Adobe Systems 2024 1 Pathophysiology of gastrointestinal tract pt. 1, upper GIT Jaromír Gumulec Adobe Systems The GIT 1- esophagus 2- peritoneal cavity 3- stomach (1.5l) 4- gastroesophageal junction 5- pylorus 6- small intestine (4.5 – 6m) 7- duodenum 8- jejunum 9- ileum 10- ileocoecal valve 11- large intestine ascendent transversal descendent colon rectum + anus E_digestiv Adobe Systems 3 Head and neck squamous cell cancer ̶Etiology: tombacco, alcohol, HPV, UV light, poor oral hygiene, exposure environmental polutants ̶ The changing therapeutic landscape of head and neck cancer | Nature Reviews Clinical Oncology Oral squamous cell carcinomas: state of the field and emerging directions | International Journal of Oral Science Adobe Systems 4 Head and neck squamous cell cancer Pathogenesis: ̶Initiation: Exposure to carcinogens or oncogenic viruses (e.g., HPV) leads to genetic alterations (mutations, deletions, amplifications) ̶Promotion: Proliferation of initiated cells driven by continued exposure of carcinogens. ̶Progression: additional genetic alterations, leading to invasive carcinoma. Molecular Alterations: ̶TP53 mutations: Commonly observed in HNSCC, associated with resistance to apoptosis and poor prognosis. ̶HPV infection: Integration of HPV DNA into host genome, leading to overexpression of viral oncoproteins (e.g., E6, E7), inactivation of tumor suppressor genes (e.g., p53, Rb), and promotion of cellular proliferation. ̶EGFR (epidermal growth factor receptor) overexpression: Associated with tumor proliferation, angiogenesis, and resistance to therapy Head and neck squamous cell carcinoma (HNSCC) – BioGraphix p53_cancer Adobe Systems 5 EGFR in head and necjsquamous cell cancer Impact on Tumor Behavior: ̶Proliferation: EGFR signaling stimulates cell proliferation and tumor growth. ̶Survival: Enhances cell survival by inhibiting apoptosis Invasion and Metastasis: Clinical Implications: ̶Prognostic Marker: Higher EGFR expression associated with poorer prognosis ̶Therapeutic Target: EGFR inhibitors (e.g., cetuximab) used in targeted therapy ̶Resistance Mechanisms: Development of resistance to EGFR inhibitors through HER2, MET or mutations in EGFR itself. Cetuximab Overview - Creative Biolabs Adobe Systems Esophagus - anatomy •Upper sphincter (cricopharyngeal muscle) •Upper 2/3 – skeletal muscle, squamous epithelium •Lower 1/3 – smooth muscle •Lower sphincter (LES) •Cylindrical epithelium in the terminal part • • http://flylib.com/books/3/98/1/html/2/153_files/da2db3dc7c153ff1.png Esophageal diverticula Weakness in the esophageal wall leading to outpouching formation •true diverticula (traction) – include muscular layer •pseudodiverticula – only mucous layer • Localization •Zenker's Diverticulum: Located in the posterior hypopharyngeal wall, just above the upper esophageal sphincter. •Epiphrenic Diverticulum: Arises in the distal esophagus, typically just above the lower esophageal sphincter. Factors contributing to the development: •Zenker's Diverticulum: Dysfunction of the cricopharyngeal muscle (upper esophageal sphincter dysfunction) leads to increased pressure in the hypopharynx during swallowing, causing mucosal herniation. •Epiphrenic Diverticulum: Associated with esophageal motility disorders such as achalasia or diffuse esophageal spasm, leading to increased intraluminal pressures in the distal esophagus. true diverticulum pseudodiverticulum divertikl Esophageal diverticula Factors contributing to the development: •Increased intraesophageal pressure •Dysfunction of the esophageal sphincters •Structural abnormalities •Motor disorders (e.g., achalasia) Pathophysiology: •Result of mediastinal or periesophageal inflammation or fibrosis •Traction on the esophageal wall leads to outpouching Clinical features and complications: •Often asymptomatic •Dysphagia if large enough to obstruct the esophageal lumen •Diverticulitis: Inflammation or infection of diverticula, usually resulting from fecal stasis and microperforation of diverticular wall. true diverticulum pseudodiverticulum divertikl Adobe Systems Dysphagia Functional •Inflammation in gastroesophageal reflux •Sclerodermia •Neuropathy (e.g. in diabetes) •Amyotrophic lateral sclerosis •Achalasia • • Obstructive Tumours Strictures Peptic ulcers •Difficulty swallowing, a common symptom in esophageal diverticula •Mechanisms: •Mechanical obstruction caused by the diverticulum •Functional impairment due to associated motility disorders Adobe Systems Esophageal achalasia The lower sphincter is incapable of relaxation This leads into esophageal dilatation and loss of peristaltic movements •The primary cause is the disorder of myenteric plexus (plexus Auerbachi), which produces NO •NO acts as a neurotransmitter, leading to relaxation of the LES Most often, it is caused by autoimune destruction Complications: Esophageal dilation, aspiration pneumonia. http://www.achalasie.com/images/a2.gif Esophagus Diseases - General and Hepato-Pancreato-Biliary Surgeon Hiatal hernias sliding Lower esophageal sphincter and upper part of stomach slides into thoracic cavity Low external pressure in the thoracic cavity leads into the loss of function of LES and gastroesophageal reflux paraesophageal Part of stomach‘s fundus is squeezed into thoracic cavity paralelly with esophagus This can lead into its incarceration or strangulation with necrosis (life-threatening) Mostly, it manifests by pain and vomiting •Weakness in Diaphragmatic Structures: •phrenoesophageal ligament and muscular diaphragmatic crura, allowing the stomach to herniate through the esophageal hiatus. •Increased Intra-abdominal Pressure: (obesity, pregnancy, chronic cough, or heavy lifting) •Aging: Age-related changes in connective tissue Adobe Systems Hiatal hernias – risk factors, complications ̶Wide hiatus ̶Obesity ̶High intraabdominal pressure ̶Gravidity Complications: •Gastroesophageal Reflux Disease •Esophagitis: Barrett's esophagus •Bleeding Adobe Systems Gastroesophageal reflux disease (GERD) Retrograde movement of gastric juice = Loss of anti-reflux barrier Pathophysiology: •Incompetent lower esophageal sphincter (LES) allowing retrograde flow of gastric contents. •Impaired esophageal clearance mechanisms. •Factors contributing to LES dysfunction: •Hiatal hernia •Obesity •Smoking •Certain medications (e.g., anticholinergics, calcium channel blockers) Adobe Systems GERD – symptoms and complications •Clinical Features: •Heartburn: Retrosternal burning sensation, often exacerbated by lying down or after meals. •Regurgitation: Sour or bitter taste in the mouth due to refluxed gastric contents. •Dysphagia: Sensation of difficulty swallowing, especially in severe cases. •Complications: •Esophagitis: Inflammation of the esophageal mucosa. •Barrett's esophagus: Metaplastic change in the esophageal epithelium, predisposing to esophageal adenocarcinoma. Barrett‘s esophagus metaplastic change in the esophageal epithelium, where normal squamous epithelium is replaced by columnar epithelium containing goblet cells. Causes •GERD •Hiathal hernia •Genetic factors •Lifestyle (obesity, smoking), age, male gender, NSAID overuse Barrett‘s esophagus Mechanism •Activation of signaling pathways involved in epithelial cell differentiation and proliferation •Wnt/β-catenin, Notch, and Hedgehog signaling, contributes to the development and maintenance of metaplasia. • Complications: •Esophageal Adenocarcinoma (EAC) (not Esophageal Squamous Cell Carcinoma!) •Dysplasia: •Gastroesophageal Reflux Disease (GERD) Esophageal varices Definition: dilated, tortuous veins located in the submucosa of the esophagus, typically as a result of portal hypertension. Pathophysiology •Portal hypertension from liver cirrhosis. •Collateral vessels form, causing varices. •Varices prone to rupture, leading to bleeding. Causes of Portal Hypertension: •Liver Cirrhosis: Main cause. •Portal Vein Thrombosis. •Budd-Chiari Syndrome (hepatic venous outflow obstruction). Esophageal varices - complications Esophageal varices Bleeding Diagnosis: •Upper endoscopy. •Imaging: Doppler ultrasound, CT, MRI. •Liver function tests. Complications: •Variceal hemorrhage. •Hypovolemic shock. •Hepatic encephalopathy. Adobe Systems Stomach physiology ̶Motor functions of the stomach ̶storage ̶mixing and propulsion ̶emptying ̶Secretions ̶parietal cells - HCl, intrinsic factor ̶chief cells – enzymes (pepsinogen, gastric lipase) ̶surface cells - mucous, sodium bicarbonate 23.4 The Stomach – Anatomy & Physiology Mucous neck cell Parietal cell Chief cell •Secretion of Hydrochloric Acid (HCl): •Activated by histamine, gastrin, and acetylcholine. •Lowers pH of gastric contents for optimal enzymatic activity and antimicrobial defense. •Secretion of Intrinsic Factor: •Essential for absorption of vitamin B12 in the ileum. •Deficiency leads to pernicious anemia. •Secretion of Pepsinogen: •Inactive precursor of pepsin, a proteolytic enzyme. •Activated to pepsin by low pH in the stomach. •Contribution to Protein Digestion: •Breaks down dietary proteins into peptides and amino acids. •Production of Mucus and bicarbonate: Forms protective layer over gastric mucosa. •Prevents self-digestion by gastric acid and pepsin. •Facilitates smooth passage of food through stomach. Adobe Systems 22 Other cell types •Enterochromaffin-like (ECL) Cells: •Secretion of Histamine: •Acts as a paracrine signaling molecule to stimulate parietal cells. •Potentiates secretion of HCl in response to gastrin and acetylcholine. •G Cells (Gastric Cells): •Secretion of Gastrin: •Stimulates acid secretion by parietal cells. •Promotes gastric motility and emptying. •Regulated by luminal pH and presence of food in stomach. •D Cells: •Secretion of Somatostatin: •Inhibits acid secretion by parietal cells. •Acts as a negative feedback regulator of gastric acid secretion. ̶ Adobe Systems Zápatí prezentace 23 Phases of gastric secretion regulation Phase Trigger Mechanism Contribution to Secretion Cephalic Phase Smell, taste, sight, thought of food Vagus nerve (ACh) stimulates parietal cells, G cells ~30% of total secretion Gastric Phase Food enters stomach (distension, peptides, pH change) Gastrin (G cells), vagus nerve (ACh), histamine (ECL cells) ~60% of total secretion Intestinal Phase Chyme enters duodenum Enterogastric reflex (inhibitory), secretin, CCK, GIP ~10% of secretion, mainly inhibitory Adobe Systems 24 Neural Regulation of Gastric Secretion Neurotransmitter Effect Acetylcholine (ACh) Stimulates parietal cells, G cells, and ECL cells (histamine release) Gastrin-releasing peptide (GRP) Stimulates G cells (gastrin release) VIP (Vasoactive Intestinal Peptide) Inhibits gastric secretion, stimulates bicarbonate secretion Somatostatin (from D cells) Inhibits gastrin, parietal cells, and histamine release •Vagus nerve (parasympathetic system) plays a major role: •Stimulates parietal cells (HCl secretion). •Stimulates G cells (gastrin release). •Stimulates chief cells (pepsinogen release). •Increases mucus production. •Local enteric nervous system (ENS): •Controls peristalsis, secretion, and feedback inhibition. Neurotransmitters Involved Adobe Systems 25 Hormonal Regulation of Gastric Secretion Gastrin (Key Stimulatory Hormone): ̶Secreted by: G cells (in the antrum of the stomach). •Stimulus: •Presence of peptides/amino acids in the stomach. •Gastric distension. •Vagal stimulation (via GRP). •Effects: •Stimulates parietal cells → ↑ HCl secretion. •Stimulates chief cells → ↑ pepsinogen secretion. •Stimulates ECL cells → ↑ histamine, which further stimulates acid secretion. •Enhances gastric motility. Histamine (Paracrine Regulation) •Secreted by: Enterochromaffin-like (ECL) cells. •Stimulus: Gastrin and vagal stimulation. •Effect: Binds H₂ receptors on parietal cells → potentiates acid secretion. •Clinical relevance: H₂ blockers (e.g., ranitidine) reduce acid secretion Adobe Systems Hydrochloric acid secretion in parietal cells •Stimulation: Triggered by various stimuli including histamine, gastrin, and acetylcholine. •Activation of H+/K+ ATPase Pump: •Proton pump located on the apical membrane of parietal cells. •Exchanges cytoplasmic K+ for luminal H+ ions, generating an electrochemical gradient. •Secretion of HCl: •H+ ions are actively pumped into the stomach lumen. •Cl- ions follow passively via anion channels, forming HCl. •Acidification of Gastric Contents: •Lowers pH to around 1-2, creating an acidic environment optimal for digestion and microbial defense. 1.Chloridové ionty jsou aktivně transportovány z cytoplazmy do kanalikulu a sodné ionty jsou aktivně transportovány z kanalikulu do bb. Toto vytváří negativní potenciál v kanalikulu, který zapříčiňuje difuzi draselných a malého množství sodných iontů zpět do kanalikulu. 2.Voda disociuje v buňce a hydrogenový iont je aktivně transportován do kanalikulu HK ATP-ázou. 3.Voda prochází pasivní difuzí do kanalikulu, takže v kanalikulu máme roztok HCl s malou příměsí KCl a stopami NaCl. 4.Oxid uhličitý reaguje za katalýzy karboanhydrázy s hydroxylem a opouští bb. Adobe Systems •key inhibitory regulator of gastric acid secretion •Released by D cells in response to low luminal pH and inhibits acid secretion by parietal cells. Feedback loop helps maintain gastric pH balance and prevent excessive acid production. •Release Stimuli: •Low pH (acidic conditions, pH <3 in stomach) → Direct stimulation of D cells. •Secretin (from S cells in duodenum) → Enhances somatostatin release. •CCK (from I cells in duodenum) → Also promotes somatostatin release. •Vagal stimulation (ACh, via M3 receptors) inhibits somatostatin (during the cephalic and gastric phases). • • Somatostatin : Negative Regulation of HCl Adobe Systems Pathology •Pathophysiology: •Peptic Ulcer Disease (PUD): Erosion of gastric or duodenal mucosa due to imbalance between protective factors (mucus, bicarbonate) and damaging factors (acid, pepsin). •Gastritis: Inflammation of gastric mucosa, often due to infection (Helicobacter pylori), NSAID use, or alcohol abuse. •Gastric Cancer: Malignant tumor arising from gastric epithelium, often associated with chronic gastritis, H. pylori infection, or genetic predisposition. •Zollinger-Ellison syndrome •Gastroparesis •Common Symptoms: •Dyspepsia: Epigastric discomfort, bloating, early satiety. •Hematemesis: Vomiting of blood, indicative of gastrointestinal bleeding. •Melena: Dark, tarry stools due to digested blood. •Nausea, vomiting, weight loss. Dobře definována jedině histologicky, ostatní definice závisí na úhlu pohledu – klinická gastritida, endoskopická, rentgenologická atd. Adobe Systems 29 Gastritis Inflammation of the gastric mucosa, characterized by mucosal injury and infiltration of inflammatory cells. ̶Acute Gastritis: ̶Sudden onset, often due to irritants such as NSAIDs, alcohol, or infectious agents (e.g., H. pylori). ̶Chronic Gastritis: ̶Persistent inflammation, typically associated with H. pylori infection, autoimmune conditions (e.g., autoimmune gastritis), or long-term use of NSAIDs. ̶Etiology: ̶Helicobacter pylori (H. pylori) infection: Most common cause of chronic gastritis, implicated in peptic ulcer disease and gastric cancer. ̶NSAID Use: Direct mucosal injury leading to erosions and inflammation. ̶Alcohol: Disruption of mucosal barrier and stimulation of acid secretion. ̶Autoimmune Disorders: Antibodies target gastric mucosal cells, leading to chronic inflammation (e.g., autoimmune gastritis). ̶Severe inless Adobe Systems Acute Gastritis mechnaism Etiology: •Helicobacter pylori (H. pylori) infection: Most common cause of chronic gastritis, implicated in peptic ulcer disease and gastric cancer. •NSAID Use: Inhibtion of prostaglandins, Direct mucosal injury leading to erosions and inflammation. •Alcohol: Disruption of mucosal barrier and stimulation of acid secretion. •Severe inless •Disruption of mucosal barrier → acid-induced injury → inflammation. •Symptoms: Epigastric pain, nausea, vomiting, GI bleeding (if severe). Adobe Systems Gastritis mechnaism •Activation: •H. pylori: Release of virulence factors (e.g., cytotoxin-associated gene A, CagA) causing mucosal damage. •NSAIDs/Alcohol: Direct injury to gastric mucosa, disrupting barrier function. •Inflammatory Response: •Recruitment of immune cells (neutrophils, lymphocytes) to the gastric mucosa. •Release of pro-inflammatory cytokines (e.g., interleukin-1β, tumor necrosis factor-α). •Mucosal Damage: •Disruption of epithelial integrity, erosion of gastric mucosa. •Activation of inflammatory pathways, amplifying tissue injury. •Consequences: •Chronic Inflammation: Persistence of inflammatory •Ulcer Formation •Carcinogenesis: Chronic inflammation-associated Adobe Systems Gastritis mechnaism •Type A (Autoimmune metaplastic atrophic gastritis): •Pathophysiology: Autoantibodies against parietal cells & intrinsic factor → achlorhydria, pernicious anemia (B12 deficiency). •Associations: Increased risk of gastric cancer. • •Type B (H. pylori-associated gastritis): •Pathophysiology: H. pylori colonizes antrum → inflammation, increased gastrin → increased acid secretion → risk of peptic ulcer disease. •Associations: Can progress to MALT lymphoma, gastric adenocarcinoma. Adobe Systems H Pylori •Gram-negative, spiral-shaped, microaerophilic bacterium •Resides in the gastric mucosa, primarily in the antrum of the stomach •50-60% of the global population infected, but only some develop clinical disease •Adherence •Colonization •Inflammatory Response • Helicobacter pylori •Urease Production: •H. pylori converts urea to NH3+CO2, buffering gastric acid. •Movement: •Flagella enable motility, facilitating penetration of mucus layer. •Adhesins: •BabA, SabA, AlpA/B: Bind to gastric epithelial cells, facilitating colonization. •Cytotoxin-Associated Gene A (CagA): •Injected via Type IV Secretion System (T4SS). •Phosphorylated CagA alters host cell signaling, contributing to gastric carcinogenesis. •Vacuolating Cytotoxin A (VacA): •Forms pores, causing vacuolation and cellular damage. •Induces apoptosis and modulates immune response. •Gamma-Glutamyl Transpeptidase (GGT): •Generates reactive oxygen species, promoting oxidative stress. •Impairs host immune response and mucosal integrity. •Outer Inflammatory Protein A (OipA): •Induces inflammation and enhances adherence. • PDF] Host-bacterial interactions in Helicobacter pylori infection. | Semantic Scholar Adobe Systems 35 H Pylori ̶Induction of Chronic Inflammation •H. pylori triggers an immune response, but evades clearance. •Inflammation leads to: •Chronic gastritis (lymphocyte infiltration, epithelial damage). •Increased gastrin secretion → acid hypersecretion (→ duodenal ulcers). •Metaplasia & dysplasia → potential progression to gastric adenocarcinoma. •Diagnostic Tests: •Stool antigen test (detects H. pylori antigens). •Endoscopic biopsy with histology or urease test. •Urea breath test (detects CO₂ from urease activity). Adobe Systems Peptic ulcer ̶Mucosal defect reaching deeper than muscularis mucosae layer, localized in areas exposed to acid-pepsin secretions. ̶Causes: ̶Helicobacter pylori (H. pylori) infection ̶NSAIDs Disrupt mucosal integrity, inhibit prostaglandin synthesis, increasing susceptibility to injury. ̶Excessive alcohol consumption, smoking, stress, and genetic predisposition. •Most Common Locations: •Gastric ulcers → Lesser curvature of the stomach (near the antrum). •Duodenal ulcers → First part of the duodenum. ̶ Pathological anatomy Diagnosis: •Upper Endoscopy: Direct visualization of ulcers, biopsy for H. pylori testing and histological examination. •H. pylori Testing: Serology, urea breath test, stool antigen test. •Imaging Studies: Upper GI series, CT scan, MRI, to assess ulcer size and complications. Adobe Systems Zápatí prezentace 38 Stomach vs. Duodenal Ulcers Differences Feature Gastric Ulcers (Stomach) Duodenal Ulcers Location Lesser curvature of the stomach (antrum) First portion of the duodenum Primary Cause ↓ Mucosal protection (weakened barrier) ↑ Acid secretion H. pylori association ~70% of cases >90% of cases Gastrin levels Normal or decreased Increased (due to reduced acid inhibition) Gastric acid secretion Normal or low (mucosal damage is primary issue) ↑ Increased (H. pylori affects inhibitory feedback) Pain Pattern Worsens with food (acid secretion directly irritates ulcer) Improves with food (bicarbonate-rich secretions neutralize acid), worsens 2-3 hours later or at night Cancer Risk Higher (gastric adenocarcinoma risk) Lower risk of malignancy Complications Bleeding (gastric artery erosion), perforation, gastric outlet obstruction Perforation (into pancreas), bleeding (gastroduodenal artery erosion) Adobe Systems Complications of peptic ulcer Complications: ̶Bleeding: Major complication, requires urgent medical attention and may necessitate endoscopic hemostasis or surgery. ̶Perforation: Ulcer penetration through the gastric wall, leading to peritonitis and requiring emergency surgery. ̶Gastric Outlet Obstruction: Scar tissue formation or edema may obstruct gastric emptying, requiring endoscopic dilation or surgical intervention. Adobe Systems bleeding Perforation Adobe Systems •Eradication of H. pylori: Antibiotics (e.g., clarithromycin, amoxicillin) with proton pump inhibitors (PPIs). • •Acid Suppression: PPIs or H2-receptor antagonists to reduce acid secretion and promote ulcer healing. • •NSAID Use: Discontinue or reduce dosage, consider alternative medications or gastroprotective agents. • •Lifestyle Modifications: Smoking cessation, moderation of alcohol intake, stress management. Treatment Adobe Systems Treatment •Histamine Receptor Antagonists (H2 Blockers): •Examples: Ranitidine, Cimetidine, Famotidine. •Mechanism: Block histamine receptors (H2 receptors) on parietal cells, reducing gastric acid secretion. •Proton Pump Inhibitors (PPIs): •Examples: Omeprazole, Esomeprazole, Lansoprazole. •Mechanism: Irreversibly inhibit the H+/K+ ATPase pump on parietal cells, preventing acid secretion. •Antacids: •Examples: Aluminum hydroxide, Magnesium hydroxide, Calcium carbonate. •Mechanism: Neutralize gastric acid, providing rapid but short-term relief from ulcer symptoms. •Result: Temporary reduction in acidity and symptomatic relief, but not effective for long-term ulcer management. Adobe Systems Zápatí prezentace 43 Stomach vs duodenal ulcers Gastric Duodenum Causes H. pylori infection. NSAID use. Excessive alcohol consumption. Smoking. H. pylori infection NSAID use. Hypersecretory states (e.g., Zollinger-Ellison syndrome). Clinical presentation Epigastric pain worsened by meals. Nausea and vomiting. Hematemesis or melena. Epigastric pain relieved by meals (hunger pain). Nighttime awakening due to pain. Hematemesis or melena Adobe Systems Zápatí prezentace 44 Gastric Cancer •Types: •Adenocarcinoma (most common). •MALT lymphoma (associated with H. pylori). •Risk Factors: •H. pylori (chronic inflammation → atrophic gastritis → metaplasia → dysplasia). •Diet: High salt, smoked foods, nitrosamines. •Chronic gastritis (autoimmune or H. pylori-related). •Genetic syndromes (e.g., Lynch syndrome). •Clinical Features: •Weight loss, early satiety, epigastric pain. •Acanthosis nigricans (paraneoplastic sign). •Virchow’s node (supraclavicular), ̶ Adobe Systems Zápatí prezentace 45 Gastroparesis •Definition: Delayed gastric emptying without mechanical obstruction. •Causes: •Diabetes mellitus (autonomic neuropathy). •Vagal nerve damage (post-surgical, idiopathic). •Medications (e.g., opioids, anticholinergics). •Symptoms: •Nausea, bloating, early satiety, vomiting undigested food. •Diagnosis: •Gastric emptying scintigraphy. •Treatment: •Dietary modifications, prokinetic agents (metoclopramide, erythromycin). Adobe Systems 46 Zollinger-Ellison Syndrome •Pathophysiology: •Gastrin-secreting tumor (gastrinoma) → excessive acid production. •Leads to multiple peptic ulcers, diarrhea, acid-related complications. •Diagnosis: •Elevated serum gastrin levels. •Secretin stimulation test (gastrin remains elevated). •Treatment: •High-dose proton pump inhibitors (PPIs). •Surgical removal if localized.