Gastritis and Peptic Disease 2024-2025 PDF

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024-2025 Digestive System Diseases Gastritis and P...

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024-2025 Digestive System Diseases Gastritis and Peptic Disease Monia Baldoni STOMACH STOMACH: STOMACH STOMACH STOMACH DUODENUM  STOMACH: functional anatomy Three basic functions: ❖ Motor function ❖ Secretory function ❖ Antibacterial function Motor function Gastric Motility. Contractions of gastric smooth muscle serve two basic functions: ingested food is crushed, ground, and mixed, liquefying it to form what is called chyme. Chyme is forced through the pyloric canal into the small intestine, a process called gastric emptying. The stomach can be divided into two regions based on a motility pattern: an accordion-like reservoir that applies constant pressure on the lumen and a highly contractile grinder.  STOMACH: functional anatomy Motor function Proximal part fundus + proximal portion of the gastric body - Tonic contractions Function: food storage Distal part Distal portion of the gastric body + antrum Peristaltic propulsive activity Function: mixing and propulsion of food. Low-frequency circular contraction  STOMACH: functional anatomy During the Interdigestive phase the proximal stomach, shows low-frequency, sustained contractions that are responsible for generating basal pressure within the stomach. These tonic contractions also generate a pressure gradient from the stomach to the small intestine and are thus responsible for gastric emptying. During the ingestion of food, the motor pattern changed dramatically: the proximally part of the stomach relaxes, and consequent gastric distention inhibits contraction of this region of the stomach, allowing it to balloon out and form a large reservoir without a significant increase in pressure. The distal stomach develops strong peristaltic waves of contraction that increase in amplitude as they propagate toward the pylorus, the Post- prandial motor pattern. These powerful contractions constitute a very effective gastric grinder; they occur about 3 times per minute in people. Gastric distention strongly stimulates this type of contraction, accelerating liquefaction and hence, gastric emptying. The pylorus is functionally part of this region of the stomach - when the peristaltic contraction reaches the pylorus, the tone that keeps it close is effectively exceeded - chyme is thus pushed into the small intestine in spurts. STOMACH: functional anatomy  STOMACH: functional anatomy Secretory and antibacterial function The gastric epithelium is characterized by different cell types with specific functions and a significant cell turnover that regulates the balance between exfoliation and cell regeneration cellular half-life 2 days 500,000 cells/min exfoliation STOMACH: functional anatomy STOMACH: functional anatomy GASTRIC MUCOSA The stomach mucosa’s Gastric secretion epithelial lining consists of surface mucus cells, which secrete a protective coat of alkaline mucus. A great number of gastric pits dot the surface of the epithelium, they mark the entry to each gastric gland. In the middle region of the gastric glands are parietal cells, relatively large cells that produce both Located primarily in the basal hydrochloric acid (HCl) and regions of gastric glands are intrinsic factor chief cells, which secrete pepsinogen The glands of the cardia and pylorus are composed primarily of mucus-secreting cells. Cells that make up the pyloric antrum secrete mucus several hormones, such as G CELLs producing gastrin and D CELLs producing somatostatin  Gastric secretion Intrinsic factor: glycoprotein secreted by parietal cells that is necessary for intestinal absorption of vitamin B12. The lack of this hormone causes pernicious anemia (megaloblastic anemia).  Gastric secretion Parietal cells in the stomach secrete roughly two liters of acid a day in the form of hydrochloric acid. Acid in the stomach functions to kill bacteria, and to aid digestion by solubilizing food. The acid is also important to establish the optimal pH (between 1.8-3.5) for the function of the digestive enzyme pepsin. A key protein for acid secretion is the H+/K+-ATPase (or proton pump). This protein, which is expressed on the apical membrane of parietal cells, uses the energy derived from ATP hydrolysis to pump hydrogen ions into the lumen in exchange for potassium ions. Stimulation of acid secretion involves the translocation of H+/K+- ATPases to the apical membrane of the parietal cell. When the cell is resting (not stimulated), H+/K+-ATPases are located in vesicles inside the cell. When the cell is stimulated, these vesicles fuse with the plasma membrane, thereby increasing the surface area of the plasma membrane and the number of proton pumps in the membrane.  Gastric secretion Hydrochloric acid is first secreted into large canaliculi, deep invaginations of the plasma membrane which are continuous with the lumen of the stomach.  HCL secretion HCL releasing factors: Acetilcoline (Ach): released from the vagal nervous system, stimulates the parietal cell directly via M3 receptors interaction. Histamine: produced by enterochromaffin-like cells (ECL), it binds H2 receptor. Gastrin: Secreted by G cells located in the antrum, strongly stimulates HCL production. HCL inhibiting factors: Somatostatin: is present in D cells of the gastric oxyntic and pyloric mucosa. It inhibits acid secretion (negative feedback) in a paracrine fashion directly by inhibiting secretion from the parietal cell, as well as indirectly by inhibiting histamine secretion from the ECL cell and gastrin secretion from the G cell. HCL secretion  Gastric secretion Pepsinogen: is a powerful and abundant protein digestive enzyme secreted by the gastric chief cells as a proenzyme and then converted by gastric acid in the gastric lumen to the active enzyme pepsin. Pepsinogens are synthesized and secreted primarily by the gastric chief cells of the human stomach before being converted into the proteolytic enzyme pepsin, which is crucial for digestive processes in the stomach. Furthermore, pepsin can activate additional pepsinogen autocatalytically. Pepsinogens are also called acid proteinases because they act between pH 1.5 and 5.0. The gastric chief cells of human gastric mucosa produce two types of pepsinogen: pepsinogen I (PGI) and pepsinogen II (PGII). Hydrochloric acid removes some of its amino acids and forms pepsins that digest proteins. Pepsin digests dietary proteins into shorter peptide chains. Protein digestion is completed in the small intestine.  Gastric secretion The stomach is protected from self-digestion by the mucosal barrier. The gastric mucosal barrier is a complex system made up of submucosal, epithelial and mucus elements. Bicarbonate-rich mucus: The mucus gel layer, rich in bicarbonate, is a thick tenaciously organized layer (about 1-2 mm) adherent to the epithelium, secreted from mucous cells and surface epithelial cells. This mucus forms a physical barrier to mechanical damage, and its bicarbonate ions neutralize the acid. Despite these properties, it is composed of more than 95% water, the organization being provided by long interacting glycoprotein molecules (mucus glycoprotein or mucin). These molecules are largely made up of carbohydrate which is present in large numbers of relatively small oligosaccharide units packed around the polypeptide core. Besides mucus, the epithelial cells also secrete pepsin-resistant, LMW-proteins, called trefoil factor (>viscosity). Tight junctions: seal adjacent epithelial cells in a narrow band just below their apical surface. They consist of a network of claudins and other proteins. Tight junctions perform two vital functions: They limit the passage of molecules and ions through space between cells, so they block gastric juice from penetrating the underlying tissue layers. Epithelial Stem Cells: epithelial tissues self-renew throughout life due to the presence of multipotent stem cells and/or unipotent progenitor cells. Epithelial stem cells are specified during development and are controlled by epithelial-mesenchymal interactions. These cells quickly replace damaged epithelial mucosal cells, when the epithelial cells are lost. Gastric mucosal Blood Flow: is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. It provides nutrients and trophic elements to mucosal cells and their self-renew. It is guaranteed from many compounds and the most important appears to be the prostaglandins.  Gastric secretion Three phases The cephalic phase of gastric secretion occurs before food enters the stomach, is initiated by the sight, smell, thought or taste of food. Neurological signals originate from the cerebral cortex and in the appetite centers of the amygdala and hypothalamus. They are transmitted through the dorsal motor nuclei of the 20% vagus, and then through the vagus nerve to the stomach. This enhanced secretory activity is a conditioned reflex. The gastric phase accounts for about two-thirds of gastric secretions. Ingested food stimulates gastric activity by stretching the stomach and raising the pH of its contents; this causes a cascade of events that leads to the release of hydrochloric acid by the parietal cells that lower the pH and break apart the food. 70% Gastric secretion is stimulated chiefly by three chemicals: acetylcholine (ACh), histamine, and gastrin. Below pH of 2, stomach acid inhibits the parietal cells and G cells; this is a negative feedback loop that winds down the gastric phase as the need for pepsin and HCl declines. The intestinal phase occurs in the duodenum as a response to the arriving chyme, and it moderates gastric activity via hormones and nervous reflexes. The duodenum initially enhances gastric secretion, but soon inhibits it. The stretching of the duodenum enhances gastric function via the vagal nerve, as the chyme causes the secretion of gastrin, which stimulates the stomach. The acid and semi-digested fats in the duodenum trigger the 10% enterogastric reflex: the duodenum sends inhibitory signals to the stomach by way of the enteric nervous system. The newly arrived chyme also stimulates enteroendocrine cells of the intestine to release compounds that stimulate the pancreas and gall bladder, while also suppressing gastric secretion and motility to allow the duodenum to process the chyme before receiving more from the stomach.  Gastric secretion https://www.youtube.com/watch?v=NIbclTo3duU  Gastric secretion GASTRIC LEPTIN: Leptin has an important role in regulating food intake and energy expenditure. At first, considered as a hormone specific to the white adipose tissue, it was rapidly found to be expressed by other tissues. Among these, the gastric mucosa has been demonstrated to secrete large amounts of leptin. Secretion of leptin by the gastric chief cells was found to be an exocrine secretion. Exocrine-secreted leptin survives the hydrolytic conditions of gastric juice by forming a complex with its soluble receptor. Once this complex reaches the small bowel (duodenum) it interacts with its transmembrane receptors expressed at the luminal membrane of the duodenal enterocytes and, through transcytosis, is released into the bloodstream, thus reaching the hypothalamus where its action regulates food intake. Production of Leptin is stimulated by food intake, gastrin, cholecystokinin, and Secretin. Exocrine-secreted gastric leptin participates in the short-term regulation of food intake independently from that secreted by the adipose tissue. Adipose tissue leptin, on the other hand, regulates long-term energy storage. Both tissues work in tandem to ensure the management of food intake and energy expenditure. Mouse models knock out for leptin gene induces lack in leptin-mediated satiety signal in the brain leading to morbid obesity  Gastric secretion GASTRIC GHRELIN: Ghrelin is a 28-amino-acid peptide that was discovered in rat and human stomachs in 1999. Although there are several neuropeptides stimulating food intake, ghrelin is the only known appetite-stimulating hormone in humans. Its circulating levels increase during fasting and decrease following a meal. Ghrelin is a gut-brain peptide in that ghrelin is found in the stomach and hypothalamus but is abundantly produced from endocrine cells in the gastrointestinal mucosa (ghrelin cells are most abundant in the stomach and are localized in gastric mucosal layers). Ghrelin is the only established appetite-stimulant gut peptide to date, maybe one factor involved in increased appetite, cravings and food intake following weight loss. Ghrelin levels, which increase following diet-induced weight loss and stimulate appetite, may contribute to weight regain. Leptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Ghrelin is a fast-acting “go” hormone that tells you to eat, seemingly playing a role in meal initiation. Ghrelin is considered a classical orexigenic (appetite stimulant) peptide hormone since its plasma levels rise before and decrease after ingestion of food in animals and humans. Leptin on the other hand is the hormone that tells you to stop eating and thereby inducing weight loss.  GASTRITIS DEFINITION Gastritis is a condition in which the stomach lining is inflamed due to different causes. GASTRITIS  GASTRITIS Acute gastritis is characterized by the presence of neutrophils in the stomach lining. It can be a mild or a severe condition with different modality of presentation: Acute superficial gastritis Acute erosive gastritis Acute haemorrhagic gastritis NSAIDs related gastritis Stress-induced gastritis  GASTRITIS Chronic gastritis is characterized by the presence of monocytes, lymphocytes, and plasma cells in the stomach lining: ❖ Autoimmune chronic gastritis (type A) ❖ Chronic gastritis related to H.P. infection (type B) ❖ Bile reflux gastritis (type C)  ACUTE GASTRITIS The outcome of direct damage from exogenous and/or endogenous factors ▪ Drugs ▪STRESS-INDUCED GASTRITIS ▪ Alcohol ▪ Caustics ▪ Radiation STRESS-INDUCED GASTRITIS It can occur in the case of: ❖ Extensive burns ❖ Trauma ❖ Haemorrhagic shock ❖ Respiratory failure ❖ Severe sepsis ❖ MOF ❖ Surgery with Extracorporeal circulation  ALCOHOLIC GASTRITIS The severity of gastric lesions depends on: ❖ Amount of alcohol consumed ❖ Fasting intake ❖ Binge drinking  ACUTE GASTRITIS Stress-induced and alcoholic induced gastritis pathogenesis: Stress-induced Hypovolemic shock mucosal hypoxia and back diffusion of hydrogen ions Alcoholic Impaired mucus synthesis and secretion Increased capillary permeability leads to interstitial edema Direct cell membrane damage  DRUG-induced GASTRITIS Non-steroidal anti-inflammatory drugs (NSAID) gastritis Major cause of acute gastritis Every day more than 30 million people take NSAIDs The risk varies depending on specific medication, age, and comorbiditiesof the patient  DRUG-induced GASTRITIS NSAID GASTRITIS Side effects and complications due to NSAIDs are considered the most common drug-related toxicities in the United States. The spectrum of NSAID-induced morbidity ranges from nausea and dyspepsia (prevalence reported as high as 50– 60%) to a serious gastrointestinal complication such as endoscopy-documented peptic ulceration (15–30% of individuals taking NSAIDs regularly) complicated by bleeding or perforation in as many as 1.5% of users per year.  NSAID GASTRITIS The most used NSAID is the aspirin (acetylsalicylic acid); this drug is used daily by about 11-20% of the population with a consequent increase in the risk of bleeding due to gastrointestinal damage of about 5-6 times In 1 to 4% of patients using NSAIDs, serious complications can develop, often requiring hospitalization. The risk increases with the combination of NSAIDs and ASA, or ASA and clopidogrel, or NSAIDs and steroids  DRUG-induced GASTRITIS PATHOGENESIS Local Injury Systemic Injury NSAIDs biological effect result in stomach protective factors impairment through cyclooxygenase inhibition and subsequent prostaglandin deficiency Mechanism The NSAIDs induce a damaging to the mucosal barrier of the stomach, through their ability to bind with the phospholipids, reducing the viscosity of the mucus and increasing the permeability, they favor the back diffusion of the H + ions responsible for the tissue damage NSAIDs-induced GASTRITIS systemic injury PROSTAGLANDIN ROLE Maintain mucosal integrity: - Stimulate the secretion of mucus and bicarbonate -Regulate cell repair and turnover systems, 500,000 gastric mucosal cells are lost and replaced every minute - Ensure adequate blood flow, loco-regional vasodilatation DRUG-induced GASTRITIS  ACUTE GASTRITIS TREATMENT MILD: Proton-pump inhibitors SEVERE: Endoscopic therapy: APC, injective and mechanical therapy Angiography with selective embolization of the bleeding arteries Administration iv of somatostatin Surgical therapy: to be reserved for the most serious cases CHRONIC GASTRITIS Type A Body and fundus A + B = Pangastritis Type B Antrum  CHRONIC GASTRITIS Aetiology TYPE A is related to auto-immune atrophic gastritis characterized by the presence, in the serum of the patient, of parietal-cell antibodies and/or anti-intrinsic factor antibodies TYPE B gastritis correlates with a Helicobacter pylori chronic infection. Over 95% of chronic gastritis are due to this infection  CHRONIC GASTRITIS Autoimmune chronic gastritis (type A) Chronic gastritis related to H.P. infection (type B) Bile reflux gastritis (type C) CHRONIC GASTRITIS Aetiology Autoimmune Atrophic Chronic Gastritis gastritis of the body - type A Hereditary, autosomal dominant, more prevalent in Northern Europe, F / M 3: 1 1-3% of chronic atrophic gastritis Specific antibodies: Anti Parietal Cells Anti Intrinsic Factor of Castle. Parietal cell loss progressive hypochlorhydria achlorhydria I.F. of Castle loss Vitamin B12 malabsorption Macrocytic/pernicious anaemia Neurological disorders Associated with other immune disorders : thyroiditis, diabetes type I and vitiligo Cancer risk: 3 times higher than the general population Precancerous condition Autoimmune Atrophic Chronic Gastritis gastritis of the body - type A Body and fundus involvement Reduced serum concentration of pepsinogen I Hypo-achlorhydria Iron deficiency, microcytic anaemia Vitamin B12 deficiency, macrocytic or megaloblastic anaemia Hyperplasia of the endocrine cells of the antrum Hypergastrinemia Autoimmune Atrophic Chronic Gastritis gastritis of the body - type A The autoantibodies directed against the components of the parietal cells (proton pump) and the Intrinsic Factor are not responsible for the damage that is caused by CD4 + lymphocytes directed against the parietal cells. The chief cells are lost through the destruction of the glands Chronic atrophic gastritis Helicobacter pylori-related Type B It is the most common cause of chronic gastritis, > 90% Predominantly antral gastritis. In the first moment, H.p. infection determines an acute gastritis which subsequently becomes chronic. If left untreated, it leads to the development, throughout life, of active chronic gastritis, characterized by the presence of neutrophils in the lamina propria as well as the presence of chronic inflammatory infiltrate. In a subgroup of patients, it progresses to pangastritis, and multifocal atrophy, reduction of acid secretion, and intestinal metaplasia (multifocal atrophic gastritis) which represents a risk factor for the intestinal adenocarcinoma or, more rarely, for gastric lymphoma, due to the persistent immune stimulation of gastric lymphatic follicles. The effects caused by H.p. vary greatly from individual to individual and only a minority of infected individuals develop gastric cancer: 3 cases/year per 10,000 people infected CHRONIC GASTRITIS Independent Risk Factors Cigarettes smoke (↑ incidence of antral gastritis) Older age Bile reflux  CHRONIC GASTRITIS Symptoms In 50% of cases there are no symptoms Nausea or recurrent upset stomach. Abdominal bloating. Abdominal pain (Upper abdominal quadrants). Vomiting. Indigestion (Dyspepsia). Burning or gnawing feeling in the stomach between meals or at night. Hiccups or belching Loss of appetite.  CHRONIC GASTRITIS Diagnosis Esophagogastroduodenoscopy No Specific Normal mucosa Presence of spotty erythema Visualization of submucosal vessel’s pattern Rugae’s reduction (or absence) Is possible find erosions chronic lesions ulcers Biopsy examination always!  CHRONIC GASTRITIS PATHOLOGY There are 2 main types of chronic inflammation: Chronic, active, Superficial gastritis H.p.-related (more frequently) Chronic Multifocal Atrophic gastritis is characterized by inflammation and thinning of the mucosa, loss of gastric glandular cells, and replacement by intestinal-type epithelium, and fibrous tissue. Depending on magnitude of inflammation and the level of loss of glandular elements, atrophic gastritis can be classified:  MILD  MODERATE  SEVERE  CHRONIC GASTRITIS Intestinal metaplasia DEFINITION: the replacement of the surface, foveolar, and glandular epithelium of the gastric mucosa by intestinal epithelium with the presence of Paneth cells, goblet cells and absorptive cells. Type I: «complete» intestinal metaplasia. Complete metaplasia is currently diagnosed when the epithelium resembles the small intestinal phenotype, with eosinophilic enterocytes displaying a well- defined brush border (representing absorptive microvilli) and well- formed goblet cells. Paneth cells may also be present. It expresses only sialomucins Type II: «incomplete» intestinal metaplasia. Incomplete metaplasia resembles a colonic epithelium phenotype with multiple, irregular mucin droplets of variable size in the cytoplasm and absence of a brush border. It is a hybrid form expressing a mixture of gastric (neutral) and intestinal mucins (sialomucins) Type III: «incomplete» intestinal metaplasia. It expresses sulphomucins and sialomucins. Premalignant lesion  CHRONIC GASTRITIS Intestinal metaplasia The different morphologic manifestations of the metaplastic process represent a gradual phenotypic change, with some types of mucins becoming less abundant, giving rise to new types of mucins. CHRONIC GASTRITIS Intestinal metaplasia Neutral mucins present in normal mucosa gradually decrease during the initial development of IM, whereas sialomucins appear and become the predominant type of mucin. In more advanced stages of IM, sulphomucins appear and may become the predominant mucin Intestinal Metaplasia = Premalignant lesion  Intestinal metaplasia PRECANCEROUS condition Atrophy is defined as “loss of appropriate glands” and is subtyped into two main histological variants: atrophy resulting from the disappearance of glands and replacement with fibrosis of the lamina propria; and glandular loss resulting from replacement of native glands with metaplastic, “inappropriate for location” glandular structures. Long‐term follow‐up studies conducted in different populations have consistently confirmed that the extent of the mucosal atrophy parallels gastric cancer risk. In 2005, an international group of gastroenterologists and pathologists (Operative Link on Gastritis Assessment (OLGA)) developed a histological staging system for gastric inflammatory diseases that has proved useful in simplifying medical communication, monitoring the progression of the disease and the effects of treatment, and, at the same time, expressing the cancer risk associated with the progression to intestinal metaplasia.  Intestinal metaplasia PRECANCEROUS condition  Intestinal metaplasia PRECANCEROUS condition In the OLGA staging system, gastric atrophy is considered to be the histological lesion representative of disease progression. Gastritis stage results from combining the extent of atrophy scored histologically with the topography of atrophy identified through biopsy mapping. It has been also suggested that the diagnostic report include information about the probable aetiology No atrophy: 0% SCORE 0 Sydney System, 1990 updated (Huston), 1994: 1. Chronic inflammation Mild atrophy: 1-30% SCORE 1 2. Activity 3. Atrophy Moderate atrophy: 30-60% SCORE 2 4. Intestinal metaplasia 5. Dysplasia 6. HP status Severe atrophy: > 60% SCORE 3  THE OLGA PROPOSAL The OLGA stage results from the combination of the overall “antrum score” with the overall “corpus score” Strong association between OLGA stages III-IV and GC Gastrointest Endosc 2010;71:1150-8 OLGA-OLGIM STAGING SYSTEM OLGA-OLGIM STAGING SYSTEM  Dyspepsia The term dyspepsia refers to a Organic dyspepsia: clinical syndrome characterized by chronic or recurrent symptoms gastroduodenal mucosal lesions (peptic ulcers, GERD, affecting the epigastric region: stomach cancer) upper abdominal pain and/or Bilio-pancreatic burning, post-prandial fullness, abnormalities (biliary lithiasis, chron bloating, early ic pancreatitis or pancreatic cancer) satiety, nausea, belching, and Functional dyspepsia (IBS) vomiting Warning Symptoms (RED FLAGS): Anorexia Weight loss Asthenia Anaemia  GERD GASTRITIS GASTRIC ULCER Dyspeptic Syndrome GASTRIC CANCER DUODENAL ULCER DUODENITIS ZOLLINGER-ELLISON DISEASE  PEPTIC ULCER DISEASE EROSION: is a superficial lesion, limited to the mucosa, with no involvement of the muscularis mucosae ULCER: is a lesion that penetrates the lining of the mucosa and that get through the muscolaris mucosae to involve the submucosa PEPTIC ULCER DISEASE PEPTIC ULCER DISEASE PEPTIC ULCER DISEASE: epidemiology Peptic Ulcer Disease: A Vanishing Disease! Decreased incidence in recent decades, parallel to the decline of H.p. An ulcer is present only in 5-10% of patients with dyspepsia. The yearly incidence of peptic ulcers as percentage of the total number of yearly upper gastrointestinal endoscopies PEPTIC ULCER DISEASE: epidemiology Peptic Ulcer Disease: A Vanishing Disease! Peptic ulcers are the most common source of upper GI bleeding accounting up to ~50% of cases 2 most common causes of PUD: Helicobacter pylori infection and NSAID use. As the prevalence of H. pylori infection decreases and NSAID use increases, the relative contribution of each factor to the incidence of PUD will change The yearly incidence of peptic ulcers in absolute numbers. In addition, the yearly number of patients presenting with bleeding  PEPTIC ULCER DISEASE: epidemiology GASTRIC ULCER: Incidence= 2% Less common than duodenal ulcers, perhaps due to a higher likelihood of GUs being silent and presenting only after a complication develops M/F= 1,5/1 More than half of GUs occur in males Tend to occur later in life than duodenal lesions, with peak incidence reported in the 6th decade DUODENAL ULCER: 6-15% of the Western population Incidence declined steadily from 1960 to 1980 and has remained stable since then >50% over visits have decreased over the past 30 years M/F= 3/1 Incidence peak between 4° and 5° decade The declining global prevalence is due to the declining prevalence of Helicobacter pylori infections Eradication of H. pylori has greatly reduced the recurrence rates after initial therapy PEPTIC ULCER DISEASE: PATHOGENESIS Hostile factors Protective factors HCL MUCUS PEPSIN BICARBONATE HELICOBACTER PYLORI PROSTAGLANDIN  PEPTIC ULCER DISEASE: aetiology In 2005, Robin Warren & Barry Marshall were awarded the Nobel Prize in Physiology or Medicine for their discovery that Peptic Ulcer Disease (PUD) was caused by Helicobacter Pylori PEPTIC ULCER DISEASE: aetiology Nobel 2005 HELICOBACTER PYLORI and duodenal ulcer 92% HP 1% Other 2% Cancer 5% NSAIDs Marshall WCG Los Angeles 1994 HELICOBACTER PYLORI and gastric ulcer 70% Hp 1% Other 2% Cancer 25% NSAIDs Marshall WCG Los Angeles 1994  PEPTIC ULCER DISEASE: aetiology Helicobacter Pylori infection 60 - 65% of duodenal and gastric ulcers in North America today (90 - 95% of duodenal ulcers, 80% of gastric ulcers in 1980). About 80% in Italy. One out of 6 infected persons develops an ulcer NSAIDs (5 – 35 %) Stress Corticosteroids, anticoagulants, bisphosphonates Viral infection: Herpes simplex, cytomegalovirus Zollinger-Ellison disease: Tumours that cause hypersecretion of gastric acid ( 60 anni Basso livello socio-economico predittivo di infezione HP 0 Immigrazione responsabile di isolate aree di alta prevalenza 0 10 20 30 40 50 60 70 80 AGE HELICOBACTER PYLORI Ulcer pathogenesis Alterated function ? GENETICS ? H. Pylori infection of D/G cells Parietal Cells Type B gastritis (antral gastritis) hypertrophy ↑ GASTRIN ↑ Acid production Duodenal infection Gastric metaplasia in duodenum DUODENITIS Duodenal Ulcer PEPTIC ULCER DISEASE: symptoms The symptoms of peptic disease are recurrent, coming and going over the course of days and months GASTRIC ULCER: DUODENAL ULCER: Characterized by burning epigastric pain, The pain usually occurs 2 to 3 hours after a that does not improve with food intake meal. Typically the patient may present and does not follow a fixed pattern. with pain that wakes him up during the For example, pyloric canal ulcers are night; this symptom is common and is often associated with symptoms of highly suggestive of a duodenal ulcer. obstruction Duodenal peptic ulcer pain is relieved by food and antacids. Peptic ulcer can be asymptomatic, especially in elderly patients, or manifest as a dyspeptic syndrome: bloating, nausea, and vomiting. Factors influencing ulcer recurrence include failure to eradicate H. pylori, continued use of NSAIDs, and smoking. Less commonly, the cause may be a gastrinoma. The 3-year recurrence rate for gastric and duodenal ulcers is < 10% when H. pylori is successfully eradicated, but is > 50% when it is not. PEPTIC ULCER DISEASE: Diagnosis Clinical evaluation and laboratory tests do not lead to definite diagnosis image016 GASTRIC ULCERS DUODENAL ULCERS Endoscopy + biopsies  PEPTIC ULCER DISEASE: Complications Chronic haemorrhage: FOBT+, microcytic hypochromic anaemia Haemorrhage 15-20% Acute haemorrhage: melena, hematemesis ulcer may penetrate the local Penetration organs: pancreas, liver... Free perforation Chemical peritonitis  Bacterial Gastric outlet caused by scarring, spasm, or inflammation obstruction from an ulcer in the pyloric canal 2% PEPTIC ULCER DISEASE Endoscopy  PEPTIC ULCER DISEASE: differential diagnosis Gastric Peptic ulcer Gastric cancer Every peptic ulcer must be considered as a gastric cancer, until proven otherwise.  PEPTIC ULCER DISEASE: differential diagnosis PEPTIC ULCER Malignant Ulcer Circular shape Irregular shape 2cm Clear margins Irregular margins Soft and elastic ulcer Hard ulcer PEPTIC ULCER DISEASE: treatment Nowadays, less than 1% of subjects with peptic ulcer disease need surgical treatment  PEPTIC ULCER DISEASE: treatment Triple therapy Proton pomp Inhibitors PPI + Clarithromycin + Amoxicillin or During antibiotic treatment Metronidazole 10-14 days and for a further 4 weeks (eradication rate 70-85%) Antibiotics Different therapeutic schemes Quadruple therapy Sequential therapy PPI + bismuth subsalicylate PPI + Amoxicillin for 5-7 days followed by + Metronidazole + tetracycline, each one 4 times/die Clarithromycin or Metronidazole for 5-7 days (eradication rate 75 - 90%) (eradication rate 75 - 95%) HELICOBACTER PYLORI It plays a central role in gastric disease  HELICOBACTER PYLORI Helicobacter pylori is a spiral-shaped Gram-negative bacterium (±3 μm long and with a diameter ± 0.5 μm). It has 4 or 6 flagella by which it can easily move. Produces many enzymes such as oxidase, catalase, and urease Microaerophilic bacterium:requires low levels of oxygen to survive It uses its flagella to burrow into the mucus lining of the stomach to reach the epithelial cells underneath, where it is less acidic. H. pylori can sense the pH gradient in the mucus and move towards the less acidic region (antrum), and it neutralizes the acid in its environment by producing large amounts of urease. It was discovered in 1982, initially called “Campylobacter pyloridis” The exact route of transmission is not totally well-known. The most common route of H. pylori infection is oral-to-oral contact (stomach contents are passed from mouth to mouth) or fecal-to-oral contact (from stool to mouth). Parents and siblings seem to play a primary role in transmission  HELICOBACTER PYLORI RESERVOIR suspected demonstrated Main Host Fecal-oral Oral-oral and gastro- contamination oral contamination Fecal-oral contamination Eating uncooked Contaminated water vegetables ingestion  HELICOBACTER PYLORI H. pylori has five major outer membrane protein families. The largest family includes adhesins. These proteins allow it to adhere firmly to the mucosa. Four other families are porins, iron transporters, flagellum-associated proteins, and proteins of unknown function. It breaks down the urea present in the stomach to carbon dioxide (CO2) and ammonia (NH4+) These react with the strong acids in the environment to produce a neutralized area around H. pylori HELICOBACTER PYLORI HELICOBACTER PYLORI: associated diseases HELICOBACTER PYLORI: associated diseases HELICOBACTER PYLORI: associated diseases H. Pylori infection is usually acquired during infancy, and it typically induces life-long chronic gastritis. HP is specifically adapted to survive in the hostile acidic gastric environment, with gastric colonization resulting in the development of gastritis in virtually all infected individuals. The adhesion of the bacteria to epithelial cells induces an inflammatory response, resulting in the recruitment of neutrophils, followed by B and T lymphocytes, macrophages and plasma cells. Consequently, large amounts of reactive oxygen or nitrogen species, involved in epithelial cell damage and carcinogenesis, are generated. The major virulence factors of HP with a well-established role in the induction of mucosal inflammation include the cytotoxin-associated gene (cag) pathogenicity island (PAI) - encoded virulence factors, such as the cytotoxin-associated antigen (CagA) protein, the vacuolating toxin-A (VacA), the blood group antigen-binding adhesin (BabA) and the outer inflammatory protein (OipA). These proteins are encoded in a 40-kilobase segment of DNA that includes a group of approximately 30 genes, including those for type IV secretion system components. HELICOBACTER PYLORI: associated diseases CagA, encoded by cag PAI, is translocated into the epithelial cytosol. This cytotoxin is a 121- to 145-kDa immunodominant protein that is commonly considered a putative bacterial oncoprotein. In fact, it has been used as a marker for epidemiological studies of GC. Within Western populations, CagA-positive strains are more commonly associated with peptic ulceration, atrophic gastritis and gastric adenocarcinoma than cag-negative strains. Conversely, in many populations with a high incidence of GC, such as the Eastern regions of Asia, almost all HP strains are cag-positive. Epithelial cells recognize the translocated CagA as a signaling molecule that is activated following tyrosine phosphorylation by Src kinases. This form interacts with the tyrosine phosphatase SHP-2, the C-terminal Src tyrosine kinase (SCK) and the adaptor protein Crk, together resulting in cytoskeletal reorganization and cell elongation. In turn, these changes lead to cell scattering and so- called ‘hummingbird’ morphological changes. They also induce MAP kinase signaling, resulting in abnormal cell proliferation by promoting cell cycle progression. HELICOBACTER PYLORI: associated diseases CagA-activated SHP-2 plays an important role in cell transformation and GC promotion. Phosphorylated CagA binds the adaptor protein Crk, leading to cytoskeletal reorganization, the disruption of epithelial cell tight junctions and tissue damage. Non-phosphorylated CagA also interacts with certain host cell proteins, such as epithelial tight junctions, the hepatocyte growth factor receptor C-Met, E-cadherin/β-catenin, the adaptor protein GRB-5 and kinase PAR1. These CagA-host-protein interactions disrupt tight and adherent junctions, leading to a loss of cell polarity and inducing pro-inflammatory and mitogenic effects that may be important in gastric carcinogenesis.  HELICOBACTER PYLORI: associated diseases Downstream events include the transcription of genes involved in intestinal differentiation, such as cdx1/cdx2 and the muc2 mucin gene, causing trans-differentiation from gastric to intestinal-type epithelial cells. HP stimulates gastric epithelial cells to express and release excessive amounts of pro-inflammatory cytokines, including interleukin-8 (IL-8) and IL-1. Pro-inflammatory IL-1 gene cluster polymorphisms (IL-1B, encoding IL-1B and IL-IRN, encoding its naturally occurring receptor antagonist) increase the risk of both intestinal- and diffuse-types of non-cardia GC, causing a reduction in gastric acid secretion, stimulating hypergastrinemia and promoting mucosal damage in atrophic gastritis. Thus, a high-risk IL-1 genotype increases the likelihood of non-cardia GC, a disease that is characterized by hypochlorhydria, while it has no effect on cancers associated with high-level acid exposure, such as esophageal adenocarcinoma and certain gastric cardia cancers HELICOBACTER PYLORI and Gastric Cancer World Health Organization International Agency for Research on Cancer Group 1 Carcinogenic to Humans Group 2A Probably carcinogenic to humans Group 2B Possibly carcinogenic to humans Group 3 Not classifiable as to its carcinogenicity to humans Group 4 Probably not carcinogenic to humans H.pylori: is a group 1 agent IARC 1994 HELICOBACTER PYLORI: DIAGNOSIS  Diagnosis of Infection INVASIVE NON INVASIVE Histology IgG in serum - ELISA Urease rapid test 13 C Urea Breath Test Culture test Fecal HP antigen Diagnosis of Infection Lee JY, Ann Trans Med, 2015  NON INVASIVE TESTS Urea breath test - UBT Is based on the ability of H. pylori, to break down orally absorbed 13C- or 14C-labeled urea into CO2 and ammonia. CO2 diffuses into the blood, is exhaled via the lungs, and can be measured in the exhaled air. 13C is a nonradioactive innocuous isotope, and it can be safely used in children and women of childbearing age but needs an expensive mass spectrometer. In contrast, 14C-urea is inexpensive but requires the use of a nuclear medicine department licensed for storage and disposal of radioactive reagents UBT is a highly accurate and reproducible test with > 95% sensitivity and specificity under standardized procedures. It is also useful for epidemiological studies and for assessing the efficacy of eradication therapy.  NON INVASIVE TESTS Urea breath test - UBT SENSITIVITY 90-100% SPECIFICITY 78-100%  UREA BREATH TEST – UBT: 13C equipment Infrared spectrometer Mass spectrometer IR: infrared analysis ◼ Need time to analyse samples ◼ Can test only few samples at a time Mass spectrometer ◼ Need time to analyse samples ◼ Really expensive ◼ Need trained staff  UREA BREATH TEST – 13C UBT: procedure Do not take any antibiotics for at least 4 weeks before the test Do not take any proton pump inhibitors or Pepto-Bismol for at least 2 weeks before the test. Do not eat or drink anything (including water) for four hours before the procedure.  UREA BREATH TEST – 13C UBT: procedure Time zero: blow into the baseline breath bag Take a urea 13C-labeled capsule with water After 30 min: blow into the post-dose breath bag  BREATH TEST Breath testing: Direct index of enzymatic reactions taking place on a cellular level Quantify these reactions Measuring exhaled CO2. It’s safe, simple and non-invasive.  BREATH TEST Breath test application: ◼ Diagnosis : can identify an infection. ◼ Metabolic assessement : can evaluate organ function. ◼ Therapy follow-up  BREATH TEST 13C BREATH TEST H2 BREATH TEST 13C - UREA LACTOSE 13C – OCTANOIC ACID GLUCOSE 13C - AMINOPYRINE LACTULOSE 13C – SODIUM OCTANOATE SORBITOL 13C – MIXED TRIGLYCERIDES FRUCTOSE HELICOBACTER PYLORI: future approach High prevalence infection Antimicrobal resistance Carcinogenic agent Uneffective immune response Vaccine could be a solution there are currently no advanced BUT… vaccine candidates, with only a single vaccine in Phase I clinical trial: no protective effect