Chapter 348 – Peptic Ulcer Disease and Related Disorders

PUD complex symptoms - burning epigastric pain exacerbated by fasting and improved with meals

Ulcer
 disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active
inflammation
 chronic in nature
 breaks in the mucosal surface >5 mm in size, with depth to the submucosa

GASTRIC PHYSIOLOGY

Noxious agent
 constantly attacks the gastroduodenal mucosa
 acid (HCL) , pepsin, bile acids, pancreatic enzymes, drugs, and bacteria

GASTRIC ANATOMY

Intricate system
 maintains the mucosal integrity
 provides mucosal defense and repair

Gastric Cardia
 <5% gastric gland
 contain mucous and endocrine cells

Oxyntic mucosa
 75% of gastric glands
 contain mucous neck, parietal, chief, endocrine, enterochromaffin, and enterochromaffin-like (ECL) cells

Parietal cell
 also known as the oxyntic cell
 found in the neck, or isthmus, or in the oxyntic gland

Pyloric glands

 found in the antrum

 contain mucous and endocrine cells (including gastrin cells)

Study figure 348 – 1

Study figure 348 – 2

Resting or unstimulated parietal cell

 has prominent cytoplasmic tubulovesicles and intracellular canaliculi
 short microvilli
 canaliculus, H+, K+-adenosine triphosphatase (ATPase), tubulovesicles

H+, K+-adenosine triphosphatase (ATPase)

 expressed in the tubulovesicle membrane

Stimulated parietal cell

 transforms into a dense network of apical intracellular canaliculi
 long microvilli
 canaliculus, H+, K+-adenosine triphosphatase (ATPase), Active pump, gastrin, Ach, histamine

GASTRODUODENAL MUCOSAL DEFENSE

The mucosal defense system as a three-level barrier:

1. preepithelial
2. epithelial
3. subepithelial

Mucus-bicarbonate-phospholipid layer
 serves as a physicochemical barrier to multiple molecules, including hydrogen ions
 Mucus
 secreted by gastroduodenal surface epithelial cells
 composed of water (95%) and a mixture of phospholipids and glycoproteins (mucin)
 the mucous gel functions as a nonstirred water layer impeding diffusion of ions and molecules such as pepsin

Surface epithelial cells

 another line of defense
 including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and
intracellular tight junctions
 generate heat shock proteins that prevent protein denaturation and protect cells from certain factors such as increased
temperature, cytotoxic agents, or oxidative stress
 generate trefoil factor family peptides and cathelicidins, which also play a role in surface cell protection and regeneration

Restitution
 gastric epithelial cells migration to restore the injured preepithelial barrier
 occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment
 angiogenesis, FGF and vascular endothelial growth factor (VEGF), also occurs

Modulate the process of restitution

 epidermal growth factor (EGF)
 transforming growth factor (TGF) α
 basic fibroblast growth factor (FGF)

Cell proliferation
 is required if a larger defects that are not effectively repaired by restitution

Epithelial cell regeneration

 regulated by prostaglandins and growth factors such as EGF and TGF-α

Bicarbonate – neutralizes the acid generated by the parietal cell

Gastric epithelial defense and repair:

1. Prostaglandins
2. Nitric Oxide Synthase
3. CNS and hormonal factor

Prostaglandins
 regulate the release of mucosal bicarbonate and mucus
 inhibit parietal cell secretion
 important in maintaining mucosal blood flow and epithelial cell restitution

Phospholipid (cell membrane) -- phoholipase A2 --  Esterified arachidonic acid  Prostaglandins

Cyclooxygenase (COX)
 rate-limiting step in prostaglandin synthesis
 two isoforms COX – 1 and COX – 2

COX – 1
 expressed in a host of tissues
 stomach, platelets, kidneys, and endothelial cells
 plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal (GI) mucosal
integrity

COX – 2
 inducible by inflammatory stimuli
 macrophages, leukocytes, fibroblasts, and synovial cells

Nonsteroidal anti-inflammatory drugs (NSAIDs)

 effects on tissue inflammation is to inhibit COX-2
 toxicity: inhibition of COX – 1  GI mucosal ulceration and renal dysfunction

Study figure 348 – 3

Study figure 348 – 4
PHYSIOLOGY OF GASTRIC SECRETION

Hydrochloric acid and Pepsinogen

 two principal gastric secretory products capable of inducing mucosal injury
 play a physiologic role in protein digestion; absorption of iron, calcium, magnesium, and vitamin B12; and killing ingested bacteria

Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates
1. Cephalic
 Sight, smell, and taste of food
 stimulates gastric secretion via the vagus nerve

2. Gastric
 activated once food enters the stomach
 secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn
activates the parietal cell via direct and indirect mechanisms
 distention of the stomach wall also leads to gastrin release and acid production

3. Intestinal
 initiated as food enters the intestine
 mediated by luminal distention and nutrient assimilation

Somatostatin
 released from endocrine cells found in the gastric mucosa (D cells) in response to HCl
 inhibit acid production by both direct (parietal cell) and indirect mechanisms (decreased histamine release from ECL cells and gastrin
release from G cells)
 additional neural (central and peripheral) and humoral (amylin, atrial natriuretic peptide [ANP], cholecystokinin, ghrelin, interleukin
11 [IL-11], obestatin, secretin, and serotonin) factors play a role in counterbalancing acid secretion

Acid-secreting parietal cell

 located in the oxyntic gland
 secretes intrinsic factor (IF) and IL-11

Histamine
 stimulates gastric acid secretion indirectly by activating the histamine H3 receptor on D-cells, which inhibits somatostatin release

H+,K+-ATPase
 responsible for generating the large concentration of H+
 membrane-bound protein that consists of two subunits, α (active catalytic site) and β
 it uses the chemical energy of adenosine triphosphate (ATP) to transfer H+ ions from parietal cell cytoplasm to the secretory
canaliculi in exchange for K+
 located within the secretory canaliculus and in nonsecretory cytoplasmic tubulovesicles

Tubulovesicle
 impermeable to K+, which leads to an inactive pump in this location

Chief cell
 found primarily in the gastric fundus
 synthesizes and secretes pepsinogen (inactive precursor of the proteolytic enzyme pepsin)
Pepsinogen + stomach acid  pepsin

low pH (<2) = required for pepsin activity

pH of 4 = pepsin activity is significantly diminished
pH of ≥7 = irreversibly inactivated and denatured

Study figure 348 – 5

PATHOPHYSIOLOGIC BASIS OF PEPTIC ULCER DISEASE

Risk Factors of PUD:

 Helicobacter pylori and NSAIDs are the most common
 chronic obstructive lung disease
 chronic renal insufficiency
 current tobacco use
  former tobacco use
 older age
 three or more doctor visits in a year
 coronary heart disease
 former alcohol use
 African-American race
 Obesity
 Diabetes

Duodenal Ulcers

Epidemiology
 incidence of DUs declined steadily

Pathology
 occur most often in the first portion of the duodenum (>95%), with ~90% located within 3 cm of the pylorus
 usually ≤1 cm in diameter but can occasionally reach 3–6 cm (giant ulcer)
 sharply demarcated, with depth at times reaching the muscularis propria
 the ulcer often consists of a zone of eosinophilic necrosis with surrounding fibrosis
 extremely rare to be malignant

Pathophysiology
 H. pylori and NSAID-induced injury account for the majority of DUs
 Bicarbonate secretion is significantly decreased in the duodenal bulb of patients with an active DU

Gastric Ulcers

Epidemiology
 tend to occur later in life
 peak incidence reported in the 6th decade
 ½ of GUs occur in males and are less common than DUs
 silent and presenting only after a complication develops

Pathology
 represent malignancy and should biopsied upon discovery

Benign GU
 most often found distal to the junction between the antrum and the acid secretory mucosa
 rare in the gastric fundus
 histologically similar to DUs
 if associated with H. pylori it is also associated with antral gastritis

NSAID-related GU
 not accompanied by chronic active gastritis
 have evidence of a chemical gastropathy, typified by foveolar hyperplasia, edema of the lamina propria, and epithelial
regeneration in the absence of H. pylori

Pathophysiology
 majority of GUs can be attributed to either H. pylori or NSAID-induced mucosal damage
 GUs that occur in the prepyloric area or those in the body associated with a DU or a duodenal scar are similar in pathogenesis to DUs
 gastric acid output normal or decreased
 impairment of mucosal defense factors  develop in the presence of minimal acid levels

Classified into 3 types based on their location:

1. Type 1 3. Type 3
 Occurs in the gastric body  Occur within 3 cm of the pylorus
 associated with low gastric acid  commonly accompanied by DUs
production  normal or high gastric acid production

2. Type 2 4. Type 4
 occur in the antrum  Found in cardia
 gastric acid can vary from low to  associated with low gastric acid
normal production
H. pylori infection and acid peptic disorders
 plays a role in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma
 initially named Campylobacter pyloridis
 gram-negative microaerophilic rod
 commonly found in the deeper portions of the mucous gel coating the gastric mucosa or between the mucous layer and the gastric
epithelium
 attaches to the gastric epithelium
 does not invade cells
 S-shaped
 contains multiple sheathed flagella
 initially resides in the antrum
 later, migrates toward the more proximal segments of the stomach
 genome of H. pylori encodes ~1500 proteins
 first step in infection is dependent on the bacteria’s motility and its ability to produce urease
 Urease produces ammonia from urea, an essential step in alkalinizing the surrounding pH
 always associated with chronic active gastritis
 >90% of all DUs were associated with H. pylori, but H. pylori is present in only 30–60% of individuals with GUs and 50–70% of
patients with DUs

Additional bacterial factors

 catalase, lipase, adhesins, platelet-activating factor, and pic B (induces cytokines).

Risk factors for H. pylori infection

 poor socioeconomic status and less education (higher colonization rates)
 birth or residence in a developing country
 domestic crowding
 unsanitary living condition
 unclean food or water
 exposure to gastric contents of an infected individual

Transmission: oral-oral or fecal-oral route

Result of infection: gastritis, PUD, gastric MALT lymphoma, gastric cancer

Bacterial factors:
 H. pylori is able to facilitate gastric residence, induce mucosal injury, and avoid host defense
 inhibit parietal cell H+,K+-ATPase activity through Cag A–dependent mechanism  low acid production
 produce surface factors that are chemotactic for neutrophils and monocytes  epithelial cell injury
 produces proteases and phospholipases  break down the glycoprotein lipid complex of the mucous gel 
weakens the first line mucosal defense
 expresses adhesins facilitate attachment of the bacteria to gastric epithelial cells
 H. pylori LPS has low immunologic activity LPS  smoldering chronic inflammation

Pathogenicity Island (cag-PAI)

 specific region of the bacterial genome
 encodes the virulence factors Cag A and pic B
 cause mucosal damage by targeting the host immune cells
 strains that are cag-PAI positive are associated with PUD, premalignant gastric lesions, and gastric cancer

Vac A
 contributes to pathogenicity, although it is not encoded within the pathogenicity island
 targets human CD4 T cells, inhibiting their proliferation and can disrupt normal function of B cells, CD8 T cells,
macrophages, and mast cells

Urease
 allows the bacteria to reside in the acidic stomach
 generates NH3, which can damage epithelial cells

Host factors:
 The pathogen leads to local injury by binding to class II major histocompatibility complex (MHC) molecules expressed on
gastric epithelial cells, leading to cell death (apoptosis)
 H. pylori infection also leads to both a mucosal and a systemic humoral response
 Additional mechanisms by which H. pylori may cause epithelial cell injury include:
 1. activated neutrophil-mediated production of reactive oxygen or nitrogen species and enhanced
epithelial cell turnover
2. apoptosis related to interaction with T cells and IFN-γ

Study figure 348 – 6 Study figure 348 – 7 Study figure 348 – 8

Antral-predominant gastritis - associated with DU formation

Gastritis in the corpus - development of GUs, gastric atrophy and gastric carcinoma

NSAID-induced disease
 even the lowest dose of aspirin  serious GI ulceration
 no dose of NSAID is completely safe
 H. pylori infection increases the risk of PUD-associated GI bleeding in chronic users of low-dose aspirin
Risk factors include:
1. advanced age 8. serious of multisystem
2. history of ulcer disease
3. usage of glucocorticoids 9. infection with hp
4. high-dose NSAIDs 10. cigarette smoking
5. multiple NSAIDs 11. alcohol consumption
6. use of anticoagulants
7. clopidogrel

 Interrupts prostaglandin synthesis  impair mucosal defense and repair

 aspirin and many NSAIDs are weak acids that remain in a nonionized lipophilic form
 migrate across lipid membranes of epithelial cells leading to cell injury if trapped as ionized form intracelularly
 alter the surface mucous layer, permitting back diffusion of H+ and pepsin  further epithelial cell damage

Study figure 348 – 9

Pathogenetic factors unrelated to H. pylori and NSAIDs in acid peptic disease

1. Cigaretter Smoking
 decrease healing rates
 impair response to therapy
 increase ulcer-related complications
2. Genetic predisposition
3. Blood group O and nonsecretor status
 H. pylori preferentially binds to group O antigens
4. Psychological stress
5. Diet

Specific chronic disorders have been shown to have a strong association with PUD:
1. Advance age 5. nephrolithiasis
2. chronic pulmonary disease 6. α1-antitrypsin deficiency
3. chronic renal failure 7. systemic mastocytosis
4. cirrhosis 8. hyperparathyroidism
9. coronary artery disease 13. obesity
10. polycythemia vera 14. African-American race
11. chronic pancreatitis 15. three or more doctor visits in a year
12. former alcohol use

Study Table 348 - 1

CLINICAL FEATURES

Abdominal pain
 common to many GI disorders, including GU and DU
 poor predictive value for the presence of either DU or GU
 elderly patients are less likely to have abdominal pain as a manifestation of PUD and may instead present with a complication such
as ulcer bleeding or perforation

Epigastric Pain
 burning or gnawing discomfort (ill-defined, aching sensation or as hunger pain)
 present in both DU and GU
 Pain pattern in DU
 90 minutes to 3 hours after a meal
 relieved by antacids or food
 2/3 of DU patients experience pain that awakes them from sleep (between midnight and 3 A.M.) is the most
discriminating symptom, also present in 1/3 of NUD patient

Pain pattern in GU
 discomfort may actually be precipitated by food
 nausea and weight loss occur more commonly in GU patients

Ulcer complication
 variation in the intensity or distribution of the abdominal pain, with associated symptoms such as nausea and/or vomiting

Penetrating ulcer (pancreas)

 dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates at the back

Perforation
 sudden onset of severe, generalized abdominal pain
 severely tender, board-like abdomen

Gastric outlet obstruction

 pain worsening with meals, nausea, and vomiting of undigested food
 presence of a succussion splash indicates retained fluid in the stomach

Bleeding
 tarry stools or coffee-ground emesis

Physical examination
 critically important for discovering evidence of ulcer complication

Tachycardia and orthostasis

 dehydration secondary to vomiting or active GI blood loss

Epigastric tenderness
 most frequent finding in patients with GU or DU

PUD-Related Complications

Gastrointestinal bleeding
 most common complication observed in PUD
 bleeding and complications ulcer disease occur more often in individuals >60 years of age
 higher incidence in the elderly is due to increased use of NSAIDs

Perforation
 second most common ulcer-related complication
 increseased use of NSAIDs  increased incidence of perforation in the elderly

Penetration
 is a form of perforation in which the ulcer bed tunnels into an adjacent organ
 DU: penetrate posteriorly into the pancreas  pancreatitis
 GU: penetrate into the left hepatic lobe

Gastrocolic fistulas
 Associated with GU

Gastric outlet obstruction

 least common ulcer-related complication
 due to inflammation and edema in the peripyloric region
 resolves with ulcer healing
 early satiety, nausea, vomiting, increase of post prandial abdominal pain, and weight loss indicative of gastric outlet obstruction

Fixed, mechanical obstruction

 due to scar formation in the peripyloric areas
 requires endoscopic (balloon dilation) or surgical intervention
Differential Diagnosis

NUD
 most commonly encountered diagnosis among patients seen for upper abdominal discomfort
 also known as functional dyspepepsia or essential dyspepsia
 a group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer

Ulcer like Symptoms:

1. proximal GI tumors
2. gastroesophageal reflux
3. vascular disease
4. pancreaticobiliary disease (biliary colic, chronic pancreatitis)
5. gastroduodenal Crohn’s disease

Diagnostic Evaluation
 documentation of an requires either a radiographic (barium study) or an endoscopic procedure

H. pylori and antibiotic therapy

 appropriate for individuals who are otherwise healthy and <45 years of age before embarking on a diagnostic evaluation

Barium studies of the proximal GI tract

 occasionally used as a first test for documenting an ulcer
 sensitivity for detection is decreased in small ulcers (<0.5 cm)

DU
 well-demarcated crater, most often seen in the bulb

GU
 may represent benign or malignant disease
 radiographic studies that show a GU must be followed by endoscopy and biopsy

Benign GU
 appears as a discrete crater with radiating mucosal folds originating from the ulcer margin

Malignant GU
 ulcers >3 cm in size or those associated with a mass are more often malignant

Endoscopy
 provides the most sensitive and specific approach for examining the upper GI tract
 facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori
 helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities,
or to determine if an ulcer is a source of blood loss

Three types of studies routinely used:

1. serologic testing
2. 13C- or 14C-urea breath test
3. Fecal Hp antigen test

Urinary Hp antigen test and Refined monoclonal antibody stool antigen test - appears promising

Study Table 348 – 2

Treatment of Peptic Ulcer Disease

Eradication of H. pylori and therapy/prevention of NSAID-induced disease – mainstay of treatment

Study Table 348 – 3

ACID-NEUTRALIZING/INHIBITORY DRUGS

Antacids
 neutralization of secreted acid with antacids constituted the main form of therapy for peptic ulcers
 Aluminum hydroxide and Magnesium hydroxide - most commonly used agents
 Aluminum hydroxide
 produce constipation and phosphate depletion
 in CRF: hypermagnesemia
Magnesium hydroxide
 cause loose stools
 in CRF: chronic neurotoxicity
 Calcium carbonate and sodium bicarbonate are potent antacids
 Long term use:
o Calcium carbonate -> milk-alkali syndrome hypercalcemia, hyperphosphatemia with possible renal calcinosis and
progression to renal insufficiency)
o Sodium bicarbonate  induce systemic alkalosis
H2 Receptor Antagonists
 cimetidine, ranitidine, famotidine, and nizatidine are the available drugs
 all will significantly inhibit basal and stimulated acid secretion
 similar ulcer-healing rates are achieved with each drug when used at the correct dosage
 used for treatment of active ulcers (4–6 weeks) in combination with antibiotics directed at eradicating H. pylori

Cimetidine
 the first H2 receptor antagonist used for the treatment of acid peptic disorders
 recommended dosage for cimetidine was 300 mg qid
 800 mg at bedtime for treatment of active ulcer
 weak antiandrogenic side effects  reversible gynecomastia and impotence
 Adverese effects: confusion, elevated levels of serum aminotransferases, creatinine, and serum prolactin

Ranitidine, famotidine, and nizatidine

 more potent H2 receptor antagonists than cimetidine
 Each can be used once a day at bedtime for ulcer prevention

Cimitidine and Ranitidine

 can bind to hepatic cytochrome P450
 famotidine and nizatidine do not

Proton Pump (H+,K+-ATPase) Inhibitors

 half-life of PPIs is 18 hrs
 pumps need to be activated for these agents to be effective
 efficacy is maximized if they are administered before a meal except for omeprazole
 mild to moderate hypergastrinemia
 IF production is also inhibited
 long-term use of PPIs was associated with the development of hip fractures in older women

Omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole

 substituted benzimidazole derivatives that covalently bind and irreversibly inhibit H+,K+-ATPase
 most potent acid inhibitory agents available

Omeprazole and lansoprazole

 PPIs that have been used for the longest time
 acid-labile
 interact with cytochrome P450 system
 Rabeprazole, pantoprazole, and esomeprazole do not appear to interact significantly with drugs metabolized by the
cytochrome P450 system
 development of iron and magnesium deficiency

The sodium bicarbonate has two purposes:

1. to protect the omeprazole from acid degradation
2. to promote rapid gastric alkalinization and subsequent proton pump activation (facilitates rapid action of the PPI)

Pantoprazole and rabeprazole

 lipophilic compounds
 potently inhibit all phases of gastric acid secretion
 onset of action is rapid

CYTOPROTECTIVE AGENTS
Sucralfate
 insoluble in water
 becomes a viscous paste within the stomach and duodenum
 binding primarily to sites of active ulceration

Act by several mechanism:

1. serving as a physicochemical barrier
2. promoting a trophic action by binding growth factors such as EGF
3. enhancing prostaglandin synthesis
4. stimulating mucus and bicarbonate secretion
5. enhancing mucosal defense and repair
 Toxicity: constipation- MC
 should be avoided in patients with chronic renal insufficiency to prevent aluminum-induced neurotoxicity
 standard dosing of sucralfate is 1 g qid

Bismuth-Containing Preparations
 the drug of choice for treating PD considered by Sir William Osler
 Colloidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS, Pepto-Bismol) are the most widely used preparations
 Adverse effects:
Short term: black stools, constipation, and darkening of the tongue
Long term w/ high dosage: neurotoxicity

Prostaglandin Analogues
 rapidly absorbed drug
 enhancement of mucosal defense and repair
 Toxicity: diarrhea – MC, uterine bleeding and contractions

Miscellaneous Drugs
 Anticholinergic agents and tricyclic antidepressants

THERAPY OF H. PYLORI
Physician’s goal in treating PUD:
1. Provide relief of pain or dyspepsia
2. promote ulcer healing
3. prevent ulcer recurrence and complications

 greatest influence of understanding the role of H. pylori in peptic disease has been the ability to prevent recurrence
 eradication of the organism may lead to diminished recurrent ulcer bleeding
 H. pylori should be eradicated in patients with documented PUD
 testing and eradicating H. pylori in patients who will be using NSAIDs on a long-term basis especially if there is a prior history of PUD
 These individuals will require continued PPI treatment as well as eradication treatment because eradication of the organism alone
does not eliminate the risk of gastroduodenal ulcers in patients already receiving long-term NSAIDs

H. pylori treatment in gastric cancer prevention and recommends that eradication should be considered in the following situations:
1. first-degree relatives w/ gastric ulcer
2. previous gastric neoplasm treated by endoscopic or subtotal resection
3. individuals with a risk of gastritis or severe atrophy
4. patients with gastric acid inhibition for more than 1 year
5. strong environmental risk factors for gastric cancer (heavy smoking; high exposure to dust, coal, quartz, or cement; and/or
work in quarries)
6. H. pylori–positive patients with a fear of gastric cancer

 no single agent is effective in eradicating the organism

 combination therapy for 14 days provides – provides the greatest efficacy
 sequential administration of antibiotics – also appear promising
o amoxicillin, metronidazole, tetracycline, clarithromycin, and bismuth compounds
 agents used with the greatest frequency
Study Table 348-4

 Factors influenced the choice of a particular regimen:

1. efficacy
2. patient tolerance
3. existing antibiotic resistance
4. cost of the drugs
Bismuth, metronidazole, and tetracycline
 first triple regimen found effective against H. pylori
 the combination of two antibiotics plus either a PPI, H2 blocker, or bismuth compound has comparable success rates
Bismuth - black stools, constipation or darkening of the tongue
Amoxicillin - pseudomembranous colitis (most feared complication)
- also lead to antibiotic-associated diarrhea, nausea, vomiting, skin rash, and allergic reaction
Tetracycline - cause rashes, hepatotoxicity and anaphylaxis

Antibiotic-resistant strains
 most common cause for treatment failure in compliant patients

Triple Therapy
 effective in eradicating the organism in >50% of patients infected with a resistant strain
Triple Therapy  resistant  Quadruple Therapy

Quadruple Therapy
 substituted for metronidazole

Unfortunately, there is no universally accepted treatment regimen recommended for patients who have failed two courses of antibiotics. If
eradication is still not achieved in a compliant patient, then culture and sensitivity of the organism should be considered. Additional factors that
may lower eradication rates include the patient’s country of origin and cigarette smoking

THERAPY OF NSAID-RELATED GASTRIC OR DUODENAL INJURY

Medical intervention for NSAID-related mucosal injury:
 treatment of an active ulcer and primary prevention of future injury
Study Table 348-5
 injurious agent should be stopped as the first step in the therapy of an active NSAID-induced ulcer  then treatment with one of the
acid inhibitory agents (H2 blockers, PPIs) is indicated
 Only PPIs can heal GUs or DUs, independent of whether NSAIDs are discontinued
Approach to primary prevention:
1. avoiding the agent
2. using the lowest possible dose of the agent
3. using NSAIDs that is les injurious
4. using newer topical NSAID preparation
5. using concomitant medical therapy to prevent NSAID-induced injury

Diclofenac, aceclofenac, and ibuprofen

 nonselective NSAIDs associated with a lower likelihood of GI toxicity
 beneficial effect may be eliminated if higher dosages of the agents are used

Misoprostol (200 μg qid) or a PPI

 primary prevention of NSAID-induced ulceration

Celecoxib and Rofecoxib

 highly selective COX-2 inhibitors
 increase cardiovascular event

Gastric protection therapy

 required in individuals taking COX-2 inhibitors and aspirin prophylaxis

Not at risk for cardiovascular events, do not use aspirin and are w/ot risk for GI complications
 receive nonselective NSAIDs without gastric protection
W/o cardiovascular risk factors but high potential risk for NSAID-induced GI toxicity
 cautious use of a selective COX-2 inhibitor and co-therapy with misoprostol or high-dose PPI are recommended
Moderate GI risk w/o cardiac risk factors
 treated with a COX-2 inhibitor alone or with a nonselective NSAID with misoprostol or a PPI
W/ Cardiovascular risk factors, who require low-dose aspirin and have low potential for NSAID-induced toxicity
 considered for a non-NSAID agent or use of a traditional NSAID in combination with gastric protection
Cardiovascular and GI risks who require aspirin
 considered for non-NSAID therapy, but if that is not an option, then gastric protection with any type of NSAID must be considered

Study Table 348 – 6

APPROACH AND THERAPY: SUMMARY

Empirical therapeutic trial with acid suppression

 if a patient <50 years of age presented with dyspepsia and without alarming signs or symptoms suggestive of an ulcer complication
or malignancy

H. pylori infection w/o NSAID status

 triple therapy is recommended for 14 days, followed by continued acid-suppressing drugs (H2 receptor antagonist or PPIs) for a total
of 4–6 weeks

Monoclonal stool antigen test or a urea breath test (UBT)

 test of choice for documenting eradication

Two approaches toward documentation of eradication exist:

1. Test for eradication only in individuals with a complicated course or in individuals who are frail or with multisystem disease
who would do poorly with an ulcer recurrence
2. test all patients for successful eradication

GU

 body and fundus has a potential to be malignant

 multiple biopsies of a GU should be taken initially
 if these are negative for neoplasm, repeat endoscopy to document healing at 8–12 weeks should be performed

DU

 repeat endoscopy is warranted if symptoms persist despite medical therapy or a complication is suspected

Refractory

 GU: fails to heal after 12 weeks

 DU: does not heal after 8 weeks of therapy
 Can be heal after 8 weeks of treatment with higher doses of PPI

If all factors are excluded next to consider is ZES (Zollinger-Ellison Syndrome)

 gastric acid hypersecretory state

 can be excluded with fasting gastrin or secretin stimulation test

Study Figure 348 – 12

SURGICAL THERAPY

 Surgical intervention in PUD can be viewed as:

o Elective - for treatment of medically refractory disease or
o Urgent/ emergent - for the treatment of an ulcer related complication
 required for treatment of an ulcer-related complication
o Hemorrahage
 MC complication
 Often seen in older patients
 PPIs decreases ulcer rebleeding in patients undergoing endoscopy therapy
 Required in unresponsive or refractory to endoscopic intervention

Posterior DU
 penetrate into the pancreas, colon, liver, or biliary tree
Pyloric channel ulcers or DUs  gastric outlet obstruction
 result from chronic scarring or from impaired motility due to inflammation and/or edema with pylorospasm
 may present early satiety, nausea, vomiting of undigested food, and weight loss
 conservative management: nasogastric suction, intravenous hydration/nutrition and antisecretory agents
 if a mechanical obstruction persist: endoscopic intervention with balloon dilation, Surgery should be considered if all else fails

SPECIFIC OPERATIONS FOR DUODENAL ULCERS

 Surgical treatment designed to decrease gastric acid secretion
o Most commonly performed:
 Vagotomy and drainage (by pyloroplasty, gastroduodenostomy, or gastrojejunostomy)
 Highly selective vagotomy (which does not require a drainage procedure)
 Vagotomy with antrectomy
 Vagotomy
o aimed at decreasing acid secretion
o lowest ulcer recurrence rate
o highest complication rate
o performed only if a DU is present
 Pyloroplasty or gastroduodenostomy
o Drainage is required in an effort to compensate for the vagotomy-induced gastric motility disorder
 Highly selective vagotomy
o minimize gastric dysmotility
o also known as parieta cell, super-selective, or proximal vagotomy
o ulcer recurrence rates are higher
o lowest complication rates
o less GI disturbance
 Antrectomy
o aimed at eliminating an additional stimulant of gastric acid secretion
o Two principal types of reanastomoses are used after antrectomy:
 Gastroduodenostomy (Billroth I) more preferred
 Gastrojejunostomy (Billroth II)

Specific Operations for Gastric Ulcers

Antrectomy with a Billroth I

o treatment of choice for an antral ulcer

Subtotal gastrectomy with a Roux-en-Y esophagogastrojejunostomy

o ulcers located near the esophagogastric junction

Surgery-Related Complications
1. Recurrent ulceration
o risk of ulcer recurrence is directly related to the procedure performed

o Stomal or marginal ulcer

 ulcers that recur after partial gastric resection and tend to develop at the anastomosis
o Epigastric abdominal pain – most common complaint

Reasons for ulcer recurrence:

 incomplete vagotomy (can be ruled out by gastric acid analysis coupled with sham feeding
o increase in gastric acid output= intact vagus nerve
o rise in serum pancreatic polypeptide = intact vagus nerve

 inadequate drainage
 retained antrum (test of fasting plasma gastrin indicates its presence)
o elevated fasting plasma gastrin levels = retained antrum or ZES
 persistent or recurrent H. pylori infection
 use of NSAIDs

Hp and NSAIDs excluded  incomplete vagotomy or retained antrum  increase fasting plasma gastrin levels  retained antrum or ZES

2. Afferent loop syndromes

 Two types:
o bacterial overgrowth in the afferent limb secondary to satasi – most common
o incomplete drainage of bile and pancreatic secretions from an afferentloop that is partially obstructed
3. Dumping syndrome
 Occurs in patients who have undergone vagotomy and drainage
 most noticeable after meals rich in simple carbohydrates (especially sucrose) and high osmolarity
 Dietary modification: cornerstone of therapy for patients with dumping syndrome
 Two phases:
o Early Dumping: takes place 15–30 min after meals and consists of crampy abdominal discomfort, nausea, diarrhea,
belching, tachycardia, palpitations, diaphoresis, light-headedness, and, rarely, syncope
 Due to rapid emptying of hyperosmolar gastric contents into the small intestine and release of
vasoactive GI hormones
o Late Dumping: occurs 90 min to 3 h after meals
 Due to hypoglycaemia

4. Postvagotomy diarrhea
 intermittent diarrhea that occurs typically 1–2 h after meals
 due to motility disorder from interruption of the vagal fibers supplying the luminal gu

5. Bile reflux gastropathy

6. Maldigestion and malabsorption
 Reasons for maldigestion/malabsorption:
o decreased gastric acid production
o rapid gastric emptying
o decreased food dispersion in the stomach
o reduced luminal bile concentration
o reduced pancreatic secretory response to feeding
o rapid intestinal transit

 Reduced vitamin B12

 Iron-deficiency anemia
 Malabsorption of vitamin D and calcium
 Copper deficiency

7. Gastric adenocarcinoma
8. Reflux esophagitis
9. Gallstones and Cholecystitis (decreased gallbladder contractility)