Journal of Gastroenterology and Hepatobiliary Disorders

Peptic Ulcer Disease

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Published Date: December 30, 2015

Peptic Ulcer Disease

Lauret ME, Rodriguez-Pelaez M, Perez I, Rodrigo L*

Gastroenterology Service, University Hospital Central of Asturias, Oviedo, Spain

*Corresponding author: Luis Rodrigo, Gastroenterology Service, Central University Hospital of Asturias (HUCA), Avda. Hospital Universitario, s/n. 33011, Oviedo, Principality of Asturias, Spain, Tel: 003-498-510-8000; Fax: 003-498-510-8115; E-mail: lrodrigosaez@gmail.com

Citation: Lauret ME, Rodriguez-Pelaez M, Perez I, Rodrigo L (2015) Peptic Ulcer Disease. J Gastro Hepato Dis 1(1): 105. Doi: http://dx.doi.org/10.19104/jghd.2015.105

 

Abstract

 

Peptic ulcer disease (PUD) is a prevalent disease, it affecting around 5-10% of the general population worldwide, but with notable regional and racial variations. The two most common etiological causes are the chronic infection with Helicobacter pylori (Hp) and the use of non-steroidal anti-inflammatory drugs (NSAIDs). Its diagnosis is based mainly in the endoscopy and the active search of concomitant Hp presence. The discovery of the link between H. pylori and peptic ulcer has changed dramatically its management, because it has become a curable infectious disease.

The eradication therapy of is the best choice to achieve the  final cure of PUD  in infected patients. Several current international recommend a standard triple therapy as first-line therapy, including a proton pump inhibitor and a combination of amoxicillin and clarithromycin. This combination therapy has shown a decreased efficacy over the years. The main reason is increasing antibiotic resistance, particularly to clarithromycin and metronidazol, of certain Hp strains. Several new treatment options or modifications of already established regimens have been introduced in last years, to overcome these treatment failures.

For the subgroup of patients with H. pylorinegative ulcers, avoiding NSAIDs intake also has a clear influence in evolution of the disease and in some cases drives to the complete healing of the peptic ulcer. In refractory or recurrent cases, continuous therapy with anti-secretory agents and/or the replacement of conventional NSAIDs by selective drugs for inhibition of cyclooxygenase-2 (COX-2) are useful treatment options.    

Keywords: Peptic Ulcer Disease; Helicobacter pylori; Nonsteroidal Anti-inflammatory Drugs; Eradication Treatment

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Definition and Etiology

 

Peptic ulcer (PU) can be defined as the presence of a profound loss of substance affecting the mucosa of the stomach and/or duodenum, reaching beyond the muscularis mucosa, generally to the muscle layer due to the environmental gastric acid secretion.

The two most common etiological causes are the chronic infection with Helicobacter pylori (Hp) and the use of non-steroidal anti-inflammatory drugs (NSAIDs), including of course, the acetylsalicylic acid (ASA). There are other less common causes that can cause a PU, which are considered  together, account for less than 5% of cases. Zollinger-Ellison syndrome or gastrinoma is one among them which is a neuroendocrine tumor, usually located at the head of the pancreas or in the duodenal wall, overactive and gastrin secretory (Table 1).

Table 1. Etiology of PUD

 

However, we must remember that approximately 5-15% of patients considered Hp negative, despite performing wide comprehensive etiological studies, do not get to find again the precise cause of PU, which are referred to as "idiopathic”.

Tobacco abuse and O blood group, are considered as the risk factors for development of ulcer disease. Regarding the existence of genetic factors is unknown, although some cases with familial aggregation can occur. Tobacco consumption,  complicates ulcer healing and promotes  its recurrences, especially in patients Hp (+) or in common NSAIDs takers.

The digestive and extra-digestive diseases, most frequently associated with peptic ulcer, among which are included the concomitant presence of chronic  gastroesophageal reflux disease (GERD), Barrett's esophagus, chronic obstructive pulmonary disease (COPD), liver cirrhosis, chronic renal failure, while in other clinical situations, their presence is lower, as in the atrophic gastritis, Addison's disease, autoimmune thyroiditis and hyperparathyroidism.

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Epidemiology

 

It is a fairly heterogeneous disease with worldwide distribution, but the disease affects people from all countries and different races. It’s average prevalence is between 5-10% of the general population over a lifetime [1,2].

This represents approximately 10-20% of people infected with Helicobacter pylori globally, with wide variations between different races and countries of the world having been confirmed, as its prevalence is inversely related to the economic level of the population,  degree of development and level of  hygienic social environmental. The average incidence of peptic ulcer among the persons infected by Hp, is approximately 1% per year [3].

The prevalence for both the sexes is fairly close. The adjusted incidence in relation to age, some experts establishesd the average age for onset of gastric and duodenal ulcer. The peak incidence of gastric ulcer is between 55-65 years, while the average age of duodenal ulcer onset is a decade earlier, at around 45 years [4].

There are significant epidemiological differences worldwide. So, in developing countries the prevalence of H. pylori infection is much higher (two to five times) than in developed, probably because of the worst existing hygiene and dietary conditions that favor the transmission of infection. There are also clear differences as regards the use of antibiotics and NSAIDs. This also justifies that the percentage of negative Hp peptic ulcers  is much less in developing, compared with the observed percentages found in developed countries [5-7].

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Pathogeny

 

The mechanisms through which the Hp favours the development of PU, are better known in the duodenal, than in gastric side. In patients infected with the bacteria, triggers an inflammatory and immunological response to the level of the gastric and duodenal mucosa, with release of number of pro-inflammatory cytokines such as IL-8 and TNF-α. Thus appears  acute and chronic gastritis, which reduces the thickness and quality of mucus layer [8].

In Hp infected patients, gastric hypersecretion occurs, due to a decrease in the density of the antral D cells and therefore decreased secretion of somatostatin, which determines the loss of inhibitory stimulus. The resulting hypergastrinemia stimulates gastric parietal cells, causing an increase of acid secretion, with decrease of pH in lumen of the stomach and duodenum, which also continuously determines the appearance of duodenal gastric metaplasia level. This in turn, causes the duodenal mucosa impair its ability to segregate bicarbonate, thus facilitating duodenitis development and later onset of duodenal ulcer. After Hp eradication, the gastrin levels return to normal [9].

Ulcerogenic potential of different Hp strains vary in terms of their ability to produce the cytotoxic protein (CagA) and the so-called vacuolating protein (Vac A) [10].

Consumption of NSAIDs and/or ASA, is the second most common cause of ulcers. Both groups of drugs  are causative agents in 70-85%, once safely ruled out the presence of Hp. Overall, it is estimated that they may cause up to 10% of duodenal ulcers and 20-30% of gastric ulcers. It is estimated that up to 50% of chronic NSAID takers have little clinically relevant erosive lesions, ulcers may reach up to 30%, of which about 1% annually are complicated [11].

There are two main mechanisms by which NSAIDs cause damage to the gastric and duodenal mucosa. On one hand, these drugs behave as weak non-ionized acids, that can penetrate into the mucus layer easily, and inside the epitelial cells. Another and most important effect is the ability of cyclo-oxygenase inhibitory enzyme, thereby decreasing the intracellular concentration of prostaglandins. These play an important role in maintaining the integrity of the gastroduodenal mucosa role, because of its intramucosal vasodilator effect maintaining intact the blood flow and secondarily stimulate the local secretion of mucus and bicarbonate, facilitating the cell turnover and epithelization [12,13].

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Clinical Manifestations

 

The most typical manifestation of  the uncomplicated peptic ulcer is the presence of a burning or corrosive pain, mainly located at the epigastrium. Sometimes, it can be characterized as a vague abdominal pain, nausea, vomiting, diffuse discomfort, or may be perceived as a pressure or feeling of abdominal fullness or hunger.

Typically in the duodenal ulcer, epigastric pain appears during the fasting state, between one and three hours after meals or at night. It can also occur in relation to stress situations.

This epigastric pain is relieved by eating any kind of food or taking antacids pills in few minutes, and reappears cyclically again, within two hours. Symptoms may persist for several days, weeks or months.Two- third of patients with duodenal ulcer refer that the pain wakes them at night, being uncommon to have pain upon waking in the morning. There is infrequent presence of anorexia and/or weight loss in these patients. By contrary, most of them often manifest hyperphagia and weight gain, probably because the pain usually subsides with ingestion of food. This is the well known three steps - sequence of  “pain/ingestion of food/alleviation”  [14].

Sometimes the pain radiates to the back or right upper quadrant suggesting that the appearance of an ulcer of the probable localization at the posterior surface of the duodenal bulb, even if it lose the characteristic rate of three steps and becomes continuous and intense. Then, it can be considered to have a penetrating complication to the pancreas.

In gastric ulcer, the pain usually occurs in the postprandial period, and appears earlier than in the duodenal ulcer and does not alleviate with the food intake and/or antacids. Only one third of the patients wake up at night by  pain, and up to 50% may have anorexia and weight loss, because of a concomitant delayed gastric emptying.

The classic clinical pattern  in three steps has low sensitivity, appearing only in 50-70% of duodenal ulcers and in less than 50% of gastric ulcers. It is also less specific, since patients with dyspepsia and GERD may also have shown very similar symptoms. On clinical examination, the most common finding is to find pain on palpation at the epigastrium.

However, in many patients, ulcers can be asymptomatic and the first manifestation may be related to the presence of one ulcer-related complication, especially in elderly patients who take NSAIDs. It has been proposed that NSAIDs may mask pain of ulcer processes [15].

Possible differential diagnoses should include multiple entities such as functional dyspepsia, gastroesophageal reflux disease, gastric cancer, gallbladder or pancreatic disease. When symptoms are in concordance with the presence of a peptic ulcer, objective evidence is needed to confirm the diagnosis.

After the symptoms improvement, it is frequently observed to have recurrences. The most important factors explaining ulcer recurrence are concomitant H. pylori infection not eradicated and frequent use of NSAIDs. Eradication of H. pylori has dramatically changed the natural history of the PUD, preventing their recurrences. Moreover, NSAIDs stop intake also has a  clear influence in the evolution of the disease and in some cases drives to the complete healing of the peptic ulcer.

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Complications

 

Several complications can occur in patients with peptic ulcer disease of any etiology. They are  the main reasons for the high morbidity and mortality associated with this disease found until now.

The routine application of different gastroprotection strategies and eradication therapies for Helicobacter pylori infection, have reduced significantly the incidence relative to that seen in the previous decades. They are more common in habitual smokers and chronic NSAIDs users [16,17]. There are four major complications of peptic ulcer disease: Bleeding, perforation, penetration and obstruction.

Bleeding

Although its incidence has declined a little in the recent years; however  remains being the most common complication and appears in around 10-20% of patients. It is a frequent cause of admission in emergencies.

Ulcers related with NSAIDs are more likely to bleed than those caused only by H. pylori chronic infection. Populations at a greatest risk are the elderly and those with other serious conditions, such as respiratory, cardiac, cerebrovascular o renal problems [18].

A total of 80-90% of upper gastrointestinal  hemorrhage are not from variceal bleeding origin , and  around 40-50% of these are caused by peptic ulcer disease. The mean associated mortality is around 5.5% [19].

It can take various clinical manifestations: 15% have melenas, 30% hematemesis, 50% have both and about 5% have hematochezia caused by severe bleeding [20].

In other cases, ulcer bleeding may have a chronic course, manifestating as iron deficiency anemia or a positive fecal occult blood. There is a strong correlation between ulcer bleeding and use of NSAIDs or aspirin, because these drugs predispose to ulceration and inhibition of platelet aggregation.

Although not seems that the exclusive use of corticosteroids substantially increase the risk of ulcer bleeding, the combined use of these drugs together with NSAIDs, may increase by tenfold the risk of this complication.

Perforation

It occurs in up to 5% of patients with peptic ulcer. Usually correspond to 60% of duodenal ulcers cases, most of them located at the anterior wall of the duodenal bulb and 40% of gastric ulcers, often affecting lesser curvature. Free perforation of a duodenal or gastric ulcer into the peritoneal cavity may endanger the patient's life.

It usually appears as a sudden, severe abdominal pain, located in the epigastrium, which may radiate to back or become diffuse and associated with acute shock suggests a complicated ulcer perforation with peritonitis.

Typically the patient usually remains motionless and thighs flexed on the abdomen giving the impression of gravity. On examination, a hard, rigid abdomen is seen with rebound. Auscultation may initially shows increased intestinal noises and as the condition progresses, they diminish and finally almost disappear.  Around 70% of cases, present visible pneumoperitoneum at plain radiologic abdomen.

The etiology of duodenal ulcer perforated appears to be multifactorial such as alcohol, tobacco, Helicobacter pylori, and especially intake of NSAIDs, since more than a third of the perforations are related to taking these, even to reaching figures of up to 50%, mainly in the elderly and being sometimes the only acetylsalicylic acid NSAID used even in small doses [21,22]. Another cause  although much less common, is cocaine chronic consumption. The pathophysiology of duodenal ulcer perforated by cocaine, remains speculative. There are chances for perforation by a localized vasoconstriction or vascular thrombosis [23]. It has been reported that in these cases the majority (40%) are placed mostly in juxta-pyloric area.

Penetration

This complication occurs when an ulcer cross the wall of the stomach or duodenum, but instead of drilled freely into the peritoneal cavity, burrow into an adjacent organ. It occurs in approximately 25% of duodenal ulcers and 15% of gastric ulcers. Adjacent organs that extend most often are the pancreas, liver or omentum.

The clinical presentation may be similar to that of uncomplicated ulcer but the pain is usually more severe and persistent [24]. Pain cannot be relieved by eating, or even may worse and more often, wakes the patient at night. Typically, pain radiating to the back, when an ulcer penetrated to the pancreas or to right upper quadrant, appears when penetration is in the gastrohepatic omentum.

Rarely, penetrating peptic ulcers may form fistulas between the duodenum and bile duct (choledoco-duodenal fistula) or between the stomach and colon (gastro-colic fistula).

Obstruction

It is an uncommon complication, which represents approximately 5% of ulcer-related complications. Until about 1970, peptic ulcers represented the most common cause of obstruction to gastric emptying [25]. In the last years, however, has decreased the frequency of obstruction secondary to peptic ulcer and currently gastric malignancies are the leading cause of gastric outlet obstruction [26].

Ulcers which causes obstruction are usually located in the pyloric channel or duodenal bulb, occurrs as a result of the swelling and edema accompanying active ulceration or the healing process of the ulcer and shrinkage.

The main symptoms of obstruction are nausea, vomiting, early satiety, and anorexia. Vomiting tends to occur between 30 and 60 minutes after meals and patients are often satisfied for hours after meals.

On clinical examination, they may show signs of thinning and dehydration and splash produced by air and liquid retained within the distended stomach. The diagnostic suspicion should be confirmed by endoscopy, that also will serve to exclude a possible malignant origin stenosis.

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Diagnosis

 

It is mandatory to perform a good clinical history and a complete physical examination, in order to make a complete data collection of all the symptoms and signs of PUD. Also, it is extremely important to register all the past medical antecedents, and the duration of alcohol intake, history of NSAIDs and smoking consumption, and also for the posible existence of previous  episodes of peptic ulcer.

There are two major considerations in the diagnosis of peptic ulcer. One, is to assess if the refered symptoms are not related to functional dyspepsia and the second is to determine the specific etiology of the ulcer.

Endoscopic findings

Upper GI endoscopy is the most accurate diagnostic test for PUD. It gives information about the size and the location of the lesion. In addition, mucosal biopsies can be performed, in order to do a differential diagnosis and to carry out endoscopic treatments in case of bleeding peptic ulcer. Also several biopsies from the mucosa of antrum and corpus must be taken, in order to discover or rule-out the presence of concomitant H. Pylori infection.

The signs suggesting benign origin are the presence of regular mucosal folds surrounding the ulcer base and the fibrin deposit at the crater base (Figure 1). The features that suggests malignancy, are the finding of overhanging margins, irregular or thickened borders and/or the presence of an ulcerated mass, that protrudes into the lumen (Figure 2).

Figure 1.  Endoscopic images a) Active ulcer, b) Ulcer scar, c) Last stage of the mucosal healing in benign peptic gastric ulcers

 

Figure 2. Endoscopic picture of malignant gastric fundus ulcerated lesion (retroflexion)

 

Malignancy of the duodenal ulcers is exceptional. Therefore, it is rutinary biopsy is not recommended. However, it is mandatory to take several mucosal biopsies form the margins at any gastric ulcer, despite it is benign appearance. A follow-up endoscopy will be performed until the healing is completed [27].

The presence of H. pylori infection must be investigated in every patient presenting peptic ulcer. Since it is discovery in 1983, the management has changed a lot. It is known that the prevalence of the infection increases with the age, and there is no difference between women and men.

Diagnostic tests for H. pylori are divided into direct (based upon the need for endoscopy) and indirect tests, and several tests are used not only for diagnosis, but also in the follow-up after the eradication treatment in order to confirm this one (Table 2 and 3) [28].

Table 2. Diagnostic methods for Helicobacter pylori infection

 

Table 3. Selection of diagnostic method for the Hp infection in different situations

 

Radiology

Barium gastroduodenal studies have been almost completely happily substituted by the endoscopic explorations in the routine diagnostic protocols, although they can still be useful in few patients who refuse to perform it, or in the cases that endoscopy is inaccessible by narrowing of the esophagus. The sensitivity and specificity of barium radiographic studies, depends on the radiologist experience, the technique used, the size of the lesion (if they are < 0.5 cm in diameter, it can be difficult to detect) and ulcer depth. Radiologic signs suggesting on benign nature are regular margins and symmetrical mucosal folds, a smooth translucent band or collar, surrounding the ulcer crater suggesting edema and indentation of the opposite wall (Figure 3). The signs that suggest malignancy by contrary, are a big size of the ulcer, irregular mucosal folds, contrast absence or irregular filling (Figure 4).

Figure 3. A benign gastric ulcer at the lesser curve

   

Figure 4. Malignant lesion in the gastric body                        

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Treatment

 

The discovery of the link between H. pylori and peptic ulcer has changed dramatically its management, because it has become a curable infectious disease. For the subgroup of patients with H. pylori-negative ulcers, the therapy with anti-secretory agents or the replacement of conventional NSAIDs by selective drugs for inhibition of cyclooxygenase-2 (COX-2) are other treatment options.

General care

It is essential to avoid potential contributing agents such as NSAIDs or tobacco. There are no firm recommendations on alcohol intake or dietary habits, apart from not eating foods that can aggravate the symptoms [29]. 

Helicobacter pylori-negative

The main etiology is related to the use of NSAIDs, so withdrawing these treatments is a crucial step. In H. pylorinegative, NSAID-negative ulcers, a detailed search should be made to detect other contributing factors, such as medical comorbidities, poor nutritional status, ischemia and acid hyper-secretory disorders. The management of uninfected patients is based on the classic anti-secretory therapy [29,30].

The two groups of anti-secretory drugs most commonly used in these conditions are the histamine-2 receptor antagonists (H2RAs) and the proton pump inhibitors (PPIs). The mechanism of action is by suppression of acid secretion by gastric parietal cells. First drugs got the effect by blocking the histamine H2 receptors placed on the cell basolateral membrane, they are seldom used actually and have been substituted almost completely by PPIS that acts by irreversible binding and inhibition of the hydrogen-potassium ATPase pump, located on the luminal surface of the cell membrane. All PPIs achieve a similar level of acid secretory inhibition and healing rates in the treatment of PUD.

PPIs are most effective when taken 30-60 minutes before meals. Global ulcer healing rates are above 75%, although PPIs achieve better results than H2RAs (near 100%). Therefore, the use of PPIs is recommended whenever possible. If a standard PPI therapy fails to heal a peptic ulcer, it is recommended to try twice daily dosing or switch to another PPI. For large ulcers (>2-3 cm), double dose of PPI is recommended for 12 weeks. Higher doses are necessary to control symptoms in other hypersecretory states, such as the Zollinger-Ellison syndrome.

The probability of ulcer recurrence with the classic antisecretory therapy is approximately 80% per year, after the end of treatment. For this reason, a long-term maintenance treatment with a PPI is recommended in patients with increased risk, defined by a history of previous complications, frequent recurrences, torpid evolution (refractory, giant or fibrosed ulcers) or when NSAIDs cannot be discontinued. For this latter condition, the use of COX-2 inhibitors as an alternative, requires a careful individual assessment of the possible gastrointestinal and cardiovascular risks. There are no conclusive data from controlled trials, regarding the appropriate duration of prolonged therapy, although this should be maintained at least until ulcer´s healing has been confirmed, or NSAIDs have been stopped.

 The recommended schedule for each of these drugs is the standard dose once a day during four and six to eight weeks, for acute duodenal and gastric ulcers respectively. H2RAs are well absorbed after oral dosing and is not reduced by concomitant food intake. The H2RAs and PPIs are usually well tolerated with a low incidence (< 3-4%) of side- effects [29,31]. Most are reversible and mostly occur in patients over 50 years old. For H2RAs, it is advised to perform some dose adjustments in patients with renal failure. Ranitidine binds to cytochrome P-450 (CYP) enzyme system and may inhibit the elimination of other drugs that are metabolized through the same metabolic route.

PPI are remarkable safe drugs and does not require dose adjustments for renal or liver insufficiency. The main concerns regarding the long-term use of these agents include the presence of hypergastrinemia produced by the inhibition of acid secretion and the association with gastric atrophy. However, so far, it has not been yet reported any significant clinical consequences of these risks. Other adverse effects of prolonged PPIs use, such as potential onset of enteric infections (Clostridium difficile) and nutritional deficiencies (hypomagnesemia, decreased calcium absorption with increased risk of bone fractures, vitamin B12 deficiency) should be considered. PPIs are metabolized by cytochrome P450 enzymes, with CYP2C19 having the main role, and the dominance of this route varies among the different agents, which can lead to changes in the interaction profiles. In this regard, it has been described that pantoprazole has the lowest potential for P450 metabolism and drug interactions [32]. The antagonism between PPIs and clopidogrel has been one of the most relevant described. However, the potential clinical negative impact of some PPIs on the therapeutic effect of clopidogrel, remains controversial. In view of the inconclusive data, PPIs with weaker inhibition power of CYP2C19, are preferred in combination with clopidogrel, compared with those with stronger inhibition such as omeprazole [33].

Helicobacter pylori-positive PUD

The eradication therapies of H. pylori infection are based on the scientific evidence, collected in the most recent consensus reports [34]. In settings with a high prevalence of H. pylori infection and in the absence of NSAID use, is reasonable to consider the empiric eradication treatment. Drugs that have demonstrated efficacy include amoxicillin, clarithromycin, metronidazole, tetracycline and bismuth (Table 4).

Table 4. Recommendations for pharmacological treatment of PUD. *Omeprazol 40mg, Lansoprazol 60mg, Pantoprazol 80mg, Rabeprazol 40mg, Esomeprazol 40 mg, **In patients with Penicillin Allergy, a Levofloxacin-containing regimen (together with a PPI and Clarithromycin) represents a second-line alternative

 

The most recent data shows that classic triple therapy containing PPI?clarithromycin and amoxicillin or metronidazole has lost some efficacy, mainly due to the increase resistance to clarithromycin observed in the latest years. For this reason, this standard regimen is currently recommended for first-line treatment, only in areas of low resistance rate. Double doses of PPI (twice daily) and extend treatment to 14 days improve the eradication rates. In regions with high clarithromycin resistance, quadruple therapy (the so called “concomitant” treatment) which includes the combination of PPIs, amoxicillin, clarithromycin and metronidazole, is recommended as first-line empirical treatment. If these combinations fail to achieve the eradication, either a bismuth-containing quadruple therapy, or a rescue treatment with levofloxacin, are recommended. After the failure with three different regimens, it is better to refer the patient to a center with greater expertise in the management of multi-drug resistant H. Pylori

H. pylori eradication alone should be considered sufficient for small or moderate size ulcers and for compliant patients with confirmed eradication, in the absence of NSAIDs use. Patients with gastric ulcers, complicated duodenal ulcers or other markers of increased risk (giant ulcers, fibrosed lesions or prior history of relapse) require maintenance treatment with antisecretory drugs; at least until the eradication of H. pylori and/or ulcer healing, have been confirmed. Long-term therapy with normal dose of PPIs is indicated in these high-risk subgroups, if the infection persists.

The combined treatments are generally well tolerated and the rate of adverse effects depends on the antibiotics used in the different treatment regimens. The most frequently registered are diarrhea, rash and candidiasis (amoxicillin); nausea, metallic taste, peripheral neuropathy and antabus-like effect with alcohol intake (metronidazole); prolongation of QT interval and seizures can appears in predisposed patients for other reasons (fluoroquinolones) and in few cases transient pigmentation of the tongue and dark stools (bismuth).

Endoscopic surveillance

An endoscopic control is recommended to monitor the healing in giant duodenal ulcers and gastric ulcers, regardless of their size. In this last case, repeat the procedure with biopsy after six to eight weeks of treatment is a good way to ensure that the lesions are benign. 

Treatment in special situations

H. pylori infection in NSAIDs users: H. Pylori infection is associated with an increased risk of the development of gastroduodenal ulcers and its complications in NSAIDs and low-dose aspirin users [34]. The available data helps in H. pylori eradication before starting NSAIDs treatment. It is also appropriate to test and treat this infection, following the presentation of any clinical ulcer. If NSAIDs or aspirin are continued, treatment of such patients with a PPI in addition to the eradication therapy, can reduce the risk of recurrent ulcer complications.

Refractory ulcers: Peptic ulcers that have not healed after proper treatment for 12 weeks are considered as refractory lesions [29]. In this context, the following conditions must be investigated: Persistence of H. pylori infection or false negative in the initial diagnosis, hidden NSAIDs use, non-compliance of prescribed treatment, giant or fibrotic ulcers, ulcerated tumors, tobacco consumption and acid hypersecretory states. Chronic ischemia caused by the narrowing of celiac artery may also be considered, in this situation.  In the absence of all these risk factors, it is recommended to insist on all medical options before indicating surgery.

Pregnancy and lactation: Omeprazole is listed by the FDA as a pregnancy class C medication, whereas all other currently available PPIs, and H2RAs such as cimetidine and ranitidine, are class B. Although the results in some analysis of prospective data have shown that the global risk is low in pregnancy with potential toxicity during lactation, the lack of data in humans, precludes to achieve definitive conclusions regarding their safety [35]. Currently, there are no guidelines to treat H. pylori infection during pregnancy. It has been suggested that eradication should be deferred after delivery and lactation [36].

Stress-related erosive syndrome: These lesions are typically described affecting to patients admitted in intensive care units and affected with a serious systemic disease, such as sepsis, major trauma, massive burn injury and multiorgan failure. In this scenario, coagulopathy and mechanical ventilation have been identified as the most important risk factors for stress-related complications [29,30]. The approach to treatment of these lesions is similar to that for the rest of peptic ulcers. Routine prophylaxis is only recommended in patients at high-risk of stress ulcer bleeding. It has been suggested that PPIs are more effective than H2RAs in preventing clinically important and overt upper gastrointestinal bleeding [37].   

Treatment of complicated PUD

General approach: All patients with complicated peptic ulcer disease require appropriate supportive care, such as fluid resuscitation, administration of acid suppressive therapy, H. pylori infection treatment, if present, and discontinuation of NSAIDs, if possible. It is also essential the early coordination of care among medical, intensive care unit, surgical and radiologist teams, allowing to take appropriate decisions without dangerous delays.

Bleeding: Peptic ulcer bleeding is a major clinical problem in the emergency setting, in Western countries. The first priority in patient management is correcting fluid losses and restoring the hemodynamic stability. High-dose of intravenous PPIs therapy (80mg in bolus followed by 8mg/h in continuous-infusion for 72 hours) initiated prior to endoscopy, is recommended, because this treatment significantly reduces the rates of ulcers with high-risk stigmata of recent hemorrhage, the need for endoscopic hemostasis and promotes rapid healing [38-40].

Endoscopic therapy has generally been recommended as the first-line of treatment, for upper gastrointestinal bleeding and it should be performed within the 24 hours of the patient admission. It has been shown to reduce further bleeding (OR = 0.38; 95% CI, 0.32-0.45); need for surgery (OR = 0.36; 95% CI, 0.28-0.45) and the global mortality (OR = 0.55; 95% CI, 0.40-0.76). Endoscopic therapy can be divided into injection therapy, which is the oldest technique and usually involves the use of epinephrine with addition of a second agent; mechanical methods with clips and thermal procedures with argon plasma coagulation and bipolar probes [40,41].

Only a minority of patients with bleeding ulcers, would require surgical treatment. The indications for emergency surgery, include the repeated fail of endoscopic therapy, persistent hemodynamic instability despite resuscitation measures, recurrent bleeding after a second attempt at endoscopic treatment and continued high transfusion requirements. Under these conditions and for some cases, an alternative to surgery is angiography and this procedure may be considered in patients at high risk of surgery. It is also effective for the management of bleeding recurrence after surgery.

The perforations are more usual in duodenal, than in gastric ulcers (60 vs. 40%), mainly in elderly and in patients with a previous history of heavy alcohol consumption, highly tobacco users and/or NSAIDs intake. In these cases, surgical treatment is indicated. However, in patients with penetrating ulcers, may initially attempt a conservative medical treatment (nasogastric tube, fluid intravenous, parenteral nutrition and broad-spectrum antibiotics) with close monitoring, and if worsening of patient´s status, surgery must be performed [29].

This complication should be initially managed with medical treatment measures (nasogastric tube for decompression, intravenous fluid, PPIs to decrease gastric secretion and promote ulcer healing, H. pylori eradication). In many cases, these measures can reverse the obstruction by reducing the edema and spasm associated with the lesion. Endoscopic balloon dilation should be attempted quite soon, if obstruction is not reversed and also if there is no response with drug therapy and the healing process has conditioned a severe stenosis [42]. Surgery is the last resort, if no improvement is achieved, with either pharmacological and/or endoscopic treatments [29]. 

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