Medical School · Year 2 · Gastrointestinal · includes a quiz and discussion video

Lecture 6: Gastric Disorders

Unit 2.2: Gastrointestinal System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the pathophysiology and management of peptic ulcer disease
2. Explain the role of H. pylori in gastric disease
3. Describe gastroparesis and its management
4. Explain gastric neoplasms including adenocarcinoma and GIST
5. Describe other gastric conditions including gastritis and Zollinger-Ellison syndrome
6. Explain the approach to upper GI bleeding

Lecture Content

Peptic Ulcer Disease Overview

Peptic ulcer disease (PUD) is defined by mucosal defects that extend through the muscularis mucosae into deeper layers of the stomach or duodenum. This important distinction separates ulcers from erosions, which are confined to the mucosa. The lifetime prevalence is 5-10% of the population, though incidence has declined substantially with H. pylori eradication and widespread PPI use. Duodenal ulcers are more common than gastric ulcers in most populations.

The pathophysiology of PUD reflects an imbalance between aggressive factors (acid, pepsin, H. pylori, NSAIDs) and defensive factors (mucus, bicarbonate, prostaglandins, mucosal blood flow). The classic dictum "no acid, no ulcer" reflects the necessity of acid for ulcer formation, though acid alone rarely causes ulcers without additional insults.

The two major causes account for the vast majority of peptic ulcers. Helicobacter pylori infection underlies 70-90% of duodenal ulcers and 60-70% of gastric ulcers. NSAIDs cause 20-25% of ulcers by inhibiting prostaglandin synthesis, which compromises mucosal defenses. Stress ulcers occur in critically ill ICU patients due to mucosal ischemia. Hypersecretory states (Zollinger-Ellison syndrome) account for less than 1%. Truly idiopathic ulcers (H. pylori-negative, NSAID-negative) are increasingly recognized and may represent 5-10% of cases.

Duodenal and gastric ulcers differ in important ways. Duodenal ulcers typically occur in patients with high acid output; H. pylori colonizes the antrum and triggers hypergastrinemia, leading to acid hypersecretion. Pain classically improves with eating because food buffers acid, but returns 2-3 hours later as the stomach empties. Gastric ulcers occur in patients with normal or low acid output; the defect is impaired mucosal defense rather than excess acid. Pain may worsen with eating. Gastric ulcers carry approximately 5% malignancy risk and always require biopsy to exclude cancer; duodenal ulcers are rarely malignant.

<image>Panel A: Balance concept with aggressive factors including acid, pepsin, H. pylori, and NSAIDs on one side of a scale and defensive factors including mucus, bicarbonate, prostaglandins, and mucosal blood flow on the other, with ulcers forming when aggressive factors predominate. Panel B: H. pylori mechanism showing the bacterium in the mucus layer producing urease to create local ammonia toxicity, stimulating gastrin release from G cells, and increasing acid secretion. Panel C: Comparison of duodenal ulcers with antral H. pylori, high acid output, pain relieved by food, and low cancer risk versus gastric ulcers with body and fundal involvement, normal or low acid, pain with food, and 5% cancer risk requiring biopsy. Panel D: Etiology pie chart showing H. pylori causing 70-80% of peptic ulcers, NSAIDs causing 20%, and other causes including stress ulcers, Zollinger-Ellison syndrome, and idiopathic ulcers.</image>

Helicobacter pylori

Helicobacter pylori is a gram-negative, spiral-shaped, flagellated bacterium that colonizes the human gastric mucosa. This remarkably successful pathogen infects approximately 50% of the world's population, with prevalence highest in developing countries and lower socioeconomic settings. Transmission occurs via fecal-oral and oral-oral routes, typically during childhood.

The pathogenic mechanisms of H. pylori explain its disease associations. Urease, the most important virulence factor, converts urea to ammonia and carbon dioxide. The ammonia neutralizes local acid, allowing bacterial survival, but is toxic to epithelial cells. CagA (cytotoxin-associated gene A) is injected into host cells via a type IV secretion system; CagA-positive strains cause more severe inflammation and carry higher gastric cancer risk. VacA (vacuolating cytotoxin) damages epithelial cells. The chronic inflammatory response to H. pylori damages the mucosa and alters gastric physiology.

H. pylori is causally linked to several conditions. Peptic ulcer disease is the most common clinical consequence. Gastric adenocarcinoma risk is increased approximately sixfold, leading WHO to classify H. pylori as a Class I carcinogen. MALT lymphoma (mucosa-associated lymphoid tissue) is an H. pylori-driven lymphoma that can regress with antibiotic eradication alone in localized disease. Functional dyspepsia shows modest association, and some patients improve with eradication.

Diagnosis of H. pylori uses invasive or non-invasive methods. Non-invasive tests include the urea breath test (patient ingests labeled urea; if H. pylori urease is present, labeled CO2 is exhaled), the stool antigen test (detects H. pylori proteins in feces), and serology (IgG antibodies; indicates past or current infection but cannot confirm active infection or eradication). Invasive tests performed during endoscopy include rapid urease testing (biopsy placed in urea-containing medium; color change indicates urease activity), histology (visualizes organisms and gastritis), and culture (allows antibiotic susceptibility testing but is technically demanding).

A critical requirement for accurate testing is that PPIs must be stopped for at least 2 weeks and antibiotics for 4 weeks before non-invasive testing; otherwise, false negatives occur because reduced bacterial load temporarily suppresses urease activity.

<image>Panel A: H. pylori organism morphology as a spiral-shaped, flagellated bacterium colonizing the gastric mucus layer, with virulence factors labeled including urease converting urea to ammonia and carbon dioxide, CagA injected into host cells via type IV secretion system, and VacA causing epithelial cell vacuolation. Panel B: Disease associations showing peptic ulcer disease as the most common consequence, gastric adenocarcinoma with WHO Class I carcinogen status and 6-fold increased risk, MALT lymphoma that can be cured with eradication, and functional dyspepsia with modest benefit from treatment. Panel C: Non-invasive diagnostic tests including the urea breath test with labeled carbon dioxide exhalation, stool antigen test, and serology for IgG antibodies, with a note to stop PPIs for 2 weeks and antibiotics for 4 weeks before testing. Panel D: Invasive diagnostic tests performed during endoscopy including rapid urease test with color change indicating urease activity, histology visualizing organisms and gastritis, and culture allowing antibiotic susceptibility testing.</image>

Peptic Ulcer Disease Management

The approach to PUD management depends on the underlying cause. For H. pylori-positive ulcers, eradication therapy is essential. For NSAID-induced ulcers, discontinuing the NSAID and treating with PPIs promotes healing. For all ulcers, acid suppression with PPIs accelerates healing and relieves symptoms.

H. pylori eradication requires combination antibiotic therapy because monotherapy rapidly induces resistance. Current regimens reflect increasing clarithromycin resistance. Bismuth quadruple therapy (PPI plus bismuth subsalicylate plus metronidazole plus tetracycline for 14 days) is increasingly preferred as first-line therapy and is required in areas with clarithromycin resistance exceeding 15%. Concomitant therapy (PPI plus amoxicillin plus clarithromycin plus metronidazole for 14 days) is an alternative when bismuth is unavailable. Traditional triple therapy (PPI plus amoxicillin plus clarithromycin for 14 days) has declining efficacy due to clarithromycin resistance and is no longer recommended in many regions.

Confirmation of eradication is essential because treatment failure allows persistent infection, recurrent ulceration, and continued cancer risk. The urea breath test or stool antigen test should be performed at least 4 weeks after completing treatment (with PPIs stopped for 2 weeks beforehand). Serology cannot confirm eradication because antibodies persist.

NSAID-induced ulcers require stopping the NSAID if possible and treating with PPIs for 4-8 weeks. If continued NSAID use is necessary, co-therapy with a PPI reduces ulcer risk. COX-2 selective NSAIDs (celecoxib) have lower GI toxicity than non-selective NSAIDs but still carry some risk. Testing for H. pylori and eradicating if present reduces ulcer risk in NSAID users.

PPI therapy promotes ulcer healing by maintaining intragastric pH above 4, which allows mucosal repair. Duodenal ulcers typically heal within 4-8 weeks; gastric ulcers require 8-12 weeks because they heal more slowly. Complicated ulcers (bleeding, perforation) may require longer therapy. Repeat endoscopy is recommended for gastric ulcers to confirm healing and exclude malignancy.

<image>Panel A: Initial testing to confirm H. pylori status with the appropriate diagnostic test, branching into H. pylori-positive and NSAID-induced pathways. Panel B: H. pylori-positive pathway showing eradication regimens with bismuth quadruple therapy preferred, concomitant therapy as an alternative, and declining triple therapy, all for 14 days, with eradication confirmed 4 or more weeks after treatment using the urea breath test or stool antigen. Panel C: NSAID-induced pathway showing discontinuation of the NSAID if possible with PPI therapy, or if continued NSAID use is necessary then PPI co-therapy or switching to a COX-2 selective agent, with PPI healing durations of 4-8 weeks for duodenal ulcers and 8-12 weeks for gastric ulcers. Panel D: Follow-up showing repeat endoscopy recommended for gastric ulcers to confirm healing and exclude underlying malignancy.</image>

Peptic Ulcer Complications

Peptic ulcers can cause life-threatening complications that require prompt recognition and management.

Bleeding is the most common complication, occurring in 15-20% of patients with PUD. Ulcers erode into submucosal vessels, and posterior duodenal ulcers may erode into the gastroduodenal artery. Patients present with hematemesis (vomiting blood or coffee-ground material), melena (black tarry stools), or hematochezia if bleeding is brisk. Management involves initial resuscitation (IV access, crystalloid fluids, blood transfusion targeting hemoglobin 7-8 g/dL in stable patients), IV PPI infusion (reduces rebleeding after endoscopic therapy), and urgent upper endoscopy for diagnosis and therapy.

Perforation occurs when an ulcer erodes completely through the wall. Anterior duodenal ulcers more commonly perforate. Patients present with sudden, severe epigastric pain radiating to the back, followed by signs of peritonitis (rigid abdomen, rebound tenderness). Upright chest or abdominal X-ray may show free air under the diaphragm. CT scan is more sensitive for detecting perforation. Treatment is typically surgical repair (Graham patch omentoplasty) with antibiotics; some small, contained perforations may be managed non-operatively in select patients.

Gastric outlet obstruction results from edema and scarring at the pylorus or duodenum, typically from chronic or recurrent ulceration. Patients present with nausea, vomiting (often of food eaten many hours earlier), early satiety, and weight loss. A succussion splash on examination may be present. Diagnosis is confirmed by endoscopy or imaging showing a dilated stomach with retained material. Management includes NG decompression, IV fluids, electrolyte correction (hypochloremic metabolic alkalosis is common), PPI therapy, H. pylori eradication, and endoscopic or surgical intervention for fixed strictures.

Penetration occurs when an ulcer erodes into an adjacent organ without free perforation. Posterior duodenal ulcers may penetrate into the pancreas, causing pancreatitis and pain radiating to the back. Treatment is typically surgical.

<image>Panel A: Bleeding complication showing a posterior duodenal ulcer eroding into the gastroduodenal artery, presentation with hematemesis and melena, Forrest classification from Ia spurting through III clean base, and endoscopic therapy with clips and cautery. Panel B: Perforation showing an anterior duodenal ulcer perforating through the serosa, free air under the diaphragm on upright X-ray, peritonitis signs with rigid abdomen, and surgical Graham patch omentoplasty repair. Panel C: Gastric outlet obstruction showing pyloric and duodenal narrowing from chronic scarring, dilated stomach with retained food, succussion splash on examination, and nasogastric tube decompression. Panel D: Penetration showing a posterior ulcer eroding into the pancreas causing pancreatitis and back pain, with conservative versus surgical management options.</image>

Gastritis

Gastritis refers to inflammation of the gastric mucosa and encompasses several distinct entities with different etiologies and clinical significance.

Acute gastritis represents acute mucosal inflammation and injury. NSAIDs cause prostaglandin inhibition leading to reduced mucosal blood flow, decreased mucus and bicarbonate secretion, and direct mucosal toxicity. Alcohol causes direct mucosal injury. Stress gastritis occurs in critically ill patients (mechanical ventilation, coagulopathy, shock) due to mucosal ischemia and acid injury; prophylaxis with PPIs is indicated in high-risk ICU patients. Caustic ingestion from strong acids or bases causes severe injury potentially requiring emergency surgery.

Chronic gastritis persists over time and is classified by anatomic pattern and etiology. Type A (autoimmune) gastritis targets the acid-producing parietal cells of the gastric body and fundus. Autoantibodies against parietal cells and intrinsic factor lead to progressive parietal cell destruction. Consequences include achlorhydria (loss of acid production), intrinsic factor deficiency causing B12 malabsorption and pernicious anemia, hypergastrinemia (loss of acid-mediated feedback inhibition of gastrin), and ECL cell hyperplasia from chronic gastrin stimulation with potential development of carcinoid tumors. Laboratory findings include elevated gastrin, anti-parietal cell antibodies, anti-intrinsic factor antibodies, and low B12. Autoimmune gastritis associates with other autoimmune conditions (thyroid disease, type 1 diabetes).

Type B (bacterial) gastritis is caused by H. pylori and primarily affects the antrum. It is far more common than autoimmune gastritis. Chronic H. pylori gastritis increases risk of peptic ulcers and gastric cancer. Treatment is H. pylori eradication.

Reactive (chemical) gastritis results from bile reflux (often post-gastric surgery), NSAIDs, or other chemical injury. Histology shows foveolar hyperplasia with minimal inflammation.

Special forms of gastritis include lymphocytic gastritis (associated with celiac disease), granulomatous gastritis (Crohn's disease, tuberculosis, sarcoidosis), eosinophilic gastritis (eosinophil infiltration), and Ménétrier disease (giant hypertrophic folds with protein-losing gastropathy and increased gastric cancer risk).

<image>Panel A: Acute gastritis causes including NSAIDs with prostaglandin inhibition leading to reduced mucosal defenses, alcohol causing direct mucosal injury, and stress in ICU patients causing mucosal ischemia. Panel B: Chronic Type A autoimmune gastritis showing body and fundus location on the stomach diagram, anti-parietal cell antibodies targeting parietal cells, and consequences including achlorhydria, loss of intrinsic factor leading to B12 deficiency and pernicious anemia, and hypergastrinemia driving ECL cell hyperplasia with carcinoid tumor risk. Panel C: Chronic Type B H. pylori gastritis showing antral location, bacterial colonization, and progression to peptic ulcers and gastric cancer, with a comparison table of location, antibodies, acid level, and cancer risk for Type A versus Type B. Panel D: Special forms of gastritis including Menetrier disease with giant hypertrophic folds and protein-losing gastropathy, granulomatous gastritis from Crohn's disease, tuberculosis, or sarcoidosis, eosinophilic gastritis, and lymphocytic gastritis associated with celiac disease.</image>

Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome (ZES) is a hypersecretory condition caused by gastrin-producing tumors (gastrinomas) that stimulate massive acid hypersecretion. This rare disorder illustrates the consequences of uncontrolled acid production.

Gastrinomas arise most commonly in the "gastrinoma triangle" defined by the junction of the cystic and common bile ducts superiorly, the junction of the second and third portions of the duodenum inferiorly, and the junction of the neck and body of the pancreas medially. About 60% arise in the duodenum and 30% in the pancreas. Importantly, 60-90% of gastrinomas are malignant and may have metastasized at diagnosis. Approximately 25% of gastrinomas occur in the context of MEN1 (multiple endocrine neoplasia type 1), an autosomal dominant syndrome also featuring parathyroid adenomas and pituitary tumors.

Clinical manifestations result from massive acid hypersecretion. Peptic ulcers are often multiple, in unusual locations (distal duodenum, jejunum), refractory to standard therapy, or recurrent after treatment. Diarrhea occurs because excess acid inactivates pancreatic enzymes and damages small intestinal mucosa. Steatorrhea reflects impaired lipase activity. GERD is often severe.

Diagnosis requires demonstrating elevated fasting serum gastrin. Gastrin levels exceeding 1000 pg/mL with gastric pH less than 2 are diagnostic (the low pH rules out secondary hypergastrinemia from achlorhydria). Gastrin levels between 100 and 1000 pg/mL require the secretin stimulation test: IV secretin paradoxically increases gastrin in ZES (by >120 pg/mL within 10 minutes) whereas in other causes of hypergastrinemia, secretin suppresses or has no effect on gastrin. PPIs must be stopped before testing if safe to do so, because PPIs themselves cause hypergastrinemia by reducing acid-mediated feedback.

Localization uses CT, MRI, endoscopic ultrasound, and somatostatin receptor scintigraphy (octreotide scan) or Gallium-68 DOTATATE PET. Treatment involves controlling acid secretion with high-dose PPIs (often twice the usual dose or more) and, when possible, surgical resection of the tumor for cure. MEN1 patients typically have multiple small duodenal tumors that are difficult to cure surgically. Chemotherapy or targeted therapies are used for metastatic disease.

<image>Panel A: Gastrinoma triangle anatomy bounded by the junction of the cystic and common bile ducts superiorly, the junction of the second and third portions of the duodenum inferiorly, and the junction of the neck and body of the pancreas medially, with most common tumor locations indicated. Panel B: Disrupted gastrin-acid feedback loop showing the gastrinoma secreting gastrin autonomously, parietal cells massively stimulated, excess acid production, and clinical manifestations including multiple ulcers in unusual locations, severe GERD, and diarrhea with steatorrhea from acid inactivating pancreatic enzymes. Panel C: Diagnostic workup showing fasting gastrin exceeding 1000 pg/mL with gastric pH less than 2 as diagnostic, and the secretin stimulation test with a graph illustrating the paradoxical gastrin rise in ZES versus suppression in other causes of hypergastrinemia. Panel D: Treatment with high-dose PPIs for acid control, surgical resection for localized disease, and MEN1 screening including parathyroid hormone, calcium, and prolactin levels.</image>

Gastroparesis

Gastroparesis is defined as delayed gastric emptying in the absence of mechanical obstruction. The stomach fails to contract effectively and cannot grind solid food or propel contents into the duodenum in a timely manner.

The most common identifiable cause is diabetes mellitus, accounting for approximately one-third of cases. Diabetic autonomic neuropathy damages the vagal nerve fibers that coordinate gastric motility. Chronic hyperglycemia itself slows gastric emptying acutely, creating a vicious cycle where delayed emptying causes unpredictable absorption, which worsens glycemic control. Idiopathic gastroparesis, without identifiable cause, accounts for another third of cases and may follow viral illness. Post-surgical gastroparesis occurs after vagotomy or other gastric surgery. Medications that slow motility (opioids, anticholinergics, GLP-1 receptor agonists) can cause or worsen gastroparesis.

The pathophysiology involves multiple components. Vagal neuropathy impairs the cholinergic signals that coordinate antral contractions. Loss of interstitial cells of Cajal disrupts the electrical pacemaker activity that generates gastric slow waves. Smooth muscle dysfunction may contribute in advanced cases.

Symptoms reflect gastric retention and distension. Nausea is the most common complaint. Vomiting may be delayed and contain recognizable food eaten hours earlier. Early satiety occurs because the stomach cannot accommodate normal meal volumes. Bloating and abdominal distension are common. Weight loss develops as patients eat less to minimize symptoms. Bezoars (solid masses of undigested material) can form in severely delayed stomachs.

Diagnosis requires demonstrating delayed emptying after excluding mechanical obstruction. Upper endoscopy rules out pyloric obstruction, ulcers, and other structural lesions. Gastric emptying scintigraphy is the gold standard: patients eat a radiolabeled solid meal, and gamma camera imaging quantifies retention over time. Delayed emptying is defined as more than 60% retention at 2 hours or more than 10% retention at 4 hours. The 4-hour value is more specific.

<image>Panel A: Causes of gastroparesis as a pie chart with diabetic as the largest segment followed by idiopathic, post-surgical, and medication-induced, with the diabetic pathway detailed from chronic hyperglycemia to autonomic neuropathy to vagal damage to impaired gastric coordination. Panel B: Stomach with impaired motility showing normal antral contraction waves compared to weak or absent waves, pylorus dysfunction, and food retention in the gastric body. Panel C: Symptoms including nausea as the most common complaint, delayed vomiting containing recognizable undigested food, early satiety, bloating, weight loss, and bezoar formation as a complication. Panel D: Diagnostic approach with upper endoscopy first to exclude mechanical obstruction, followed by gastric emptying scintigraphy as the gold standard showing sequential images at 1, 2, and 4 hours with delayed emptying defined as more than 60% retention at 2 hours or more than 10% retention at 4 hours.</image>

Gastroparesis Management

Treatment of gastroparesis aims to relieve symptoms, maintain nutrition, and optimize glycemic control in diabetic patients. The approach is stepped, starting with dietary modification and progressing to pharmacotherapy and, if refractory, advanced interventions.

Dietary modifications form the foundation. Small, frequent meals reduce gastric distension. Low-fat content accelerates emptying because fat slows gastric motility. Low-fiber meals are easier to empty because fiber delays gastric emptying. Liquid calories (nutritional shakes) often pass through more easily than solids. Patients should remain upright after eating to allow gravity to assist emptying. Chewing thoroughly aids mechanical digestion.

Glycemic control is critically important in diabetic gastroparesis. Hyperglycemia directly slows gastric emptying, while gastroparesis causes erratic nutrient absorption that complicates glucose control. This creates a negative feedback loop that optimal glucose management can help break.

Prokinetic agents increase gastric motility. Metoclopramide is the only FDA-approved prokinetic for gastroparesis; it blocks dopamine D2 receptors (removing dopamine's inhibitory effect on motility) and stimulates 5-HT4 receptors. Because it crosses the blood-brain barrier, it carries significant risk of extrapyramidal side effects including tardive dyskinesia with long-term use; FDA mandates a black box warning and limits use to 12 weeks. Domperidone is a D2 antagonist that does not cross the blood-brain barrier, reducing CNS effects, but causes QT prolongation; it is not FDA-approved but is available through compassionate use programs. Erythromycin is a motilin receptor agonist that powerfully stimulates gastric emptying; IV erythromycin is useful for acute exacerbations, but oral erythromycin develops tachyphylaxis (rapid tolerance) limiting chronic use.

Additional therapies address symptoms and refractory disease. Antiemetics (ondansetron, promethazine, prochlorperazine) control nausea. Gastric electrical stimulation (Enterra device) delivers high-frequency, low-energy pulses to the gastric wall; it is FDA-approved through humanitarian device exemption and reduces nausea and vomiting in some patients, though it does not accelerate emptying. Pyloric interventions (botulinum toxin injection, gastric peroral endoscopic myotomy [G-POEM], surgical pyloroplasty) target pyloric dysfunction. Feeding jejunostomy bypasses the stomach for nutrition in severe, refractory cases. Total parenteral nutrition is a last resort.

<image>Panel A: Dietary modifications as the foundation including small frequent meals, low-fat and low-fiber content, liquid nutritional supplements for easier passage, upright positioning after eating, and thorough chewing, alongside glycemic control in diabetic patients with bidirectional arrows showing the vicious cycle of hyperglycemia slowing emptying and gastroparesis worsening glucose control. Panel B: Prokinetic pharmacotherapy showing metoclopramide as a D2 antagonist and 5-HT4 agonist with a black box warning for tardive dyskinesia limited to 12 weeks, domperidone as a peripheral D2 antagonist with QT prolongation risk, and erythromycin as a motilin receptor agonist for acute use with tachyphylaxis limiting chronic oral use. Panel C: Antiemetic agents including ondansetron and promethazine for symptom control alongside gastric electrical stimulation with the Enterra device delivering high-frequency low-energy pulses to reduce nausea and vomiting. Panel D: Advanced therapies for refractory disease including pyloric interventions such as botulinum toxin injection, gastric peroral endoscopic myotomy, and surgical pyloroplasty, feeding jejunostomy to bypass the stomach, and total parenteral nutrition as a last resort.</image>

Gastric Neoplasms

Gastric adenocarcinoma is the fifth most common cancer worldwide and the third leading cause of cancer death. Its incidence varies dramatically by geography: highest in East Asia, Eastern Europe, and South America; lower in North America and Western Europe. Incidence has been declining due to reduced H. pylori prevalence, improved food preservation, and dietary changes.

Risk factors include H. pylori infection (the dominant risk factor, causing chronic gastritis that progresses through atrophy, intestinal metaplasia, dysplasia, and carcinoma), autoimmune gastritis (particularly for tumors in the gastric body), dietary factors (salt, smoked foods, nitrates; low fruit and vegetable intake), smoking, and family history. Hereditary diffuse gastric cancer (HDGC) syndrome results from germline CDH1 mutations encoding E-cadherin; carriers have 70% lifetime risk of diffuse gastric cancer and prophylactic gastrectomy is recommended.

Two histologic types are distinguished by Lauren classification. Intestinal-type adenocarcinoma forms glands and typically arises in the setting of H. pylori gastritis, intestinal metaplasia, and dysplasia; it is more common in older patients and high-incidence regions and has a relatively better prognosis. Diffuse-type adenocarcinoma (including signet ring cell carcinoma) consists of discohesive cells infiltrating the gastric wall; it is more common in younger patients, is associated with E-cadherin loss, and has worse prognosis.

Clinical presentation is often late. Early gastric cancer (confined to mucosa or submucosa) is usually asymptomatic and is detected through screening programs in high-incidence countries like Japan. Advanced disease presents with weight loss, abdominal pain, dysphagia (for proximal tumors), early satiety, anorexia, and GI bleeding. Metastatic disease may present with specific signs: Virchow node (left supraclavicular lymph node), Sister Mary Joseph nodule (periumbilical metastasis), Krukenberg tumor (ovarian metastases from signet ring cells).

Diagnosis is by upper endoscopy with biopsy. Staging includes CT of chest, abdomen, and pelvis; endoscopic ultrasound for T and N staging; and PET-CT for distant disease. Staging laparoscopy may detect peritoneal metastases missed on imaging. Treatment depends on stage: endoscopic resection for T1a tumors without lymphovascular invasion, surgery with perioperative chemotherapy for resectable disease, palliative chemotherapy for metastatic disease. HER2-positive tumors benefit from trastuzumab. Overall 5-year survival is approximately 30%, but exceeds 90% for early gastric cancer.

<image>Panel A: Risk factors for gastric adenocarcinoma including H. pylori as the dominant risk factor, autoimmune gastritis with parietal cell antibodies, dietary factors such as salt and smoked foods, smoking, and germline CDH1 mutations causing hereditary diffuse gastric cancer syndrome. Panel B: Lauren classification comparing intestinal-type adenocarcinoma with gland-forming histology in older patients related to H. pylori with better prognosis versus diffuse-type with discohesive signet ring cells in younger patients with E-cadherin loss and worse prognosis. Panel C: Clinical presentation with early gastric cancer often asymptomatic and detected by screening programs, advanced disease showing weight loss, pain, dysphagia, and bleeding, and metastatic signs including Virchow node in the left supraclavicular area, Sister Mary Joseph nodule at the umbilicus, and Krukenberg tumor in the ovary. Panel D: Staging and treatment with endoscopic resection for early T1a tumors, perioperative chemotherapy plus surgery for resectable disease, palliative chemotherapy with or without HER2-targeted therapy for metastatic disease, and survival statistics of 30% overall but exceeding 90% for early gastric cancer.</image>

Other Gastric Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract. They arise from interstitial cells of Cajal (the pacemaker cells of gut motility) or their precursors. The stomach is the most common location (60%), followed by small intestine (30%).

The hallmark molecular feature is activating mutations in the KIT gene (encoding the CD117 receptor tyrosine kinase) in 80% of cases or PDGFRA mutations in another 5-10%. These mutations drive proliferation and are therapeutic targets. Histologically, GISTs stain positive for CD117 (KIT) and DOG1.

Clinical behavior is variable; size and mitotic rate predict malignancy. Small GISTs with low mitotic activity are often benign, while large, highly mitotic tumors are aggressive. Presentation includes GI bleeding, abdominal pain, or mass effect. Treatment of localized GIST is surgical resection. Imatinib (Gleevec), a tyrosine kinase inhibitor targeting KIT and PDGFRA, is used for unresectable or metastatic GIST with remarkable efficacy and has transformed outcomes for this previously untreatable disease.

Gastric polyps are commonly encountered during endoscopy. Fundic gland polyps are the most common type in Western populations, often associated with PPI use; they are benign and require no treatment unless large. Hyperplastic polyps arise in inflamed mucosa and have low but non-zero dysplasia risk; H. pylori should be tested and treated. Adenomatous polyps are premalignant and should be removed.

Gastric carcinoid tumors (neuroendocrine tumors, NETs) are classified into three types. Type 1 carcinoids arise from ECL cell hyperplasia in autoimmune atrophic gastritis due to hypergastrinemia; they are typically multiple, small, and have excellent prognosis. Type 2 carcinoids occur in MEN1/ZES, also driven by hypergastrinemia. Type 3 carcinoids are sporadic, solitary, and behave aggressively with significant metastatic potential. Management varies: Type 1/2 may be observed or resected endoscopically; Type 3 requires oncologic resection.

Gastric lymphoma includes MALT lymphoma, which is strongly associated with H. pylori; localized gastric MALT lymphoma often regresses completely with H. pylori eradication alone, representing a remarkable example of treating cancer with antibiotics. Diffuse large B-cell lymphoma (DLBCL) requires chemotherapy.

<image>Panel A: Gastrointestinal stromal tumor showing origin from interstitial cells of Cajal in the gut wall, molecular features of KIT/CD117 mutation and DOG1 positivity, CT imaging of a gastric mass, and treatment with surgical resection for localized disease or imatinib for unresectable and metastatic tumors. Panel B: Gastric polyps comparing three types including fundic gland polyps that are small, multiple, PPI-associated, and benign, hyperplastic polyps with inflamed base and low dysplasia risk requiring H. pylori testing, and adenomatous polyps that are premalignant and should be removed. Panel C: Gastric carcinoid tumors in three types with Type 1 arising from ECL hyperplasia in autoimmune gastritis-driven hypergastrinemia with good prognosis, Type 2 occurring in MEN1 and ZES with similar mechanism, and Type 3 as sporadic, solitary, and aggressive tumors with significant metastatic potential. Panel D: Gastric lymphoma showing MALT lymphoma associated with H. pylori that regresses with eradication therapy in localized disease, and diffuse large B-cell lymphoma requiring chemotherapy.</image>

Approach to Upper GI Bleeding

Upper gastrointestinal bleeding is a medical emergency defined by bleeding proximal to the ligament of Treitz. It requires systematic evaluation and management to reduce morbidity and mortality.

Presentation varies by severity. Hematemesis (vomiting blood) indicates active or recent bleeding; bright red blood suggests ongoing brisk bleeding, while coffee-ground emesis suggests blood has been altered by gastric acid. Melena (black, tarry, foul-smelling stools) results from degradation of blood during intestinal transit and typically indicates an upper GI source. Hematochezia (bright red blood per rectum) usually indicates lower GI bleeding but can occur with massive upper GI bleeding that transits rapidly. Hemodynamic instability (tachycardia, hypotension, orthostatic changes) indicates significant blood loss.

Common causes include peptic ulcer disease (30-40% of cases, the leading cause), esophageal or gastric varices (10-20%, seen in portal hypertension), erosive disease (gastritis, esophagitis, 15-20%), Mallory-Weiss tear (linear mucosal tear at GE junction from retching, 5-10%), and malignancy (5%). Dieulafoy lesion (aberrant submucosal vessel) and angiodysplasias are less common but important causes.

Initial management prioritizes resuscitation. Establish two large-bore IV lines. Administer crystalloid fluids. Transfuse packed red blood cells targeting hemoglobin 7-8 g/dL in stable patients (higher threshold if active bleeding or coronary artery disease). Risk stratification with the Glasgow-Blatchford score identifies patients requiring intervention versus those safe for outpatient management. Begin IV PPI infusion, which reduces rebleeding and need for intervention in ulcer bleeding. If variceal bleeding is suspected (history of cirrhosis, stigmata of liver disease), administer octreotide and antibiotics.

Endoscopy is both diagnostic and therapeutic. Timing depends on severity: urgent endoscopy (within 12 hours) for hemodynamic instability or active bleeding after resuscitation; early endoscopy (within 24 hours) for most patients. The Forrest classification describes ulcer stigmata and predicts rebleeding risk, guiding intervention: Class Ia (spurting, 90% rebleed risk) and Ib (oozing, 50%) require endoscopic therapy; Class IIa (visible vessel, 40%) typically warrants therapy; Class IIb (adherent clot, 20%) is debated; Class IIc (flat spot, 10%) and III (clean base, <5%) do not require intervention. Endoscopic therapies include injection (epinephrine), thermal (cautery, heater probe), and mechanical (clips) methods.

<image>Panel A: Presentation spectrum of upper GI bleeding showing hematemesis with bright red blood or coffee-ground emesis, melena as black tarry stools, hematochezia if bleeding is massive, and hemodynamic instability signs including tachycardia and hypotension. Panel B: Common causes with percentages showing peptic ulcer disease at 30-40% as the leading cause, esophageal or gastric varices at 10-20%, erosive disease at 15-20%, Mallory-Weiss tear at 5-10%, and malignancy at 5%. Panel C: Initial management steps including establishing two large-bore IV lines, crystalloid resuscitation and blood transfusion targeting hemoglobin 7-8 g/dL, Glasgow-Blatchford risk stratification, IV PPI infusion, and octreotide with antibiotics if variceal bleeding is suspected. Panel D: Forrest classification guiding endoscopic intervention with Ia spurting at 90% rebleed risk requiring treatment, Ib oozing at 50%, IIa visible vessel at 40%, IIb adherent clot at 20% with debated treatment, IIc flat spot at 10% for observation, and III clean base at less than 5% requiring no intervention, with endoscopic therapies including injection, thermal cautery, and clips.</image>

Summary

• PUD: H. pylori and NSAIDs are main causes; test and treat H. pylori
• H. pylori: Diagnose with UBT or stool Ag; bismuth quadruple therapy preferred
• Gastritis: Type A (autoimmune, body) vs Type B (H. pylori, antrum)
• Zollinger-Ellison: Gastrinoma; elevated gastrin; refractory ulcers; secretin test
• Gastroparesis: Delayed emptying; diabetes most common; prokinetics
• Gastric adenocarcinoma: H. pylori, intestinal vs diffuse; perioperative chemo
• GIST: KIT mutation; imatinib for unresectable
• Upper GI bleeding: Resuscitate; early EGD; Forrest classification guides therapy

Key Terms

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