Peptic ulcer disease

Definitions

• Peptic ulcers
  • Are defects in the gastric or proximal duodenal mucosa that extend through the muscularis mucosa
• Peptic ulcer disease
  • Is a relapsing and chronic disease which involves duodenal ulcers and gastric ulcers
• An infectious disease
  • Peptic ulcer disease is today considered an infectious disease caused by the bacteria Helicobacter pylori (Hp)
  • However, at least 25% of the gastric ulcers and a small number of duodenal ulcers are caused by ulcerogenic drugs like NSAIDs and salicylates
• Chronic and relapsing disease
  • A patient with a previous detected peptic ulcer, in whom the Hp has not been eradicated, has by definition still a peptic ulcer disease
  • Again, ulcers caused by ulcerogenic drugs are an exception
• Further reading
  • See separate article about complications in peptic ulcer disease
  • See separate article about Helicobacter pylori

Incidence/prevalence

• Lifetime prevalence
  • About 10% of the population will some time during life develop peptic ulcer disease, although this proportion is decreasing
• Incidence
  • The incidence of duodenal ulcers has dropped significantly during the last 30 years, while the incidence of gastric ulcers has shown a small increase, mainly caused by the widespread use of NSAIDs
  • The drop in incidence is considered to be a cohort-phenomena independent of the progress in treatment of the disease. The cohort-phenomena is probably explained by improved standards of living which has lowered the incidence of Hp-infections
• Gender
  • Nowadays peptic ulcer disease is about just as common among women (9,5%) as among men (10,5%)¹
• Age
  • Duodenal ulcers are most frequent among individuals 30 to 55 years of age, while gastric ulcers are more common among individuals 55 to 70 years of age
• Location
  • Duodenal ulcers occur fime times as frequent as gastric ulcers
• Hp epidemiology
  • In the general population 20-50% are infected with Hp, the prevalence increases with age
  • It is estimated that only 15-20% of the infected individuals will develop a peptic ulcer²

Etiology and pathology

• According to American figures Hp-infection (48%) and NSAIDs (24%) are the dominating causes of peptic ulcers³
• A number of other infections and co-morbidity increase the risk of developing a peptic ulcer, like cytomegalic virus, tuberculosis, Crohn's disease, cirrhosis of the liver, chronic renal failure, sarcoidosis, myeloprolipherative conditions⁴
• Critical illness, surgery or hypovolemia can induce splanchnic hypoperfusion and may result in gastroduodenal erosions or ulcers (stressulcers) - such lesions can be asymptomatic and manifest themselves with bleeding and perforation⁵
• Increased production of gastric acid and pepsin is of importance in duodenal ulcers
• Zollinger-Ellison's disease, a gastrin producing tumor, is a very rare cause of an aggressive type of peptic ulcer disease
• Smoking is an important risk factor for relapse, and it delays the process of healing

Etiology - infection with Helicobacter pylori

• Hp is recognised as the main causative factor for peptic ulcer disease - it is a Gram negative bacteria
• Hp-infection and risk of peptic ulcer disease
  • Only 10-15% of Hp-positives will develop peptic ulcer disease⁶
• Frequency of Hp-infection
  • More than 95% of all duodenal ulcers and about 75% of gastric ulcers are Hp-positive
  • Except from patients using NSAIDs or salicylates, the prevalence of Hp is close to 100% also in patients with gastric ulcer
• Additional effects of Hp-infection
  • Patients with Hp-infection have increased resting and meal stimulated levels of gastrin, reduced production of mucus in the stomach and reduced production of bicarbonate in the duodenum - all are factors that contribute to the development of peptic ulcer
• Effect of Hp-elimination
  • Eradication of H. pylori was in one study found to reduce the relapse rate of duodenal ulcers from 67% to 6% and in gastric ulcers from 59% to 4%⁷

Etiology - NSAIDs

• About 25% of gastric ulcers and a small proportion of duodenal ulcers are caused by side-effects from NSAIDs and salicylates
• NSAIDs is the commonest reason for peptic ulcer in patients without H. pylori-infection⁸
• Pathophysiology
  • Locally NSAIDs can cause submucosal erosions. Besides, by inhibition of the cyclooxygenase, NSAIDs hinder the formation of prostaglandins and their protective cyclooxygenase-2-mediated (COX-2) effects
  • COX-2 enhances the protection of the gastric mucosa by stimulation of the production of mucus and bicarbonate, fascilitates the proliferation of epitelial cells and increases the blood flow in the submucosa
  • Infection with H. pylori adds to the risk and extent of NSAID-induced lesion⁹
• Ulcer complications
  • The annual risk of lifethreatening ulcer-related complications is 1-4% among patients on longterm treatment with NSAIDs, with the highest risk among the oldest patients¹⁰
  • NSAIDs are the cause of approximately half of all perforated ulcers, which occur most frequently among elderly patients who take aspirin or other NSAIDs for protection of cardiovascular disease or artropathia^11-12
• Protective drugs
  • Protonpump inhibitors and misoprostole reduce the ulcerogenic potential from NSAIDs and reduce the relapse rate of NSAIDs-related peptic ulcers

Pathogenesis of ulcer development

• A defect (an ulcer) occurs in the mucosa of the stomach or duodenum when protective factors are weakened or the mucosa is exposed to large amounts of aggressive luminal factors, like acid and pepsin
• The ulcer extend trough the muscularis mucosa and is usually more than 5 mm in diameter
• More than 95% of the duodenal ulcers are located in the bulbar part of the duodenum or in the pyloric region
• Benign gastric ulcers are usually located in the antrum (60%) or in the transission zone between the antrum and corpus on the minor curve of the stomach (25%)

Risk factors

• NSAIDs
  • NSAIDs increases the risk 5-7 times of developing a gastric ulcer within the first three months after the start of NSAIDs treatment, later the risk is increased 4 times. Two months after cessation of the treatment the risk is back to normal¹³
  • There is a clear dose-response relation
  • An additive risk is observed when NSAIDs are combined with SSRI treatment^14-15
  • COX-2 reduces the frequency of milder forms of dyspepsia and also lowers the risk of perforation, obstruction and bleeding¹⁶
• Salicylates
  • Relative risk was in one study found to be increased with 2.6 and low dosage reduced the risk (Ia)¹⁷
  • In another study the relative risk was 1.6 among patients using 50-162 mg daily and 1.7 among patients using 163-1500 mg daily (Ia)¹⁸
• SSRI
  • Use of SSRI is associated with increased risk (RR = 3.6) of bleeding in the digestive tract^14-15
  • This risk is significantly increased if NSAIDs are used at the same time (RR = 12.2)
• Family history
  • Peptic ulcer disease among parents or siblings increases the risk by 2-2.5
• Smoking
  • Increases the incidence of peptic ulcer disease with appr. 1.5
• Rheumatic problems and low socioeconomic status
  • Increase the risk of peptic ulcer disease
• Psychosocial factors (stress)
  • Is shown to be of importance among Hp-infected individuals and when the disease will manifest itself
• Dietary factors
  • Do not alter the risk of peptic ulcer disease

ICPC

• D85 Duodenal ulcer
• D86 Other types of peptic ulcers

ICD-10

• K25 Gastric ulcer
• K26 Duodenal ulcer
• K27 Peptic ulcer disease, unspecified location

Diagnostic criteria

• Upper GI endoscopy is the diagnostic gold standard
• Radiology has a clearly lower sensitivity, ulcers are overlooked and the method does not allow for biopsy
• Medical history identifies only 20-40% of the patients with peptic ulcer

Differentials

• Functional dyspepsia
• Gastrooesophageal reflux disease
• Gastric cancer
• Gallstone disease

History

Symptomatology

• Symptoms in peptic ulcer disease occur periodically, they vary strongly and are to a small extent typically^19-20
• The intensity of the symptoms fluctuate from day to day and during the same day²¹
• Symptoms are usually relieved by eating and antacids, although nearly half the patients deny such meal-related association
• About 2/3 of patients with duodenal ulcer and 1/3 of patients with gastric ulcer experience night pains that may awake them
• Nausea, vomiting, early satiety and anorexia are more prominent among patients with gastric ulcer than with duodenal ulcer
• Anorexia and weight loss increases the suspicion of malignancy

Predictive value of medical history

• The natural course and the clinical presentation of peptic ulcer disease varies between individual populations^22-24
• Low predictive value
  • The medical history has a limited diagnostic value - positive predictive value is only about 25% in general practice
  • Among previously non-endoscoped patients only 1 in 4 in whom the physician predicts an ulcer, will prove to have an ulcer at endoscopy
• Following factors are the best anamnestic indicators of peptic ulcer¹⁹:
  • Age above 40 years
  • Relief from eating, although half the patients reject such an association
  • Relief from antacids
  • Night pains
  • Smoking
  • Even if all these factors are present, the probability of having a peptic ulcer is not higher than 50%
• NSAIDs or salicylates
  • Significantly increase the risk of peptic ulcer, and this risk is further increased with length of treatment and dosage
  • About 30-50% av these ulcers are asymptomatic (camuflated by the analgesic effect of the drugs)

Complicated peptic ulcer

• Unreliable symptoms
  • Although the majority of these patients have dyspepsia in advance, up to 20% of patients with gastric bleeding have been symptomfree until the bleeding started
  • In patients with NSAID-induced complications, nearly 60% have no symptoms in advance, maily due to the analgesic effect
• Bleeding
  • Anemia, hematemesis, melena and detection of fecal occult blood may indicate bleeding
• Penetration and perforation
  • Persistent upper abdominal pain which radiculate to the back may indicate penetration
  • A dramtic increase in pain indicates a perforated peptic ulcer
• Retention
  • Vomiting indicates obstruction
• Malignancy
  • Anorexia and weight loss may indicate cancer

Physicals

• No specific findings influence the probability of a peptic ulcer
• Usually the clinical examination is normal
  • Still, it is important to perform a clinical examination in order to exclude other explanations of the patients symptoms
• In acute illness caused by a bleeding or perforated ulcer the clinical examination is decisive to judge the severity of the condition

Lab tests in general practice

Biochemical tests

• Except for detection of fecal blood, no tests have any positive predictive value in peptic ulcer disease
• Detection of fecal blood may indicate a small bleeding from a peptic ulcer and demands further exploring
• In the diagnostic workup of dyspepsia other tests may also be useful

Detection of fecal Hp-antigen

• A monoclonal antibody kit is available, provides stabile responses and has a sensitivity of 95% and specificity of 97% according to one study²⁵ - and is less expensive than the urea breath test, but costs more than serologic tests
• Disadvanteges
  • The patient must stop the intake of proton pump inhibitor at least two weeks prior to the test or H2-antagonist at least one day before the test²⁶
  • Antibiotics should not have been taken the last four weeks
• Method
  • The test applies laboratory methods similar to the serologic tests, and the test may be used in general practice²⁷
• Usefulness
  • The test can be applied both in the diagnostic workup and to confirm the eradication of the infection following treatment^{26, 28}

Serology?

• Should be substituted by fecal antigen test
• Can be useful in the workup of dyspepsia
• Rapid tests versus ELISA-tests
  • Rapid tests have lower sensitivity (85% vs 95%) and lower specificity (70-90% vs 90-95%)^29-31
  • Thus, rapid tests have a higher probability of both false positive and false negative results and therefor should be omitted
• Test of treatment effect?
  • Serology is unreliable in the control of the effect of anti-Hp-therapy, the antibody titer is declining slowly over months and years

Hp-status and clinical implications

• Patients under 50 years
  • Should be tested
  • A positive test implies that endoscopy should be done, or test-and-treat^32-34
  • A negative test almost excludes organig disease, and there should be no need to do endoscopy
• Patients over 50 years
  • Need not be tested, they should be referred to have an upper GI endoscopy

Investigations

Upper GI endoscopy

• Diagnosis is verified by endoscopy, which also allows for biopsy of gastric ulcers and invasive tests of H pylori³²
  • PCR is the preferred test
  • Alternatives are rapid urease test, culture with test of resistence, and histology
• Biopsy
  • Is done to exclude malignancy
  • Five percent of gastric ulcers are malignant
  • 8-10 samples are taken from the edge of the ulcer, an alternative is brush cytology
  • Duodenal ulcer are almost never malignant, and they need not be biopsied
• Erythromycin prior to endoscopy for acute upper gastrointestinal haemorrhage?
  • Erythromycin is a potent stimulator of gastrointestinal motility. Studies have shown that intravenous erythromycin fastens the clearance of blood from the stomach before oesophago-gastroduodenoscopy (EGD) for acute upper gastrointestinal haemorrhage (UGIH) (Ia)³⁵
  • Because of the implications for cost saving and increase in QALY, it is recommended to give erythromycin prior to EGD for UGIH

Lab tests in hospitalized patients

• Hb, bloodtyping in bleeding
• Measurements of serum-gastrin if Zollinger-Ellison's syndrom is suspected (multiple ulcers)

Radiology?

• Double-contrast radiography performed by an experienced radiologist might approach the diagnostic accuracy of upper GI endoscopy (70% versus 95%). However, it has been replaced largely by diagnostic endoscopy, when available
• Radiology could be indicated to rule out malignancy, in particular linitis plastica
  • In such situations CT and MRI should be considered

Hp-tests in bleeding peptic ulcer

• The following is based on a systematic review (Ia)³⁶
• Biopsy-based methods like rapid urease test, histology and culture have low sensitivity, bur high specificity
• Radioactive labelled urea breath test has high diagnostic accuracy
• Fecal antigen test is less accurate
• Serology can not be recommended as the initial diagnostic test under such circumstances

Referral

• It is unnecessary to refer patients with known duodenal ulcer disease, except when there is complications or strikingly changes in the symptomatology
• Patients with earlier gastric ulcer should be considered for a new upper GI endoscopy when symptoms relapse - there is alway a risk for underlying malignancy
• Relapse in a patient who has been adequately treated with anti-Hp-therapy, but who is still Hp-positive, may need a bacterial resistance determination

Treatment aims

• Eliminate the Hp-infection - today's treatment regimens have a success rate of 90% in clinical studies, but the success rate in clincal practice is lower³⁷, and has dropped further during the latest years³⁸
• Eliminate other risk factors in peptic ulcer disease - NSAIDs, salicylates, smoking, stress

Overview of management

• A valid diagnosis
  • Ideally, treatment should be based on an endoscopic diagnosis, otherwise a lot of patients will be treated unnecessary
  • Patients with an earlier endoscopically confirmed duodenal ulcer disease and still suffering from symptoms, should be considered as infected and can be treated without going through a new endoscopy
• Treatment failures
  • Most often caused by non-compliant patients or bacterial resistance^39-41
• Consider your treatment strategy according to the following guidelines:

Incident cases of Hp-infected duodenal or gastric ulcers

• The endoscopist prescribes triple therapy (or quadruple therapy)^42-44
• Treatment effect should be actively controlled in patients with gastric ulcer

Recurrence of known, uncomplicated duodenal ulcer disease

• Re-endoscopy and Hp-tests are not necessary
• All patients should be offered treatment
• The patients can be treated by the general practitioner
• Systematic control of treatment effect is unnecessary

Recurrence of known duodenal ulcer disease with earlier complication

• Prescribe anti-Hp-therapy
• Control that the eradication of Hp has been successful

Recurrence of known gastric ulcer disease

• Assess the risk of malignancy and decide on that background whether you will treat or refer the patient to endoscopy
• If you choose to treat, the effect of the treatment should be controlled

Self treatment

• There is no scientific evidence to recommend any dietary changes
• Stop smoking, since smoking delays the healing process and increases the risk of relapse
• Avoid salicylates and NSAIDs
• A moderate intake of alcohol is not harmful
• Advice the patient temporarilly to avoid foods and drinks the patient by personal experience knows may provoke symptoms

Patient involvement in drug treatment

• The recommended treatment regimens below have a maximum success rate of 90%
• Treatment success demands that the patient follows the treatment instructions strictly
• Any forgotten tablet reduces the chances for a successful result

Medications

• Currently, there is no ideal treatment available for Hp-positive patients. A combination therapy of at least three different drugs is needed

Treatment regimens

• In the regimens below, omeprazole may be replaced by another proton pump inhibotor. The numbering of the regimens does not indicate any priority
• Some experts warn that clarithromycin should be restricted to patients who have experienced a treatment failure. In spite of that, the majority of the most frequently applied regimens include clarithromycin
• Se avsnittet nedenfor om synkende suksessrater
• Course 1
  • Omeprazole (Losec^®) 20 mg x 2
  • Metronidazole (Flagyl^®) 400 mg x 2
  • Clarithromycin (Klacid^®) 500 mg x 2
• Course 2
  • Omeprazole (Losec^®) 20 mg x 2
  • Amoxicillin (Amoxicillin^®) 500 mg (750) mg x 2
  • Clarithromycin (Klacid^®) 500 mg x 2
• Course 3
  • Omeprazole (Losec^®) 20 mg x 2
  • Amoxicillin (Amoxicillin^®) 500 mg x 2
  • Metronidazole (Flagyl^®) 400 mg x 2
• Course 4
  • Bismuth subcitrate (Denol^®) 240 mg x 2
  • Metronidazole (Flagyl^®) 400 mg x 3
  • Tetracycline (Tetracyklin^®) 500 mg x 4
• Course 5
  • Ranithidine bismuth citrate (Pylorid^®)
  • Clarithromycin (Klacid^®) 500 mg x 2
  • Possibly + amoxicillin or metronidazole
• Course 6
  • Esomeprazole (Nexium^®) 20 mg x 2
  • Clarithromycin (Klacid^®) 500 mg x 2
  • Amoxicillin (Amoxicillin^®) 1 g x 2
• Quadruple course
  • Omeprazole (Losec^®) 20 mg x 2
  • Bismuth subcitrate (Denol^®) 240 mg x 2
  • Tetracycline (Tetracyklin^®) 500 mg x 4
  • Metronidazole (Flagyl^®) 400 mg x 2
• After ended triple therapy patients with large ulcers could benefit from furter 4 weeks of treatment with a proton pump inhibitor

Triple therapy - general information

• Duration of treatment
  • Usually 7-10 days
  • In a study it was shown that one week's treatment with omeprazole, amoxicillin and clarithromycin given twice a day was just as efficacious as to weeks of treatment. Besides, the costs become lower and the treatment is less cumbersome to the patient (Ib)⁴⁵
• Treatment failure
  • Which means that Hp is not eradicated, is mostly due to patients who do not comply with the treatment instructions
• Side-effects
  • Occur quite frequently, the worst is bismuth-medications, but they are seldom serious
• Bacterial resistance
  • Both metronidazole and clarithromycin resistance is a frequent cause of treatment failure^39-40
  • Prevalence of resistance to metronidazole is about 25%⁴⁶
  • Prevalence of resistance to clarithromycin is 10-20%⁴⁶
• Success rates are falling
  • International statistics show falling success rates with conventional triple therapy. The explanation can be the increasing use of eradication regimens in the treatment of functional dyspepsia, less pathogenic types of H pylori or an increased incidence of resistance to macrolids³⁸
  • A sequential regimen is recently shown to improve the results (Ib)⁴⁷
  • Example of a sequential regimen: Proton pump inhibitor + amoxicillin 1 g for 5 days, followed by proton pump inhibitor + clarithromycin + metronidazole for 5 days
• Increased gastrooesophageal reflux after Hp-eradication?
  • It has been claimed that eradication of H pylori will increase gastrooesophageal reflux, but recent studies find few signs of that^48-51

Hp + and peptic ulcer caused by NSAID

• Acute therapy
  • Stop, if possible, the treatment with NSAID⁵²
  • Give anti-Hp-therapy
• Patients who need longterm treatment with NSAIDs
  • If the patient needs to be treated with NSAID, both misoprostol, proton pump inhibitors and a double dose of H2-antagonists seems to provide effective prophylaxis against peptic ulcer (Ia)^53-54
    • Diarrhoea is a frequent side-effect of misoprostol
  • Eradication of Hp reduces the incidence of peptic ulcer among NSAIDs-users. However, eradication is less effective than maintenancetreatment with a proton pump inhibitor with regard to protection against ulcer (Ia)⁵⁵
• Longterm treatment with lowdose of salicylate^56-57
  • Hp-positive patients should have H pylori eradicated
  • Acid reducing agent should be used prophylactic when longterm treatment with salicylate is needed
  • Salicylic acid combined with a proton pump inhibitor lowers the risk of rebleeding compared to clopidogrel used alone. The combination is also a less expensive alternative than clopidogrel used alone⁵⁸
• COX-2 specific NSAIDs?
  • Be aware of the negative effects of this group of NSAIDs
    • There is serious doubt about the safety of this subgroup of NSAIDs in comparison to conventional NSAIDs, since COX-2-inhibitors increase the frequency of thromboembolic diseases, heart failure and other oedematous disorders, and reduced liver function¹⁶
  • Reduces the number of peptic ulcers, although the risk of symptomatic ulcers, perforation and bleeding is to a very little degree affected^59-60
    • NNT = 200, which means that 200 patients have to be treated for 1 year in order to hinder the development of one ulcer⁶¹
    • COX-2-agents is so far not studied as an alternative treatment in NSAID-induced ulcers
• NSAID + SSRI
  • Use of SSRI is associated with an increased risk (RR = 3.6) of bleeding in the digestive tract^14-15
  • This risk is significantly increased it NSAIDs are used together with SSRI (RR = 12.2)

Medication in Hp -negative ulcers

• Treatment alternatives, apply also for NSAID-induced ulcers
  • H2-antagonists
  • Proton pump inhibitors
• Acid reducing treatment
  • Seems to give a more rapid and better symptomatic relief the more potent the acid inhibition is
  • Proton pump inhibitors are definitely most potent, ex. Losec 20 mg x 1
• Treatment duration
  • Should be 4-6 weeks in duodenal ulcer and 6-8 weeks in gastric ulcer
  • Longterm treatment with an acid reducing agent can be necessary in such patients
• Antithrombotic therapy in patients with earlier bleeding ulcer
  • Combination therapy with aspirin + proton pump inhibitor twice daily was in one study found to be safer thant clopidogrel with regard to bleeding in the stomach (Ib)⁶²
  • The study raises doubt about the safety of using clopidogrel (Plavix) in such patients

Ongoing bleeding from a verified peptic ulcer⁶³

• First priority is given to handling a potential shock, to establish a correct diagnosis, risk assessment (i.e. Hp-status) and determination of relevant endoscopic treatment⁶⁴
• Endoscopic haemostasis
  • Many bleedings stop spontaneously
  • Potential interventions are use of hemoclips; injection of adrenalin, alcohol or a sclerosing agent, or a combination of the methods⁶⁵
  • Risk of rebleeding is highest from ulcers with "bleeding stigmata":
    • Visible vessels, clots, a bleeding point in the bottom of the ulcer crater
    • In such situations one aims at endoscopic treatment with infiltration of adrenalin 0.1 mg/ml attenuated 1:5 with NaCl 0.9%, potentially followed by aetoxysclerol
  • In one study pantoprazole was found to be more effective than somatostatin to prevent rebleeding after a successful endoscopic hemostasis (Ib)⁶⁶
• Intravenous proton pump inhibitor?
  • In vitro trials demonstrate that hemostatic mechanisms are enhanced with a neutral pH by improving the function of the thrombocytes and restrain the fibrinolysis⁶⁴
  • In cases with less bleeding, nausea, vomiting, stenosis og acute severe oesophagitis which causes dysphagia, a proton pumb inhibitor can be given, ex. Losec 20-40 mg x 1 intravenously until the patient take liquid food, followed by oral treatment
  • Reduced rebleeding (NNT 12) and reduced need for surgery (NNT 20), but did not affect the overall mortality (Ia)^67-68
  • Since the clinical significance of acid reduction is modest, it can be just as important to get started with conventional oral ulcer treatment as soon as the condition allows it - usually within one day
• Other surgical interventions in ongoing or rebleeding episodes
  • Angiographic embolisation or surgery can be indicated⁶⁵
  • Possible gastroduodenotomi and oversewing of blood vessels with or without vagotomi and drainage of duodenal ulcer; and excision of the ulcer with vagotomi and drainage or partial gastrectomi in bleeding gastric ulcer
• Anti-Hp-therapy
  • Hp-positives should have eradication treatment⁶⁹
• Longterm prophylaxis with proton pump inhibitor or misoprostol
  • If continued treatment with salicylate or NSAID is mandatory, the patient should also be given treatment with misoprostol or PPI^70-71
• Longterm prophylaxis with H2-antagonist?
  • In patients who have suffered from a bleeding ulcer, long term prophylaxis with H2-antagonist should be considered and Hp-diagnostics performed
  • A follow-up study of patients with bleeding ulcer who were eradicated of Hp, showed no difference in prognosis between those who got protective treatment and those who did not get such treatment⁷²

In therapeutic resistant cases^{63, 73}

• Check compliance - is the patient taking the drugs as instructed?
• Is the patient taking salicylate or NSAID?
• Smokers shoud stop smoking
• Zollinger Ellison's syndrome? Measure s-gastrin
• Consider the possibility of a submucosal tumor with ulceration
• Hp-tests should be repeated. Antigen test or urea breath test?
• Consider determination of bacterial resistance in connection with endoscopy
• A second treatment regimen should not include metronidazole if the drug has been given in the initial course

Surgery

• If recurrent treatment failures with medications, consider surgery in Hp-negative patients
• Hp-positive ulcer disease should not be operated

Indications⁶³

• Perforated ulcer
  • Has traditionally been treated with open surgery, but laparoscopic interventions seem to give at least as good results - although more evidence is needed (Ia)⁷⁴
  • Treatment is started with infusion of liquid, nasogastric suction and broadspectered antibiotics intravenously
• Severe bleeding
  • Associated with a fall in bloodpressure to below 100 mm Hg in spite of infusion of blood and saline and endoscopic therapy
  • Arterial embolization can often replace surgery in ulcer bleeding⁷⁵
• Rebleeding
  • Rebleeding after an initial stop in the acute bleeding og failed endoscopic haemostasis
  • Duodenal ulcer located on the posterior wall are sometimes associated with severe bleeding which often involves arteria gastroduodenale, and in this situation endoscopic therapy is seldom sufficient
• Prolonged bleeding
  • Bleeding which lasts more than 24h and with a need for bloodtransfusion that surpasses 6 units
• Suspicion of malignancy
• Retention/pyloric stenosis
  • Acute retension responds well on nasogastric decompression, use of H2-blocker or proton pump inhibitor and eradication of H. pylori
  • Endoscopic balloon dilatation of the pylorus or surgery - vagotomi or pyloriplastic, antrectomi or gastroenterostomi - are options to alleviate chronic obstruction⁷⁶
• Unsatisfactory effect of medical treatment

Gastric ulcer⁶³

• Methods
  • Resection of the ulcer and gastroduodenostomi a.m. Bilroth I
  • Alternatively, excision of the ulcer and suture in severely ill patients
• A perforated gastric ulcer
  • Is usually treated with tegmentatio
  • Several biopsies are needed, or even better, excision of the ulcer to exclude malignancy

Duodenal ulcer⁶³

• Nearly all these patients are Hp-infected, in principle the condition should not be operated on
• General strategy
  • PGV (proximal gastric vagotomi) and resections are done only in extraordinary cases wherein medical therapy has failed
  • The type of intervention which conserves most of the stomach, is preferred
• Perforation
  • Tegmentatio
  • Thorough irrigation of the peritoneal cavity (min 2 liters)
• Bleeding
  • Longitudinal incision of the pylorus and crossectional closure
  • Closure of the bleeding vessel and identification and ligature of a. gastroduodenal on the duodenal outside, preferably on both sides
  • Alternatively, Bilroth II-resection

Post operative regimen⁶³

• Nasogastric tube should not be used as routine
• Aspiration is performed if the patient is nauseous or there are signs of gastric retention
• Patients with perforation treated with just tegmentatio, should have proton pump inhibitor 80 mg x 1 i.v. for 3 days
  • Alternatively, 3 mg/h infusion with pump, followed by oral therapy with 20 mg x 1 for 3 weeks

Prophylactic treatment

• No known treatment with regard to Hp-infection, although good hygiene and sanitation in the childhood years is of obvious significance
• Research is ongoing with regard to immunization

Ulcers caused by NSAIDs

• In patients with a predisposition for peptic ulcer, and who require longterm therapy with NSAID, there are three alternatives⁵³:
  • (1) Shift to a COX-2-inhibitor? It is uncertain how useful this is
  • (2) Combine the NSAID with misoprostol
  • (3) Combine the NSAID with a double dose of H2-antagonist or a normal dose of proton pump inhibitor

Ulcers caused by salicylates

• Salicylate + proton pump inhibitor (esomeprazole) was significantly better than clopidogrel in the prevention of rebleeding (Ib)⁶²
• Results from studies indicate that patients in need of prophylactic treatment with salicylate against cardiovascular disease should continue with salicylate + PPI in stead of clopidogrel

Clinical course

• Peptic ulcer disease is a chronic, recurrent disease if the Hp-infection is not cleared⁷⁷
• Without treatment the risk of developing a new ulcer is 70% within a year
• Relapse rates
  • Successful anti-Hp-therapy may reduce the incidence of ulcer relapse to 1% per year, which implies that patients may be cured of their peptic ulcer disease
  • An overview showed that eradication of Hp reduced the relapse rate from 67% to 6% in patients with duodenal ulcer disease, and from 59% to 4% in patients with gastric ulcer⁷⁸
• The probability of spontaneous eradication of a Hp-infection, is very small

Complications

• Silent ulcers and complications are more frequent among elderly patients and among patients taking NSAIDs^23-24
• The incidence of serious upper gastrointestinal complications among patients not taking NSAIDs is extremely low, less than 1 in 1000 personyears⁷⁹

In untreated Hp-infection

• Bleeding
  • Occurs in 10-15% of patients with peptic ulcer disease
  • Is the most common cause of death from peptic ulcer disease and the most frequent indication for surgery
  • Among elderly 20% of the episodes of bleeding are caused by asymptomatic ulcers²⁴
  • The patient may present himself with hematemesis, melena, fatigue due to anemia, syncope
• Perforation
  • Occurs in 1-2% of patients with peptic ulcer disease
  • Is located to the anterior duodenal wall (60%), although the perforation may also be located in antral gastric ulcers (20%) and along the minor curve of the stomach (20%)
  • A perforated ulcer with chemical and bacterial peritonitis has a high mortality and a high frequency of post operative complications⁸⁰
  • A subphrenical abscess may develop
  • Age, ASA-score (risk assessment prior to anesthesia) and time elapsed between start of symptoms and operation are important prognostic factors
  • Mortality among elderly patients may be as high as 30-50%
  • Ultrasound, CT and gastroduodenography are confirmative investigations
• Gastric retention
  • Gastric ulcer is the cause of only 5-8% of the cases with gastric outlet obstruction
  • Patients with recurrent duodenal ulcers or ulcers in the pyloric channel may develop pyloric stenosis as a result of acute inflammation, spasms, oedema, scarring and fibrosis
  • Malignant ulcer is a common cause of gastric retention - must be excluded⁸¹
• About 5% of the gastric ulcers are malignant

Prognosis

• Successful Hp-therapy cures the peptic ulcer disease when H. pylori is the cause of the disease
• The incidence of reinfection is about 1% per year, but can be higher in endemic areas⁸²
• Patients with peptic ulcer caused by NSAID/ASA, are in high risk of a relapse if exposed again

Plan

Uncomplicated duodenal ulcer

• No systematic control is necessary except in symptomatic relapse

Gastric ulcer

• Patients with gastric ulcers should be controlled with endoscopy due to the potential risk of malignancy (5%)
• Endoscopic control is performed with at least 5 biopsies after 8 and 16 weeks
• Further follow-up is individualized

Complicated peptic ulcer disease

• Patients who have experienced bleeding or perforation, should have their Hp-status controlled after treatment
• Failure to eradicate H. pylori renders the patient still at risk of getting a new lifethreatening ulcer
• If the patient still is Hp-positive, a new triple therapy should be given based on the results from a test of bacterial resistance

Symptomatic relapse after anti-Hp-therapy

• The patient should be endoscoped and tissue samples should be taken for culture and determination of bacterial resistance

Assessment of histology⁶³

• The endoscopist or the endoscopic unit has the responsibility
• Detected dysplasia
  • If dysplasia is detected, the patient should be controlled soon with 20 biopsies, since the original biopsy could have been taken from a site close to a carcinoma
  • In marked dysplasia the patient should be controllet every 6. month
  • In light to moderate dysplasia, the patient should be controlled after 1 year, thereafter every 5. year only in moderate dysplasia
• Focal foveolar hyperplasia, glandular cysts in the corpus and hyperplastic polyps
  • They have no malignancy potential, and should accordingly not be controlled
• Adenomas in the stomach
  • Are potentially malignant
  • Sling resection, the patient should be monitored for 1 night due to risk of bleeding
  • Control after 6 months, thereafter annually
• Intramucosal carcinoma in the stomach
  • In younger individuals without complicating diseases - operation
  • Exceptionally in elderly with high operationrisk: Laser therapy and regular controls

Follow-up after resection

• Following the operation a control is scheduled after 4-6 weeks, thereafter control with the GP
• Hb, s-iron and B₁₂ are measured annually after a gastric resection, and supplement should be given if needed
• All acute operated patients due to complications (bleeding or perforation), should have their Hp-status tested 4 weeks after the operation
  • In the mean time they should be put on acid reducing therapy, which should be stopped 5 days prior to the Hp-test
• Gastric resected patients should be controlled after 15-20 years
  • Biopsies are taken both from the major and minor curves
  • Further controls should be undertaken no more frequent thatn every 5. year

What to control

• Fecal antigen
  • Is the recommended test today
  • Has a high validity and an intermediate price
  • The test can confirm the eradication of the infection following treatment^{26, 28}
• Serology?
  • Has a low value in the control of anti-Hp-therapy when taken earlier than 4 months after the treatment course
  • At that time a titer fall could be expected
  • A prerequisite is that the blood samples taken before and after therapy are examined at the same time
• Urea breath test
  • Should be taken some months after treatment in patients with previous complications
  • Therapy with acid reducing agents should be stopped 5-7 days before the test
  • A breath test, wherein the patient is swallowing a mixture of ¹³C or ¹⁴C labelled urea which is split by the Hp's urease and thereafter expelled during expiration, is a valid and patient friendly method, but expensive. Equipment can be ordered from laboratories that make the measurements
  • ¹³C-urea blood test has higher sensitivity than fullblood antibody-tests⁸³

What to inform the patient about

• The necessity to strictly follow the treatment instructions for triple therapy

Available patient information leaflets

• Peptic ulcer disease
• What is endoscopy?
• Triple therapy
• Helicobacter pylori
• Peptic ulcers caused by NSAIDs

Animations

• Peptic ulcer disease

Images

• Radiograph of normal stomach (standing
• Radiograph of normal stomcah (supine)

Drawings

• Illustration of endoscopy
• Illustration of a stomach
• Illustration showing gastric and duodenal ulcers