Pathogenesis of Cholera

The Organism

• Harrison's Principles of Internal Medicine 22E, p. 1369
• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 1247

Step 1 - Ingestion and Gastric Transit

• Hypochlorhydric patients
• Those using antacids or proton pump inhibitors
• When gastric acid is buffered by a meal

Step 2 - Intestinal Colonization

1. Toxin-coregulated pilus (TCP) - long filamentous pili that mediate adherence to the intestinal epithelium. TCP is absolutely essential for V. cholerae to survive and multiply in the small intestine. TCP expression is regulated coordinately with cholera toxin production.
2. Flagellar proteins - required for motility and efficient penetration of the intestinal mucus layer to reach the epithelial surface.

• Harrison's, p. 1370
• Robbins & Kumar Basic Pathology, p. 449
• Sherris, p. 1247

Step 3 - Virulence Gene Regulation

• Harrison's, p. 1370

Step 4 - Cholera Toxin (CT) Structure

• Sherris, p. 1247
• Robbins Pathology, p. 449

Step 5 - Molecular Mechanism of Action

1. B subunit binding: The B pentamer binds to GM1-ganglioside on the luminal surface of enterocytes.
2. A subunit internalization: The disulfide bond between A1 and A2 is reduced; the A1 fragment is released and translocated into the cytosol (via the endoplasmic reticulum).
3. ADP-ribosylation of Gsα: The A1 subunit catalyzes ADP-ribosylation of Gsα (the stimulatory G protein that regulates adenylate cyclase). This modification locks Gsα in its active state, preventing it from hydrolyzing GTP back to GDP - the normal "off switch."
4. Persistent adenylate cyclase activation: ADP-ribosylated Gsα constitutively activates adenylate cyclase, which continuously converts ATP → cyclic AMP (cAMP).
5. cAMP accumulation: Intracellular cAMP rises to very high levels, activating protein kinase A and the cystic fibrosis transmembrane conductance regulator (CFTR).

• Harrison's, p. 1370
• Sherris, p. 1247-1248
• Robbins & Kumar Basic Pathology, p. 449

Step 6 - Net Effect on Ion Transport (The Diarrhea)

• Cl- pours into the intestinal lumen.
• Na+, K+, and HCO3- follow the electrochemical gradient.
• Water follows passively to maintain osmolality.
• The result is massive isotonic fluid accumulation in the intestinal lumen - secretory diarrhea.

• Harrison's, p. 1370
• Robbins & Kumar Basic Pathology, p. 449

Key Histopathological Point

• No mucosal invasion
• No significant inflammation
• No fever (in most cases)
• No ulceration or tissue destruction

• Robbins & Kumar Basic Pathology, p. 449
• Sherris, p. 762

Summary Flowchart

Ingestion of V. cholerae (contaminated water/food)
        ↓
Survival through stomach (aided by achlorhydria, food buffering)
        ↓
Flagellar motility → penetrates mucus → reaches small intestinal epithelium
        ↓
TCP (toxin-coregulated pilus) → adherence/colonization
        ↓
ToxR/ToxT regulatory cascade → virulence gene activation
        ↓
Cholera toxin secreted into intestinal lumen
        ↓
B pentamer → GM1-ganglioside receptor binding
        ↓
A1 subunit enters cytosol → ADP-ribosylates Gsα
        ↓
Gsα locked in ON state → adenylate cyclase permanently active
        ↓
Massive intracellular cAMP accumulation → CFTR activation
        ↓
↓ Villus Na+ absorption + ↑ Crypt Cl- secretion → Na+, K+, HCO3-, H2O into lumen
        ↓
Profuse isotonic "rice-water" diarrhea (up to 1 L/hr)
        ↓
Dehydration → hypovolemic shock → metabolic acidosis (HCO3- loss) → death

Why ORS Works

• Harrison's, p. 1370

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 173
• Robbins & Kumar Basic Pathology (Robbins Pathology), Chapter on GI infections
• Sherris & Ryan's Medical Microbiology, 8th Ed., Chapter 32
• Goldman-Cecil Medicine, Chapter 278

Parasites Infecting the GIT - Classification & Hookworm Infections

Classification of Parasites Infecting the GIT

A. Protozoa

B. Helminths

The Clinical Case Explained

Hookworm Infections - Full Discussion

The Pathogens

1. Necator americanus - predominant worldwide (tropics, subtropics); cutting plates; ~10,000 eggs/day/female; survives 2-5 years
2. Ancylostoma duodenale - North Africa, Middle East, northern India; buccal teeth; ~28,000 eggs/day/female; survives ~1 year
3. Ancylostoma ceylanicum - mainly Southeast Asia; less common

• Harrison's Principles of Internal Medicine 22E, p. 2020
• Goldman-Cecil Medicine, p. 3477

Life Cycle

Eggs passed in feces onto warm, moist soil (23-33°C)
           ↓ (1 week)
Rhabditiform (non-infective) larvae hatch
           ↓
Filariform (infective, L3) larvae develop in soil
           ↓
SKIN PENETRATION (usually feet/legs)
           ↓
Enter venous circulation → Heart → Lungs
           ↓
Penetrate alveolar walls → ascend bronchial tree → Larynx
           ↓
SWALLOWED → reach small intestine
           ↓
Mature to adult worms (takes 5-9 weeks; prepatent period ~6-8 weeks)
           ↓
Adults attach to small bowel mucosa
A. duodenale → buccal TEETH
N. americanus → CUTTING PLATES
           ↓
Secrete enzymes → invade submucosa → ingest blood + villous tissue
           ↓
Female produces eggs → passed in feces → cycle repeats

• Harrison's 22E, p. 2022
• Goldman-Cecil, p. 3477

Pathogenesis

1. At the Skin

• Filariform larvae penetrate intact skin, producing a hypersensitivity "ground itch" reaction
• Pruritic, erythematous, maculopapular rash - most common between the toes/ankles

2. Larval Migration (Loeffler-like Syndrome)

• Larvae pass through the lungs, causing mild transient pneumonitis
• Dry cough, wheezing, low-grade fever - less severe than in Ascaris

3. In the Intestine - The Key Pathology

• Attaching to small bowel mucosa using cutting teeth (Ancylostoma) or cutting plates (Necator)
• Secreting enzymes that allow invasion of submucosal tissues
• Ingesting blood and villous tissue
• Hemoglobinases within the worm's digestive canal degrade host hemoglobin for nutrition

• A. duodenale: 0.15-0.26 mL/day (higher blood sucker)
• N. americanus: 0.03-0.10 mL/day

• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 1848
• Goldman-Cecil, p. 3477-3478
• Harrison's 22E, p. 2026

Clinical Features

Stage 1 - Skin Penetration

• "Ground itch" - pruritic, erythematous papular rash at penetration site (feet, ankles, between toes)
• More common with N. americanus

Stage 2 - Pulmonary (Larval Migration)

• Mild transient pneumonitis: dry cough, sore throat, wheezing, low-grade fever
• Less severe and less frequent than in Ascaris

Stage 3 - Gastrointestinal

• Epigastric pain, abdominal bloating, abnormal peristalsis
• Eosinophilia
• In early intestinal phase: abdominal pain + diarrhoea

Stage 4 - Chronic Infection (Most Significant)

• Iron deficiency anaemia (hypochromic, microcytic) - the hallmark
• Weakness, fatigue, palpitations, dyspnoea, dizziness, lassitude, headache
• In heavy infections: hypoproteinaemia, hypoalbuminaemia, anasarca
• In children: growth retardation, cognitive impairment, cardiac failure, kwashiorkor
• Diarrhoea with occult blood; occasionally frank melena in children

• Harrison's 22E, p. 2026
• Goldman-Cecil, p. 3478
• Sherris, p. 1848

Laboratory Diagnosis

1. Stool Microscopy (Gold Standard)

• Characteristic oval eggs, 40 × 60 μm, thin-walled, with segmented/cleaved contents (visible blastomeres - this is the "segmented ovum" in the case)
• Eggs of N. americanus and A. duodenale are morphologically indistinguishable by light microscopy; species identification requires PCR (research tool only)

• Important: If stool is not fresh, eggs may hatch to release rhabditiform larvae, which must be differentiated from Strongyloides larvae (S. stercoralis has a short buccal canal; hookworm has a longer buccal canal)
• Stool concentration techniques may be needed for light infections
• Quantitative egg count (Kato-Katz technique) estimates worm burden

2. Blood Tests

• Hypochromic microcytic anaemia (low Hb, low MCV, low MCH)
• Eosinophilia (peripheral blood)
• Hypoalbuminaemia in heavy infections
• Low serum iron, low ferritin, high TIBC

3. PCR

• Species-specific diagnosis, currently only a research tool
• Harrison's 22E, p. 2027-2028
• Sherris, p. 1849

Treatment

Anthelmintic Therapy

Note: Growing concern that benzimidazoles (albendazole, mebendazole) are becoming less effective due to emerging resistance. - Harrison's 22E, p. 2037

• Ivermectin 200 μg/kg daily × 1-2 days (preferred)
• Alternative: Albendazole 400 mg daily × 3 days

Management of Anaemia

• Mild-moderate anaemia: Oral iron supplementation alone is often sufficient
• Severe anaemia with protein loss and malabsorption: Nutritional support + oral iron + deworming
• Very severe anaemia: Blood transfusion may be required

Prevention

• Improved sanitation and proper disposal of human waste
• Wearing shoes - key preventive measure (blocks skin penetration)
• Mass drug administration (albendazole/mebendazole) to at-risk populations in endemic areas
• Harrison's 22E, p. 2036-2037
• Goldman-Cecil, Table 327-1
• Sherris, p. 1849