Saturday, 2 November 2013


           History  of epigastric pain present in 80-90 % of patient, but is nonspecific.
Burning epigastric pain exacerbated by fasting and improved with meals is a symptom complex associated with peptic ulcer disease (PUD).
An ulcer is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation. Ulcers occur within the stomach and/or duodenum and are often chronic in nature.
Acid peptic disorders are very common in the United States, with 4 million individuals (new cases and recurrences) affected per year. Lifetime prevalence of PUD in the United States is ~12% in men and 10% in women. Moreover, an estimated 15,000 deaths per year occur as a consequence of complicated PUD. The financial impact of these common disorders has been substantial, with an estimated burden on direct and indirect health care costs of ~$10 billion per year in the United States.
Why  does the ulcer appear ? Let remember the physiology of gastric secretion.
Physiology of Gastric Secretion
Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Acid secretion should be viewed as occurring under basal and stimulated conditions. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours. Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates (cephalic, gastric, and intestinal).
- Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve.
- The gastric phase is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production.
- The last phase of gastric acid secretion is initiated as food enters the intestine and is mediated by luminal distention and nutrient assimilation. A series of pathways that inhibit gastric acid production are also set into motion during these phases. The gastrointestinal hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms [decreased histamine release from enterochromaffin-like (ECL) cells and gastrin release from G cells. Additional neural (central and peripheral) and hormonal (secretin, cholecystokinin) factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases are occurring simultaneously.
The gastric epithelium is under a constant assault by a series of endogenous noxious factors including HCl, pepsinogen/pepsin, and bile salts. In addition, a steady flow of exogenous substances such as medications, alcohol, and bacteria encounter the gastric mucosa. A highly intricate biologic system is in place to provide defense from mucosal injury and to repair any injury that may occur.
The mucosal defense system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial elements. The first line of defense is a mucus-bicarbonate layer, which serves as a physicochemical barrier to multiple molecules including hydrogen ions. Mucus is secreted in a regulated fashion by gastroduodenal surface epithelial cells. It consists primarily of water (95%) and a mixture of lipids and glycoproteins. Mucin is the constituent glycoprotein that, in combination with phospholipids (also secreted by gastric mucous cells), forms a hydrophobic surface with fatty acids that extend into the lumen from the cell membrane. The mucous gel functions as a nonstirred water layer impeding diffusion of ions and molecules such as pepsin. Bicarbonate, secreted by surface epithelial cells of the gastroduodenal mucosa into the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric luminal surface and reaching 6 to 7 along the epithelial cell surface. Bicarbonate secretion is stimulated by calcium, prostaglandins, cholinergic input, and luminal acidification.

Surface epithelial cells provide the next line of defense through several factors, including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and intracellular tight junctions. If the preepithelial barrier were breached, gastric epithelial cells bordering a site of injury can migrate to restore a damaged region (restitution). This process occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment. Several growth factors including epidermal growth factor (EGF), transforming growth factor (TGF) α, and basic fibroblast growth factor (FGF) modulate the process of restitution. Larger defects that are not effectively repaired by restitution require cell proliferation. Epithelial cell regeneration is regulated by prostaglandins and growth factors such as EGF and TGF-α. In tandem with epithelial cell renewal, formation of new vessels (angiogenesis) within the injured microvascular bed occurs. Both FGF and vascular endothelial growth factor (VEGF) are important in regulating angiogenesis in the gastric mucosa.
An elaborate microvascular system within the gastric submucosal layer is the key component of the subepithelial defense/repair system. A rich submucosal circulatory bed provides HCO3-, which neutralizes the acid generated by parietal cell secretion of HCl. Moreover, this microcirculatory bed provides an adequate supply of micronutrients and oxygen while removing toxic metabolic by-products.
Prostaglandins play a central role in gastric epithelial defense/repair . The gastric mucosa contains abundant levels of prostaglandins. These metabolites of arachidonic acid regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution.

P.  Seguence of events in the pathophysiology of duodenal ulceration


Multiple factors play a role in the pathogenesis of PUD. The two predominant causes are H. pylori infection and NSAID ingestion. PUD not related to H. pylori or NSAIDs may be increasing. Independent of the inciting or injurious agent, peptic ulcers develop as a result of an imbalance between mucosal protection/repair and aggressive factors. Gastric acid plays an essential role in mucosal injury.
PUD encompasses both gastric and duodenal ulcers.
Ulcers are defined as a break in the mucosal surface >5 mm in size, with depth to the submucosa. Duodenal ulcers (DUs) and gastric ulcers (GUs); share many common features in terms of pathogenesis, diagnosis, and treatment, but several factors distinguish them from one another.
DUs are estimated to occur in 6 to 15% of the western population. The incidence of DUs declined steadily from 1960 to 1980 and has remained stable since then. The death rates, need for surgery, and physician visits have decreased by >50% over the past 30 years. The reason for the reduction in the frequency of DUs is likely related to the decreasing frequency of Helicobacter pylori. Before the discovery of H. pylori, the natural history of DUs was typified by frequent recurrences after initial therapy. Eradication of H. pylori has greatly reduced these recurrence rates.
GUs tend to occur later in life than duodenal lesions, with a peak incidence reported in the sixth decade. More than half of GUs occur in males and are less common than DUs, perhaps due to the higher likelihood of GUs being silent and presenting only after a complication develops. Autopsy studies suggest a similar incidence of DUs and GUs.
Cigarette smoking has been implicated in the pathogenesis of PUD. Not only have smokers been found to have ulcers more frequently than do nonsmokers, but smoking appears to decrease healing rates, impair response to therapy, and increase ulcer-related complications such as perforation. The mechanism responsible for increased ulcer diathesis in smokers is unknown. Theories have included altered gastric emptying, decreased proximal duodenal bicarbonate production, increased risk for H. pylori infection, and cigarette-induced generation of noxious mucosal free radicals. Acid secretion is not abnormal in smokers. Despite these interesting theories, a unifying mechanism for cigarette-induced peptic ulcer diathesis has not been established.
Genetic predisposition has also been considered to play a role in ulcer development. First-degree relatives of DU patients are three times as likely to develop an ulcer; however, the potential role of H. pylori infection in contacts is a major consideration. Increased frequency of blood group O and of the nonsecretor status have also been implicated as genetic risk factors for peptic diathesis. However, H. pylori preferentially binds to group O antigens. Therefore, the role of genetic predisposition in common PUD has not been established.
Psychological stress has been thought to contribute to PUD, but studies examining the role of psychological factors in its pathogenesis have generated conflicting results. Although PUD is associated with certain personality traits (neuroticism), these same traits are also present in individuals with nonulcer dyspepsia (NUD) and other functional and organic disorders. Although more work in this area is needed, no typical PUD personality has been found.
Diet has also been thought to play a role in peptic diseases. Certain foods can cause dyspepsia, but no convincing studies indicate an association between ulcer formation and a specific diet. This is also true for beverages containing alcohol and caffeine. Specific chronic disorders have been associated with PUD. Those with a strong association are (1) systemic mastocytosis, (2) chronic pulmonary disease, (3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, and (6) α1-antitrypsin deficiency. Those with a possible association are (1) hyper- parathyroidism, (2) coronary artery disease, (3) polycythemia vera, and (4) chronic pancreatitis.
Multiple factors play a role in the pathogenesis of PUD. The two predominant causes are H. pylori infection and NSAID ingestion. PUD not related to H. pylori or NSAIDs may be increasing. Independent of the inciting or injurious agent, peptic ulcers develop as a result of an imbalance between mucosal protection/repair and aggressive factors. Gastric acid plays an essential role in mucosal injury.

It is now clear that H. pylori and NSAID-induced injury account for the majority of DUs. Gastric acid contributes to mucosal injury but does not play a primary role.
Many acid secretory abnormalities have been described in DU patients. Of these, average basal and nocturnal gastric acid secretion appear to be increased in DU patients as compared to control; however, the level of overlap between DU patients and control subjects is substantial. The reason for this altered secretory process is unclear, but H. pylori infection may contribute to this finding. Accelerated gastric emptying of liquids has been noted in some DU patients but is not consistently observed; its role in DU formation, if any, is unclear. Bicarbonate secretion is significantly decreased in the duodenal bulb of patients with an active DU as compared to control subjects. H. pylori infection may also play a role in this process.
As in DUs, the majority of GUs can be attributed to either H. pylori or NSAID-induced mucosal damage. GUs that occur in the prepyloric area or those in the body associated with a DU or a duodenal scar are similar in pathogenesis to DUs. Gastric acid output (basal and stimulated) tends to be normal or decreased in GU patients. When GUs develop in the presence of minimal acid levels, impairment of mucosal defense factors may be present.
Gastric infection with the bacterium H. pylori accounts for the majority of  PUD. This organism also plays a role in the development of gastric mucosal-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma. Although the entire genome of H. pylori has been sequenced, it is still not clear how this organism, which is in the stomach, causes ulceration in the duodenum, or whether its eradication will lead to a decrease in gastric cancer.
The Bacterium  initially named Campylobacter pyloridis, is a gram-negative microaerophilic rod found most commonly in the deeper portions of the mucous gel coating the gastric mucosa or between the mucous layer and the gastric epithelium. It may attach to gastric epithelium but under normal circumstances does not appear to invade cells. It is strategically designed to live within the aggressive environment of the stomach. It is S-shaped (~0.5 × 3 µm in size) and contains multiple sheathed flagella. Initially, H. pylori resides in the antrum but, over time, migrates toward the more proximal segments of the stomach.
The bacterium, initially named Campylobacter pyloridis, is a gram-negative microaerophilic rod found most commonly in the deeper portions of the mucous gel coating the gastric mucosa or between the mucous layer and the gastric epithelium. It may attach to gastric epithelium but under normal circumstances does not appear to invade cells. It is strategically designed to live within the aggressive environment of the stomach. It is S-shaped (~0.5 × 3 µm in size) and contains multiple sheathed flagella. Initially, H. pylori resides in the antrum but, over time, migrates toward the more proximal segments of the stomach.
Two factors that predispose to higher colonization rates include poor socioeconomic status and less education
Transmission of H. pylori occurs from person to person, following an oral-oral or fecal-oral route. The risk of H. pylori infection is declining in developing countries. The rate of infection in the United States has fallen by >50% when compared to 30 years ago.
H. pylori infection is virtually always associated with a chronic active gastritis, but only 10 to 15% of infected individuals develop frank peptic ulceration. The basis for this difference is unknown. Initial studies suggested that >90% of all DUs were associated with H. pylori, but H. pylori is present in only 30 to 60% of individuals with GUs and 70% of patients with DUs. The pathophysiology of ulcers not associated with H. pylori or NSAID ingestion [or the rare Zollinger-Ellison syndrome (ZES)] is unclear.
The particular end result of H. pylori infection (gastritis, PUD, gastric MALT lymphoma, gastric cancer) is determined by a complex interplay between bacterial and host factors
About 20,000 patients die each year from serious gastrointestinal complications from NSAIDs. Unfortunately, dyspeptic symptoms do not correlate with NSAID-induced pathology. Over 80% of patients with serious NSAID-related complications did not have preceding dyspepsia. In view of the lack of warning signs, it is important to identify patients who are at increased risk for morbidity and mortality related to NSAID usage. Even 75 mg/d of aspirin may lead to serious gastrointestinal ulceration, thus no dose of NSAID is completely safe.
1. Localization
- GU
-  DU
- сочетанные язвы желудка и 12-перстной кишки
- гастроеюнальная язва.
2. Etiology
 - Нр-positive
- Нр- negative
- mixed (HP + other factor s: stress-, drug-induced
Смешанная (НР+другой установленный этиологический фактор)
 3. Стадия (фаза) язвенного процесса:
 - активная (острая, свежая)
- рубцующаяся
- стадия рубца
- длительно не рубцующаяся
4. Сопутствующие морфофункциональные изменения:
- локализация и активность гастрита и дуоденита
- наличие и степень выраженности атрофии слизистой оболочки
- наличие кишечной метаплазии
- наличие эрозий, полипов
- наличие гастроэзофагеального или дуоденогастрального рефлюксов
- характеристика секреторной и моторной функции.
5. Осложнения (кровотечение, перфорация, пенетрация, стеноз, малигнизация).
Примеры формулирования диагноза:
- ЯБ тела желудка в активной фазе, НР- положительная, гастрит тела желудка с атрофией и кишечной метаплазией.
- ЯБ луковицы 12-перстной кишки в активной фазе, НР-положительная,  хронический антральный гастрит, дуоденит с выраженной желудочной метаплазией.

Abdominal pain is common to many gastrointestinal disorders, including DU and GU, but has a poor predictive value for the presence of either DU or GU. Up to 10% of patients with NSAID-induced mucosal disease can present with a complication (bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical examination are essential components of the approach to a patient suspected of having peptic ulcers.
Epigastric pain described as a burning or gnawing discomfort can be present in both DU and GU. The discomfort is also described as an ill-defined, aching sensation or as hunger pain. The typical pain pattern in DU occurs 90 min to 3 h after a meal and is frequently relieved by antacids or food. Pain that awakes the patient from sleep (between midnight and 3 A.M.) is the most discriminating symptom, with two-thirds of DU patients describing this complaint. Unfortunately, this symptom is also present in one-third of patients with NUD. The pain pattern in GU patients may be different from that in DU patients, where discomfort may actually be precipitated by food. Nausea and weight loss occur more commonly in GU patients. In the United States, endoscopy detects ulcers in <30% of patients who have dyspepsia. Despite this, 40% of these individuals with typical ulcer symptoms had an ulcer crater, and 40% had gastroduodenitis on endoscopic examination.
Variation in the intensity or distribution of the abdominal pain, as well as the onset of associated symptoms such as nausea and/or vomiting, may be indicative of an ulcer complication.
 Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation. Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction. Tarry stools or coffee ground emesis indicate bleeding.
Physical Examination
Epigastric tenderness is the most frequent finding in patients with GU or DU. Pain may be found to the right of the midline in 20% of patients. Unfortunately, the predictive value of this finding is rather low. Physical examination is critically important for discovering evidence of ulcer complication. Tachycardia and orthostasis suggest dehydration secondary to vomiting or active gastrointestinal blood loss. A severely tender, boardlike abdomen suggests a perforation. Presence of a succussion splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.
Diagnostic Evaluation
Including such methods as
Barium studies of the proximal gastrointestinal tract,
Several biopsy urease tests
Serologic testing,
The 13C- or 14C-urea breath test (UBT),
and the fecal H. pylori antigen test
In view of the poor predictive value of abdominal pain for the presence of a gastroduodenal ulcer and the multiple disease processes that can mimic this disease, the clinician is often confronted with having to establish the presence of an ulcer. Documentation of an ulcer requires either a radiographic (barium study) or an endoscopic procedure. However, a large percentage of patients with symptoms suggestive of an ulcer have NUD; empirical therapy is appropriate for individuals who are otherwise healthy and <45, before embarking on a diagnostic evaluation.
Barium studies of the proximal gastrointestinal tract are still commonly used as a first test for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast study providing detection rates as high as 90%. Sensitivity for detection is decreased in small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated crater, most often seen in the bulb. A GU may represent benign or malignant disease. Typically, a benign GU also appears as a discrete crater with radiating mucosal folds originating from the ulcer margin. Ulcers >3 cm in size or those associated with a mass are more often malignant. Unfortunately, up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery. Radiographic studies that show a GU must be followed by endoscopy and biopsy.
Endoscopy provides the most sensitive and specific approach for examining the upper gastrointestinal tract. In addition to permitting direct visualization of the mucosa, endoscopy facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori.
          Tests for H. pylori can be divided into two groups: invasive tests, which require upper gastrointestinal endoscopy and are based on the analysis of gastric biopsy specimens, and noninvasive tests.
          Although the methods for diagnosing H. pylori a brief summary will be included here (Table). Several biopsy urease tests have been developed (PyloriTek, Clotest, Hpfast, Pronto Dry) and have a sensitivity and specificity of >90 to 95%. Several noninvasive methods for detecting this organism have been developed. Three types of studies routinely used  include serologic testing, the 13C- or 14C-urea breath test (UBT), and the fecal H. pylori antigen test.
Table Tests for Detection of H. pylori

Sensitivity/Specificity, %


Rapid urease
Simple, false negative with recent use of PPIs, antibiotics, or bismuth compounds
Requires pathology processing and staining; provides histologic information
Time-consuming, expensive, dependent on experience; allows determination of antibiotic susceptibility

Inexpensive, convenient; not useful for early follow-up
Urea breath test
Simple, rapid; useful for early follow-up; false negatives with recent therapy; exposure to low-dose radiation with 14C test
Stool antigen
Inexpensive, convenient; not established for eradication but promising

Note: PPIs, proton pump inhibitors.
Endoscopy often is not performed in the initial management of young dyspeptic patients without worrying symptoms but is commonly used in older people to exclude malignancy. If endoscopy is performed, the most convenient biopsy-based test is the biopsy urease test, in which one large or two small antral biopsy specimens are placed into a gel containing urea and an indicator. The presence of H. pylori urease elicits a color change, which often occurs within minutes but can require up to 24 h. Histologic examination of biopsy specimens is accurate, provided that a special stain (e.g., a modified Giemsa or silver stain) permitting optimal visualization of H. pylori is used. If biopsies from both antrum and corpus are obtained, histologic study yields additional information, including the degree and pattern of inflammation, atrophy, metaplasia, and dysplasia. Microbiologic culture is most specific but may be insensitive because of difficulty with H. pylori isolation. Once cultured, the identity of H. pylori can be confirmed by its typical appearance on Gram's stain and its positive reactions in oxidase, catalase, and urease tests. Moreover, the organism's antibiotic sensitivities can be determined. The occasional biopsy specimens containing the less common non-pylori helicobacters give only weakly positive results in the biopsy urease test. Positive identification of these bacteria requires visualization of the characteristic long, tight spiral bacteria in histologic sections.
TABLE 135-1 Tests Commonly Used to Detect Helicobacter pylori



Biopsy urease test
Quick, simple
Some commercial tests not fully sensitive before 24 h
May give additional histologic information
Sensitivity dependent on experience and use of special stains
Permits determination of antibiotic susceptibility
Sensitivity dependent on experience

Inexpensive and convenient
Cannot be used for early follow-up; some commercial kits inaccurate
13C or 14C urea breath test
Inexpensive and simpler than endoscopy; useful for follow-up after treatment
Low-dose irradiation in 14C test
Stool antigen test
Inexpensive and convenient; useful for follow-up after treatment; may be useful in children
New test; role not fully established; appears less accurate than urea breath test

Noninvasive H. pylori testing is now the norm if gastric cancer does not need to be excluded. The most consistently accurate test is the urea breath test. In this simple test, the patient drinks a labeled urea solution and then blows into a tube. The urea is labeled with either the nonradioactive isotope 13C or a minute dose of the radioactive isotope 14C. If H. pylori urease is present, the urea is hydrolyzed and labeled carbon dioxide is detected in breath samples. The stool antigen test is another simple assay that is dependent on the detection of H. pylori antigens in stool. It is more convenient and less expensive than the urea breath test but has been slightly less accurate in some comparative studies. The urea breath test, the stool antigen test, and biopsy-based tests can all be used to assess the success of treatment. However, because these tests are dependent on H. pylori load, their use <4 weeks after treatment may lead to false-negative results. These tests are also unreliable if performed within 4 weeks of intercurrent treatment with antibiotics or bismuth compounds or within 2 weeks of the discontinuation of PPI treatment. In the assessment of treatment success, noninvasive tests are normally preferred; however, after gastric ulceration, endoscopy should be repeated to ensure healing and to exclude gastric carcinoma by further histologic sampling.

Occasionally, specialized testing such as serum gastrin and gastric acid analysis or sham feeding may be needed in individuals with complicated or refractory PUD (see “Zollinger-Ellison Syndrome,” below). Screening for aspirin or NSAIDS (blood or urine) may also be necessary in refractory H. pylori–negative PUD patients.

        The aims of management are:

-  to relieve symptoms,
-  induce ulcer healing in the short term,
-        cure the ulcer in the long term.
   H. pylori eradication is the cornerstone of therapy for peptic ulcers, as this will successfully prevent relapse and eliminate the need for long-term therapy in the majority of patients.

Before the discovery of H. pylori, the therapy of PUD disease was centered on the old dictum by Schwartz of “no acid, no ulcer.” Although acid secretion is still important in the pathogenesis of PUD, eradication of H. pylori and therapy/prevention of NSAID-induced disease is the mainstay. A summary of commonly used drugs for treatment of acid peptic disorders is shown in Table .

TABLE.  Drugs Used in the Treatment of Peptic Ulcer Disease

Drug Type/Mechanism

Acid-suppressing drugs

Mylanta, Maalox, Tums, Gaviscon
100–140 meq/L 1 and 3 h after meals and hs
  H2 receptor antagonists
400 mg bid
300 mg hs
40 mg hs
300 mg hs
  Proton pump inhibitors
20 mg/d
30 mg/d
20 mg/d
40 mg/d
20 mg/d
Mucosal protective agents

1 g qid
  Prostaglandin analogue
200 µg qid
  Bismuth-containing compounds
Bismuth subsalicylate (BSS)
See anti-H. pylori regimens

Regimens Recommended for Eradication of H. pylori Infection

1. Pantoprazol plus
    Metronidazole plus
Amoxicillinc                                          2 weeks
40 mg bid
500 mg tid
500 mg qid
2.  Pantoprazole (lansoprazole) plus
    Clarithromycin plus
    Metronidazole                    1 week
40 mg bid (30 mg bid)
 500 mg bid
500 mg bid

Triple therapy, although effective, has several drawbacks, including the potential for poor patient compliance and drug-induced side effects. Compliance is being addressed somewhat by simplifying the regimens so that patients can take the medications twice a day.
Two anti-H. pylori regimens are available in prepackaged formulation: Prevpac (lansoprazole, clarithromycin, and amoxicillin) and Helidac (bismuth subsalicylate, tetracycline, and metronidazole). The contents of the Prevpac are to be taken twice per day for 14 days, whereas Helidac constituents are taken four times per day with an antisecretory agent (PPI or H2 blocker), also taken for at least 14 days.
One important concern with treating patients who may not need treatment is the potential for development of antibiotic-resistant strains. The incidence and type of antibiotic-resistant H. pylori strains vary worldwide. Strains resistant to metronidazole, clarithromycin, amoxicillin, and tetracycline have been described, with the latter two being uncommon. Antibiotic-resistant strains are the most common cause for treatment failure in compliant patients. Unfortunately, in vitro resistance does not predict outcome in patients. Culture and sensitivity testing of H. pylori is not performed routinely. Although resistance to metronidazole has been found in as many as 30% and 95% of isolates in North America and Asia, respectively, triple therapy is effective in eradicating the organism in >50% of patients infected with a resistant strain. Clarithromycin resistance is seen in about 10% of persons in the United States.
Failure of  H. pylori eradication with triple therapy is usually due to infection with a resistant organism. Quadruple therapy (), where clarithromycin is substituted for metronidazole (or vice versa), should be the next step.

Bismuth subsalicylate
40 mg bid
120 mg  qid
500 mg qid
500 mg qid

        Interection with warfarin, phenytoin, fewer drugs
Side effects of therapy
have been reported in up to 20 to 30% of patients on triple therapy. Bismuth may cause black stools, constipation, or darkening of the tongue. The most feared complication with amoxicillin is pseudomembranous colitis, but this occurs in <1 to 2% of patients. Amoxicillin can also lead to antibiotic-associated diarrhea, nausea, vomiting, skin rash, and allergic reaction. Tetracycline has been reported to cause rashes and very rarely hepatotoxicity and anaphylaxis.
        Prostaglandins exert complex In low doses protect against injury induced by aspirin and NSAIDs by enhancing mucosal blood flow, and by stimulating mucus and bicarbonate secretion and epithelial cell proliferation.
        At high doses acid secretion is inhibited. Misoprostol is effective for the prevention and treatment of NSAID-induced ulcers, but in clinical practice IPP are preferred, since they are at least as effective and have fewer side-effects.

Once an ulcer (GU or DU) is documented, then the main issue at stake is whether H. pylori or an NSAID is involved. With H. pylori present, independent of the NSAID status, triple therapy is recommended for 14 days, followed by continued acid-suppressing drugs (H2 receptor antagonist or PPIs) for a total of 4 to 6 weeks. Selection of patients for documentation of H. pylori eradication (organisms gone at least 4 weeks after completing antibiotics) is an area of some debate. The test of choice for documenting eradication is the UBT. The stool antigen study may also hold promise for this purpose, but the data have not been as clear cut as in the case of using the stool antigen test for primary diagnosis. Further studies are warranted, but if the UBT is not available, a stool antigen should be considered to document eradication. Serologic testing is not useful for the purpose of documenting eradication since antibody titers fall slowly and often do not become undetectable. Two approaches toward documentation of eradication exist: (1) test for eradication only in individuals with a complicated course or in individuals who are frail or with multisystem disease who would do poorly with an ulcer recurrence, and (2) test all patients for successful eradication. Some recommend that patients with complicated ulcer disease or who are frail should be treated with long-term acid suppression, thus making documentation of H. pylori eradication a moot point. In view of this discrepancy in practice, it would be best to discuss with the patient the different options available.
If the ulcer has closed, but the tests on H.P. stayed positive, recommended
Long-term supported antirelaps therapy
Long-term treatment
3 year for DUs and 2 year for Gus
Ranitidine 150mg to night  or
Pantoprazole 20-40 mg before breacfest
On demand treatment (for DUs)
3-4 days whole dose of medicine, and after – in a half-dose 2 weeks
Intermittent therapy
according to endoscopy (ulcer)
Week-end therapy
Treatment in Friday, Saturday, Sunday

Several issues differentiate the approach to a GU versus a DU. GUs, especially of the body and fundus, have the potential of being malignant. Multiple biopsies of a GU should be taken initially; even if these are negative for neoplasm, repeat endoscopy to document healing at 8 to 12 weeks should be performed, with biopsy if the ulcer is still present. About 70% of GUs eventually found to be malignant undergo significant (usually incomplete) healing.
The majority (>90%) of GUs and DUs heal with the conventional therapy outlined above. A GU that fails to heal after 12 weeks and a DU that does not heal after 8 weeks of therapy should be considered refractory. Once poor compliance and persistent H. pylori infection have been excluded, NSAID use, either inadvertent or surreptitious, must be excluded. In addition, cigarette smoking must be eliminated. For a GU, malignancy must be meticulously excluded. Next, consideration should be given to a gastric hypersecretory state, which can be excluded with gastric acid analysis. Although a subset of patients have gastric acid hypersecretion of unclear etiology as a contributing factor to refractory ulcers, ZES should be excluded with a fasting gastrin or secretin stimulation test (see below). More than 90% of refractory ulcers (either DUs or GUs) heal after 8 weeks of treatment with higher doses of PPI (omeprazole, 40 mg/d; lansoprazole 30 to 60 mg/d). This higher dose is also effective in maintaining remission. Surgical intervention may be a consideration at this point; however, other rare causes of refractory ulcers must be excluded before recommending surgery. Rare etiologies of refractory ulcers that may be diagnosed by gastric or duodenal biopsies include: ischemia, Crohn's disease, amyloidosis, sarcoidosis, lymphoma, eosinophilic gastroenteritis, or infection [cytomegalovirus (CMV), tuberculosis, or syphilis].
 of peptic ulcer disease
         gastric outlet obstruction

Surgical Therapy
Surgical intervention in PUD can be viewed as being either elective, for treatment of medically refractory disease, or as urgent/emergent, for the treatment of an ulcer-related complication.
 - Perforation
 - Haemorrhage
 - Gastric outflow obstruction
 - Recurrent ulcer following gastric surgery

The development of pharmacologic and endoscopic approaches for the treatment of peptic disease has led to a substantial decrease in the number operations needed for this disorder. Refractory ulcers are an exceedingly rare occurrence. Surgery is more often required for treatment of an ulcer-related complication. Gastrointestinal bleeding perforation, and gastric outlet obstruction are the three complications that may require surgical intervention.

Examples of clinical diagnosis:
Duodenal ulcer disease, active study, HP-positive

Severe peptic ulcer diathesis secondary to gastric acid hypersecretion due to unregulated gastrin release from a non-β cell endocrine tumor (gastrinoma) defines the components of the ZES. Initially, ZES was typified by aggressive and refractory ulceration in which total gastrectomy provided the only chance for enhancing survival. Today ZES can be cured by surgical resection in up to 30% of patients.
Clinical Manifestations
Gastric acid hypersecretion is responsible for the signs and symptoms observed in patients with ZES. Peptic ulcer is the most common clinical manifestation, occurring in >90% of gastrinoma patients. Initial presentation and ulcer location (duodenal bulb) may be indistinguishable from common PUD. Clinical situations that should create suspicion of gastrinoma are ulcers in unusual locations (second part of the duodenum and beyond), ulcers refractory to standard medical therapy, ulcer recurrence after acid-reducing surgery, ulcers presenting with frank complications (bleeding, obstruction, and perforation), or ulcers in the absence of H. pylori or NSAID ingestion. Symptoms of esophageal origin are present in up to two-thirds of patients with ZES, with a spectrum ranging from mild esophagitis to frank ulceration with stricture and Barrett's mucosa.
Diarrhea is the next most common clinical manifestation, in up to 50% of patients. Although diarrhea often occurs concomitantly with acid peptic disease, it may also occur independent of an ulcer. Etiology of the diarrhea is multifactorial, resulting from marked volume overload to the small bowel, pancreatic enzyme inactivation by acid, and damage of the intestinal epithelial surface by acid. The epithelial damage can lead to a mild degree of maldigestion and malabsorption of nutrients. The diarrhea may also have a secretory component due to the direct stimulatory effect of gastrin on enterocytes or the cosecretion of additional hormones from the tumor, such as vasoactive intestinal peptide.
The first step in the evaluation of a patient suspected of having ZES is to obtain a fasting gastrin level. A list of clinical scenarios that should arouse suspicion regarding this diagnosis is shown in Table 274-5. Fasting gastrin levels are usually <150 pg/mL. Virtually all gastrinoma patients will have a gastrin level >150 to 200 pg/mL. Measurement of fasting gastrin should be repeated to confirm the clinical suspicion.
TABLE 274-5 When to Obtain a Fasting Serum Gastrin Level

Multiple ulcers
Ulcers in unusual locations; associated with severe esophagitis; resistant to therapy with frequent recurrences; in the absence of NSAID ingestion or H. pylori infection
Ulcer patients awaiting surgery
Extensive family history for peptic ulcer disease
Postoperative ulcer recurrence
Basal hyperchlorhydria
Unexplained diarrhea or steatorrhea
Family history of pancreatic islet, pituitary, or parathyroid tumor
Prominent gastric or duodenal folds

The next step in establishing a biochemical diagnosis of gastrinoma is to assess acid secretion. Nothing further needs to be done if decreased acid output is observed. In contrast, normal or elevated gastric acid output suggests a need for additional tests. Gastric acid analysis is performed by placing a nasogastric tube in the stomach and drawing samples at 15-min intervals for 1 h during unstimulated or basal state (BAO), followed by continued sampling after administration of intravenous pentagastrin (MAO). Up to 90% of gastrinoma patients may have a BAO of ≥15 meq/h (normal, <4 meq/h). Up to 12% of patients with common PUD may have comparable levels of acid secretion. A BAO/MAO ratio >0.6 is highly suggestive of ZES, but a ratio <0.6 does not exclude the diagnosis. Pentagastrin is no longer available in the United States, making measurement of MAO virtually impossible. If the technology for measuring gastric acid secretion is not available, a basal gastric pH ≥3 virtually excludes a gastrinoma.
Treatment of functional endocrine tumors is directed at ameliorating the signs and symptoms related to hormone overproduction, curative resection of the neoplasm, and attempts to control tumor growth in metastatic disease.
PPIs are the treatment of choice and have decreased the need for total gastrectomy. Initial doses of omeprazole or lansoprazole should be in the range of 60 mg/d. Dosing can be adjusted to achieve a BAO <10 meq/h (at the drug trough) in surgery-naive patients and to <5 meq/h in individuals who have previously undergone an acid-reducing operation. Although the somatostatin analogue has inhibitory effects on gastrin release from receptor-bearing tumors and inhibits gastric acid secretion to some extent, PPIs have the advantage of reducing parietal cell activity to a greater degree.

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