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A. Etiology [1] navigator

  1. Helicobacter pylori [2]
    1. H. pylori is a Gram Negative, comma-shaped organism
    2. Organism binds to gastric epithelium via receptors for Lewis b blood group antigens
    3. More than 75% of chronic active gastritis associated with H. pylori
    4. H. pylori eradication improves histology of atrophic gastritis [3]
    5. H. pylori eradication in patients taking low-dose aspirin reduces risk of GI bleeding [4]
    6. Risk of gastric ulceration with H. pylori ~3.2X that of general population
    7. Also associated with gastric and duodenal ulcers and gastric cancer
    8. H. pylori is clearly an etiologic agent for gastric (MALT) lymphomas
    9. H. pylori may play a role in ~20% of non-ulcer dyspepsia [5]
  2. Nonsteroidal Anti-Inflammatory Drug [1]
    1. Classical NSAIDs inhibit both cylooxygenase 1 (COX 1) and COX 2
    2. COX 2 associated with inflammatory prostaglandins (PG)
    3. COX 1 associated with gastric mucosal protection by PG (mainly prostacyclin)
    4. Classical NSAIDs cause gastric mucosal damage, account for ~20% of active gastritis
    5. Ulcerative gastritis is most common finding ~15-22% of users of NSAIDs
    6. Aspirin (ASA) >1000mg/daymore ulcerogenic than other classical NSAIDS
    7. Enteric coating or buffering of ASA does not reduce risk of serious bleeding
    8. Non-specific ulceration of the small intestine occurs in 8% of NSAID users
    9. H. pylori infection is synergistic with NSAIDs to cause gastritis and ulceration [10,11]
    10. COX-2 selective agents do not cause gastric or intestinal ulceration [6,12]
  3. Chronic Atrophic Gastritis (CAG) Type A [13,14]
    1. Autoimmune mediated disease, mainly affecting fundus
    2. Anti-parietal cell and intrinsic factor autoantibodies
    3. Causes pernicious anemia due to Vitamin B12 deficiency
    4. May be associated with polyendocrine failure syndrome
    5. Type A CAG affects the fundus and body of stomach but spares the antrum
    6. Lack of stomach acidity (achlorhydria) due to parietal cell destruction
    7. May increase susceptibility to certain pathogens
    8. Increased serum gastrin, increased risk of carcinoids
    9. Increased risk of gastric adenocarcinoma [15]
  4. Chronic Atrophic Gastritis (CAG) Type B [2,14]
    1. Associated with H. pylori initiated inflammation
    2. Risk elevated in smokers and alcoholics
    3. Increased risk with chronic ingestion of smoked foods
    4. Occurs preferentially in gastric antrum transition zone, but affects entire stomach [13]
    5. Low serum gastrin are usually found due to destruction of antral gastrin-producing cells
    6. Autoantibodies against parietal cell H+/K+ ATPase may be produced
    7. Associated with gastric mucosal (MALT) lymphomas and gastric adenocarcinoma
    8. Iron deficiency anemia may occur as well
    9. Eradication of H. pylori improves histology of atrophic gastritis in ~60% of patients [2,3]
  5. Smoking
    1. Significantly reduces gastric PG concentrations
    2. Normal aging also results in reduction of PG concentrations
    3. Slows healing of ulcers
  6. Other Causes of Gastritis and Gastric Ulceration
    1. Inflammatory: Crohn's Gastritis, Eosinophilic Gastritis, Sarcoidosis
    2. Malignant Neoplasma: Gastric Carcinoma, Gastric Lymphoma, MALT, Metastatic Disease
    3. Carcinoid: Zollinger-Ellison Syndrome (gastrinoma, multiple gastric and duodenal ulcers)
    4. MALT: mucosal associated lymphoid tissue, often with low-grade B cell lymphoma
    5. Infectious: resistant H. pylori, syphilis, tuberculosis

B. Diagnosis [1,2]navigator

  1. Symptoms
    1. Chronic epigastric burning pain, often increases with eating (gastritis)
    2. Duodenitis is typically improved with eating (due to bicarbonate production)
  2. Signs are non-specific
  3. Drugs: NSAID use, alcoholism, glucocorticoids
  4. Laboratory Diagnosis of H. pylori [2]
    1. Serological tests for H. pylori (often found in asymptomatic persons)
    2. Urea breath test -14C-labelled urea is ingested, broken down by H. pylori urease
    3. Breath test is better method than serology for following following therapeutic effects
    4. Barium swallow detection of ulcers may be combined with other tests
    5. The sensitivites of urea breath tests and H. pylori serology may be equal to endoscopic biopsy staining
  5. Endoscopic Proceedures
    1. Generally indicated in patients with symptoms, although this is under discussion
    2. Mucosal biopsies are taken and analyzed for H. pylori and evidence of carcinoma
    3. May not be required in patients with recurrent duodenal ulcers

C. Therapy [1,18] navigator

  1. H. pylori eradication therapy is strongly recommended in the following [2]:
    1. Any patient with PUD (whether or not H. pylori is present)
    2. Atrophic gastritis
    3. Recent resection of gastric cancer
    4. First degree relative of patient with gastric cancer
    5. H. pylori eradication clearly reduces risk of gastric cancer development
    6. Gastric MALT tumors should be treated with eradication therapy
    7. Desire of patient after full consultation with physician
  2. H. pylori Eradication Advised [2]
    1. Functional dyspepsia (demonstration of ulcer not required) [37]
    2. Reflux esophagitis in patients receiving long term profound acid suppression
    3. Use of NSAIDs, particularly chronic agents
  3. Proton Pump Inhibitors (PPI) [19,20,21]
    1. Omeprazole (Ome; Prilosec® and OTC) 20-40mg po qd; now over the counter 20mg qd [16]
    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. Acid-suppression therapy (H2-blockers, proton-pump inhibitors) ~1.7X increased risk of community acquired pneumonia (CAP) [17]
    7. High dose omeptrazole 80mg IV bolus then 8mg/hour infusion) accelerated resolution of peptic ulcer bleeding and reduced need for endoscopic therapy in PUD [43]
  4. Eradication of H. pylori [2,45]
    1. PPI with two antibiotics is easy, provides 80-90% eradication in 7-10 days
    2. Sequential 10 day therapy is superior to standard 7-10 day concomitant therapy [45]
    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 [8]
    4. Ome 20mg bid + Clar 500mg bid + Amox) 1gm bid x 7-10 days
    5. Lan 30mg bid (or Eso 40mg qd) + Clar 500mg bid + Amox 1gm bid x 10 days
    6. Lan 30mg tid + Amox 1gm tid x 2 weeks
    7. Ranitidine bismuth citrate (RBC) 400mg bid + clarithromycin 500mg bid or tid x 2 weeks, then RBC 400mg bid x 2 weeks (older regimen not generally used)
  5. NSAID and other Non-H. pylori Ulceration [1]
    1. Proton pump inhibitors (PPI) are mainstay of therapy
    2. PPI permit rapid healing of gastric ulcers in 4-8 weeks (NSAIDs continued) [22]
    3. Standard dose H2 blockers are not very effective at healing during NSAID therapy [22]
    4. For peptic ulcers with signs of recent bleeding, omeprazole decreased rate of further bleeding and the need for surgery (reduced rebleeding by about 65%)
    5. Omeprazole and misoprostal were equal for prevention of NSAID induced GI lesions [24]
    6. Omeprazole was better tolerated than misoprostal [24]
    7. Coating agent: Sucralfate (Carafate®) - barrier protection; some healing promotion
    8. Combination therapy may be considered
    9. Misoprostol, double-dose H2-blockers, and PPI are equally effective at preventing endoscopic and clinically significant ulcers due to NSAIDs [25]
    10. Switching to COX-2 selective NSAIDs will prevent most gastrointestinal (GI) ulceration and reduces the need for adjunctive GI medications [6]
    11. Misoprostol and COX-2 selective NSAIDs similarly reduce GI complications and ulcers
  6. Chronic Atrophic Gastritis (CAG) Type A [14]
    1. Pernicious anemia is treated with Vitamin B12 replacement
    2. Vitamin B12 as injection (1000U/month maintenance) or new nasal spray (Nascobal®)
    3. Other endocrine failure syndromes are treated appropriately
    4. Lack of stomach acidity (achlorhydria) may increase susceptibility to certain pathogens
    5. These include salmonella, shigella and other agents
    6. Increased serum gastrin, increased risk of carcinoids requires monitoring
  7. Zollinger-Ellison Syndrome (see also below)
    1. High dose PPI (for example, omeprazole 40mg po bid-tid) usually required
    2. Attempt at localization and resection of tumor
    3. Gastrin sampling from venous systems, Computerized Tomography used
  8. Gastric Ulcer Bleeding

D. Ulcer Preventionnavigator

  1. Patients with history of upper GI bleeding, gastritis, duodenitis can use H-2 blockers
  2. H. pylori eradication therapy should cure most patients
  3. PPI are very effective for prevention of ulceration, even with NSAID use
  4. NSAID Use and Ulcer Prevention [1,40]
    1. High dose H2-blockers are somewhat effective in preventing NSAID induced ulceration
    2. Misoprostal is superior to H-2 blockers for gastric ulcer prevention
    3. PPI are superior to H-2 blockers for preventing NSAID induced gastritis
    4. Sucralfate does not prevent NSAID induced gastric ulcers
    5. COX2 selective NSAIDs do not cause PUD above placebo rates
    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]
  5. Misoprostol (Cytotec®) [26]
    1. Approved only for prophylaxis against NSAID induced gastric / peptic ulcer
    2. Effectively prevents NSAID induced GI bleeding in arthritis patients
    3. Superior to ranitidine or sucralfate for prevention of NSAID induced gastric ulcers [1]
    4. Reduces GI complications, ulcer risk similar to switching to COX-2 selective NSAIDs [7]
    5. Standard dose is 200µg po qid; most effective for PUD prevention
    6. Lower doses (200µg bid-tid) are nearly as effective and better tolerated
    7. Major side effect is diarrhea; reduced incidence at doses of 100-200µg bid
  6. Sucralfate (Carafate®) [27]
    1. Sucralfate is aluminum containing coating agent
    2. Bone deposition of aluminum can lead to bone fragility and fractures, and constipation
    3. Long term aluminum renal toxicity can also occur
    4. Therefore, use is recommended < 1 year
    5. Not effective for NSAID induced gastritis; role in H. pyrlori therapy is unclear
  7. Stress Ulcer Prophylaxis in Hospitalized Patients
    1. Patients with respiratory failure and/or coagulopathy should receive prophylaxis
    2. Sucralfate or H2 blockers are frequently chosen
    3. Lower gastric pH with H2 blockers may increase incidence of nosocomial pneumonia
    4. Sucralfate associated with lower pneumonia rates than antacids or ranitidine [28]
  8. CNS reactions to H2 Blockers occur at low but significant frequency [29]
    1. More common in ICU patients (up to 80%)
    2. Overall rates in inpatients ~0.4%; less common in outpatients (~0.1%)
    3. Include confusion, agitation, hostility, delirium, hallucinations
    4. Obtundation or somnolence occurred in very few patients
    5. Liver or renal disease do not appear to contribute independently to likelihood of CNS symptoms
    6. Sucralfate or PPI should generally be used in these settings

E. Nonulcer Dyspepsia (NUD) [2,5,30] navigator

  1. Causes as described above
    1. Gastritis syndromes
    2. Malabsorption - usually carbohydrates
    3. Duodenitis
    4. Biliary (enterogastric) reflux
    5. Small-instestinal parasite, especially Giardia, Strongyloides
    6. Chronic Pancreatitis
    7. Psychiastric disorders
    8. Reflux esophagitis - nonerosive
    9. Gastroparesis - idiopathic, diabetic, others
    10. Small intestinal dysmotility
    11. Abnormal gallbladder and biliary tract motility
    12. No clear etiology in ~60% of cases ("functional" dyspepsia" - see below)
  2. Functional Dyspepsia [42]
    1. Ulcer-like, dysmotility-like
    2. No structural lesions causing symptoms are found
    3. Believed to be due to abnormal upper GI function
  3. High Risk for Serious Organic Causes of Dyspepsia
    1. Age >49 years
    2. Anorexia or weight loss
    3. Dysphagia or Odynophagia
    4. Vomiting
    5. Anemia
    6. Positive fecal occult blood test
    7. Jaundice
    8. Failure of several empirical treatments
    9. Strong familial history of cancer
  4. Evaluation
    1. Must rule out serious causes of dyspepsia
    2. Clinical history cannot reliably distinuish between organic and functional dyspepsia [23]
    3. Endoscopy is generally considered the gold standard
    4. Strongly consider endoscopy if likelihood of organic disorder is high (see below)
    5. Empiric therapy may be tried if patient is unlikely to have serious cause of NUD
  5. Empiric Therapy [2,30]
    1. Dietary modification - limited evidence to support therapeutic benefit
    2. Psychological therapy - improves quality of life, reduces physician visits
    3. Helicobacter pylori eradication - small but significant benefit (NNT = 14) [30]
    4. H. pylori eradication for pure non-ulcer dyspepsia is beneficial in ~20% of patients [31,32]
    5. Proton pump inhibitors - benefit over placebo with NNT 9-14 [41]
    6. Antidepressants / anxiolytics - probably most effective (>50% reduction)
    7. Prokinetic Agents - efficacy 2X of placebo (NNT >4)
    8. Metoclopramide - poorly documented efficacy but often used
    9. Droperidone - improves global symptoms as assessed by clinician
    10. Itopride (dopamine D2 antagonist with cholinesterase inhibition activity) used in Japan
    11. Itopride 100mg and 200mg po tid superior to placebo on improving symptoms [42]
    12. Multiple agents often used together with psychological therapy
  6. Single Day Eradication of H. Pylori in Dyspepsia [38,39]
    1. May be as effective as 7 day therapy but not yet FDA approved
    2. Each of these is given over 1 day:
    3. 2 tablets 262mg bismuth subsalicylate 4 times
    4. Amoxicillin 2gm suspension 4 times
    5. Lan 30mg one tablet
    6. Eradication rates of 20-95% reported

F. Menetrier's Diseasenavigator

  1. Rare, acquired, premalignant hypertrophic lesion of the stomach
    1. Main symptom is epigastric pain
    2. Excess mucous secretion
    3. Hypochlorhydria
    4. Anorexia and weight loss
    5. Hypoproteinemia in later stages
    6. May progress to gastric carcinoma
  2. Large tortuous hypertrophic gastric folds
    1. May be focal or diffuse within the stomach
    2. Hyperplasia of surface and glandular mucous cells
    3. No inflammation
  3. May be associated with cytomegalovirus (CMV) or Helicobacter pylori infection
  4. Increased signalling through epidermal growth factor receptor (EGF-R)
  5. May progress to a protein losing gastropathy with hypoalbuminemia and edema
  6. Diagnosis by deep mucosal biopsy (to rule out gastric malignancy)
  7. Treatment
    1. Largerly empirical with mixed results
    2. Anti-cholinergic agents or histamine blockers may be helpful
    3. Proton pump inhibitors (PPI)
    4. Weekly treatments for one month with anti-EGF-R antibody reduced symptoms and induced regression of hypertrophy in one case report [33]

G. Gastric Cancer navigator

  1. About 10% of gastric ulcers are neoplastic (adenocarcinoma)
    1. Infection with H. pylori was strongly associated with of gastric cancer [2]
    2. No absolute causal role has been demonstrated to date
  2. Gastric Lymphoma has been linked to H. pylori [2,34]
    1. H. pylori is causative for Mucosal Associated Lmphoma Tissue (MALT)
    2. In a study of 25 patients with MALT Lymphoma, 15 patients had complete or near complete tumor regression when H. pylori was eradicated

H. Zollinger-Ellison Syndrome [35] navigator

  1. Hypersecretion of gastrin leads to hyperacidity and ulceration
  2. Symptoms
    1. Hearburn
    2. Epigastric and Non-specific Abdominal Pain
    3. Diarrhea
    4. Multiple peptic ulcers including in the jejunum
    5. Refractory ulcer disease or multiple, large ulcers
  3. Diagnosis
    1. Fasting gastrin level elevated (normal <100ng/L)
    2. Abnormal increase gastrin level post secretin challenge
    3. Normal response: gastrin level <200ng/L
    4. Basal acid output increased (normal <10mEq/hr)
    5. 65% of ZE patients patients have basal acid outputs >10mEq/hr; 50% >15 mEq/hr
    6. Evaluation for other MEN-1 syndromes
  4. Imaging for Gastrinoma [36]
    1. CT scan is usually primary modality
    2. MRI is now used for metastatic disease and is more sensitive than CT
    3. Nearly 30% of cases will have liver metastates at diagnosis (~25% 5 year survival)
    4. Angiography is now secondary modality
    5. Selective venous sampling
  5. Treatment
    1. Blockade of acid secretion with high dose PPI
    2. Surgical removal of tumor - patients without liver metastates have >90% 5 year survival
    3. Chemotherapy: streptozocin and 5-fluorouracil or doxorubicin
    4. Interferon alpha may slow growth of some tumors

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