WeBSurg, the e-surgical reference of Laparoscopic surgery

PEPTIC ULCER DISEASE

D Mutter, MD, PhD , Hôpitaux Universitaires de Strasbourg, Strasbourg, France
L Forbes, MD , Hôpitaux Universitaires de Strasbourg, Strasbourg, France

1. Introduction

2. Anatomy/pathology

3. Diagnosis

4. Complementary exams

5. Therapeutic strategy

6. Medical treatment

7. Duodenal ulcers

8. Gastric ulcers

9. Surgical treatment

10. References

1. Introduction

1.1. Overview

Epidemiologic studies have shown that the risk of developing peptic ulcer disease (PUD) in the course of a lifetime is approximately 10%.
The incidence in the adult population is 0.2%. In France, alone, there are 60 000 to 80 000 new cases each year.
Post-mortem series reveal a prevalence rate of 8.1% to 10.8% ( Zerbib et al ., 1993 ).
The gender ratio is 3:1 male to female.
Duodenal ulcer disease is known to have a high recurrence rate (60% after healing with medical therapy), justifying the use of long-term medical therapy and/or radical surgical treatment.

1.2. PUD and gastritis

Type A gastritis is an autoimmune gastritis characterized by achlorhydria and the presence of serum antibody to parietal cells. Less than 5% of the population is affected by this type of gastritis.

Type B gastritis affects the pyloric antrum of the stomach. It is often associated with gastric and duodenal ulcers. The prevalence of Helicobacter pylori ( H pylori ) is high in type B gastritis (90% of the cases). The relative risk of developing an ulcer is 10 times higher in persons with gastritis.

Role of H pylori :

the bacteria are present in 90% of patients suffering from ulcers;
eradication of H pylori significantly reduces the risk of recurrence;
medical therapy (1 antisecretory and 2 antibiotic medications) is successful in 90% of the cases.

Figure 1.2

2. Anatomy and pathophysiology

2.1. Gastro-duodenal ulcer: anatomical/pathophysiological definition

Ulcers are characterized by a loss of tissue, usually round or oval-shaped and of varying size. They are usually located:

at the level of the gastric lesser curvature;
at the level of the duodenal bulb.

Ulcers are associated by several pathophysiological features:

interruptions in the gastric and duodenal mucosal lining and muscularis layer due to a sclerotic process;
arterial vascular lesions;
hyperplasia of the nerve plexus.

Of note: Not all the above features are present during the early phases of ulceration.

2.2. Pathophysiology

Ulcers are thought to be precipitated by a combination of local environmental factors and factors pertaining to the “defense system” of the mucosal lining ( National Institute of Health Conference, USA, 1994 ).

Local environmental factors	Defense system factors
Hydrochloric acid Proteolytic enzyme activity Bile salts NSAIDs – Acetylsalicylic acid Helicobacter pylori Nitric oxide (at a high concentration)	Mucus-producing cells Surface glycoprotein gel Endoluminal bicarbonate secreted by the gastric and duodenal mucosa Microvascular supply of mucosa Repair of the mucosa

Risk factors are:

gender (male to female ratio is 3:1);
stress;
cigarette smoking.

Gastric (and peptic) acid hypersecretion (secretion of greater than 15 mmol of hydrogen protons per hour ( Baron, 1978 )), is an important factor in ulcer formation, thought to provoke intestinal bulb metaplasia and colonization in the antrum of the stomach and/or duodenum.

2.3. Epidemiology of H pylori infection

The prevalence of H pylori infection ranges from 20%-90% with an inverse relationship between prevalence of infection and socioeconomic status:

70-90% prevalence in developing countries;
20-30% prevalence in industrialized countries.

Males and females are affected equally.

The incidence of H pylori infection:

regularly increases with age (1% per year);
decreases in incidence with each generation;
direct contamination usually occurs during the first five years of life;
direct contamination in adults is rare (via endoscopy?).

Transmission of H pylori :

mostly by direct environmental contamination;
poor sanitary conditions;
often related to crowded living conditions.

3. Examination and diagnosis

3.1. Clinical characteristics

Clinical symptoms of gastric and duodenal ulcers are:

pain;
nausea and vomiting;
dyspepsia.

The pain is often described as:

located in the epigastric region;
“cramp-like”;
only rarely radiating;
of several hours duration;
usually occurring during the late postprandial period (2 to 3 hours after meals);
intermittently recurring (usually over a year or more).

The physical examination is usually normal, excepting cases presenting with complications.

3.2. Diagnostic criteria

Important facts to remember:

the variability of clinical signs and symptoms of duodenal ulcer disease;
the lack of correlation between the extent of pathology and the clinical symptoms;
complications of ulcer disease: ie, hemorrhage, perforation and stenosis.

The diagnosis is usually confirmed by endoscopy, during which biopsies are taken to check for H pylori infection.

In the case of a gastric ulcer:

at least 10 biopsies must be taken during endoscopy to check for cancerous lesions;
repeat endoscopy is performed on a routine basis after 6 weeks of medical treatment to verify proper healing of the ulcer.

A barium upper GI series with small bowel follow-through may be performed if the patient refuses fiberoptic endoscopy and/or it is not possible to perform a satisfactory exam.

Endoscopy is also useful for demonstrating:

anatomy in both static and “real time” images;
both direct and indirect evidence of ulcer disease;
signs of complicated disease i.e. gastric stasis, in cases of stenotic lesions.

3.3. Differential diagnosis

Differential diagnosis of other primary conditions:

gastroesophageal reflux disease (GERD);
biliary or hepatic etiology;
pancreatitis;
cardiac etiology.

Differential diagnosis of other complications:

other organ perforations (ie, small intestine, colon);
other hemorrhagic lesions;
stenosis at the level of the duodenal bulb due to extrinsic compression or invasive pancreatic cancer.

4. Complementary exams

4.1. Diagnosing Zollinger-Ellison syndrome

Zollinger-Ellison syndrome is characterized by inappropriate and paradoxical excessive secretion of gastrin.
It is caused by a tumor, which is often malignant (50% to 70% of the cases).

Zollinger-Ellison syndrome should be suspected in the following scenarios:

multiple or ectopic ulcers (located in the genu superius or descending part of duodenum);
erosive duodenitis;
resistance to medical treatment;
recurrence after medical or surgical treatment;
serious complications;
severe watery diarrhea.

Diagnosis is confirmed by:

fasting serum gastrin level;
secretin test.

Tumors may be diagnosed by:

endoscopy (in cases of duodenal or gastric tumors);
ultrasonography, especially endosonography;
CT scan;
selective abdominal angiography;
serum gastrin levels.

In case of a positive diagnosis, the patient should be checked for a polyendocrinopathy (Wermer syndrome).

Figure 4.1

4.2. Testing for H pylori

Indications for testing:
It is always advisable to check for the presence of H pylori , in order to rule out patients with negative results for whom another etiology should be established:

NSAID use;
Crohn’s disease;
Zollinger-Ellison syndrome;
cancerous lesions;
lymphoma ( H pylori is associated with a higher recurrence rate of MALT lymphoma).

Testing methods:
There exist both invasive and non-invasive methods for H pylori testing and different strategies for evaluating the outcome of multiple tests. Methods used to determine the outcome of H pylori testing should be tailored to each individual case, keeping in mind the sensitivity and specificity of each type of test.

Our recommendations for evaluation of outcomes:

positive test: if at least 2 tests are positive;
negative test: only when all tests are negative;
refractory case: if one post-treatment test is positive.

Invasive methods	Sensitivity
Rapid urease test Anatomical/path test: Histological test Culture Polymerase chain reaction	+ (88-95%) + (93-96%) +++ (80-98%) +++
Non-invasive methods	Sensitivity
Serologic test Urea breath test (UBT, 13 C or 14 C)	++ (86-94%) ++ (90-96%)

Howden, 1998

Rapid urease test on biopsy specimens:
This test is based on urease production by H pylori .
This enzyme converts urea to ammonia and carbon dioxide. As the ammonia increases the pH of a medium, a pH indicator changes color.

Anatomical/path test/Histological test:
The organism H pylori may be seen on microscopic examination of the biopsy specimens. It has a characteristic morphology; typically spiral, but may appear curved, and may be attached to the gastric mucous-producing cells.

Culture:
This is a standard bacteriologic exam. The samples are placed at -4°C for transport and then rapidly cultured.
The different staining properties are:

red or purple with Gram stain,
orange with Acridine stain.

Polymerase chain reaction (PCR) test:
The amplification of H pylori specific DNA sequences is achieved using pairs of specific oligonucleotides (primers).

13 C or 14 C urea breath test:
This test is based on the urease produced by H pylori . The patient is given oral carbon 13 C or 14 C isotope (natural and non radioactive) attached to urea. If H pylori is present, its urease cleaves to the carbon urea bond and forms ammonia and 13 C or 14 C. This gas is taken up by the bloodstream and later exhaled by the lungs where it can be detected.
The test is performed in fasting patients after administering a test meal. The analysis of the 13 C/ 12 C ( 14 C/ 12 C) ratio is done with a mass spectrometer, a laser spectrometer or an infrared spectrometer.

5. Therapeutic strategy

From Howden et al ., 1998 and Zerbib et al ., 1996

5.1. Principles of medical management of PUD

Eradication of H pylori :

antisecretory treatment;
antibiotic treatment;
second-line treatment medications.

5.2. Treatment of duodenal ulcers

medical treatment strategy for H pylori positive duodenal ulcers,
medical treatment strategy for H pylori negative duodenal ulcers.

5.3. Treatment of gastric ulcers

medical treatment of gastric ulcers,
medical treatment of chronic gastritis.

5.4. Indications for surgical treatment of PUD

surgical treatment of duodenal ulcers,
surgical treatment of gastric ulcers.

6. Medical treatment for PUD

6.1. Antisecretory medications

6.1.1. H2 antagonists
The H2 antagonists (cimetidine, ranitidine, famotidine, nizatidine) are effective in the treatment of duodenal ulcer. The length of the treatment is the main determining factor of the treatment’s efficacy (more so than the dosage of which is usually 300 mg/day). The recommended length of treatment varies from 2 to 6 weeks for this therapeutic class.

In Europe, the efficacy of healing is estimated at:

58% after 4 weeks;
71% after 6 weeks;
84% after 8 weeks;
91% after 12 weeks.

The medication should be taken once daily in the evening after dinner for the initial treatment.
One half of the dosage is taken for maintenance therapy. Hernia diagnosis is essentially done by physical examination.
Generally, the patient consults for a lump in the groin. The physician should find out when the lump appeared, and if it appeared progressively or abruptly and with pain following a physical effort or while coughing, defecating or urinating.
This swelling can cause functional problems ranging from a simple feeling of discomfort to true pain linked to straining, affecting the patient’s activities. Occasionally, there is no visible swelling and the symptomatology is limited to pain in the region of the groin, inguinal canal or testicles in males.

6.1.2. Proton pump inhibitors (PPIs)
These include omeprazole, lansoprazole, pantoprazole, rabeprazole sodium, and esomeprazole .
The recommended dosage is from 20 mg/day to 40 mg/day.
The healing efficacy of the PPIs parallels its ability to control clinical symptoms ( Howden et al ., 1993 ). It is reported as:

22% to 27% after 2 weeks;
69% to 93% after 4 weeks;
92% to 100% after 6 weeks.

The recovery rate has been shown to be faster after PPI treatment is higher than that after H2 antagonist treatment.
Recurrence rates also appear to be lower after PPI treatment as compared to H2 antagonist treatment.

The difference in healing efficacy of a 40mg/day dosage as opposed to a 20 mg/day dosage remains controversial.

6.2. Antibiotics

Several antibiotics are approved for eradication of H pylori . The following are usually cited:

clarithromycine – 1g/day, 2 to 4 times a day;
amoxicilline – 2g/day, b.i.d.;
metronidazole – 1g/day, b.i.d.;
tinidazole – 1g/day, b.i.d.;
tetracycline – 1g/day, b.i.d.

6.3. Other medications

Sucralfate stimulates increased synthesis of prostaglandines and growth factors by the gastric mucosa.
The usual dose is 1g/day.
Its healing efficacy after 8 weeks of treatment is 78%, comparable to that of H2 antagonists, but inferior to that of PPIs.

7. Management of duodenal ulcers

7.1. Management of duodenal ulcers H pylori infected patients

The major objective is to eradicate H pylori in the setting of duodenal ulcers.

Historically, antibiotics were first used in the management of PUD in 1990 ( Tatsuta et al ., 1990 ). Today, combination therapy is recommended, as follows, for the both the eradication of H pylori and the treatment of PUD.

Recommendations of the American College of Gastroenterology ( Howden et al. , 1993 )
(for dosages: see part 6)
1. Combination of a PPI, clarythromycine and amoxycilline for 2 weeks;
2. Combination of a PPI, clarythromycine and metronidazole for 2 weeks;
3. Combination of an H2 antagonist, clarythromycine and amoxycilline/metronidazole or tetracyclines for 2 weeks;
4. Combination of a PPI and metronidazole for 1 to 2 weeks;
5. Combination of a PPI, bismuth subsalicylate and tetracycline for 1 to 2 weeks.

Consensus conference recommendation, Paris, 1995
Bismuth citrate (4 x 120 mg/day) is sometimes added to combination therapies in an attempt to prevent the development of resistance to macrolides.
The length of treatment varies from 7 to 14 days.
A healing efficacy of 90% to 100% after 6 months has been reported.

Figure 7.1

7.2. Treatment of acutely symptomatic duodenal ulcers with a negative diagnosis for H pylori

If the H pylori test is negative, different etiologies must be considered:

NSAIDs usage;
Crohn’s disease;
Zollinger-Ellison syndrome;
tumor;
lymphoma.

In 3% of cases, the etiology of duodenal ulcers is neither infection with H pylori, nor NSAID use, nor disease related. These cases are seemingly on the rise.
A 4 to 6 week antisecretory treatment is prescribed, followed by maintenance therapy.
It is still important to continue trying to determine the etiology in these cases.
Surgical treatment should be considered for:

benign tumors such as a gastrinoma;
PUD refractory to standard medical treatment;
patient non-compliance.

7.3. Routine eradication of H pylori

Prophylactic eradication of H pylori in asymptomatic patients is generally not indicated. An exception is anticoagulation therapy.

Bleeding complications of PUD have been shown to occur more frequently if H pylori infections are not eradicated (20%-40% of cases) than if they are eradicated (0 to 5% of cases).

Eradication of H pylori has been also been shown to prevent recurrences of PUD after perforation ( Ng et al. , 2000 ).

In patients who have already had PUD complications, the goal of the treatment is to reduce recurrences and/or further complications.
The therapeutic algorithm is identical in these cases to the treatment for acutely symptomatic PUD.

8. Treatment of gastric ulcers

8.1. Treatment of gastric ulcers

The prevalence of H pylori infection in gastric ulcer disease is lower than for duodenal ulcer disease (70% of cases).
When an H pylori infection is diagnosed, a triple agent therapeutic to eradicate H pylori , similar to those used in the above treatment regimens for symptomatic H pylori positive duodenal ulcers.
In the absence of H pylori infection, single agent PPI therapy is recommended.

Endoscopic follow-up is very important. It is useful for quick detection of potentially cancerous lesions. Endoscopies and biopsies should be performed regularly for long-term follow-up.

If endoscopy shows an absence of healing 2 months after medical therapy, the medical treatment is restarted and follow-up endoscopy is performed 2 months later.

Surgical intervention should be considered for ulcers refractory to medical therapy.

8.2. Treatment of chronic gastritis

Chronic gastritis is determined by histological analysis of endoscopic biopsy specimens.

50% of patients with chronic gastritis are symptomatic, 35% are asymptomatic.
Infection by H pylori is reported in 90% of patients with chronic gastritis, but prophylactic eradication of H pylori has not been shown to be beneficial in the treatment.

Symptomatic chronic gastritis is treated in the same manner as gastric ulcer disease.

9. Surgical treatment of PUD

9.1. Duodenal ulcers

Deciding whether to implement medical vs. surgical treatment is based upon:

patient compliance with the treatment;
patient tolerance to the treatment;
efficacy of the treatment;
cost of the treatment (both to society and to the patient).

Indications for surgical treatment are:

disease refractory to medical treatment;
patient non-compliance with medical treatment;

Often due to:

high cost of medications (esp. in developing countries),
lack of medical follow-up.

The contraindications for surgical treatment are:

general medical contraindications to surgery,
history of previous major gastric surgery.

The types of surgical procedures for this pathology include:

truncal vagotomy (TV);
selective vagotomy (SV);
super selective vagotomy (SSV);
posterior truncal vagotomy and anterior gastric seromyotomy, combined with draining:
pyloroplasty,
antrectomy,
gastroenteroanastomosis.

The fact that vagotomies are now being performed electively has resulted in a decrease in the overall rate of complications of PUD, but the ulcer recurrence rate is increasing. However, when a selective vagotomy is performed, less than 50% of recurrences are actually symptomatic.
Complications following various procedures and incidence:

Procedure	Severe diarrhea	Severe dumping	Recurrent ulcer
VT	9.8%	5.9%	28.5%
SV	11.8%	19.6%*	37.4%
SSV	4.4%	2.2%*	39.3%

From Hoffmann et al ., 1989. *Significant statistical difference compared to TV (p < 0.05, 11-15 year follow-up).

The surgical approach is either conventional or laparoscopic.

The complications of surgical treatment include:

intraoperative mortality (0.1% to 1%);
diarrhea (1.8%to 40%);
dumping syndrome;
recurrent ulcer;
risk of gallbladder stones (multiplied by 3).

9.2. Gastric ulcers

The prevalence of gastric ulcers is from 2% to 14% of all gastro-duodenal ulcers.
The goal of surgical treatment is to:

prevent ulcer recurrence;
prevent complications;
treatment of potentially cancerous lesions (5% to 10% of cancers are not diagnosed by preoperative biopsies).

The types of surgical procedures include:

simple resection of the ulcer;
atypical gastric resection;
gastrectomy with vagotomy;
restoration of continuity.

10. References

NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA 1994;272:65-9.
Baron HJ. Clinical tests of gastric secretion. London: Mac Milan Press, 1978.
Conférence de consensus - Paris 12-13 Octobre 1995. Maladie ulcéreuse et gastrites à l’heure d’ Helicobacter pylori . Gastroenterol Clin Biol 1996;20:S1-S165.
Hoffman J, Jensen HE, Christiansen J, Olesen A, Loud FB, Hauch O. Prospective Controlled Vagotomy Trial for Duodenal Ulcer. Results after 11-15 years. Ann Surg 1989;209:40-5.
Howden CW, Burget DW, Wilkinson J, Hunt RH. A comparison of different drug classes with respect to rapidity of healing of gastric ulcer. Gastroenterology 1993;104:A105.
Ng EK, Lam YH, Sung JJ, Yung MY, To KF, Chan AC et al. Eradication of Helicobacter pylori prevents recurrence of ulcer after simple closure of duodenal ulcer perforation: randomized controlled trial. Ann Surg 2000;231:153-8.
Tatsuta M, Ishikawa H, Iishi H, Okuda S, Yokota Y. Reduction of gastric ulcer recurrence after suppression of Helicobacter pylori by cefixime. Gut 1990;31:973-6.
Zerbib F, Vialette G, Cayla R, Rudelli A, Sauvet P, Bechade D, et al . Les gastrites folliculaires de l’adulte. Relations avec Helicobacter pylori , aspects histologiques et endoscopiques. Gastroenterol Clin Biol 1993;17:529-34.

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