Peptic Ulcer Disease (PUD)

Definition

Epidemiology

• More than 4 million individuals in the United States are treated annually
• Lifetime risk: ~10% in males, ~4% in females
• Worldwide, ~70% of duodenal ulcers and ~50% of gastric ulcers are related to H. pylori colonization
• In many developed countries, NSAIDs have overtaken H. pylori as the leading cause of gastric ulcers, partly due to aging populations on low-dose aspirin
• Duodenal ulcers are more common than gastric ulcers overall
• Robbins & Kumar Basic Pathology, p. 555; Harrison's Principles of Internal Medicine 22E, p. 1345

Sites

Figure: Causes and most common ulcer sites (Guyton and Hall Textbook of Medical Physiology)

• Guyton and Hall Medical Physiology, p. 825; Bailey and Love, p. 1178; Robbins, p. 555

Pathophysiology

Mucosal Defense Mechanisms

1. Mucus layer - secreted by surface epithelial cells, mucous neck cells, deep pyloric glands, and Brunner's glands of the duodenum
2. Bicarbonate secretion - from pancreas, Brunner's glands, and bile neutralizes luminal acid
3. Feedback inhibition - excess duodenal acid triggers:
   • Neural reflexes inhibiting gastric secretion and emptying
   • Secretin release → stimulates pancreatic bicarbonate secretion
4. Mucosal blood flow - maintains cellular integrity and removes back-diffused H⁺

Aggressive Factors

• Hydrochloric acid (from parietal cells)
• Pepsinogen (activated to pepsin by low pH)
• H. pylori virulence factors
• NSAIDs/aspirin (topical injury + COX inhibition reducing prostaglandins)
• Bile salts (back-diffusion in gastric ulcers)

Etiology and Risk Factors

1. Helicobacter pylori (~70% of duodenal, ~50% of gastric ulcers)

• Only 5-10% of infected individuals develop ulcers, so host factors and strain variation matter
• Key evidence: (1) infection is a risk factor; (2) non-NSAID ulcers rarely occur without it; (3) eradication virtually abolishes long-term relapse; (4) experimental infection in gerbils produces gastric ulcers
• Mechanism: H. pylori breaks down the mucosal barrier by secreting urease (generates ammonia), proteases, phospholipases, and vacuolating cytotoxin (VacA); the cagA pathogenicity island strains are particularly virulent
• Harrison's, p. 1345; Robbins, p. 555

2. NSAIDs / Aspirin

• Dual mechanism: direct topical injury (weakly acidic drugs penetrate mucosal cells) + systemic COX-1 inhibition (reduces prostaglandin E₂ and I₂, impairing mucus/bicarbonate secretion and mucosal blood flow)
• In the US, NSAID use is becoming the most common cause of gastric ulcers as H. pylori rates fall

3. Hyperacidity States

• Zollinger-Ellison syndrome (gastrinoma): Multiple ulcers in stomach, duodenum, and even jejunum; massive acid production from unregulated gastrin
• Parietal cell hyperplasia, excessive secretory responses, or loss of inhibitory signals

4. Other Risk Factors

• Cigarette smoking - reduces mucosal blood flow, increases relapse rate
• Corticosteroids - suppress prostaglandin synthesis
• Alcohol-related cirrhosis, COPD, chronic renal failure, hyperparathyroidism (hypercalcemia stimulates gastrin → increased acid secretion)
• Stress ulcers (critically ill patients)
• Robbins & Kumar, p. 555-556; Bailey and Love, p. 1179

Morphology

• Duodenal ulcers: 4x more common than gastric; usually anterior wall of duodenal bulb; anterior = perforate, posterior = bleed (by eroding the gastroduodenal artery)
• Gastric ulcers: Near the body-antrum interface; always biopsy (up to 10 targeted biopsies) to exclude malignancy
• Solitary in >80% of patients
• "Kissing ulcers" - both anterior and posterior duodenal walls involved simultaneously

(A) Endoscopic view of typical antral NSAID ulcer with punched-out appearance. (B) Gross resected specimen - clean edges. (C) Histology: necrotic base with granulation tissue overlaid by degraded blood. - Robbins & Kumar Basic Pathology, Fig. 13.15

Clinical Features

• Epigastric pain/burning - the cardinal symptom; occurs 1-3 hours after meals, worse at night
• Pain relieved by food or antacids (classically duodenal ulcer)
• Nausea, vomiting, bloating, belching
• A significant fraction present initially with complications: iron-deficiency anemia, hemorrhage, or perforation
• Pattern of remission and relapse is characteristic (unlike nonulcer dyspepsia, which tends not to remit)
• Robbins, p. 556; Bailey and Love, p. 1178

Endoscopic view - Duodenal Ulcer

Duodenal ulcer at gastroduodenoscopy - Bailey and Love's Short Practice of Surgery, Fig. 67.10

Diagnosis

• All gastric ulcers must be regarded as potentially malignant until proven otherwise by biopsy and follow-up re-endoscopy to confirm healing. Modern PPIs can heal the ulceration of a gastric cancer without treating the malignancy. - Bailey and Love, p. 1180

Medical Treatment

1. Acid Suppression

• Proton pump inhibitors (PPIs) are the mainstay - omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole
• H₂-receptor antagonists (ranitidine, famotidine) - second-line; less potent
• Antacids - symptomatic relief only

2. H. pylori Eradication

• Bismuth quadruple therapy is recommended first-line in most countries; OCA/OCM only where clarithromycin resistance <20%
• Failure of triple therapy in a compliant patient is usually due to antibiotic resistance (especially clarithromycin)
• Test-of-cure with UBT or stool antigen at least 4 weeks after completion

3. NSAID-Associated Ulcers

• Discontinue NSAID if possible
• Start PPI; 4-8 week courses heal most ulcers
• If NSAID cannot be stopped: use lowest effective dose + long-term PPI, or switch to a selective COX-2 inhibitor
• A 2025 Cochrane review (PMID 40337979) confirms PPIs are effective for prevention of NSAID-induced ulcers and dyspepsia

Complications

• Based on: age, pulse, BP, comorbidity, diagnosis, endoscopic stigmata
• Score ≥8: rebleeding ~42%, mortality ~41% - Sleisenger & Fordtran's GI and Liver Disease, Table 20.3

Surgery (Now Rarely Required)

• Uncontrollable hemorrhage
• Perforation not managed conservatively
• Pyloric obstruction refractory to endoscopic dilatation
• Failure of medical therapy (rare)

• Truncal vagotomy + pyloroplasty/gastroenterostomy
• Highly selective (proximal gastric) vagotomy
• Partial gastrectomy (Billroth I / Billroth II)

Summary

"No acid, no ulcer" - the old dictum remains valid. But H. pylori eradication has transformed PUD from a lifelong relapsing condition into a curable disease. The goals of management are: eradicate H. pylori, suppress acid, eliminate causative drugs, and confirm healing of all gastric ulcers endoscopically.

Absorption of Protein — Guyton and Hall Textbook of Medical Physiology

Step 1 — Digestion of Proteins

Stage 1: Stomach — Pepsin (10-20% of total digestion)

• Is most active at pH 2.0–3.0 and inactive above pH 5.0
• Converts proteins into proteoses, peptones, and a few polypeptides (only 10–20% of total digestion)
• Uniquely digests collagen - an important first step, since collagen holds meat fibers together and must be broken down to allow other enzymes to reach the meat proteins

Stage 2: Small Intestine (Duodenum & Jejunum) — Pancreatic Enzymes (majority of digestion)

• Trypsinogen → activated by enterokinase (expressed on the luminal membrane of small intestine epithelial cells)
• Trypsin then activates all the others (chymotrypsinogen, procarboxypeptidases A & B, proelastase) in a cascade

Figure 66.2: Digestion of proteins - Pepsin → proteoses/peptones/polypeptides → pancreatic enzymes → polypeptides + amino acids → peptidases → amino acids. (Guyton and Hall Medical Physiology)

Figure 66.3: Enterokinase on the small intestinal brush border activates trypsinogen → trypsin, which then activates all other pancreatic proenzymes. (Guyton and Hall Medical Physiology)

Stage 3: Brush Border — Enterocyte Peptidases (final luminal digestion)

• Aminopolypeptidase and multiple dipeptidases project through the microvillar membrane into the intestinal lumen
• They split remaining larger polypeptides into tripeptides, dipeptides, and some free amino acids
• These are then easily transported across the microvillar membrane into the enterocyte interior

Step 2 — Absorption (Transport Across the Intestinal Epithelium)

Form in which proteins are absorbed

More than 99% of the final protein digestive products absorbed are individual amino acids. Only rare absorption of peptides occurs, and very rare absorption of whole protein molecules. - Guyton and Hall, p. 821

Mechanism of Transport — Sodium Co-Transport (Secondary Active Transport)

1. Na⁺-K⁺-ATPase on the basolateral membrane actively pumps Na⁺ out of the enterocyte → creates a low intracellular Na⁺ concentration
2. On the luminal (brush border) membrane, a specific carrier protein will not transport the amino acid/peptide unless it also binds Na⁺
3. Na⁺ moves down its electrochemical gradient into the cell and carries the amino acid or peptide along with it (co-transport)
4. Once inside the cell, amino acids exit through the basolateral membrane (by facilitated diffusion or active transport) into the paracellular space → then into the blood

After Absorption — Blood Amino Acids and Fate

• Normal blood amino acid concentration: 35–65 mg/dL (~2 mg/dL per amino acid on average)
• Amino acids exist in the blood in the ionized state and account for 2–3 mEq/L of anions

Why blood amino acid concentration rises only slightly after a meal:

1. Protein digestion and absorption are spread over 2–3 hours → only small quantities absorbed at a time
2. After entering the blood, amino acids are taken up by cells (especially the liver) within 5–10 minutes

Renal handling:

Summary Flow

Dietary Protein
    ↓  [Stomach: Pepsin, pH 2-3]
Proteoses, Peptones, Polypeptides (10-20%)
    ↓  [Small intestine: Trypsin, Chymotrypsin, Carboxypeptidases, Elastase]
    ↓  [Activated by: Enterokinase → Trypsin → all others]
Dipeptides + Tripeptides + some Free Amino Acids
    ↓  [Brush border peptidases: Aminopolypeptidase, Dipeptidases]
Dipeptides, Tripeptides, Free Amino Acids
    ↓  [Absorbed across microvillar membrane by Na⁺ co-transport]
Inside Enterocyte → Cytosolic peptidases complete hydrolysis
    ↓
Free Amino Acids
    ↓  [Exit via basolateral membrane → Portal blood]
>99% absorbed as free amino acids

• Guyton and Hall Textbook of Medical Physiology, Chapter 66 (Digestion and Absorption in the GI Tract) and Chapter 70 (Protein Metabolism)

Absorption of Protein — Guyton and Hall Textbook of Medical Physiology

Step 1 — Digestion of Proteins

Stage 1: Stomach — Pepsin (10–20% of total digestion)

• Pepsin is active at pH 2.0–3.0 and inactive above pH 5.0
• Gastric HCl (secreted by parietal cells at pH ~0.8) acidifies the contents to pH ~2.0–3.0, creating ideal conditions for pepsin
• Pepsin converts proteins into proteoses, peptones, and a few polypeptides — only 10–20% of total protein digestion
• A key unique role of pepsin: it digests collagen, which holds meat fibers together. Without pepsin, other digestive enzymes cannot penetrate meats adequately → poor digestion

Stage 2: Small Intestine — Pancreatic Proteolytic Enzymes (majority of digestion)

• Trypsinogen → Trypsin via enterokinase (a proteolytic enzyme expressed on the luminal membrane of small intestine epithelial cells)
• Trypsin then activates all the others: chymotrypsinogen → chymotrypsin; proelastase → elastase; procarboxypeptidase A & B → carboxypeptidase A & B

Fig. 66.3: Enterokinase on the small intestinal brush border activates trypsinogen → trypsin, which activates all other pancreatic proenzymes. (Guyton & Hall)

Stage 3: Brush Border Peptidases of Enterocytes (final digestion)

• Aminopolypeptidase and multiple dipeptidases split remaining polypeptides into tripeptides, dipeptides, and free amino acids
• These small units are then transported into the enterocyte
• Inside the cytosol, further peptidases complete hydrolysis — within minutes, virtually all dipeptides and tripeptides are broken down to single amino acids

Fig. 66.2: Stepwise digestion: Pepsin → proteoses/peptones/polypeptides → pancreatic enzymes → dipeptides/tripeptides + some amino acids → brush border peptidases → amino acids. (Guyton & Hall)

Step 2 — Absorption (Transport Across the Intestinal Epithelium)

Form in which proteins are absorbed

More than 99% of the final absorbed products are individual amino acids. Only rarely are peptides absorbed, and whole protein molecules are absorbed in very small amounts (sufficient to trigger allergic/immunological reactions in some individuals).

Mechanism — Sodium Co-Transport (Secondary Active Transport)

1. Na⁺-K⁺-ATPase on the basolateral membrane pumps Na⁺ out of the enterocyte → creates low intracellular Na⁺
2. On the luminal membrane, a carrier protein requires Na⁺ binding before it will transport the amino acid/peptide
3. Na⁺ moves down its electrochemical gradient into the cell, pulling the amino acid or peptide with it — this is secondary active transport (co-transport)
4. The energy ultimately comes from Na⁺-K⁺-ATPase on the basolateral side

• At least 10 different transport proteins exist for amino acids and peptides in the intestinal epithelial cells, required because of the diverse binding properties of different amino acids and peptides
• A few amino acids do not need Na⁺ co-transport; instead they use facilitated diffusion via special membrane carriers (similar to fructose absorption)

Exit from Enterocyte → Blood

After Absorption — Blood Amino Acids

• Normal blood amino acid concentration: 35–65 mg/dL (~2 mg/dL per amino acid on average)
• Amino acids exist in the ionized state in blood and account for 2–3 mEq/L of anions

Why blood amino acid level rises only slightly after a meal:

1. Protein digestion and absorption are spread over 2–3 hours → only small quantities absorbed at a time
2. After entering the blood, amino acids are rapidly taken up by cells (especially the liver) within 5–10 minutes

Renal handling:

Summary Flow

Dietary Protein
    ↓  Stomach: Pepsin (pH 2–3)  →  10–20% digestion
Proteoses, Peptones, Polypeptides
    ↓  Duodenum/Jejunum: Trypsin, Chymotrypsin,
       Carboxypeptidases, Elastase
       (Trypsinogen activated by Enterokinase → Trypsin
        activates all other proenzymes)
Dipeptides + Tripeptides + some Free Amino Acids
    ↓  Brush border: Aminopolypeptidase + Dipeptidases
Dipeptides, Tripeptides, Free Amino Acids
       ↓  Absorbed via Na⁺ co-transport across luminal membrane
Inside Enterocyte → Cytosolic peptidases hydrolyze all residual di/tripeptides
       ↓
Free Amino Acids → exit basolateral membrane → Portal blood
>99% absorbed as free amino acids