Contents 1 Learning Objectives 1.1 Duodenum 1.2 Stomach 2 Acid production 3 Symptoms and Signs (brief overview of the causes behind these signs and symptoms) 4 Differentials for the above symptoms 5 Alcohol 6 Peptic Ulcer Disease 7 H. pylori infection 8 Medications

[edit] Learning Objectives

1. Describe the normal function of gastric mucosa in digestion and resistance to infection.

• Digestion: Acid secretion & motility aide in digestion – Acid activates pepsinogen & degrades food particles; motility breaks down food further.
• Infection resistance: Acid secretion

2. List the three phases of gastric acid secretion and describe the regulation by gastrin, the vagus nerve, gastric distention and somatostatin.

• Cephalic phase: food in mouth – chewing, swallowing; smell, taste of food
  • Parietal cell stimulus: ACh, gastrin (vagus nerve to parietal & G cells) – Autonomic response
• Gastric phase: gastric distension
  • Stimulus: ACh, gastrin (local & vagovagal reflexes to parietal & G cells) – ENS response
• Intestinal phase: protein digestions products in duodenum
  • Intestinal G cells
• Somatostatin inhibits acid secretion via parietal cell (STIM absorption) by decreasing cAMP levels

3. List and describe the mucosal cell types found in the stomach.

• Surface epithelial (mucus) cells – secrete visible mucus that adheres to epithelial surface
• Mucus neck cell – secrete mucus in neck region of gastric gland (of body) & bicarb
• Enteroendocrine cell
• G cell – in antrum; gastrin secretor
• Gastrin promotes secretion of HCl & pepsinogens
• Parietal – HCl secretor
• Chief cell – pepsinogen secretor
• D cells – somatostatin secretor – found in pylorus & fundus

4. Describe the role of prostaglandins in gastric mucosal defense barrier.

• Prostaglandins are inflammatory agents that cause either
  • IMPT regulators of bicarb & mucus release → inhibit parietal cell secretion
  • Maintain subepithelial blood flow via vasodilation & epithelial restitution
    • Vasodilation dilutes acid

5. Describe how NSAIDs contribute to the formation of peptic ulcer disease (PUD).

• NSAIDs work by inhibiting the final step in prostaglandin synthesis by cyclooxygenases; COX1 & COX2 are targeted. Prostaglandins stimulate HCO3- & mucus secretion while inhibiting parietal cell secretion . NSAIDs are weak acids that can migrate across lipid membrane and cause cell injury.
  • Ulcers are mostly gastric in greater curvature

6. Explain how Helicobacter pylori contributes to PUD.

• H. pylori contains a urease that produces NH3 to protect itself from acid injury. Acid production is increased and increased gastric acidity leads to increased risk of PUD in stomach and duodenum. H. pylori is able to attach to gastric epi cell luminal surface.
  • ~60% cause of gastric ulcers, ~80% cause of duodenal ulcers

7. Describe the common presentation of PUD.

• Dizzy
• Non-radiating upper abdominal pain
• Fatigue
• Melena
• Low hemoglobin

8. Compare and contrast gastric and duodenal ulcers.

• Gastric ulcer
  • Etiology: fast emptying – pancreatic secretions, duodenum cannot neutralize gastric contents fast enough
• Duodenal ulcer
  • Etiology: slow emptying – more acid secretion results

9. List and describe the medical treatment of PUD.

• PPI – proton pump inhibitor
  • Omeprazole (Prilosec)
  • Esomeprazole (Nexium)
  • Lansoprazole (Prevacid)
• H2A inhibitors
  • Ranitidine (Zantac)
  • Cimetidine (Tagamet)
  • Famotidine (Pepcid)
• Antacids
• Antibiotics (in combination w/ PPI)
  • Clarithromycin
    • Blocks RNA-mediated protein synthesis (bact)
  • Amoxicillin
    • Inhibit 3rd step in bact coat synthesis
• Mucosa protective agents
  • Sucralfate – adheres to ulcer craters when exposed to gastric acids → forms protective barrier to prevent further acid attack
• Bismuth – forms complex w/ mucus → coat ulcer craters
• Prostaglandin E analogs – enhance mucus defense mechs & inhibits gastric acid secretion

10. List and describe the surgical treatment of PUD.

• Surgery is elective, treatment of ulcer-related complication, etc.
• Complications inc. GI bleeding, perforation, gastric outlet obstruction
• Surgical tx designed to decrease gastric acid secretion
• Vagotomy & drainage (by pyloroplasty, g-d-ostomy, or g-j-ostomy)
• Highly selective vagotomy w/o drainage
• Vagotomy w/ antrectomy

[edit] Duodenum

• Structure

~25 cm long is the first, shortest and widest part of the small intestine. Begins at the pylorus of the stomach and ends at the duodenojejunal junction

Source: Ross Histology

NKhan

• Cell types

5 cell types:

Enterocytes: primary fxn is absorption

Goblet cells: unicellular mucin-secreting glands

Paneth cell: primary fxn is to maintain mucosal innate immunity by secreting antimicrobial substances

Enteroendocrine cells: produce various paracrine and endocrine hormones

CCK, secretin, GIP, and motilin most active regulators of GI physiology

In duodenum specifically,

CCK = stimulates gallbladder contraction, inhibits gastric emptying

Secretin = stimulates enzyme secretion, inhibits gastric acid secretion

GIP = stimulates insulin realease, inhibits gastric acid secretion

Motilin = stimulates gastric motility

(From Table 16.1)

M cells: modified enterocytes that cover enlarged lymphatic nodules in the lamina propria. Phagocytize, transport, and present intraluminal antigens to CD4 T lymphocytes in the nodules.

Source: Ross Histology

NKhan

• Histology

Pilcao circulares, villi, and microvilli increase absorptive surface area

Pilcae circulare, (valves of Kerckring) = transverse folds that contain a core of submucosa. Folds appear ~ 5-6 cm beyond pylorus. Each circular fold is circularly arranged and extends about one half to tow thirds of the way around the circumference of the lumen. Villi = finger like projections of mucosa that extend from mucosal surface into the lumen. Microvilli = enterocytes provide amplification of the luminal suface. Give the striated border appearance.

Submucosal glands (von Brunner) are located in the duodenum. They secrete an alkaline mucus to neutralize acidic chyme, gastric inhibitory peptide, and motilin.

Source: Ross Histology

NKhan

• • What white blood cells would you be looking for with the ulcer/infection?
• Physiology

[edit] Stomach

• Structure

• Histology

The basic histology is typical of the GI tract. A mucosa, submucosa, muscularis externa, and a serosa are present. The chief difference between the stomach and other regions of the GI tract is that the muscularis externa contains an innermost oblique layer in addition to a middle circular and outer longitudinal layers. There are also differences in glandular architecture (no crypts of Lieberkuhn).

Cell types

Parietal cells: secrete HCL and intrinsic factor. Chief cells: secrete pepsinogen. Enteroendrocine cells include ECL cells which secrete histamine, D cells which secrete. somatostatin, and G cells which secrete gastrin. Mucous cells: secrete mucous and HCO3-. Stem cells

Gastric glands

Cardiac glands mostly consist of mucous cells but contain all cell types except chief cells. Fundic glands contain all cell types, especially parietal cells, contiains some D cells. Pyloric glands contain mostly consists of mucous cells but contains all cell types except chief cells, are the location of D cells and G cells.

• Physiology

There are two main pathways to regulate gastric acid secretion.

The minor pathway is the direct parasympathetic stimulation of parietal cells and D cells.

The major pathway is the parasympathetic stimulation of G cells to produce gastrin. Gastrin stimulates ECL cells to produce histamine and D cells to produce somatostatin, also has a minor stimulatory effect on parietal cells. Histamine stimulates parietal cells to secrete H+. Somatostatin inhibits both G cells and parietal cells

See Berne fig. 32-15 for a diagram

Intracellular signal transduction

Stimulation by Ach activation of muscarinic receptors to activate a PIP2/IP3,DAG/Ca2+,PKC pathway, gastrin activation of a PIP2/IP3,DAG/Ca2+,PKC pathway, and histamine activation of a Gs/cAMP/PKA pathway

Inhibition: Somatostatin activates a Gi pathway to decrease cAMP and inhibit PKA

See Berne fig. 32-14 for a diagram

NCB Sources: Ross histology, Berne physiology

[edit] Acid production

• How does your gut make acid?

Parietal cells pumps H+ against a concentration gradient (approx pH 7 in cytosol of parietal cells to a pH 1 in the lumen of the gastric gland) and Cl- enters the gastric lumen against a chemical and electrical potential difference.

Three main proteins are used

1) The H+ and K + ions are pumped with an exchange transporter against their electrochemical potential gradients. This H+, K+ -ATPase is located on the apical membrane of the parietal cells in the secretory canaliculus. Once the H+ is pumped out of the parietal cells bicarbonate is left behind.

2) The Cl-, HCO3- countertransporter protein will move Cl- into the parietal cytosol and bicarbonate across the basolateral membrane. The downhill movement of bicarbonate across the membrane supplies the energy for Cl- to move against its electrochemical potential gradient into the cell.

3) Cl- that is concentrated in the parietal cells will leave through an electrogenic anion channel at the apical membrane.

source: Berne& Levy Physiology

NKhan

• Why is acid needed?

HCl is responsible for killing most ingested microorganisms and bacteria

Catalyzes the cleavage of inactive pepsinogens to active pepsins and provides the acidic environment needed for active pepsins

Aids in the break down of large molecules into smaller one for absorption in small intestine

source: Berne & Levy Physiology

NKhan

• Is there a problem if stomach acid secretion is turned off
• How do the stomach and duodenum protect themselves from acid

[edit] Symptoms and Signs (brief overview of the causes behind these signs and symptoms)

• Dizzy
  • dehydration due to GI blood loss
• Non-radiating upper abdominal pain
  • Improves w/meals and over the counter antacids
  • w/out guarding or rebound
  • Pain may be due to acid-induced activation of chemical receptors in the duodenum
• Fatigue
• Melena
  • black, "tarry" stools due to upper GI bleeding; black color is caused by oxidation of iron in hemoglobin during its passage through the ileum and colon
• Developed two or three weeks ago
• Orthostatic blood pressure changes
  • dehydration due to GI blood loss
• Has been taking ibuprofen (for two weeks)
  • this most likely exacerbated the injured mucosa (see below)
• Low hemoglobin and hematocrit
• Afebrile
• Fast heart rate

ASR, Access Medicine and Wikipedia ("melena")

[edit] Differentials for the above symptoms

• Think hereditary, inflammatory, benign, malignant
• Most common – NUD (functional or essential dyspepsia) – refers to a group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer
• Proximal gastrointestinal tumors
• Gastroesophageal reflux
• Vascular disease
• Pancreaticobiliary disease (biliary colic, chronic pancreatitis)
• Gastroduodenal Crohn’s disease

Emi Bays, access medicine

[edit] Alcohol

• is this affecting her problem?
• Is there a connection between alcohol and ibuprofen
• Look into alcohol’s absorption by the stomach – is it significant that she is drinking wine w/meals?

[edit] Peptic Ulcer Disease

• What is it?

An ulcer is defined histologically as a hole through the mucosal layer that extends through the muscularis mucosa into the submucosa or beyond. This term needs to be kept separate from erosion, which is used to describe mucosal disruption that does not include the muscularis mucosa.

Robbins

JT

• Causes

Peptic ulcers are produced by an imbalance between gastroduodenal mucosal defense mechanisms and the damaging forces, particularly gastric acid and pepsin.

Defense mechanisms: surface mucus secretion; bicarbonate secretion into mucus; mucosal blood flow; apical surface membrane transport; epithelial regenerative capacity; elaboration of prostaglandins.

Damaging forces: gastric acidity, peptic enzymes

Hyperacidity is not a prerequisite, as only a minority of patients with duodenal ulcers has hyperacidity, and it is even less common in those with gastric ulcers. Rather, gastric ulceration occurs when mucosal defenses fail, as when mucosal blood flow drops, gastric emptying is delayed, or epithelial restitution is impaired.

Robbins Pathology

MDM

• Is there a difference between gastric and duodenal ulcers?

Gastric ulcer: Pain increases with meals; weight loss. Caused by decreased mucosal protection against gastric acid.

Duodenal ulcer: Pain decreases with meals; weight gain. Caused by increased gastric acid secretion or decreased mucosal protection.

First Aid.

MDM

• • What part of the duodenum is involved?

At least 98% of peptic ulcers are located in the first portion of the duodenum or in the stomach, in a ratio of about 4:1.

Most duodenal ulcers occur within a few centimeters of the pyloric ring. The anterior wall of the duodenum is affected more often than the posterior wall.

Although the majority of individuals have a single ulcer, in 10-20% of patients with gastric ulceration there may be a coexistent duodenal ulcer.

Robbins Pathology

MDM

• How can an infection in her stomach cause an ulcer in her small intestine?
• What are the complications from ulcer disease?

Bleeding, perforation, obstruction from edema or scarring.

Robbins Pathology

MDM

• • Anemia?

[edit] H. pylori infection

• What is it?

Flagellated, gram-negative bacteria; it has adapted the ability to colonize the gastric mucus layer; it is able to buffer the low pH around itself with ammonia, produced by a urease that it encodes. H. pylori is found in nearly all cases of duodenal ulcers, and about 70% of gastric ulcers.

Robbins

JT

• • Why is she afebrile?

Many people infected with H. pylori are asymptomatic, although most exhibit gastritis.

Robbins

JT

• Causes?
• Diagnostic criteria
• Natural History
• How does it cause an ulcer?
  • Still not clear how this organism, which is in the stomach, causes ulceration in the duodenum
    • Potentially, gastric metaplasia in the duodenum of DU patients permits H. pylori to bind to it and produce local injury secondary to the host response …or…
    • H. pylori antral infection could lead to increased acid production, increased duodenal acid, and mucosal injury
    • Basal and stimulated gastrin release are increased and somatostatin-secreting D cells may be decreased
    • Might induce increased acid secretion through direct and indirect actions of H. pylori and proinflammatory cytokines on G, D, and parietal cells
    • Also has been associated with decreased duodenal mucosal bicarbonate production

emi bays access medicine

A non-sporing, gram negative rod. H. pylori have adapted to the ecologic niche of the gastric mucosa through several mechanisms:

• • • Motility: flagella that allow it to swim through the mucus
    • Elaboration of urease that produces ammonia from endogenous urea thereby buffering the gastric acid in the immediate vicinity of the organism
    • Binding to gastric epithelial cells: via a bacterial adhesin. This binding is enhanced with epithelial cells that bear the blood group O antigen.

Source: Robbins

NKhan

• What else does it cause?
  • Virtually always associated with chronic active gastritis, but only ten to fifteen percent of infected individuals develop frank peptic ulceration
  • Gastritis, PUD, gastric MALT lymphoma, gastric cancer – end result is determined by a complex interplay between bacterial and host factors

emi bays, access medicine

• Risk factors?
  • Poor socioeconomic status and less education
  • Birth or residence in a developing country
  • Domestic crowding
  • Unsanitary living conditions
  • Unclean food or water
  • Exposure to gastric contents of an infected individual
  • Transmission occurs following an oral-oral or fecal-oral route

Emi Bays access medicine

• Treatment?

• • Bismuth subsalicylate plus metronidazole plus tetracycline
  • Ranitidine bismuth citrate plus tetracycline plus clarithromycin or metronidazole
  • Omeprazole plus clarithromycin plus metronidazoe or amoxicillin
  • Omeprazole, bismuth subsalicylate, metronidazole, and tetracycline

Emi Bays access medicine

[edit] Medications

• Omeprazole
  • proton pump inhibitor
  • Despite its potency, must be used in combination with antibiotics to be effective against Helicobacter pylori
  • Suppress gastric acid secretion by inhibiting the H+/K+ATPase enzyme system of parietal cells
  • Following activation in an acidic pH, omeprazole binds irreversibly to the H+/K+ATPase pump on the secretory surface of the parietal cell membrane; subsequently, the secretion of hydrogen ions into the gastric lumen is inhibited

• Amoxicillin
  • More stable to gastric acid than is penicillin and more bioavailable than oral ampicillin
  • Mainly bactericidal – inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins that are located inside the bacterial cell wall
  • Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell

• Clarithromycin
  • Macrolides
  • Penetrates lung tissue and macrophages to a greater degree than does erythromycin
  • Binds to the 50 S subunit of the 70 S ribosome, thereby blocking RNA-mediated bacterial protein synthesis…can be bacteriostatic or bactericidal in action, depending on the concentration as well as the particular organism and its inoculum

Emi Bays, Access Medicine drug monographs

• Ibuprofen (how does it affect this problem?)
  • Prostaglandins play a critical role in maintaining gastroduodenal mucosal integrity and repair…thus the interruption f prostaglandin synthesis can impair mucosal defense and repair, thus facilitating mucosal injury via a systemic mechanism
  • Aspirin and many NSAIDS are weak acids that remain in a nonionized lipophilic form when found within the acid environment of the stomach…under these conditions, NSAIDS migrate across lipid membranes of epithelial cells, leading to cell injury once trapped intracellularly in an ionized form
  • Topical NSAIDs can also alter the surface mucous layer, permitting back diffusion of H+ and pepsin, leading to further epithelial cell damage

Emi Bays, Access Medicine

Just to elaborate: aspirin and NSAIDs are thought to disrupt the mucous layer by inhibiting the secretion of mucous and bicarbinate from gastric epithelial cells.

Prostaglandins of the I and E series inhibit gastric acid production. NSAIDs inhibit prostaglandin synthesis, as Emi said. Therefore negative control of acid release is less well regulated.

Berne and Levy

JT

• What happens if the drugs are not effective?
  • Surgical options? (always look at the indication for a specific surgery – is it bleeding? b/c of an ulcer?? Etc..)
  • Alternative treatments?