20241
Pathophysiology of gastrointestinal tract
pt. 1, upper GIT
Jaromír Gumulec
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
3
Head and neck squamous cell cancer
̶ Etiology: tombacco, alcohol, HPV, UV light, poor oral hygiene, exposure environmental polutants
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
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.
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
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 diverticulumpseudodiverticulum
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
true diverticulumpseudodiverticulum
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
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.
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
Hiatal hernias – risk factors, complications
̶ Wide hiatus
̶ Obesity
̶ High intraabdominal pressure
̶ Gravidity
Complications:
•Gastroesophageal Reflux Disease
•Esophagitis: Barrett's esophagus
•Bleeding
Gastroesophageal reflux disease (GERD)
Retrograde movement of gastric juice = Loss of antireflux
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)
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.
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
Mucous neck cellParietal 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:Forms
protective layer over gastric
mucosa.
•Prevents self-digestion by gastric
acid and pepsin.
•Facilitates smooth passage of food
through stomach.
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.
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.
Regulation of HCl secretion
• Histamine: (ECL) in response to
gastrin or acetylcholine stimulation.
• Gastrin: (G cells) in the antrum of
the stomach in response to
stomach distention, amino acids,
and gastrin-releasing peptide
(GRP).
• Acetylcholine: Released by vagal
nerve fibers and stimulates parietal
cells directly or via ECL cells.
• Somatostatin: 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.
Negative Regulation of HCl secretion
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.
• 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.
Zápatí prezentace27
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).
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
H Pylori
estimated that over half of the world's population
is infected with H. pylori.
•Adherence: H. pylori adheres to gastric epithelial
cells via adhesins (e.g., BabA, SabA).
•Colonization: Bacterium penetrates the gastric
mucous layer and adheres to epithelial cells.
•Inflammatory Response: Activation of host
immune response leads to chronic gastritis and
tissue damage.
Helicobacter pylori
•NH4 Production:
• H. pylori converts urea to NH4, 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.
Peptic ulcer
̶ Mucosal defect reaching deeper
than muscularis mucosae layer,
localized in areas exposed to acidpepsin
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.
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.
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.
bleeding Perforation
• 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
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 shortterm
relief from ulcer symptoms.
• Result: Temporary reduction in acidity and symptomatic relief,
but not effective for long-term ulcer management.
Zápatí prezentace37
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