Peptic ulcer: modern approaches to diagnosis and therapy

Peptic ulcers with localization of recurrent ulcers (acute erosion) in the stomach and/or duodenum and other parts include:

Gastric ulcer (peptic ulcer), including peptic ulcer of the pyloric and other parts of the stomach.
Duodenal ulcer (duodenal ulcer), including septic ulcer of all parts of the duodenum.
Gastrojejunal ulcer, including peptic ulcer of the anastomosis of the stomach, afferent and efferent loops of the small intestine, anastomosis with the exception of a primary ulcer of the small intestine.

Definition

Peptic ulcer (PU) is a chronic relapsing disease involving, along with the stomach and duodenum (DU), other organs of the digestive system, leading to the development of complications that threaten the patient’s life. The pathophysiology of ulcer includes the aggressive action of HCl and pepsin and a decrease in the resistance of gastroduodenal fluid as a result of inflammation, metaplasia, dysplasia, and atrophy, most often caused by contamination of HP. With an exacerbation of ulcer, a recurrent ulcer (acute erosion), chronic active gastritis, and more often active gastroduodenitis associated with Helicobacter pylori are usually detected.

Peptic ulcer: modern approaches to diagnosis and therapy

In 1586, Marcellus Donatus of Mantua, during an autopsy, first described a gastric ulcer, and almost a century later, in 1688, Johannes von Marault described a duodenal ulcer [1]. However, despite the improvement of preventive, therapeutic and diagnostic methods, among diseases of the digestive system, peptic ulcer disease (PU) continues to be one of the most common reasons for patients seeking medical help, and today it is difficult to imagine a practicing doctor who would not be familiar with this pathology .

In the International Classification of Diseases, X Revision, the term Peptic Ulcer is absent, which reflects two modern approaches to understanding the essence of the disease: on the one hand, consideration of peptic ulcer as a heterogeneous group of diseases united by the presence of a chronic ulcerative defect in the gastroduodenal zone, and on the other hand, as a nosological unit (disease ) with some generalized view of pathogenesis, clinical manifestations and standardized therapy. Both of these approaches are reflected in the definition of the disease: “Peptic ulcer (synonyms: duodenal ulcer, gastric ulcer) is the formation of an ulcer in the stomach or duodenum, resulting from an imbalance between the protective factors of the mucous membrane and various factors that damage the mucous membrane, understood as “etiology.” "[2].

Among the etiological factors of ulcerogenesis of the gastroduodenal zone (.), infection with Helicobacter pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs) dominate. Actually, the bacterium itself causes relatively modest damage to the epithelium - flattening and sometimes disappearance of microvilli in places of contact with H. pylori, a decrease in the number and volume of secretory granules with a corresponding decrease in mucus secretion. However, the main thing in ulcerogenesis is changes in signaling systems caused by the infection. In response to the action of signaling molecules (primarily pro-inflammatory cytokines), neutrophilic leukocytes penetrate into the mucous membrane, which in turn destroy intercellular contacts with their enzymes and free oxygen radicals, disrupting the integrity of the mucous membrane and forming a surface defect. However, it is well known that such mucosal defects can heal very quickly, leaving not only consequences, but also no traces.

With superficial damage, emergency closure occurs due to migration of the epithelium from the edges, even without increased proliferation. However, persistent infection delays the healing of ulcers, being the main cause of relapses. H. pylori inhibits the first - emergency reaction of the mucous membrane to damage - migration of the epithelium, necessary for the speedy closure of the defect; stimulates apoptosis, thereby increasing cell death in the edges of ulcers and complicating healing, and also suppresses the synthesis of epidermal growth factor with blockade of receptors for it; causes disruption of microcirculation and tissue trophism.

The main mechanism for the development of gastric and duodenal ulcers associated with NSAID use is associated with blocking the synthesis of prostaglandins. A decrease in the synthesis of prostaglandins leads to a decrease in the synthesis of mucus and bicarbonates, which are the main protective barrier of the gastric mucosa from aggressive factors of gastric juice. In turn, a decrease in the synthesis of prostacyclin and nitric oxide adversely affects microcirculation and creates an additional risk of damage to the mucous membrane of the stomach and duodenum. Changing the balance of protective and aggressive gastric environments leads to the formation of ulcers and the development of complications: bleeding, perforation, penetration.

The level of prevalence of etiological factors of ulcer in the population also determines the current epidemiological trends of the disease. Thus, if back in the 70–80s of the last century it was generally accepted that every tenth person may develop ulcer in his life, now the prevalence of ulcer has decreased several times and is, for example, 2.5% in the USA [3]. At the same time, while the frequency of ulcer perforation remained at the same level, the frequency of ulcer bleeding increased significantly (due to gastric ulcers), which is caused by the increasing intake of NSAIDs and Aspirin (Fig.). However, H. pylori infection and NSAID use alone do not exhaust all etiological factors of ulcer. About 5% of ulcerative defects of the gastroduodenal zone in the eastern population and about 30% in the western population are not associated with H. pylori/NSAIDs [4].

Thousands of research papers and reviews have been devoted to the consideration of the causative factors of ulcer formation in the gastroduodenal zone, and only a cursory description of the features of ulcerogenesis would require a separate publication. In each clinical case, the attending physician should strive for the most complete elucidation of etiological factors, their influence or on increasing the factors of aggression (increased impact of the acid-peptic factor associated with an increase in the production of hydrochloric acid and pepsin; impaired motor-evacuation function of the stomach and duodenum: delay or acceleration of the evacuation of acidic contents from the stomach, duodenogastric reflux), or on the inhibition of protective factors (resistance of the mucous membrane to the action of aggressive factors; mucus formation; adequate production of bicarbonates; active regeneration of the surface epithelium of the mucous membrane; sufficient blood supply to the mucous membrane; normal content of prostaglandins in the wall of the mucous membrane ; immune defense).

It is important to note that many of these factors of aggression and defense are genetically determined, and the balance between them is maintained by the coordinated interaction of the neuroendocrine system, including the cerebral cortex, hypothalamus, peripheral endocrine glands and gastrointestinal hormones and polypeptides.

Today, a number of genetic factors have been identified, the presence of which contributes to the occurrence of peptic ulcer disease:

hereditarily caused increase in the mass of parietal cells, their hypersensitivity to gastrin, increased formation of pepsinogen-1 and gastroduodenal motility disorder can lead to damage to the mucous membrane of the stomach and duodenum;
congenital deficiency of mucus fucomucoproteins, insufficiency in the production of secreted IgA and prostaglandins reduce the resistance of the mucous membrane;
blood group 0 (1), positive Rh factor, the presence of HLA antigens B5, B15, B35, etc. increase the likelihood of ulcer disease;
polymorphism of the TNF-alpha cytokine gene (TNF-alpha promoter single nucleotide polymorphism). Carriers of TNF-alpha-1031C and 863A have a high risk of developing duodenal ulcer and gastric ulcer in the presence of H. pylori infection: if carriers had either 1031C or 863A alleles, then the risk of developing ulcer in the presence of H. pylori is increased by 2.46 times, and in the presence of both alleles, the risk of developing ulcer in the presence of H. pylori is increased by 6.06 times. The 863CC genotype is associated with a high risk of developing intestinal metaplasia in patients with gastric ulcer.

The diagnostic process of ulcer disease includes analysis of the clinical manifestations of the disease, collection of anamnesis, examination of the patient, general clinical laboratory tests, esophagogastroduodenoscopy with biopsy, diagnosis of H. pylori infection, and (if necessary) other tests. In the Russian population, where the infection rate of the adult population in some regions reaches 90%, it is necessary to ensure the absence of bacteria in a given clinical situation, critically evaluate both the diagnostic methods used, and assess the likelihood of a false negative result in a given clinical case. If, however, the absence of infection is proven, the doctor receives an additional incentive to search for other etiological factors of ulceration in the gastroduodenal zone.

Despite the apparent simplicity of the issue, the clinical symptoms of ulcer require special attention. Which of the doctors who have undergone internship is not familiar with the description of the classic stigmas of gastroduodenal ulcers? The traditional description of the pain syndrome is nighttime, hungry, late pain in the localization of the ulcer in the duodenum and early pain in the gastric localization. However, in recent decades, the symptoms and course of ulcerative disease have become polymorphic, masked by dyspeptic symptoms of an uncertain nature, and in a certain percentage of cases (about 10%) the disease has no clinical manifestations [6]. Gastroduodenal ulcers in most elderly patients occur with a mild clinical picture and often manifest with complications, the frequency of which increases from 31% at the age of 60–65 years to 76% at the age of 75–80 years. More than 60% of bleeding from ulcerative defects of the gastroduodenal zone occurs in people over 60 years of age, who more often suffer from chronic diseases and take NSAIDs/Aspirin more often than younger people.

Once a diagnosis of ulcer is made, a decision must be made about where to treat the patient. Compliance with treatment standards using highly effective and safe agents allows one to achieve similar treatment results both in outpatient and inpatient treatment [7, 8]. Indications for hospitalization are: newly diagnosed ulcers (exclusion of symptomatic ulcers) and/or deep ulcers; persistent and severe pain lasting more than 7 days; carrying out a differential diagnosis with a tumor process); large (more than 2 cm) and long-term (more than 4 weeks) non-scarring ulcers (the need for additional examination, individual selection of medicinal and non-medicinal treatments); weakened patients or ulcers due to severe concomitant diseases. If therapy during an exacerbation of the disease is carried out on an outpatient basis, the patient should limit physical activity and follow dietary and lifestyle recommendations.

What goals do we strive to achieve when treating patients with ulcer? After all, it is important not only to relieve symptoms (if any), but also to prevent complications and relapses of the disease, and improve the quality of life of patients.

Depending on the mechanism of action, the following groups of drugs used in the treatment of patients with ulcer are distinguished:

antacids;
antisecretory agents (anticholinergics, H2 blockers, proton pump inhibitors (PPIs));
drugs with local protective action (cytoprotectors, reparants);
drugs that affect neurohumoral regulation (psychotropic drugs, regulators of motor-evacuation function - prokinetics, gastrointestinal hormones);
anti-Helicobacter therapy.

The first component of therapy is eradication when H. pylori is detected. The feasibility of eradicating H. pylori in patients with ulcer disease today is beyond doubt. Eradication of the bacterium leads to faster and better scarring of ulcerative defects, and also reduces the risk of relapse of the disease within a year from 70% to 4–5% and the likelihood of complications. These facts, obtained from studies that meet the requirements of evidence-based medicine, served as the basis for inclusion in the final document of both the 2000 and 2006 Maastricht Consensus as a strongly recommended indication for eradication therapy with the highest degree of scientific evidence, H. pylori-associated ulcer both in the acute stage and in remission, including complicated forms. The same agreement also established very stringent requirements for combination eradication therapy, capable of destroying the bacterium in controlled studies in at least 80% of cases and not causing forced withdrawal of therapy by the doctor due to side effects (acceptable in less than 5% of cases) or discontinuation the patient takes medications according to the regimen recommended by the doctor. According to consensus, therapy is carried out according to standard regimens in which PPIs are the basic drugs.

First line therapy (duration 10–14 days):

PPI in a standard dose 2 times a day;
clarithromycin 500 mg 2 times a day;
amoxicillin 1000 mg 2 times a day.
Second line therapy (duration 10–14 days):
PPI in a standard dose 2 times a day;
colloidal bismuth subcitrate (De-nol) 120 mg ´ 4 times;
Tetracycline 500 mg ´ 4 times a day;
Metronidazole 500 mg ´ 3 times a day.

When starting treatment for ulcer associated with H. pylori infection, control of infection eradication should be planned, and diagnostic tests for Helicobacter should be performed no earlier than 4–6 weeks from the end of taking the drugs.

The second component of therapy is suppression of the acid-peptic factor [9]. During an exacerbation of the disease, it is important to maintain a certain pH level, since healing of a mucosal defect in a duodenal ulcer occurs on average in 3–4 weeks, and in a stomach ulcer in 4–6 weeks, provided that it is possible to maintain a pH in the stomach > 3 less than 18 hours [10]. Compliance with this rule is impossible without the use of IPP. According to the chemical structure, PPIs belong to the class of substituted pyridine-methyl-sulfonyl-benzimidazoles, differing in the radicals in the pyridine and benzimidazole rings. Differences in chemical structure determine differences in pharmacokinetic properties. Are these differences clinically significant? Yes, they do. For example, pantoprazole (Controloc) causes the longest suppression of acid secretion compared to other PPIs, which is due to its specific binding to the 822-position cysteine, which is immersed in the transport domain of the gastric acid pump.

This is an important factor since restoration of acid production is entirely dependent on the self-renewal of proton pump proteins. The same pharmacokinetic features also determine the low level of drug interactions, which is especially important when carrying out preventive antisecretory therapy in individuals taking NSAIDs, Aspirin, and anticoagulants [11]. Thus, in recent years it has been found that long-term use of PPIs, with the exception of pantoprazole, is associated with a decrease in the effectiveness of clopidogrel and an increase in coronary mortality by 40% [12].

The third component of therapy is cytoprotection, which is achieved by prescribing agents that stimulate the synthesis of prostaglandins and bicarbonates, normalizing motility and microcirculation. The choice of drug (bismuth drugs, antacids, antispasmodics, prokinetics, etc.) is determined by the specific clinical situation. For example, in the absence of H. pylori infection, the basis of therapy is the choice of drugs that maximally suppress aggression factors with the obligatory prescription of cytoprotective agents [13].

For uncomplicated peptic ulcers of small and medium size, endoscopy monitoring with assessment of scarring of the ulcerative defect is performed after 14 days, and for larger ulcerative defects - after 21 days from the start of therapy.

If scarring of the ulcerative defect is not achieved, it is important to exclude the most common causes of failure (slow scarring of the ulcerative defect):

persistence of H. pylori infection;
inadequate cooperation between doctor and patient (low compliance);
taking NSAIDs (including hidden ones);
dense fibrosis, heavy smoking;
inadequate inhibition of hydrochloric acid secretion;
rare causes of ulcers.

If scarring of the ulcer has taken place, and the symptoms persist, it is necessary to reconsider the diagnostic strategy for the patient with an active search for other diseases (irritable bowel syndrome, pathology of the biliary tract, pancreas, etc.).

After achieving scarring of the ulcer and relief of symptoms, the next stage of patient supervision is making a decision on the need for maintenance therapy. Who needs it? We are talking about those patients who retain the etiological factors of ulcerogenesis of the gastroduodenal zone. These are people who are forced to continue taking NSAIDs/Aspirin, cytostatics, glucocorticosteroids, with Zollinger-Ellison syndrome, etc. Prevention is carried out by taking PPIs at half the dosage (for example, Controloc 20 mg).

Clinical observation of patients with an uncomplicated course of ulcerative disease and achieved eradication is carried out for 5 years with an annual endoscopic examination of the upper digestive tract and assessment of H. pylori infection.

A modern internist has impressive diagnostic and treatment capabilities and standards for managing a patient with ulcerative disease. However, their implementation is possible only with a meaningful analysis of the clinical picture and the nature of the course of the disease, an in-depth study of the causative factors of ulcerogenesis, and the appointment of treatment regimens with the maximum degree of evidence.

Literature

Unge Peter. Helicobacter pylori treatment in the past and in the 21st century.” in Barry Marshall. Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. 2002 Victoria, Australia: Blackwell Science Asia. pp. 203–213. ISBN 0–86793–035–7.
Vakil Nimish Dyspepsia, Peptic Ulcer and H. pylori: A Remembrance of Things Past //Am J Gastroenterol. 2010; 105:572–574; doi: 10.1038/ajg.2009.709.
Shiu Kum Lam. Differences in peptic ulcer between East and West Clinical Gastroenterology. Vol. 14, no. 1, pp. 41–52, 2000 doi:10.1053/bega.1999.0058.
Weil J., Colin-Jones D., Langman M., Lawson D., Logan R., Murphy M., Rawlins M., Vessey M., Wainwright P. Prophylactic aspirin and risk of peptic ulcer bleeding // BMJ. 1995, Apr 1; 310(6983):827–830.
Lee SW, Chang CS, Lee TY, Yeh HZ, Tung CF, Peng YC Risk factors and therapeutic response in Chinese patients with peptic ulcer disease // World J Gastroenterol. 2010; 16 (16): 2017–2022.
Order of the Ministry of Health and Social Development of Russia No. 612 of September 17, 2007 “On approval of the standard of medical care for patients with stomach ulcers (when providing specialized care).”
Order of the Ministry of Health and Social Development of Russia No. 611 of September 17, 2007 “On approval of the standard of medical care for patients with duodenal ulcers (when providing specialized care).”
Karen van Rensburg. Acid suppressants and peptic ulcer disease // SAPJ. April2010, pp. 33–37, indd 33.
Could ML, Enas N., Humphries TJ, Bassion S. Results of three placebo-controlled dose-response clinical trials in duodenal ulcer, gastric ulcer and gastroesophageal reflux disease (GERD) // Dig. Dis. Sci. 1998. Vol. 43. P. 993–1000.
Thomson ABR, Sauve MD, Kassam N., Kamitakahara H. Safety of the long-term use of proton pump inhibitors // World J Gastroenterol. 2010; 16(19):2323–2330.
Juurlink David N. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel // CMAJ. 2009;180(7):713–718.
Kenneth EL McColl, How I. Manage H. ylori Negative, NSAID/Aspirin-Negative Peptic Ulcers // Am J Gastroenterol. 2009; 104: 190–193; doi: 10.1038/ajg.2008.11.

M. A. Livzan, Doctor of Medical Sciences, Professor M. B. Kostenko

PDO GOU VPO OmSMA Roszdrav , Omsk

Contact information about the author for correspondence

peptic ulcer factors

Primary required research

General blood and urine analysis, determination of blood group and Rh factor, stool analysis for occult blood, serum iron, histological and cytological examination of biopsy samples from the periulcerous zone (for gastric ulcers - at least 6 biopsies), urease test to identify HP, ultrasound liver, biliary tract and pancreas, esophagogastroduodenoscopy with targeted biopsy and brush preparation for cytological examination. Additional studies are carried out depending on the manifestations of the disease, including a study of exocrine pancreatic function with a test using monoclonal antibodies to pancreatic elastase - human. The results of treatment of exacerbation of gastric ulcer (GUP) are always assessed by clinical and endoscopic studies over time, and in case of PUD, endoscopic examination is carried out only for special indications.