Peptic Ulcer.pdf

3 Peptic Ulcer Disease ILOs At the end of this session, the student will be able to:  Define the acid related disorders including peptic ulcer diseases.  Discuss the pathogenesis and risk factors of peptic ulcer diseases.  Identify the clinical presentations and diagnostic tools o...

3 Peptic Ulcer Disease ILOs At the end of this session, the student will be able to:  Define the acid related disorders including peptic ulcer diseases.  Discuss the pathogenesis and risk factors of peptic ulcer diseases.  Identify the clinical presentations and diagnostic tools of peptic ulcer diseases.  Explain the complications of peptic ulcer diseases.  Review the treatment of peptic ulcer diseases.  Highlight Zollinger Ellison syndrome.  Highlight the H pylori as a significant pathogen for the stomach. Peptic Ulcer Disease Acid secretion regulation: There are three main regulatory molecules that stimulate acid secretion: Acetylcholine, histamine, gastrin) and one main regulatory molecule that inhibits acid secretion (somatostatin). Acetylcholine is a neurotransmitter that is released by enteric neurons. Histamine is a paracrine that is released from ECL (enterochromaffin-like) cells. Gastrin is a hormone that is released by G cells, endocrine cells that are in the gastric epithelium. somatostatin is also secreted by endocrine cells of the gastric epithelium; it can act as either a paracrine or a hormone. other inhibitors of acid secretion that stimulate somatostatin release include glucagon-like peptide, CCK (cholecystokinin), VIP (vasoactive intestinal peptide), leptin and amylin. Peptic ulcer is a break in the gastric or duodenal mucosa that arises when the normal mucosal defensive factors are impaired or are overwhelmed by aggressive luminal factors such as acid and pepsin. Page 1 of 13  Ulcers that have depth and extend through the muscularis mucosae. In contrast to erosions, which are small and superficial mucosal lesions, peptic ulcers can vary in size from 5 mm to several centimeters.  Ulcers located either in the duodenum, where over 95% are in the bulb or pyloric channel, or in the stomach, where benign ulcers are located most in the antrum (60%) or at the junction of the antrum and body on the lesser curvature.  Duodenal ulcers most commonly occur in patients between the ages of 30 and 55 years, whereas gastric ulcers are more common in patients between the ages of 55 and 70 years. The incidence of duodenal ulcer disease has been declining dramatically for the past 30 years (due to the eradication of H. pylori), but the incidence of gastric ulcers has not been declining (due to the widespread use of NSAIDs and low dose aspirin). Etiology: There are two major causes of peptic ulcer disease: NSAIDs and chronic H pylori infection. Evidence of H pylori infection or NSAID ingestion should be sought in all patients with peptic ulcer. Alcohol, dietary factors, and stress do not appear to cause ulcer disease. Less than 5– 10% of ulcers are caused by other conditions, including acid hypersecretory states (such as Zollinger-Ellison syndrome or systemic mastocytosis), CMV (especially in transplant recipients), Crohn disease, lymphoma, medications (e.g., alendronate), or chronic medical illness (cirrhosis or chronic kidney disease), or are idiopathic.  H pylori–Associated Ulcers: The prevalence of H pylori infection in duodenal ulcer patients is 70–90%. The association with gastric ulcers is lower, but H pylori is found in most patients in whom NSAIDs cannot be implicated. Eradicated H pylori reduces the recurrence rate of ulcer dramatically.  NSAID Induced Ulcers: There is a 10–20% prevalence of gastric ulcers and a 2–5% prevalence of duodenal ulcers in long-term NSAID users. Approximately 2–5%/year of long-term NSAID users will have an ulcer that causes clinically significant dyspepsia or a serious complication. Low dose aspirin also carries the same risk. Use of even low-dose aspirin (81–325 mg/day) leads to a twofold increased risk of gastrointestinal bleeding complications. Low-dose aspirin in combination with NSAIDs or coxibs increases the risk of ulcer complications by up to tenfold compared with NSAIDs or low- Page 2 of 13 dose aspirin alone. Dual antiplatelet therapy with aspirin and a thienopyridine (e.g., clopidogrel) incurs a twofold to threefold increased risk of bleeding compared with aspirin alone.  Traditional nonselective NSAIDs inhibit prostaglandins through reversible inhibition of both COX-1 and COX-2 enzymes. Aspirin causes irreversible inhibition of COX-1 and COX-2 as well as of platelet aggregation. Coxibs (or selective NSAIDs) preferentially inhibit COX-2—the principal enzyme involved in prostaglandin production at sites of inflammation—while providing relative sparing of COX-1. the risk of significant clinical events (obstruction, perforation, bleeding) is reduced by up to 50% in patients taking coxibs versus nsNSAIDs. However, a twofold increase in the incidence in cardiovascular complications (myocardial infarction, cerebrovascular infarction, and death) has been detected in patients taking coxibs compared with placebo. Celcoxib has less COX-2 selectivity than rofecoxib and valdecoxib, does not have higher risk than other nsNSAIDs.  H pylori infection increases the risk of ulcer disease and complications over threefold in patients taking NSAIDs or low-dose aspirin. Clinical Findings: A. Symptoms and Signs:  Epigastric pain: is typically well localized to the epigastrium and not severe. It is described as gnawing, dull, aching, or hunger-like. the pain is neither sensitive nor specific to peptic ulcer disease. Even Complicated ulcers might even present without prior symptoms (silent ulcer) especially in NSAIDs related ulcer.  50% of patients report relief of pain with food or antacids (especially those with duodenal ulcers) and a recurrence of pain 2–4 hours later. However, many patients deny any relationship to meals or report worsening of pain. Two-thirds of duodenal ulcers and one third of gastric ulcers cause nocturnal pain that awakens the patient from sleep. When the pain increases in intensity and becomes radiating to back it is suggested to have complications like penetration or perforation.  Nausea and anorexia may occur with gastric ulcers. Significant vomiting and weight loss are unusual with uncomplicated ulcer disease and suggest gastric outlet obstruction or gastric malignancy. Page 3 of 13   The physical examination is often normal in uncomplicated peptic ulcer disease. Mild, localized epigastric tenderness to deep palpation may be present. B. Laboratory Findings: are normal in uncomplicated peptic ulcer disease but are ordered to exclude ulcer complications or confounding disease entities.  Anemia may occur with acute blood loss from a bleeding ulcer or less commonly from chronic blood loss.  Leukocytosis suggests ulcer penetration or perforation.  An elevated serum amylase in a patient with severe epigastric pain suggests ulcer penetration into the pancreas.  A fasting serum gastrin level to screen for Zollinger-Ellison syndrome is obtained in some patients.  Fecal Occult Blood Loss (FOBT) or FIT is positive in one-third of patients. C. Upper endoscopy: (Figure 1, Figure2)  it is the procedure of choice for the diagnosis of duodenal and gastric ulcers.  Duodenal ulcers are virtually never malignant and do not require biopsy. If the gastric ulcer appears benign to the endoscopist and adequate biopsy specimens reveal no evidence of cancer, dysplasia, or atypia, the patient may be monitored without further endoscopy. If these conditions are not fulfilled, follow-up endoscopy should be performed 12 weeks after the start of therapy to document complete healing; nonhealing ulcers are suspicious for malignancy. D. Imaging:  Abdominal CT imaging is obtained in patients with suspected complications of peptic ulcer disease (perforation, penetration, or obstruction) (Figure 3 & 4). Barium upper gastrointestinal series is no longer recommended and even contraindicated in Gi bleeding. E. Testing for H pylori:  Noninvasive assessment for H pylori with fecal antigen assay or urea breath testing may be done in patients with a history of peptic ulcer disease to diagnose active infection or in patients following its treatment to confirm successful eradication. PPI may cause false-negative urea breath tests and Page 4 of 13  fecal antigen tests and should be withheld for at least 14 days before testing. If endoscopy was done gastric mucosal biopsy is necessary. Differential Diagnosis:  If the epigastric pain is severe should be differentiated from Other causes of acute abdomen; acute cholecystitis, acute pancreatitis, gastric volvulus or ischemia. The atypical GERD can be presented as epigastric pain. Treatment of Peptic Ulcer Disease: I. Pharmacological Therapy: 1) acid-antisecretory agents, (2) mucosal protective agents, and (3) agents that promote healing through eradication of H pylori. A. Acid Antisecretory Agents: 1. Proton pump inhibitors (PPI): (review GERD treatment chapter) all the six groups of PPI are equally efficacious in the treatment of peptic ulcer disease. Treatment with oral proton pump inhibitors results in over 90% healing of duodenal ulcers after 4 weeks and 90% of gastric ulcers after 8 weeks when given once daily (30 minutes before breakfast). Compared with H2-receptor antagonists, proton pump inhibitors provide faster pain relief and more rapid ulcer healing. 2. H2 receptor antagonists—Although H2-receptor antagonists are effective in the treatment of peptic ulcer disease, proton pump inhibitors are now the preferred agents because of their ease of use and superior efficacy. 3. P-CAB: (see GERD treatment): they have faster action, more efficacy in acid suppression, but still not approved as first line therapy for peptic ulcer disease. In randomized trials it is not inferior to PPI after 8 weeks in gastric ulcer healing. B. Agents Enhancing Mucosal Defenses: Bismuth sucralfate, misoprostol, and antacids all have been shown to promote ulcer healing through the enhancement of mucosal defensive mechanisms. They are less effective than antisecretory and no longer use as first line for active ulcer. C. H pylori Eradication Therapy: see H pylori section in this chapter. The goals of treatment of active H pylori–associated ulcers are to relieve dyspeptic symptoms, to promote ulcer healing, and to eradicate H pylori infection. Uncomplicated H pylori–associated ulcers should be treated for 14 days with one of the proton pump inhibitors–based H pylori eradication regimens. Page 5 of 13 For patients with large (>1cm) or complicated ulcers, an antisecretory agent should be continued for an additional 2–4 weeks (duodenal ulcer) or 4–6 weeks (gastric ulcer) after completion of the antibiotic regimen to ensure complete ulcer healing. A once daily oral proton pump inhibitor is recommended. Confirmation of H pylori eradication is recommended for all patients more than 4 weeks after completion of antibiotic therapy and more than 2 weeks after discontinuation of the proton pump inhibitor. Successful eradication reduces ulcer recurrences to less than 20% after 1–2 years. The most common cause of recurrence after antibiotic therapy is failure to achieve successful eradication. Some patients require long term antisecretory therapy in cases of unsuccessful H pylori eradication, recurrence of infection, unintentional NSAIDs use and in some patients with idiopathic ulcers (-ve H pylori, -ve NSAIDs), in these patients hypersecretory state like gastrinoma should be excluded. D. Treatment of NSAID Induced Ulcers:  Offending agents should be discontinued whenever possible.  The patients should be tested for H pylori and treated if present.  Prevention of recurrence is essential. We should weigh the benefits of NSAIDs or low dose aspirin or clopidogrel versus the cardiovascular and GIT risks.  After considering the patient’s risk of cardiovascular and gastrointestinal complications due to NSAID use, the clinician can decide what type of NSAID (nsNSAID vs coxib) is appropriate and what strategies should be used to reduce the risk of such complications.  To minimize cardiovascular and gastrointestinal risks, all NSAIDs should be used at the lowest effective dose and for the shortest time necessary.  All patients with a known history of peptic ulcer disease who are treated with NSAIDs, or antiplatelet agents (aspirin, clopidogrel) should be tested for H pylori infection and treated, if positive.  Adding PPI as a prophylaxis with NSAIDs especially in high-risk patients. Refractory Ulcers:  Unhealed ulcers after 8 weeks of once daily therapy with proton pump inhibitors, occur in Less than 5% of peptic ulcers. Page 6 of 13   Causes might be incompliance to therapy, Zollinger Ellison syndrome, malignant ulcer, Crohn’s disease, ulcers at the hiatal hernia (Cameron ulcer), drugs as iron or bisphosphonates. COMPLICATIONS OF PEPTIC ULCER DISEASE: A. Gastrointestinal hemorrhage: see chapter GI bleeding.  Peptic ulcer disease is the commonest cause of upper GI bleeding. It is more risky in elderly patients and in patients with comorbidities. B. Ulcer Perforation: Perforations develop in less than 5% of ulcer patients, usually from ulcers on the anterior wall of the stomach or duodenum. Perforation results in a chemical peritonitis that causes sudden, severe generalized abdominal pain that prompts most patients to seek immediate medical care. Elderly or debilitated patients and those receiving long-term corticosteroid therapy may experience minimal initial symptoms, presenting late with bacterial peritonitis, sepsis, and shock. On physical examination, patients appear ill, with a rigid, quiet abdomen and rebound tenderness. Hypotension develops later after bacterial peritonitis has developed. Leukocytosis is almost always present. A mildly elevated serum amylase (less than twice normal) is sometimes seen with ulcer perforation. Abdominal CT usually establishes the diagnosis. Treatment might be conservative if perforation sealed and collection is minimum and absorbed, or surgical by drainage and laparoscopic closure of the perforation. The endoscopy is contraindicated. C. Gastric Outlet Obstruction: Gastric outlet obstruction occurs in less than 2% of patients with ulcer disease and is due to edema or cicatricial narrowing of the pylorus or duodenal bulb. The most common symptoms are early satiety, vomiting, and weight loss. Later, vomiting may develop that typically occurs one to several hours after eating and consists of partially digested food contents. Patients may develop dehydration, metabolic alkalosis, and hypokalemia. On physical examination, a succussion splash may be heard in the epigastrium. The treatment includes IV fluid, kcl, PPI and nasogastric aspiration of the gastric contents. The endoscopy is essential for the diagnosis of the cause of obstruction and location, and should exclude neoplasm as a cause of obstruction. Pyloric balloon dilatation or stenting can relieve the obstruction. Surgical resection and anastomosis can be the last option. Page 7 of 13 Helicobacter pylori infection:  H pylori is a spiral gram-negative rod that resides beneath the gastric mucous layer adjacent to gastric epithelial cells. Although not invasive, it causes gastric mucosal inflammation with PMNs and lymphocytes.  Transmission is from person to person, mainly during infancy and childhood; however, the mode of transmission is unknown. It is more common in low socioeconomic status and poor sanitary condition and less common in developed countries.  Acute infection with H pylori may cause a transient clinical illness characterized by nausea and abdominal pain that may last for several days and is associated with acute histologic gastritis with PMNs. After these symptoms resolve, the majority progress to chronic infection with chronic, diffuse mucosal inflammation (gastritis) characterized by PMNs and lymphocytes. Most persons are asymptomatic and suffer no sequelae. Many patients have inflammation that predominates in the gastric antrum but spares the gastric body (where acid is secreted). This type of infection (antrum predominant) tends to have increased gastrin, increased acid production; and increased risk of developing peptic ulcers, especially duodenal ulcers. Over time, inflammation may become more diffuse, involving the gastric body lead to destruction of acid-secreting glands with resultant mucosal atrophy, decreased acid secretion, and intestinal metaplasia. This phenotype (gastric body predominance) is associated with an increased risk of gastric ulcers and gastric cancer. H pylori is estimated to account for 80–89% of non-cardia gastric cancers.  Testing for H pylori is indicated for patients with either active or a history of documented peptic ulcer disease, gastric metaplasia, gastric MALToma, and a personal or family history of gastric carcinoma. Testing for and treating H pylori in patients with functional dyspepsia and in patients on long term low dose aspirin or NSAIDs. population-based screening of all asymptomatic persons in regions in which there is a high prevalence of H pylori and gastric cancer (such as Japan, Korea, and China) to reduce the incidence of gastric cancer.  Diagnostic tests of H pylori include serological test (ELIZA) to detect the antibodies which in inaccurate to differentiate active or remote infection. This test is not recommended for diagnosis and can be used only in mass screening. Detection of H pylori antigen in stool is very sensitive and specific and comparable to Urea Breath Test and both are recommended for diagnosis of H pylori. These tests should be done while the patient is off antibiotics for 4 weeks and off PPI for 2 weeks prior to the test. Invasive Page 8 of 13  method through endoscopic biopsy inoculation into rapid urease test is also sensitive provided that the biopsy is taken from area of stomach harboring the organism. Histopathological examination of gastric biopsy can detect the h pylori organism.  Treatment should include antisecretory therapy in high dose in addition to two antibiotics. (Table 1). Recent use of P-CAB (vonoprazan) improves markedly the eradication rate and replace the PPI in triple therapy and can be used with one type of antibiotic (amoxicillin) in high dose (2-3 gm amoxicillin in two or three divided doses).  Confirmation of H pylori eradication is recommended for all patients more than 4 weeks after completion of antibiotic therapy and more than 2 weeks after discontinuation of the proton pump inhibitor either with noninvasive tests (urea breath test, fecal antigen test) or endoscopy with biopsy for histology. ZOLLINGER-ELLISON SYNDROME (Gastrinoma):  Zollinger-Ellison syndrome is caused by gastrin-secreting gut neuroendocrine tumors (gastrinomas), which result in hypergastrinemia and acid hypersecretion. Less than 1% of peptic ulcer disease is caused by gastrinomas. Primary gastrinomas may arise in the pancreas (25%), duodenal wall (45%), or lymph nodes (5–15%), and in other locations including unknown primary sites (20%). Approximately 80% arise within the “gastrinoma triangle” bounded by the porta hepatis, the neck of the pancreas, and the third portion of the duodenum. Over two-thirds of gastrinomas are malignant, and one-third have already metastasized to the liver at initial presentation. It might be part of MEN I syndrome (hyperparathyroidism, pancreatic endocrine tumors, and pituitary tumors).  The clinical presentations are secondary to hypergastrinemia, which causes hypertrophy of the gastric mucosa, leading to increased numbers of parietal cells and increased maximal acid output. Gastrin by itself also stimulates acid secretion, resulting in increased basal acid secretion. The large quantity of acid produced leads to gastrointestinal mucosal ulceration, diarrhea and malabsorption.  The most common presentation is peptic ulcers usually refractory, and in uncommon locations of the ulcer. Diarrhea occurs in one-third of patients, in some cases in the absence of peptic symptoms. Gastric acid hypersecretion can Page 9 of 13  cause direct intestinal mucosal injury and pancreatic enzyme inactivation, resulting in diarrhea, steatorrhea, and weight loss.  The most sensitive and specific method for identifying Zollinger-Ellison syndrome is demonstration of an increased fasting serum gastrin concentration (greater than 150 pg/mL) while patient off PPI and H2 blockers. The diagnosis is established in a patient with a serum gastrin level of greater than 1000 pg/mL and acid hypersecretion. An elevated serum calcium suggests hyperparathyroidism and MEN 1 syndrome. In all patients with Zollinger- Ellison syndrome, serum parathyroid hormone (PTH), prolactin, luteinizing hormone-follicle-stimulating hormone (LH-FSH), and growth hormone (GH) levels should be obtained to exclude MEN 1. Figure 6.  Radiological scanning using CT or MRI is initially done to detect ant metastasis. As gastrinoma express somatostatin receptors Somatostatin receptor scintigraphy (SRS) with single photon emission computed tomography (SPECT) allows total body imaging for detection of primary gastrinomas in the pancreas and lymph nodes, primary gastrinomas in unusual locations, and metastatic gastrinomas (liver and bone). In patients with negative SRS, endoscopic ultrasonography (EUS) may be useful to detect small gastrinomas in the duodenal wall, pancreas, or peripancreatic lymph nodes. With a combination of SRS and EUS, more than 90% of primary gastrinomas can be localized preoperatively.  Differential Diagnosis: from other neuroendocrine tumors like carcinoid, insulinoma, VIPoma, glucagonoma, and somatostatinoma. Should be differentiated from other causes of hypergastrinemia as atrophic gastritis (associated with hypochlorhydria and should be differentiated from other causes of refractor ulcers.  Treatment: surgical resection if no metastases after localization of the tumor. Surgery is not recommended in MEN syndrome. High dose PPI up to 120 mg to reduce the symptoms. In cases of liver metastases only medical treatment by PPI is enough with good survival. Page 10 of 13 Figure 1: Endoscopic picture of ulcer at the duodenal bulb. Figure 2: Endoscopic picture of gastric ulcer. Page 11 of 13 Figure 3: Transverse CT scan demonstrates extraluminal free air (arrows) surrounding 3rd portion of duodenum (D) and retroperitoneal fluid (arrowheads). Figure 4: CT- scan in patient with perforated gastric ulcer. Focal defect in lesser curvature of gastric body is caused by deep ulcer (arrow) associated with surrounding mural thickening. Note small air bubble (arrowhead) on anterior peritoneal surface of liver. Page 12 of 13 Table 1: first line therapy of H Pylori. Figure 5: Algorithm for diagnosis of Zollinger Ellison’s syndrome. Page 13 of 13