PEPTIC ULCER DISEASE


I. Definitions: "Erosion" = focal area of mucosal loss w/o extension to submucosa; "Ulcer" = ditto w/extension to submucosa; "Peptic Ulcer" = ulcer in stomach or duodenum

II. Epidemiologic aspects of peptic ulcer disease

  1. Lifetime incidence of 10%; prevalence of 1-2%
  2. DU
  1. Men:Women 2:1
  2. 1.5 times as common as gastric ulcer
  3. Peak incidence for DU is in 5th decade in men and 6th decade in women
  4. Almost always in duod. bulb or immed. postbulbar; if further distal, think Z-E or Crohn's!!
  5. Not associated with cancer
  1. Gastric ulcer
  1. Men > Women (slight)
  2. More common among elderly
  3. Us. located on lesser curvature, at jn. between body and antrum
  4. 1-3% of gastric ulcers occur in cancers

III. Risk factors/Causes

  1. Male sex
  2. First degree relative with DU (RR about 3.0)
  3. H. pylori Infection--Found in 90% of pts with duodenal ulcers and 60-80% of pts with gastric ulcers; successful eradication reduces risk of ulcer recurrence
  4. Genetic markers
  1. Elevated pepsinogen 1 levels
  2. HLA-B5
  3. Decreased RBC acetylcholinesterase
  1. Cigarette smoking
  2. Zollinger-Ellison Syndrome
  3. Chronic renal failure (DU only)
  4. COPD (DU only)
  5. Alcoholic Cirrhosis (DU only)
  6. Hyperparathyroidism
  7. NSAIDs and COX-2 Inhibitors
  1. Cause gastric and, to a lesser degree, duodenal ulcers
  2. Increases risk of bleeding from GU or DU
  3. Greatest risk is in those > 60 yo
  4. Enteric-coated or buffered ASA have equal risks
  5. Risk of use of NSAIDs and COX-2 inhibitors after a bleeding ulcer and prevention of recurrent ulcer--See below
  1. Corticosteroids
  2. Postsurgical (e.g. antral hyperplasia after SB resection)
  3. Organic Nitrates may protect against bleeding from peptic ulcer (case-control study, NEJM 343:834, 2000--JW)
  4. Physiologic stress (?--see link)
  5. Not shown to be risk factors:
  1. EtOH (though can cause acute gastritis)
  2. Caffeine
  3. Psychosocial stress

IV. Physiology & Pathophysiology

  1. Gastric secretion
  1. Mucus-secreting cells of the cardia
  2. Parietal cells of the body secrete HCl and intrinsic factor
  3. Chief cells of the body secrete pepsinogen, procompound for pepsin, which is proteolytic but only in acid environment
  4. G cells of the antrum secrete gastrin, which stimulates HCl secretion as well as certain intestinal hormones (see below)
  1. Control of gastric secretion and motility
  1. "Cephalic phase"
  1. Anticipation of eating increases vagal tone
  2. This stimulates secretion of HCl and gastrin
  1. "Gastric phase" initiated by distention of stomach by food
  1. More stimulation of HCl and gastrin secretion
  2. Gastrin secretion inhibited by acid, stimulated by protein on gastric mucosa
  1. "Intestinal phase"
  1. HCl directly stimulates secretion of intestinal hormones, inc. secretin and CCK
  2. These hormones inhibit action of gastrin on parietal cells
  1. Both DU and GU tend to be < 1.0 cm diameter; > 2.5 cm are called "giant" ulcers
  1. Duodenal Ucers:
  1. Disruption of balance between acid delivered from stomach and duodenum's defense mechanisms
  1. Increased parietal cell mass
  2. Increased capacity of parietal cells to secrete acid
  3. Increased vagal tone
  4. Defective inhibition of gastrin release and HCl secretion after gastric acidification
  5. Abnormally rapid gastric emptying
  6. Altered duodenal HCO3 secretion
  7. Altered HCl absorption be duodenal contents
  8. Other: alteration in PG synthesis, mucosal production, etc.
  1. Gastric ulcer
  1. Probably less a matter of hyperacidity than of decreased gastric mucosal barrier, e.g. from NSAID use or bile reflux from duodenum
  2. May be contributed to by pyloric stenosis (secondary to chronic DU), which leads to gastric distension.
  3. Has been associated with H. Pylori as well
  1. Helicobacter Pylori infection--For both Duodenal and Gastric ulcers, seems to promote ulcer formation through chronic inflammation

V. Clinical features

  1. DU/GU often occur together: in one VA study, 40% of GU pts had DU as well
  2. Sx are similar for DU and GU:
  1. Midline epigastric discomfort, "gnawing feeling," gnawing, burning-often not actual "pain"; sometimes also nausea and/or vomiting
  2. For DU:
  1. Discomfort usually occurs 1-3h after eating; often during sleep
  2. Relieved by food, antacids, or vomiting
  3. Only minimal pain before breakfast
  1. Pattern of sx with GU is more variable; can be just like DU, but sometimes no change or even worsening with food
  2. Weight loss occurs in 50% with benign gastric ulcer, so can't use it to distinguish benign from malignant ulcer; DU pts often gain weight b/c eat more in an attempt to control their pain.
  3. Early satiety and persistent vomiting (frequently of undigested food) occurs with pyloric obstruction
  4. Change in quality or new radiation of pain suggests penetration
  1. Px
  1. Often get localized epigastric tenderness
  2. Succussion splash > 4h postprandially is evidence of gastric outlet obstruction
  3. Need to do rectal to check for occult blood
  1. Complications
  1. Risk of death from ulcer disease is most in the 1-2y after diagnosis
  2. Risk of bleeding or perforation occur in 1-3% of pts with lifetime incidence about 20% for both DU and GU
  3. Bleeding (see also "GI BLEEDING")
  1. Occurs in 20% of pts; most often in posterior DUs, because that's where the vessels are
  2. 80-90% of bleeds stop on their own, but 35-40% rebleed within 3yr, of which <50% stop on their own
  1. Perforation
  1. Occurs most often in anterior DUs
  2. 10% present with it
  3. 0-4h post perf. get chemical peritonitis; 4-6h post get infectious peritonitis
  4. Tx with peritoneal lavage and omental patch to close perforation
  1. Gastric outlet obstruction (from edema related to inflammation, or from scarring)
  1. Usually presents with postprandial vomiting, sometimes also heartburn & regurgitation
  2. Usually doesn't require immediate surgery
  3. Tx with vagotomy and gastroenterostomy
  1. Fistulae
  2. Maintenance therapy may reduce complication rate
  1. Recurrences after tx
  1. Tend to occur in same place as original ulcer
  2. 60-80% of DU pts will have a recurrence within 1y of diagnosis
  1. Many recurrences will be asymptomatic
  2. Recurrences may decrease with time
  1. GU has less tendency to recur than duodenal ulcer

VI. Diagnosis

  1. See also "Clinical aspects" above
  2. Barium studies: 60-80% sensitive for GU and DU, using endoscopy as standard
  1. Small ulcers are most often missed
  2. Don't use when bleeding is suspected b/c residual barium can make endoscopic/angiographic attempts to tx the bleeding difficult
  3. Don't use when perforation is suspected
  4. Situations where barium studies often difficult to interpret
  1. Chronic ulcer disease with scarring
  2. After surgical anastomosis
  1. Endoscopy
  1. More sensitive than barium studies for diagnosis of ulcers
  2. Probably not nec. for every DU
  3. Should be done for suspected gastric outlet obstr. or bleeding
  4. Should be done for each gastric ulcer though not. nec. at time of dx, unless radiologic appearance is either malignant or indeterminate
  5. Should be done to confirm healing of gastric ulcers, again not to miss malignancy
  1. Serum gastrin levels
  1. Normal us. < 150 pg/ml
  2. Fasting levels useful in screening for Z-E if pt has frequently occurring ulcers or refractory to conventional tx
  3. If you're going to check, do 2 or 3 levels b/c level can fluctuate
  1. DU
  1. Us. don't need to do followup studies to confirm healing if pt is doing well (no inc. risk for malignancy like with GU)
  1. GU
  1. Can sometimes distinguish benign from malignant on Ba studies, but 3-7% of those classified radiologically as "benign" are malignant; somewhat less with air-contrast studies. Keep in mind that this is for those ulcers that can be seen on Ba studies, which still misses about 20% of GU's!
  1. Diagnosis of H. Pylori

VII. Treatment

  1. See also Gastrointestinal Bleeding including a reference there to use of PPI's IV immediately after endoscopic tx of bleeding peptic ulcers
  2. Dietary modification can affect symptoms in the short term but haven't been shown to have any effect on healing or recurrence; that includes EtOH and caffeine
  3. Address reversible risk factors
  1. Smoking cessation reduces risk of ulcer occurrence and especially recurrence (70% vs 20% 1-y recurrence rate in smokers vs. nonsmokers with DU); smoking < 10 cigs/d probably same risk as nonsmoker.
  1. Healing the ulcer
  1. With drugs, 75-80% healing in 4-6wks and 90% healing in 8 wks with DU's
  2. Pain relief usually occurs in 1st 7-10d of tx; dx should be reconsidered if pain continues > 2 wks after start of tx (GU's take longer, us. 8-12wks for healing)
  3. If documented ulcer fails to heal in 6-8 wks, treat an additional 2-4 wks with same agent, and if still present, consider Z-E w/u and/or changing to another class of drug. No evidence to support using 2 classes of drugs together (e.g. Sucralfate plus H-2 blockers)
  4. Acid reduction
  1. Histamine Type 2 ("H2")-blockers
    1. All have similar healing rates for DU and GU
    2. There is less evidence for efficacy of QD dosing of H2 blockers in Gastric Ulcer than Duodenal Ulcer
  1. Proton-pump inhibitors
    1. Faster pain relief and healing of PUD than H2-blockers (NEJM 324:965, 1991-Med. Letter)
    2. In a meta-analysis of 18 randomized trials comparing high-dose IV PPI's (40-80mg loading dose then 6mg/h or more), high-dose oral PPI's (at least 2x standard dosage), and H2-blockers for treatment of peptic ulcer with bleeding, incidence of rebleeding was sig. lower with high-dose IV PPIs than with H2-blockers (Aliment. Pharmacol. Therapeut. 21:677, 2005--abst)
    3. See section on NSAIDs for info on use of PPI's for prevention of NSAID-induced ulcers
  1. Antacids
  1. 70-80% healing rate with full-dose antacid Rx, but still rarely used as ulcer monotherapy, poss. b/c no cost or side-effect advantage (would have to take 7x/d)
  2. Side effects of overuse include hypermagnesemia, esp. if have renal impairment; Na overload, esp. if have CHF;
  3. Can get PO4 depletion, even osteoporosis and osteomalacia with AlOH-containing antacids (all of them)
  4. Can get hypercalcemia, alkalosis, and milk alkali sd. with calcium-containing antacids (Camalox)
  5. All can inhibit absorption of antibiotics, dig, anticonvulsants, NSAIDs, cimetidine, and coumadin
  1. Anticholinergic agents
  1. Weak inhibitors of acid secretion
  2. Significant side effects (anticholinergic)
  3. Pirenzepine-selective to M2 Ach receptor; few anticholinergic side effects, 70-80% healing at 6 wks; not available in US as of 1990
  1. Prostaglandins-Misoprostol (PGE1 analog)
  1. Provide acid inhibition and mucosal protection
  2. 200mg BID or QID provides ulcer healing equal to that of H2 blockers
  3. Also produces 13-33% abd. cramps and diarrhea; in women, can cause uterine contractions
  4. Lower "cytoprotective" doses (< 100mg QID) cause few side effects but don't heal ulcers!
  1. Mucosal protection-Sucralfate
  1. 1g QID between meals similar healing rate to H2 blockers
  2. 2g BID equal healing for DU but not yet FDA approved as of 1998
  3. Best choice for pregnant patients
  4. One study showed no difference in ulcer healing between smokers and non-smokers, unlike with H2-blockers (Gastroenterology 92: 1193, 1987)
  5. Binds to ulcerated mucosa to form protective barrier
  6. Inhibits pepsin
  7. May have other mechanisms
  8. Little to no systemic absorption
  9. Causes constipation in 2-4% of pts; occas. HA, dizziness, dry mouth
  10. May give less pain relief than H2-blockers or proton-pump inhibitors
  1. Surgery
  1. Indications: perforation, uncontrolled hemorrhage, gastric outlet obstruction, and intractability
  2. Rule out secondary causes, inc. Z-E sd, before surgery
  3. Duodenal ulcer:
  1. Vagotomy and pyloroplasty-lowest mortality (because quick) and highest rate of ulcer recurrence (6-8%)
  2. Vagotomy and antrectomy-higher morbidity (because long) and lowest rate of ulcer recurrence ( < 2%)
  3. Highly selective vagotomy-fewest complications; intermediate rate of recurrence
  1. Gastric ulcer:
  1. Vagotomy may not be helpful
  2. If not resected, ulcer must be biopsied & frozen sections done
  3. Postgastrectomy syndromes: dumping sd, etc.
  1. Preventing recurrences
  1. H. pylori tx-can reduce recurrence of both duodenal and gastric ulcer (from 80% to 5-10%/yr for duodenal ulcer)
  2. Maintenance drug treatment
    1. Most commonly used in pts who have recurrent PUD despite not using NSAIDs or having H. pylori infection
    2. 82 pts with H. pylori-ass'd bleeding peptic ulcers, all of whom underwent successful H. pylori eradication and 3 additional weeks of omeprazole 20mg QD, randomized to 16wks of placebo vs. one of 3 maintenance treatments (antacids, bismuth, or famotidine).  Over mean 56mo f/u, all patients remained free of peptic ulcer recurrence (assessed by EGD) and recurrent H. pylori infection. (Arch. Int. Med. 163:2020, 2003-abst)
    3. Highest risk for recurrence:
  1. > 60 yo
  2. Men
  3. Pts with COPD, CAD, or CRI
  4. Pts with h/o PUD complication
  5. Pts with refractory sx
  6. Pts who need to be on NSAIDs
  7. Cigarette smoking
  1. Therapy to prevent ulcers in high-risk pts--See NSAIDs section for details