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A. Risk Factors

  1. PUD refers to Gastric or Duodenal Ulcerations
    1. Originally believed to be due to abnormal gastric acid and pepsin secretion
    2. Major causes are now known to be only secondary to abnormal gastric acid levels
    3. Infection (H. pylori) is cause of 70% of ulcers
    4. Non-steroidal anti-inflammatory drugs (NSAIDs) causative ~10% of ulcers
    5. Non-NSAID, non-H. pylori ulcers currently account for ~20% of PUD cases
    6. PUD is major risk factor for upper gastrointestinal (GI) bleeding
  2. Helicobacter pylori Infection [2]
    1. Associated with >90% of non-NSAID peptic ulcers
    2. Risk for ulceration in seropositive (anti-H. pylori) patients is ~4X general population
    3. NSAIDs and H pylori synergize to increase risk of PUD (~2X increased risk) [3,34]
    4. Eradication of H. pylori is essential for preventing ulcer relapses (see below)
    5. H. pylori eradication reduces risk for developing PUD in chronic NSAID users [4,5,6]
  3. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
    1. Nonselective NSAIDs (COX1/2 Inhibitors) are risk factors for serious PUD, GI bleeding
    2. Nearly all persons on chronic nonselective NSAIDs develop gastritis symptoms
    3. Aspirin (ASA) has high risk of PUD due to both GI and irreversible platelet effects
    4. Buffered or enteric coated ASA does not reduce risk of GI bleeding
    5. PUD and bleeding risks of COX2 specific NSAIDs similar to placebo [8,9]
    6. Adding proton pump inhibitor (PPI) to COX1/2 inhibitor reduces PUD risk to that of COX specific NSAIDs with chronic use (6 months) [32]
    7. Thus, for long term use, COX2 specific NSAID alone or standard NSAID + PPI recommended
    8. In patients with prior bleeding ulcer, combination of COX2 inhibitor + PPI reduced rebleeding risk from ~9% without PPI to 0% at 13-months [37]
  4. Impaired Neutralization of Duodenal Acid
    1. Acid synergizes with H. pylori to increase risk of PUD
    2. H. pylori infection appears to increase acid secretion in stomach
    3. Acid alone is rarely associated with PUD
    4. Massive acid hypersecretion in Zollinger-Ellison syndrome alone causes PUD (see below)
    5. Cigarette smoking increases acidity
    6. Pancreatic insufficiency
    7. Chronic psychological stress may also contribute to PUD [10]
    8. Psychological stress may increase acid production and/or reduce neutralization
  5. Duodenal Diverticuli (2ND and 3RD parts of duodenum)
  6. Glucocorticoids
    1. Exacerbate gastritis and PUD probably by prevention of wound healing
    2. Do not initiate ulcer formation
  7. Zollinger-Ellison Syndrome (ZES)
    1. Severe hearburn and multiple peptic ulcers including jejunal ulcers
    2. Epigastric and non-specific Abdominal Pain
    3. Diarrhea
    4. ZES is due to overproduction of gastrin by carcinoid (neuroendrine) "gastrinomas"
    5. Does not require H. pylori coinfection to generate ulcers
    6. Very high doses of proton pump inhibitors (PPI) required for ulcer healing
  8. Risk Factors for GI Perforation
    1. NSAIDs ~5X increased risk (higher for lower GI perforation)
    2. Smoking 3.7X increased risk
    3. Alcohol Consumption ~11X increased risk
    4. History of arthritis contributed in multivariate analysis (independent of NSAIDs)
    5. Use of nitrovasodilator (nitrates) drugs 40% reduced risk of GI bleeding [12]

B. Pathology and Pathophysiology [1,10]

  1. H. pylori Infection [2]
    1. Causes chronic inflammation in essentially all infected persons
    2. Chronic inflammation involves high levels of IL-8, which attracts neutrophils
    3. Interleukin 1ß (IL1ß) is also produced at location of infection
    4. Thrives in acid environment by neutralizing acid with ammonia production
    5. Ammonia produced by bacterial urease cleavage of urea
    6. Attaches to gastric epithelial cells via bacterial BabA that targets Lewis B antigens
    7. H. pylori CagA protein and vacA gene product are main virulence factors
    8. H. pylori infection enhances acid secretion
    9. However, >80% of persons infected with H. pylori do not develop ulcers
    10. H. pylori is a major risk factor for gastric adenocarcinoma and MALT lymphoma
  2. Duodenal Ulcers
    1. 95% within 2cm. of pylorus
    2. Ulcers equally on anterior and posterior walls of duodenum
    3. Both acid secretion and H. pylori infection implicated
    4. Reduced duodenal bicarbonate secretion may also play a role
    5. Duodenal PUD often associated with antrum predominant gastritis
  3. Gastric Ulcers
    1. Gastric PUD typically associated with corpus-predominent or diffuse gastritis
    2. These pathologies are associated with reduced acid secretion
    3. Gastric PUD associated with much less acid than duodenal PUD
    4. Reduced gastric acid leads to distinct distribution of H. pylori
    5. H. pylori plays critical role, with preferential location of gastric ulcers
    6. H. pylori associated gastric ulcers form preferentially at antrum-corpus junction
    7. This is also called transition zone
  4. NSAID Induced Ulcers
    1. Seen primarily with COX1/2 nonselective NSAIDs due to inhibition of prostaglandins
    2. Cause direct damage to gastric and duodenal mucosa
    3. Nitric oxide may act as a protectant against NSAID induced injury
    4. NSAID induced gastritis associated with inflammation only when H. pylori is present
    5. Gastric acid probably exacerbates NSAID associated injury
  5. Atypical Duodenal Ulcers
    1. Zollinger-Ellison Syndrome
    2. Crohn's Disease
    3. Small Intestinal Carcinoma (unusual)
    4. Diverticulitis
  6. Ulcer Perforations
    1. Posterior perforation less common; may involve pancreas with pancreatitis
    2. Anterior perforation more common causing pneumoperitoneum and peritonitis
    3. Risk factors for ulcer perforation as described above

C. History and Physical Examination

  1. PUD is increasing in many age groups
  2. Males > Females
  3. Seasonal symptoms exacerbation
  4. Epigastric pain on fasting
    1. Duodenal ulcer symptoms typically decreased by eating
    2. Gastric ulcer symptoms usually increased with eating
  5. Stool negative for occult blood in most cases (except with acute bleed)
  6. Physical examination findings usually negative
  7. Smoking common

D. Diagnosis [3]

  1. Endoscopy
    1. Gold standard for diagnosis; however, it is expensive and invasive
    2. Nearly all ulcers should be biopsied, especially (recurrent) gastric ulcers
    3. Empiric therapy with proton-pump agent and antibiotics is more cost effective
    4. It is even cost effective to treat H. pylori-seropositive patients with dyspepsia rather than to perform an endoscopy
    5. However, patients with recurrent symptoms after therapy should undergo endoscopy
  2. Upper GI Barium study - less sensitive, less invasive
  3. Specialized studies: gastric analysis (pH), serum gastrin levels
  4. Diagnosis of H. pylori [2]
    1. Large numbers of asymptomatic, anti-H. pylori Ab+ persons in general population
    2. H. pylori serology is a reasonable test in patients with symptoms
    3. Eradication of H. pylori will significantly reduce recurrence of ulcers
    4. Urea breath test is considered an excellent non-invasive test for H. pylori
    5. This breath test (Meretek UBT®, about $300) uses 13C-labelled urea (non-radioactive)
    6. Use of proton pump inhibitors (PPI) can cause a false negative urea breath test
    7. At least 2 weeks should elapse between stopping PPI and doing test
    8. Endoscopy with mucosal biopsy and culture or urea test is gold standard
  5. Assess use of NSAIDs, particularly for acute musculoskeletal problems

E. Medical Therapy Overview [1,14]

  1. Overview of Therapy
    1. All patients must be tested for H. pylori (even on NSAIDs) and eradication carried out
    2. Eradication of H. pylori is critical to prevention of ulcer recurrence (see below) [2]
    3. PPI provide rapid symptomatic relief with accelerated healing
    4. H-2 blockers - symptomatic relief and ulcer healing with prolonged, high dose use
    5. Antacid therapy - symptomatic relief only; generally reserve for reflux esophagitis
    6. Smoking cessation and reducing alcohol consumption will be beneficial
    7. Failure to eradicate H. pylori will inevitably lead to relapse (see below)
  2. Patients on NSAIDs [35]
    1. High likelihood that NSAIDs are cause of or major contributor to symptoms
    2. H. pylori eradication in patients on NSAIDs clearly reduces ulcer potential [3,5]
    3. Stop NSAIDs, and treat with PPI for 4-8 weeks and eradicate H. pylori [15]
    4. If NSAIDs cannot be stopped, switch to a COX-2 selective NSAID
    5. If ASA cannot be stopped, eradicate H. pylori and add PPI [15]
    6. ASA+esomeprazole (Nexium®) 20mg qd is safe in patients with previous ASA-induced peptic ulcer bleeding; recurrent bleeding rate 0.7% over 1 year [36]
    7. Clopidogrel alone had 8.6% annual bleeding rate in patients with history of ASA-induced peptic ulcer bleeding [36]
    8. If symptoms or bleeding recur, strongly consider endoscopy and biopsy
    9. Misoprostol, double-dose H2-blockers, and PPI are equally effective at preventing endoscopic and clinically significant ulcers due to NSAIDs
  3. Histamine H2 Antagonists (H2 blockers)
    1. Cimetidine (Tagamet®) - 400mg po bid-tid; caution due to many drug interactions
    2. Ranitidine (Zantac®) - 150-300mg po qd-bid
    3. Famotidine (Pepcid®) - 20-40mg po qd-bid; IV formulation available
    4. Nizatidine (Axid®) - 150mg po bid or 300mg po qd
    5. All are now available in reduced dosages without prescription (OTC)
    6. Note that the above doses are not readily available without prescription
    7. The high doses listed must be used to ensure adequate therapeutic benefit
  4. Proton Pump Inhibitors (PPI) [16]
    1. Block H+/K+ ATPase in the stomach
    2. PPI relieve pain and heal ulcers more rapidly than H-2 blockers
    3. PPI permit rapid healing of NSAID induced ulcers, even during NSAID therapy [17]
    4. PPI + standard NSAID leads to PUD risk similar to COX2 specific NSAIDs [32]
    5. Highly effective in combination with antibiotics for H. pylori eradication
    6. Chronic lansporazole prevents rebleeding in patients continuing on ASA who have had an initial ulcer complication [15]
    7. Doses higher than those specified below may be required for ZES or severe disease
    8. Long term (1-4 years) PPI increases risk of hip fracture 1.2-1.6X [13]
  5. Specific PPI and Doses [16,19]
    1. Omeprazole (Ome; Prilosec®) 20-40mg po qd
    2. Lansoprazole (Lan; Prevacid®) 15-30mg qd
    3. Rabeprazole (Rab; AcipHex®) 20mg po qd
    4. Pantoprazole (Pan; Protonix®) 40 mg qd (least expensive); 40-80mg IV qd-bid also
    5. Esomeprazole (Eso; Nexium®) - S isomer of omeprazole, 20-40mg po qd
  6. Prostaglandin Supplementation
    1. PGE2 analog Misoprostal (Cytotec®) for gastric and duodenal ulcers due to NSAIDS
    2. Superior to H2 blockers for prevention of NSAID induced gastric ulcers
    3. Recommended for prevention of NSAID induced PUD in high risk patients
    4. Reduces NSAID-induced duodenal ulcer rate by ~60-80%
    5. Reduces GI complications, ulcer risk similar to switching to COX-2 selective NSAIDs [7]
    6. Dose is 200µg qid or 200µg po bid to tid depending on symptoms
    7. Side effects (mainly diarrhea) minimized with bid or tid dosing
    8. Arthrotec® is a combination of NSAID (diclofenac) and misoprostal
  7. Sucralfate (Carafate®) [21]
    1. Protective Barrier Drug - aluminum hydroxide-sucrose complex protects mucosal barrier
    2. Nearly as effective as H2 blockers (except in NSAID associated ulcers) for stress ulcers
    3. Not as effective as H2 blockers for stress ulcer prevention in mechanically ventilated patients [22]
    4. Fewer CNS and other systemic effects
    5. Dose is 1gm crushed tablet or slurry bid to qid
    6. Dcreases absorption of lansoprazole, ketoconazole, fluoroquinolones
  8. Antacids
    1. Provide symptomatic relief with frequent use
    2. Healing rates slower than H-2 blockers
    3. Calcium based pills may be preferred in elderly (for osteoporosis risk)
    4. Magnesium salts may cause diarrhea; aluminum salts cause constipation
    5. Chronic aluminum salt use (including sucralfate) can lead to weak bones
  9. Prokinetic Agents
    1. Unclear role in ulcer disease
    2. May be useful for gastroesophageal reflux disease (GERD) or gastroparesis
    3. Metoclopramide (Reglan®) is standard agent

F. Helicobacter Pylori Eradication [2,4]

  1. Empiric Therapy for Patients with Ulcer Symptoms and Positive Serology
    1. Endoscopy provides no overall benefit beyond empiric therapy [23]
    2. In young patients with uncomplicated ulcer symptoms, recommend empiric treatment
    3. H. pylori eradication also reduces atrophic gastritis histopathology [24]
    4. Eradication of H. pylori improves symptoms of non-ulcer dyspepsia <10% of cases [2,38]
  2. FDA Approved Treatment Regimens [2,18]
    1. PPI with two antibiotics is easy, provides >80-90% eradication in 10 days
    2. Sequential 10 day therapy is superior to standard 7-10 day concomitant therapy [18]
    3. Sequential Rab 20mg bid + amoxicillin (Amox) 1gm bid x 5 days followed by Rab 20mg bid + clarithromycin (Clar) 500mg bid + tinidazole 500mg bid x 5 days is superior to 7-day triple therapy [20,26]
    4. Ome 20mg bid + Clar) 500mg bid + Amox 1gm bid x 10 days
    5. Ome 40mg qd + Clar 500mg bid x 2 weeks, then Ome 20mg qd x 2 weeks
    6. Lan 30mg bid (or Eso 40mg qd) + Clar 500mg bid + Amox 1gm bid x 10 days
    7. Rab 20mg bid + Clar 500mg bid + Amox 1gm bid x 7 days [20]
    8. Ranitidine bismuth citrate (RBC) 400mg bid + clarithromycin 500mg bid or tid x 2 weeks, then RBC 400mg bid x 2 weeks (older regimen not usually used)
    9. In patients with reduced metablism of Ome due to CYP2C19 mutations, dual therapy with Ome 20mg/d and Amox 2gm/day was 100% effective [25]
  3. Resistant H. pylori [2,7,14]
    1. Metronidazole resistance is an increasing problem (may be >35%)
    2. Clarithromycin resistance (mainly A2143G) has been reported (~10%)
    3. Sequential 10 day therapy (above) superior to 7-day triple therapy for eradication of clarithromycin resistant H. pylori [18,26]
    4. Resistance to tetracyclines or Amox is very uncommon (<2%)
    5. Drug resistance testing should be considered with failed eradication
    6. Alternatively, high dose PPI + two antibiotics (which are active and for which the patient has not been exposed) may be used empirically in relapse or failed eradication [2]
    7. Rifabutin with amoxicillin and Pan for 10 days, provided 86% cure in refractory disease [2]
    8. Ome dose may need to be increased in ultrarapid metabolizers [25]

G. Bleeding Peptic Ulcer

  1. Risk Factors
    1. NSAID use - gastric and duodenal ulcers
    2. Prior upper GI bleed
    3. Glucocorticoids - probably no effect alone, but increased risk for NSAID bleeding by ~2X
    4. Positive H. pylori serology
    5. Serious illness and increased length of stay in hospital [27]
  2. Presentation
    1. Anemia - usually iron deficiency type, initially high reticulocyte counts
    2. Melana ~20%, Hematochezia ~30%, Both ~50%
    3. Hematochezia probably requires >1000 mL of blood loss
    4. Gastric acid level will also impact on production of melana
    5. Orthostatic vital signs with resting tachycardia
  3. Prognostic Factors
    1. Initial vital signs / stability
    2. Age >60 years carries 10-20X increase in mortality risk
    3. Concommitant medical illness
    4. Repeated hematemesis, hematochezia, failure of gastric fluid to clear with lavage
    5. Appearance - active bleeding, diameter >1-2cm, visible vessel are poorer prognostics
    6. Nonbleeding vessels with adherent clots generally better than actively bleeding ulcers
  4. Evaluation and Initial management
    1. Pass nasogastric (NG) tube and lavage: "Coffee grounds" versus "bright red blood"
    2. Occult blood test on stool is critical also
    3. Maintain adequate hydration, two large bore (18gauge or larger) intravenous lines
    4. Blood clot, CBC, electrolytes, PT/PTT ± fibrinogen levels should all be drawn
    5. Type and cross 4-6U immediately (may require emergent transfusion)
    6. Give FFP, Cryoprecipitate as needed
    7. Consider DDAVP in patients with platelet dysfunction (for example, chronic renal failure)
    8. Transfuse packed RBC to maintain HCT > ~28% (or for symptoms)
    9. Monitor heart rate constantly and frequent vital signs
    10. High dose PPI (omeprazole 80mg IV bolus, then 8mg/hr infusion) appears beneficial [11]
  5. Medications in Acute Peptic Ulcer Bleeding
    1. Intravenous H-2 blockers usually given, though without proven effect on mortality
    2. However, H-2 blockers do reduce acid, which is reasonable to allow healing
    3. Somatostatin (octreotide) with endoscopy reduces overall risk of continued bleeding [28]
    4. Somatostatin may be used before or during endoscopy as adjunctive therapy
    5. For peptic ulcers with signs of recent bleeding, Ome decreased rate of further bleeding and the need for surgery (reduced rebleeding by about 65%) [29]
    6. Ome 40mg bid did have trend toward reduced mortality versus control arm [29]
    7. Ome with endoscopy superior to endoscopy alone for nonbleeding ulcers with visible vessels and adherent clots [33]
    8. High dose Ome 80mg IV bolus then 8mg/hour infusion) accelerated resolution of peptic ulcer bleeding and reduced need for endoscopic therapy in PUD [11]
  6. Endoscopy
    1. Assess bleeding site usually with endoscopy
    2. Failure to detect site should prompt bleeeding scan or angiogram (see below)
    3. Ulcer appearance predicts rebleeding rate
    4. Clean based ulcers do not usually require intervention (~40% of ulcers, ~5% rebleeding)
    5. Flat spot / adherant clot (~20% each): ~10-20% rebleeding risk
    6. Visible vessels or active bleeeding (~17% each): >40% rebleeding and 35% require surgery
    7. For recurrent bleeding initially treated with endoscopy, retreatment with endoscopy was effective in ~70% of patients, most effective if initial ulcer <2cm [30]
    8. Rebleedling after endoscopic repair occurs in ~20% of patients
    9. Omeprazole infusion after endoscopic repair reduced rebleed rate from 22.5 to 6.7% [31]
    10. Various ulcer repair methods using the endoscope are available
  7. Other Therapy
    1. Surgery (see below)
    2. Angiography with embolization
  8. Long Term Therapy
    1. Determine contributors: NSAIDs verus H. pylori versus hypersecretory state
    2. Hypersecretory states include Zollinger-Ellison Syndrome (gastrinomas)
    3. Stop NSAIDs if possible or switch to COX-2 selective agents
    4. If stopping NSAIDs not possible, use PPI with COX-2 inhibitor initially then misoprostal
    5. H-2 blockers or PPI should then be given for at least 1 year following a major upper GI bleed
    6. In patients with prior bleeding ulcer who require NSAID therapy, combination of COX2 inhibitor + PPI reduced rebleeding risk from ~9% without PPI to 0% at 13-months [37]

H. Surgical Therapy

  1. Indications
    1. Intractable to medical and endoscopic therapy
    2. Perforation
    3. Obstruction (due to stricture formation)
    4. Hemorrhage
  2. Endoscopy for rebleeding peptic ulcers is at least as safe and effective as surgery [30]
    1. This is true even if initial bleeding event was treated endoscopically
    2. Surgery generally required for ulcers >2cm that rebleed, or when hypotension present
  3. Types of Surgery
    1. Parietal Cell Vagotomy
    2. Truncal Vagotomy and Pyloroplasty
    3. Truncal Vagotomy and Antrectomy
    4. Antral/Fundus Highly Specific Vagotomy
  4. Complications of Surgical Therapy
    1. Problem is with cutting vagus nerve nonselectively leading to intestinal dysmotility
    2. Dumping Syndrome
    3. Diarrhea
    4. Hemorrhage
    5. Anastomotic Ulcer

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