anaemia; anti-parietal cell/anti-intrinsic factor antibodies)
• NSAIDs, alcohol, bile reflux, radiation
• Stress (erosive gastritis) - critically ill patients; burns (Curling's), CNS injury (Cushing's)
• Chemical gastropathy: NSAIDs, alcohol

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7. Gastric Varices

• Occur with portal hypertension (same mechanism as oesophageal varices)
• Isolated gastric varices (type I = fundic; type II = distal including proximal duodenum) occur without oesophageal varices
• More difficult to treat than oesophageal varices
• Management: Cyanoacrylate (glue) injection preferred over band ligation

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8. Gastric Antral Vascular Ectasia (GAVE) - "Watermelon Stomach" ⭐

• Chronic renal failure
• Systemic sclerosis (scleroderma) - most common connective tissue disease association
• Cirrhosis (distinct from portal hypertensive gastropathy)
• Bone marrow transplantation

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9. Dieulafoy's Lesion ⭐⭐

• Presents as sudden, massive haematemesis with NO prior symptoms (no ulcer history, no portal hypertension)
• Notoriously difficult to find endoscopically, especially when bleeding has stopped
• Common cause of obscure GI bleeding (recurrent bleeding without diagnosis)
• Treatment: Endoscopic haemostasis (epinephrine injection + electrocoagulation) is treatment of choice
• Patient may be young and otherwise healthy

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10. Cameron Lesion

• Usually asymptomatic; found incidentally at endoscopy
• Occult bleeding causing iron-deficiency anaemia (more common than overt bleeding)
• Treatment: GERD management + endoscopic therapy if needed

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11. Gastric Cancer ⭐

• Usually presents with occult bleeding, weight loss, epigastric pain
• Overt haematemesis or melaena possible with ulcerated tumours
• H. pylori is the main risk factor
• Risk factors: gastric atrophy, intestinal metaplasia, diet (smoked/salty foods), blood group A, smoking

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A3: DUODENAL CAUSES

12. Duodenal Peptic Ulcer ⭐⭐⭐

• Same pathogenesis as gastric ulcer (see above)
• Most common cause of UGIB - duodenal ulcers bleed more than gastric ulcers
• Posterior duodenal wall ulcers erode into the gastroduodenal artery = catastrophic haemorrhage
• Classic history: intermittent epigastric pain relieved by food (duodenal pattern), then melaena/haematemesis

13. Duodenitis

• Inflammation of duodenal mucosa without frank ulceration
• Causes: H. pylori, NSAIDs, alcohol, Crohn's disease, celiac disease, radiation
• Usually self-limited bleeding; less severe than ulcer bleeding

14. Duodenal Angiodysplasia / Telangiectasia

• Abnormal, ectatic, dilated tortuous small (<10 mm) blood vessels in mucosa/submucosa
• Most common vascular malformation of GI tract
• Typically affects patients >60 years old
• Heyde's syndrome: Association of aortic stenosis + angiodysplasia (platelet dysfunction from shear stress through stenotic valve destroys vWF multimers)
• Associated with: chronic renal failure, radiation, connective tissue disease, hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu)
• Can cause occult or overt bleeding; often intermittent

15. Aorto-enteric Fistula ⭐ (EXAM FAVOURITE - Must Know)

• Primary: Aortic aneurysm eroding into the duodenum
• Secondary: Aortic graft eroding into the duodenum (after aortic reconstruction surgery)

1. "Herald bleed" - initial minor, self-limiting haematemesis/melaena
2. Asymptomatic interval (hours to days)
3. Catastrophic, exsanguinating haemorrhage - fatal if not immediately recognised and operated

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SECTION B: LOWER GASTROINTESTINAL BLEEDING (LGIB)

Epidemiology

• Incidence: ~20 cases per 100,000 per year (less than UGIB)
• Most patients >70 years of age
• Presents with painless haematochezia
• Majority (80-90%) stop spontaneously
• If haematochezia + orthostasis: exclude brisk UGIB first (15% of haematochezia from UGIB)

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B1: STRUCTURAL CAUSES OF LGIB

1. Diverticular Disease ⭐⭐⭐ (MOST COMMON CAUSE OF LGIB)

Diverticulum forms at weak point in colonic wall
         ↓
Vasa recta (penetrating blood vessel) is stretched
over the dome of the diverticulum
         ↓
Intimal thickening + medial thinning
         ↓
Vessel ruptures into diverticulum lumen
         ↓
MASSIVE painless haematochezia

• Prevalence increases with age: 5% at age 40 → >65% by age 80
• Western diet (low fibre) major risk factor
• Right-sided diverticula bleed more (despite left-sided being more common)

• Most common cause of LGIB requiring hospitalisation
• Bleeding is typically sudden, PAINLESS, massive haematochezia (dark red or maroon)
• No abdominal pain differentiates it from diverticulitis (which causes LEFT iliac fossa pain and fever)
• 75-80% stop spontaneously
• Rebleeding rate: 25-30% within 4 years
• Treatment: Endoscopic haemostasis; selective angioembolisation; surgery if uncontrolled

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2. Colorectal Polyps ⭐

• Neoplastic (adenomatous): Tubular, tubulovillous, villous adenomas - premalignant
• Hamartomatous: Peutz-Jeghers syndrome (pigmented lips), juvenile polyps
• Inflammatory: Post-inflammatory (pseudopolyps in IBD)
• Hyperplastic: Usually non-neoplastic

• Usually occult bleeding causing iron-deficiency anaemia
• Overt haematochezia can occur, especially from rectal polyps
• Villous adenomas of the rectum can cause significant rectal bleeding + mucous diarrhoea + hypokalaemia
• Postpolypectomy bleeding accounts for ~10% of LGIB

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3. Colorectal Cancer ⭐⭐

• Left-sided/rectal cancer: Overt bright red haematochezia (closer to anus, less time for blood to change)
• Right-sided/caecal cancer: Occult bleeding → iron-deficiency anaemia, fatigue (blood mixes with stool)
• Change in bowel habit + iron-deficiency anaemia in >50-year-old = colorectal cancer until proved otherwise

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4. Anal Fissure ⭐

• Hard stool tears the delicate anal canal mucosa
• Hypertonia of internal anal sphincter maintains the fissure (prevents healing)
• Chronic ischaemia due to poor blood supply in the posterior midline

• Severe pain ON and AFTER defecation (tearing pain)
• Bright red blood ON THE SURFACE of stool or toilet paper (not mixed with stool)
• Sentinel pile (skin tag) at outer end

• Non-midline fissures: suspect Crohn's disease, anal cancer, syphilis, HIV
• First-line: Increased fibre/water, sitz baths, topical glyceryl trinitrate (GTN) or diltiazem
• Refractory: Botulinum toxin injection / lateral internal sphincterotomy

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B2: VASCULAR CAUSES OF LGIB

5. Haemorrhoids (Piles) ⭐⭐⭐ (Most Common Anorectal Cause)

• Low-fibre diet → straining → ↑ intra-abdominal pressure → vascular cushion engorgement
• Pregnancy, chronic constipation, portal hypertension, pelvic tumours

• Painless bright red blood - seen on the surface of stool, in the toilet pan, or on toilet paper
• Typically at the END of defecation
• Second most common cause of LGIB requiring hospitalisation

• NEVER attribute rectal bleeding to haemorrhoids without excluding cancer
• Internal haemorrhoids are PAINLESS when they bleed
• Pain + bleeding = thrombosed external haemorrhoid or anal fissure
• Treatment: Conservative (fibre, sitz baths) → Rubber band ligation (Grade II-III) → Surgery (haemorrhoidectomy Grade III-IV)

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6. Angiodysplasia (Colonic Vascular Ectasia) ⭐⭐

Ageing → degenerative changes in submucosal veins
         ↓
Repeated episodes of raised intraluminal pressure
during muscular contractions
         ↓
Vascular dilation (Laplace's law: T = P × r, larger radius = more tension)
         ↓
Arteriovenous communications develop
         ↓
Bleeding from thin-walled vessels

• Age >60 (most important risk factor)
• Chronic renal failure (most common in dialysis patients)
• Aortic stenosis (Heyde's syndrome - acquired vWF deficiency)
• Hereditary Haemorrhagic Telangiectasia (Osler-Weber-Rendu)
• Von Willebrand disease

• Can cause occult, intermittent overt, or massive haematochezia
• Cannot be seen on barium enema - requires colonoscopy or angiography
• Treatment: Endoscopic argon plasma coagulation (APC); angioembolisation; surgery

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7. Telangiectasias

• Associated with systemic sclerosis (scleroderma): CREST syndrome (Calcinosis, Raynaud's, Oesophageal dysmotility, Sclerodactyly, Telangiectasia)
• Hereditary Haemorrhagic Telangiectasia (HHT/Osler-Weber-Rendu): Autosomal dominant; mucocutaneous telangiectasias throughout the GI tract; recurrent GI bleeding

8. Haemangiopericytoma / Haemangioma

• Benign vascular tumours; can bleed; usually in small bowel; diagnosed on CT angiography or capsule endoscopy

9. Kaposi Sarcoma

• Malignant vascular tumour; seen in AIDS patients (CD4 <200); also in immunosuppressed transplant patients
• Violaceous endoscopic lesions throughout the GI tract

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B3: INFLAMMATORY CAUSES OF LGIB

10. Inflammatory Bowel Disease (IBD) ⭐⭐

• Mucosal ulceration → erosion of submucosal vessels
• Deep ulcers in Crohn's can erode major vessels → massive haemorrhage

• UC: Bloody mucoid diarrhoea is the cardinal symptom
• UC is associated with: pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, ankylosing spondylitis
• Massive haemorrhage in UC requiring emergency colectomy = <2% of cases

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11. Ischaemic Colitis ⭐⭐

• Hypotension/shock (most common precipitant) - non-occlusive ischaemia
• Atherosclerosis of mesenteric arteries
• Vasculitis
• Colon surgery (ligation of inferior mesenteric artery)
• Hypercoagulable states, cocaine use, oral contraceptive pill

• Watershed areas = splenic flexure (between SMA and IMA territories) and sigmoid colon (rectosigmoid junction)

• Sudden onset crampy left-sided abdominal pain followed by haematochezia - classic triad
• Moderate, self-limited bleeding (not usually massive)
• Can progress to gangrenous ischaemia → peritonitis, perforation

Exam Mnemonic: Ischaemic colitis = "Splenic flexure + pain + haematochezia + precipitating event (shock/surgery)"

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12. Infectious Colitis ⭐

Exam Alert: "Dozens of patrons of a fast-food restaurant develop bloody diarrhoea" = E. coli O157:H7 / Campylobacter outbreak. "Bloody diarrhoea + haemolytic anaemia + thrombocytopenia + AKI" = HUS from EHEC.

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13. Radiation Coloproctitis ⭐

• Delayed complication of pelvic radiotherapy (prostate, cervical, rectal cancer)
• Endarteritis of submucosal vessels → mucosal ischaemia + telangiectasia formation
• Chronic, recurrent haematochezia months to years after radiation
• Endoscopy: friable, telangiectatic rectal/colonic mucosa
• Treatment: Argon plasma coagulation (APC) - first-line endoscopic therapy; sucralfate enemas; hyperbaric oxygen

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SECTION C: SMALL BOWEL (OBSCURE GI BLEEDING) (Exam Bonus)

1. Angiodysplasia (most common)
2. Small bowel tumours (GIST, carcinoid, lymphoma, adenocarcinoma)
3. Crohn's disease
4. Meckel's diverticulum (ectopic gastric mucosa → peptic ulceration)
5. NSAIDs-induced small bowel ulcers
6. Coeliac disease
7. Small bowel varices (portal hypertension)

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SECTION D: SUMMARY COMPARISON TABLE (Exam Quick Reference)

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SECTION E: RISK STRATIFICATION SCORES (Clinical Exam Points)

Rockall Score (UGIB) - Predicts Rebleeding and Mortality

Glasgow-Blatchford Score (GBS) - Pre-endoscopy; predicts need for intervention

• Uses: BUN, haemoglobin, systolic BP, heart rate, melena, syncope, liver disease, cardiac failure
• Score 0 = safe to discharge without urgent endoscopy

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SECTION F: HIGH-YIELD EXAM MNEMONICS

Causes of UGIB - "PEP + M-D-G-A"

• P - Peptic ulcer (most common)
• E - Esophageal/gastric varices
• P - Portal hypertensive gastropathy
• M - Mallory-Weiss tear
• D - Dieulafoy's lesion
• G - GAVE (watermelon stomach)
• A - Aorto-enteric fistula (must never miss)

Causes of LGIB - "DIVERT-CAHIR"

• D - Diverticulosis (most common)
• I - IBD (Crohn's + UC)
• V - Vascular (angiodysplasia, haemorrhoids, telangiectasia)
• E - Ectasia (GAVE)
• R - Rectal cancer/polyps
• T - Trauma/radiation proctitis
• C - Colitis (infectious, ischaemic)
• A - Anal fissure
• H - Haemorrhoids
• I - Ischaemic colitis
• R - Radiation coloproctitis

"Posterior ulcer Bleeds, Anterior ulcer Perforates" (DU locations)

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