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Peptic ulcer disease
Peptic ulcer disease
Peptic ulcer disease
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Peptic ulcer disease
Other namesPeptic ulcer, stomach ulcer, gastric ulcer, duodenal ulcer
Illustration depicting peptic ulcer disease, also known as a gastric ulcer
SpecialtyGastroenterology
General surgery
SymptomsHeartburn, upper abdominal pain, nausea, belching, vomiting, blood in the stool, weight loss, weight gain, bloating, loss of appetite,[1] yellowing of the skin and whites of the eyes, difficulty swallowing
ComplicationsBleeding, perforation, ulcer perforation, blockage of the stomach[2]
CausesHelicobacter pylori bacteria, non-steroidal anti-inflammatory drugs (NSAIDs), tobacco smoking, Crohn's disease[1][3]
Diagnostic methodBased on symptoms, confirmed by endoscopy or barium swallow[1]
Differential diagnosisStomach cancer, coronary heart disease, inflammation of the stomach lining, gallbladder inflammation[1]
TreatmentMedications,[1] stopping NSAIDs, stopping smoking, stopping alcohol consumption
MedicationProton pump inhibitor, H2 blocker, antibiotics[1][4]
Frequency87.4 million (2015)[5]
Deaths267,500 (2015)[6]

Peptic ulcer disease refers to damage of the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines is a duodenal ulcer.[1] The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain, and upper abdominal pain that improves with eating.[1] With a gastric ulcer, the pain may worsen with eating.[7] The pain is often described as a burning or dull ache.[1] Other symptoms include belching, vomiting, weight loss, or poor appetite.[1] About a third of older people with peptic ulcers have no symptoms.[1] Complications may include bleeding, perforation, and blockage of the stomach.[2] Bleeding occurs in as many as 15% of cases.[2]

Common causes include infection with Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs).[1] Other, less common causes include tobacco smoking, stress as a result of other serious health conditions, Behçet's disease, Zollinger–Ellison syndrome, Crohn's disease, and liver cirrhosis.[1][3] Older people are more sensitive to the ulcer-causing effects of NSAIDs.[1] The diagnosis is typically suspected due to the presenting symptoms with confirmation by either endoscopy or barium swallow.[1] H. pylori can be diagnosed by testing the blood for antibodies, a urea breath test, testing the stool for signs of the bacteria, or a biopsy of the stomach.[1] Other conditions that produce similar symptoms include stomach cancer, coronary heart disease, and inflammation of the stomach lining or gallbladder inflammation.[1]

Diet does not play an important role in either causing or preventing ulcers.[8] Treatment includes stopping smoking, stopping use of NSAIDs, stopping alcohol, and taking medications to decrease stomach acid.[1] The medication used to decrease acid is usually either a proton pump inhibitor (PPI) or an H2 blocker, with four weeks of treatment initially recommended.[1] Ulcers due to H. pylori are treated with a combination of medications, such as amoxicillin, clarithromycin, and a PPI.[4] Antibiotic resistance is increasing and thus treatment may not always be effective.[4] Bleeding ulcers may be treated by endoscopy, with open surgery typically only used in cases in which it is not successful.[2]

Peptic ulcers are present in around 4% of the population.[1] New ulcers were found in around 87.4 million people worldwide during 2015.[5] About 10% of people develop a peptic ulcer at some point in their life.[9] Peptic ulcers resulted in 267,500 deaths in 2015, down from 327,000 in 1990.[6][10] The first description of a perforated peptic ulcer was in 1670, in Princess Henrietta of England.[2] H. pylori was first identified as causing peptic ulcers by Barry Marshall and Robin Warren in the late 20th century,[4] a discovery for which they received the Nobel Prize in 2005.[11]

Signs and symptoms

[edit]
Duodenal ulcer A2 stage, acute duodenal mucosal lesion (ADML)

Signs and symptoms of a peptic ulcer can include one or more of the following:[12]

  • abdominal pain, classically epigastric, strongly correlated with mealtimes. In case of duodenal ulcers, the pain appears about three hours after taking a meal and wakes the person from sleep;
  • bloating and abdominal fullness;
  • waterbrash (a rush of saliva after an episode of regurgitation to dilute the acid in esophagus, although this is more associated with gastroesophageal reflux disease);
  • nausea and copious vomiting;
  • loss of appetite and weight loss, in gastric ulcer;
  • weight gain, in duodenal ulcer, as the pain is relieved by eating;
  • hematemesis (vomiting of blood); this can occur due to bleeding directly from a gastric ulcer or from damage to the esophagus from severe/continuing vomiting.
  • melena (tarry, foul-smelling feces due to presence of oxidized iron from hemoglobin);
  • rarely, an ulcer can lead to a gastric or duodenal perforation, which leads to acute peritonitis and extreme, stabbing pain,[13] and requires immediate surgery.

A history of heartburn or gastroesophageal reflux disease (GERD) and use of certain medications can raise the suspicion for peptic ulcer. Medicines associated with peptic ulcer include NSAIDs (non-steroidal anti-inflammatory drugs) that inhibit cyclooxygenase and most glucocorticoids (e.g., dexamethasone and prednisolone).[14]

In people over the age of 45 with more than two weeks of the above symptoms, the odds for peptic ulceration are high enough to warrant rapid investigation by esophagogastroduodenoscopy.[citation needed]

The timing of symptoms in relation to the meal may differentiate between gastric and duodenal ulcers. A gastric ulcer would give epigastric pain during the meal, associated with nausea and vomiting, as gastric acid production is increased as food enters the stomach. Pain in duodenal ulcers would be aggravated by hunger and relieved by a meal and is associated with night pain.[15]

Also, the symptoms of peptic ulcers may vary with the location of the ulcer and the person's age. Furthermore, typical ulcers tend to heal and recur, and as a result the pain may occur for few days and weeks and then wane or disappear.[16] Usually, children and the elderly do not develop any symptoms unless complications have arisen.

A burning or gnawing feeling in the stomach area lasting between 30 minutes and 3 hours commonly accompanies ulcers. This pain can be misinterpreted as hunger, indigestion, or heartburn. Pain is usually caused by the ulcer, but it may be aggravated by the stomach acid when it comes into contact with the ulcerated area. The pain caused by peptic ulcers can be felt anywhere from the navel up to the sternum, it may last from a few minutes to several hours, and it may be worse when the stomach is empty. Also, sometimes the pain may flare at night, and it can commonly be temporarily relieved by eating foods that buffer stomach acid or by taking anti-acid medication.[17] However, peptic ulcer disease symptoms may be different for everyone.[18]

Complications

[edit]
An endoscopic image showing deep gastric ulcer.
Endoscopic image of a small gastric ulcer with visible blood vessels, a potential warning sign for upper gastrointestinal bleeding
  • Gastrointestinal bleeding is the most common complication. Sudden large bleeding can be life-threatening.[19][20] It is associated with 5% to 10% death rate.[15]
  • Perforation (a hole in the wall of the gastrointestinal tract) following a gastric ulcer often leads to catastrophic consequences if left untreated. Erosion of the gastrointestinal wall by the ulcer leads to spillage of the stomach or intestinal contents into the abdominal cavity, leading to an acute chemical peritonitis.[21] The first sign is often sudden intense abdominal pain,[15] as seen in Valentino's syndrome. Posterior gastric wall perforation may lead to bleeding due to the involvement of gastroduodenal artery that lies posterior to the first part of the duodenum.[22] The death rate in this case is 20%.[15]
  • Penetration is a form of perforation in which the hole leads to and the ulcer continues into adjacent organs such as the liver and pancreas.[16]
  • Gastric outlet obstruction (stenosis) is a narrowing of the pyloric canal by scarring and swelling of the gastric antrum and duodenum due to peptic ulcers. The person often presents with severe vomiting.[15]
  • Cancer is included in the differential diagnosis (elucidated by biopsy), Helicobacter pylori as the etiological factor making it 3 to 6 times more likely to develop stomach cancer from the ulcer.[16] The risk for developing gastrointestinal cancer also appears to be slightly higher with gastric ulcers.[23]

Cause

[edit]

H. pylori

[edit]

Helicobacter pylori is one of the major causative factors of peptic ulcer disease. It secretes urease to create an alkaline environment, which is suitable for its survival. It expresses blood group antigen-binding adhesin (BabA) and outer inflammatory protein adhesin (OipA), which enables it to attach to the gastric epithelium. The bacterium also expresses virulence factors such as CagA and PicB, which cause stomach mucosal inflammation. The VacA gene encodes for vacuolating cytotoxin, but its mechanism of causing peptic ulcers is unclear. Such stomach mucosal inflammation can be associated with hyperchlorhydria (increased stomach acid secretion) or hypochlorhydria (reduced stomach acid secretion). Inflammatory cytokines inhibit the parietal cell acid secretion. H. pylori also secretes certain products that inhibit hydrogen potassium ATPase; activate calcitonin gene-related peptide sensory neurons, which increases somatostatin secretion to inhibit acid production by parietal cells; and inhibit gastrin secretion. This reduction in acid production causes gastric ulcers.[15] On the other hand, increased acid production at the pyloric antrum is associated with duodenal ulcers in 10% to 15% of H. pylori infection cases. In this case, somatostatin production is reduced and gastrin production is increased, leading to increased histamine secretion from the enterochromaffin cells, thus increasing acid production. An acidic environment at the antrum causes metaplasia of the duodenal cells, causing duodenal ulcers.[15]

Human immune response toward the bacteria also determines the emergence of peptic ulcer disease. The human IL1B gene encodes for Interleukin 1 beta, and other genes that encode for tumour necrosis factor (TNF) and Lymphotoxin alpha also play a role in gastric inflammation.[15]

NSAIDs

[edit]

Taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin[24] can increase the risk of peptic ulcer disease by four times compared to non-users. The risk of getting a peptic ulcer is two times for aspirin users. Risk of bleeding increases if NSAIDs are combined with selective serotonin reuptake inhibitor (SSRI), corticosteroids, antimineralocorticoids, and anticoagulants. The gastric mucosa protects itself from gastric acid with a layer of mucus, the secretion of which is stimulated by certain prostaglandins. NSAIDs block the function of cyclooxygenase 1 (COX-1), which is essential for the production of these prostaglandins. Besides this, NSAIDs also inhibit stomach mucosa cells proliferation and mucosal blood flow, reducing bicarbonate and mucus secretion, which reduces the integrity of the mucosa. Another type of NSAIDs, called COX-2 selective anti-inflammatory drugs (such as celecoxib), preferentially inhibit COX-2, which is less essential in the gastric mucosa. This reduces the probability of getting peptic ulcers; however, it can still delay ulcer healing for those who already have a peptic ulcer.[15] Peptic ulcers caused by NSAIDs differ from those caused by H. pylori as the latter's appear as a consequence of inflammation of the mucosa (presence of neutrophil and submucosal edema), the former instead as a consequence of a direct damage of the NSAID molecule against COX enzymes, altering the hydrophobic state of the mucus, the permeability of the lining epithelium and mitochondrial machinery of the cell itself. In this way NSAID ulcers tend to complicate faster and dig deeper in the tissue, causing more complications – often asymptomatically – until a great portion of the tissue is involved.[25][26]

Stress

[edit]

Physiological (not psychological) stress due to serious health problems, such as those requiring treatment in an intensive care unit, is well described as a cause of peptic ulcers, which are also known as stress ulcers.[3]

While chronic life stress was once believed to be the main cause of ulcers, this is no longer the case.[27] It is, however, still occasionally believed to play a role.[27] This may be due to the well-documented effects of stress on gastric physiology, increasing the risk in those with other causes, such as H. pylori or NSAID use.[28]

Diet

[edit]

Dietary factors, such as spice consumption, were hypothesized to cause ulcers until the late 20th century, but have been shown to be of relatively minor importance.[29] Caffeine and coffee, also commonly thought to cause or exacerbate ulcers, appear to have little effect.[30][31] Similarly, while studies have found that alcohol consumption increases risk when associated with H. pylori infection, it does not seem to independently increase risk. Even when coupled with H. pylori infection, the increase is modest in comparison to the primary risk factor.[32][33][nb 1]

Other

[edit]

Other causes of peptic ulcer disease include gastric ischaemia, drugs, metabolic disturbances, cytomegalovirus (CMV), upper abdominal radiotherapy, Crohn's disease, and vasculitis.[15] Gastrinomas (Zollinger–Ellison syndrome), or rare gastrin-secreting tumors, also cause multiple and difficult-to-heal ulcers.[34]

It is still unclear whether smoking increases the risk of getting peptic ulcers.[15]

Diagnosis

[edit]
Endoscopic image of gastric ulcer, biopsy proven to be gastric cancer.
A biopsy sample of a stomach ulcer that was diagnosed as stomach cancer

The diagnosis is mainly established based on the characteristic symptoms. Stomach pain is the most common sign of a peptic ulcer.[12]

More specifically, peptic ulcers erode the muscularis mucosae, at minimum reaching to the level of the submucosa (contrast with erosions, which do not involve the muscularis mucosae).[35]

Confirmation of the diagnosis is made with the help of tests such as endoscopies or barium contrast x-rays. The tests are typically ordered if the symptoms do not resolve after a few weeks of treatment, or when they first appear in a person who is over age 45 or who has other symptoms such as weight loss, because stomach cancer can cause similar symptoms. Also, when severe ulcers resist treatment, particularly if a person has several ulcers or the ulcers are in unusual places, a doctor may suspect an underlying condition that causes the stomach to overproduce acid.[16]

An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on people in whom a peptic ulcer is suspected. It is also the gold standard of diagnosis for peptic ulcer disease.[15] By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis.

One of the reasons that blood tests are not reliable for accurate peptic ulcer diagnosis on their own is their inability to differentiate between past exposure to the bacteria and current infection. Additionally, a false negative result is possible with a blood test if the person has recently been taking certain drugs, such as antibiotics or proton-pump inhibitors.[36]

The diagnosis of Helicobacter pylori can be made by:

  • Urea breath test (noninvasive and does not require EGD);
  • Direct culture from an EGD biopsy specimen; this is difficult and can be expensive. Most labs are not set up to perform H. pylori cultures;
  • Direct detection of urease activity in a biopsy specimen by rapid urease test;[15]
  • Measurement of antibody levels in the blood (does not require EGD). It is still somewhat controversial whether a positive antibody without EGD is enough to warrant eradication therapy;
  • Stool antigen test;[37]
  • Histological examination and staining of an EGD biopsy.

The breath test uses radioactive carbon to detect H. pylori.[38] To perform this exam, the person is asked to drink a tasteless liquid that contains the carbon as part of the substance that the bacteria breaks down. After an hour, the person is asked to blow into a sealed bag. If the person is infected with H. pylori, the breath sample will contain radioactive carbon dioxide. This test provides the advantage of being able to monitor the response to treatment used to kill the bacteria.

The possibility of other causes of ulcers, notably malignancy (gastric cancer), needs to be kept in mind. This is especially true in ulcers of the greater curvature of the stomach; most are also a consequence of chronic H. pylori infection.

If a peptic ulcer perforates, air will leak from inside the gastrointestinal tract (which always contains some air) to the peritoneal cavity (which normally never contains air). This leads to "free gas" within the peritoneal cavity. If the person stands, as when having a chest X-ray, the gas will float to a position underneath the diaphragm. Therefore, gas in the peritoneal cavity, shown on an erect chest X-ray or supine lateral abdominal X-ray, is an omen of perforated peptic ulcer disease.

Classification

[edit]
  1. Esophagus
  2. Stomach
  3. Ulcers
  4. Duodenum
  5. Mucosa
  6. Submucosa
  7. Muscle

Peptic ulcers are a form of acid–peptic disorder. Peptic ulcers can be classified according to their location and other factors.

By location

[edit]

Modified Johnson

[edit]
  • Type I: Ulcer along the body of the stomach, most often along the lesser curve at incisura angularis along the locus minoris resistantiae. Not associated with acid hypersecretion.
  • Type II: Ulcer in the body in combination with duodenal ulcers. Associated with acid oversecretion.
  • Type III: In the pyloric channel within 3 cm of pylorus. Associated with acid oversecretion.
  • Type IV: Proximal gastroesophageal ulcer.
  • Type V: Can occur throughout the stomach. Associated with the chronic use of NSAIDs (such as ibuprofen).

Macroscopic appearance

[edit]
A benign gastric ulcer (from the antrum) of a gastrectomy specimen.

Gastric ulcers are most often localized on the lesser curvature of the stomach. The ulcer is a round to oval parietal defect ("hole"), 2–4 cm diameter, with a smooth base and perpendicular borders. These borders are not elevated or irregular in the acute form of peptic ulcer, and regular but with elevated borders and inflammatory surrounding in the chronic form. In the ulcerative form of gastric cancer, the borders are irregular. Surrounding mucosa may present radial folds, as a consequence of the parietal scarring.[citation needed]

Microscopic appearance

[edit]
Micrograph showing erosive gastric ulcer. (H&E stain)

A gastric peptic ulcer is a mucosal perforation that penetrates the muscularis mucosae and lamina propria, usually produced by acid-pepsin aggression. Ulcer margins are perpendicular and present chronic gastritis. During the active phase, the base of the ulcer shows four zones: fibrinoid necrosis, inflammatory exudate, granulation tissue and fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis.[39]

Differential diagnosis

[edit]
Endoscopic image of gastric MALT lymphoma taken in body of stomach in patient who presented with upper GI hemorrhage. Appearance is similar to gastric ulcer with adherent clot.

Conditions that may appear similar include:

Prevention

[edit]

Prevention of peptic ulcer disease for those who are taking NSAIDs (with low cardiovascular risk) can be achieved by adding a proton pump inhibitor (PPI), an H2 antagonist, or misoprostol.[15] NSAIDs of the COX-2 inhibitor type may reduce the rate of ulcers when compared to non-selective NSAIDs.[15] PPI is the most popular agent in peptic ulcer prevention.[15] However, there is no evidence that H2 antagonists can prevent stomach bleeding for those taking NSAIDs.[15] Although misoprostol is effective in preventing peptic ulcer, its properties of promoting abortion and causing gastrointestinal distress limit its use.[15] For those with high cardiovascular risk, naproxen with PPI can be a useful choice.[15] Otherwise, low-dose aspirin, celecoxib, and PPI can also be used.[15]

Management

[edit]
Peptic ulcer treatment: pharmacology of drugs

Eradication therapy

[edit]

Once the diagnosis of H. pylori is confirmed, the first-line treatment would be a triple regimen in which pantoprazole and clarithromycin are combined with either amoxicillin or metronidazole. This treatment regimen can be given for 7–14 days. However, its effectiveness in eradicating H. pylori has been reducing from 90% to 70%. However, the rate of eradication can be increased by doubling the dosage of pantoprazole or increasing the duration of treatment to 14 days. Quadruple therapy (pantoprazole, clarithromycin, amoxicillin, and metronidazole) can also be used. The quadruple therapy can achieve an eradication rate of 90%. If the clarithromycin resistance rate is higher than 15% in an area, the usage of clarithromycin should be abandoned. Instead, bismuth-containing quadruple therapy can be used (pantoprazole, bismuth citrate, tetracycline, and metronidazole) for 14 days. The bismuth therapy can also achieve an eradication rate of 90% and can be used as second-line therapy when the first-line triple-regimen therapy has failed.

NSAIDs-induced ulcers

[edit]

NSAID-associated ulcers heal in six to eight weeks provided the NSAIDs are withdrawn with the introduction of proton pump inhibitors (PPI).[15]

Bleeding

[edit]
Endoscopic clipping placed on a gastric ulcer at risk for bleeding

For those with bleeding peptic ulcers, fluid replacement with crystalloids is sometimes given to maintain volume in the blood vessels. Maintaining haemoglobin at greater than 7 g/dL (70 g/L) through restrictive blood transfusion has been associated with reduced rate of death. Glasgow-Blatchford score is used to determine whether a person should be treated inside a hospital or as an outpatient. Intravenous PPIs can suppress stomach bleeding more quickly than oral ones. A neutral stomach pH is required to keep platelets in place and prevent clot lysis. Tranexamic acid and antifibrinolytic agents are not useful in treating peptic ulcer disease.[15]

Early endoscopic therapy can help to stop bleeding by using cautery, endoclip, or epinephrine injection. Treatment is indicated if there is active bleeding in the stomach, visible vessels, or an adherent clot. Endoscopy is also helpful in identifying people who are suitable for hospital discharge. Prokinetic agents such as erythromycin and metoclopramide can be given before endoscopy to improve endoscopic view. Either high- or low-dose PPIs are equally effective in reducing bleeding after endoscopy. High-dose intravenous PPI is defined as a bolus dose of 80 mg followed by an infusion of 8 mg per hour for 72 hours—in other words, the continuous infusion of PPI of greater than 192 mg per day. Intravenous PPI can be changed to oral once there is no high risk of rebleeding from peptic ulcer.[15]

For those with hypovolemic shock and ulcer size of greater than 2 cm, there is a high chance that the endoscopic treatment would fail. Therefore, surgery and angiographic embolism are reserved for these complicated cases. However, there is a higher rate of complication for those who underwent surgery to patch the stomach bleeding site when compared to repeated endoscopy. Angiographic embolisation has a higher rebleeding rate but a similar rate of death to surgery.[15]

Anticoagulants

[edit]

According to expert opinion, for those who are already on anticoagulants, the international normalized ratio (INR) should be kept at 1.5. For aspirin users who required endoscopic treatment for bleeding peptic ulcer, there is two times increased risk of rebleeding but with ten times reduced risk of death at eight weeks following the resumption of aspirin. For those who were on double antiplatelet agents for indwelling stent in blood vessels, both antiplatelet agents should not be stopped because there is a high risk of stent thrombosis. For those who were under warfarin treatment, fresh frozen plasma (FFP), vitamin K, prothrombin complex concentrates, or recombinant factor VIIa can be given to reverse the effect of warfarin. High doses of vitamin K should be avoided to reduce the time for rewarfarinisation once the stomach bleeding has stopped. Prothrombin complex concentrates are preferred for severe bleeding. Recombinant factor VIIa is reserved for life-threatening bleeding because of its high risk of thromboembolism.[15] Direct oral anticoagulants (DOAC) are recommended instead of warfarin as they are more effective in preventing thromboembolism. In case of bleeding caused by DOAC, activated charcoal within four hours is the antidote of choice.

Epidemiology

[edit]
Deaths from peptic ulcer disease per million persons in 2012
  0-7
  8-11
  12-16
  17-19
  20-25
  26-32
  33-40
  41-53
  54-72
  73-132
Disability-adjusted life year for peptic ulcer disease per 100,000 inhabitants in 2004.[40]
  no data
  less than 20
  20–40
  40–60
  60–80
  80–100
  100–120
  120–140
  140–160
  160–180
  180–200
  200–220
  more than 220

The lifetime risk for developing a peptic ulcer is approximately 5% to 10%[9][15] with the rate of 0.1% to 0.3% per year.[15] Peptic ulcers resulted in 301,000 deaths in 2013, down from 327,000 in 1990.[10]

In Western countries, the percentage of people with H. pylori infections roughly matches age (i.e., 20% at age 20, 30% at age 30, 80% at age 80, etc.). Prevalence is higher in third world countries, where it is estimated at 70% of the population, whereas developed countries show a maximum of a 40% ratio. Overall, H. pylori infections show a worldwide decrease, more so in developed countries. Transmission occurs via food, contaminated groundwater, or human saliva (such as from kissing or sharing food utensils).[41]

Peptic ulcer disease had a tremendous effect on morbidity and mortality until the last decades of the 20th century when epidemiological trends started to point to an impressive fall in its incidence. The reason that the rates of peptic ulcer disease decreased is thought to be the development of new effective medication and acid suppressants and the rational use of nonsteroidal anti-inflammatory drugs (NSAIDs).[15]

History

[edit]
See also: Timeline of peptic ulcer disease and Helicobacter pylori

John Lykoudis, a general practitioner in Greece, treated people for peptic ulcer disease with antibiotics beginning in 1958, long before it was commonly recognized that bacteria were a dominant cause for the disease.[42]

Helicobacter pylori was identified in 1982 by two Australian scientists, Robin Warren and Barry J. Marshall, as a causative factor for ulcers.[43] In their original paper, Warren and Marshall contended that most gastric ulcers and gastritis were caused by colonization with this bacterium, not by stress or spicy food, as had been assumed before.[44]

The H. pylori hypothesis was still poorly received,[45] so in an act of self-experimentation Marshall drank a Petri dish containing a culture of organisms extracted from a person with an ulcer and five days later developed gastritis. His symptoms disappeared after two weeks, but he took antibiotics to kill the remaining bacteria at the urging of his wife, since halitosis is one of the symptoms of infection.[46] This experiment was published in 1984 in the Australian Medical Journal and is among the most cited articles from the journal.

In 1997, the Centers for Disease Control and Prevention, with other government agencies, academic institutions, and industry, launched a national education campaign to inform health care providers and consumers about the link between H. pylori and ulcers. This campaign reinforced the news that ulcers are a curable infection and that health can be greatly improved and money saved by disseminating information about H. pylori.[47]

In 2005, the Karolinska Institute in Stockholm awarded the Nobel Prize in Physiology or Medicine to Marshall and his long-time collaborator Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease." Marshall continues research related to H. pylori and runs a molecular biology lab at UWA in Perth, Western Australia.

A 1998 New England Medical Journal study found that mastic gum, a tree resin extract, actively eliminated the H. pylori bacteria.[48] However, multiple subsequent studies (in mice and in vivo) have found no effect of using mastic gum on reducing H. pylori levels.[49][50]

Notes

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Peptic ulcer disease

View on Grokipedia
from Grokipedia
Peptic ulcer disease (PUD) is a gastrointestinal disorder characterized by the development of open sores, known as ulcers, in the mucosal lining of the (gastric ulcers) or the upper part of the , specifically the (duodenal ulcers). These ulcers arise from an imbalance between protective factors, such as and secretion, and aggressive factors like and , leading to erosion of the mucosal barrier. Duodenal ulcers are approximately four times more common than gastric ulcers, with a lifetime of PUD estimated at 5-10% globally. The primary causes of peptic ulcer disease are infection with the bacterium (H. pylori), which accounts for 70-90% of gastric ulcers and up to 90% of duodenal ulcers, and long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen. H. pylori, a gram-negative , colonizes the , producing and toxins that impair secretion and promote inflammation, while NSAIDs inhibit cyclooxygenase-1 (COX-1), reducing protective prostaglandins and mucus production. Less common causes include Zollinger-Ellison syndrome, certain malignancies, stress in critically ill patients, or conditions like . Risk factors for developing peptic ulcers include advancing age (particularly over 60), a history of prior ulcers, , excessive alcohol consumption, and concurrent use of multiple NSAIDs or high doses. , the of peptic ulcers ranges from 1% to 6%, with incidence rates declining worldwide due to improved , H. pylori eradication efforts, and better NSAID management. Common symptoms of peptic ulcer disease include or gnawing in the upper , often occurring between meals or at night, along with , belching, , , and . Severe complications can arise, such as (manifesting as black, tarry stools or blood), of the ulcer through the or duodenal wall, penetration into adjacent organs, or due to scarring. Additionally, chronic H. pylori infection is associated with an increased risk of gastric cancer.

Clinical presentation

Symptoms

The hallmark symptom of peptic ulcer disease is epigastric , typically described as burning or gnawing in quality and localized to the upper . In patients with duodenal ulcers, this often occurs 2 to 3 hours after meals or at night, particularly between 11 p.m. and 2 a.m., due to peak secretion, and it may awaken individuals from . Conversely, from gastric ulcers tends to arise within 15 to 30 minutes after eating and may be exacerbated by meals. The 's periodicity often follows a cyclic pattern, lasting for weeks followed by symptom-free intervals of similar duration. Associated symptoms commonly include , , , a sensation of abdominal fullness, early , and or acid regurgitation, which affect approximately 46% of patients. These manifestations arise from irritation of the gastric or duodenal mucosa and can contribute to discomfort after eating fatty s or large s. Symptom severity is influenced by meal timing; for instance, duodenal pain may improve with food intake or antacids, providing temporary relief by neutralizing acid, whereas gastric symptoms often persist or worsen postprandially. Atypical presentations are more frequent in elderly patients, who may experience vague symptoms such as anorexia and unintentional rather than prominent pain, potentially leading to delayed . Additionally, up to 70% of individuals with peptic ulcers are , with this proportion higher among older adults and those using nonsteroidal drugs (NSAIDs), where mucosal can occur silently. Such cases underscore the importance of considering peptic ulcer disease in at-risk populations, often linked to infection or NSAID use, even without overt symptoms.

Complications

Peptic ulcer disease (PUD) can lead to several serious complications, with upper gastrointestinal (GI) bleeding being the most frequent, affecting approximately 10 to 20% of patients with PUD. This complication arises when an ulcer erodes into a blood vessel, resulting in hematemesis (vomiting of blood), melena (black, tarry stools), or hemodynamic instability such as hypotension and tachycardia. Risk stratification for upper GI bleeding often employs the Rockall score, which incorporates factors including age, presence of shock, comorbidities (e.g., renal failure or liver disease), endoscopic diagnosis, and stigmata of recent hemorrhage to predict rebleeding and mortality risks. Perforation occurs in 5 to 10% of PUD cases and represents a , characterized by sudden, severe that may progress to due to leakage of gastric contents into the . Patients typically present with abdominal tenderness, rigidity, and signs of systemic inflammation such as fever and . The annual incidence of perforated PUD is estimated at 4 to 14 cases per 100,000 individuals, with a 30-day of approximately 23.5%, particularly elevated in older patients or those with delayed . Gastric outlet obstruction develops in 2 to 5% of PUD patients, often from , , or scarring around the , leading to symptoms of postprandial , early , and significant . Penetration, a less common , involves the ulcer eroding into adjacent structures such as the , causing to the back and potential formation. In gastric ulcers specifically, there is a 1 to 2% risk of underlying , necessitating endoscopic to rule out gastric cancer. Overall mortality from PUD complications ranges from 5 to 10%, with higher rates in elderly patients or those experiencing (up to 8.6% at 30 days) and even greater in cases. Continuation of risk factors like infection or use can exacerbate these outcomes.

Etiology and risk factors

Helicobacter pylori infection

Helicobacter pylori is a spiral-shaped, Gram-negative bacterium that colonizes the gastric mucosa and serves as the primary infectious cause of peptic ulcer disease. This microaerophilic pathogen produces urease, an enzyme that hydrolyzes urea to generate ammonia and carbon dioxide, creating a neutral microenvironment that enables survival in the acidic stomach. The bacterium's flagella facilitate motility, allowing it to penetrate the mucus layer and adhere to epithelial cells. Transmission of H. pylori occurs primarily through fecal-oral or oral-oral routes, often via contaminated water, food, or close person-to-person contact. Prevalence is markedly higher in developing countries, reaching up to 80%, compared to 20-40% in developed nations, with infection rates strongly correlated to low socioeconomic status and overcrowding. Upon colonization, H. pylori induces chronic inflammation of the gastric mucosa, known as , by recruiting neutrophils and lymphocytes that release pro-inflammatory cytokines such as interleukin-1β and interleukin-8. This inflammatory response disrupts the mucosal barrier, leading to epithelial cell damage and impaired tissue repair. The bacterium is associated with 70-90% of duodenal ulcers and 50-70% of gastric ulcers, conferring a 2- to 6-fold increased risk for peptic ulcer disease overall. Additionally, chronic infection elevates the risk of gastric cancer by approximately 6-fold through progressive mucosal and . Key virulence factors include the cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA), encoded by the cag and vacA , respectively. The CagA protein is injected into epithelial cells via a type IV secretion system, where it disrupts , induces cytoskeletal rearrangements, and promotes pro-inflammatory signaling, exacerbating mucosal injury. VacA forms anion-selective channels in cell membranes, causing vacuolation, mitochondrial dysfunction, and in epithelial cells, which further compromises the gastric barrier. Strains possessing both cagA and toxigenic vacA alleles are linked to more severe disease outcomes. Through these mechanisms, H. pylori contributes to acid hypersecretion in duodenal pathogenesis.

NSAID use

Non-steroidal drugs (NSAIDs) are a leading pharmacological cause of peptic ulcer disease, second only to infection. These agents exert their ulcerogenic effects primarily through systemic inhibition of the cyclooxygenase-1 (COX-1) enzyme, which reduces synthesis of gastroprotective prostaglandins such as and . Prostaglandins normally promote and secretion, maintain mucosal blood flow, and inhibit acid production; their depletion thus impairs the gastric mucosal barrier, facilitating acid-induced erosion and ulceration. Several factors amplify the risk of NSAID-induced ulcers. High-dose or prolonged use significantly elevates incidence, with daily aspirin doses exceeding 325 mg associated with greater mucosal damage compared to lower cardioprotective doses. Concomitant administration of corticosteroids or further heightens vulnerability by exacerbating mucosal fragility and potential. Elderly patients, due to diminished mucosal repair capacity and higher burden, experience a 2- to 4-fold increased risk relative to younger users. Traditional non-selective NSAIDs, such as ibuprofen and naproxen, inhibit both COX-1 and COX-2 isoforms, leading to a pronounced reduction in protective prostaglandins and thus a higher risk. In contrast, selective COX-2 inhibitors like celecoxib spare COX-1 to a greater extent, resulting in lower gastrointestinal —endoscopic studies show up to a 4-fold reduction in formation compared to traditional NSAIDs—although the risk is not entirely eliminated, particularly at higher doses. Among regular NSAID users, the point prevalence of endoscopic ulcers ranges from 10% to 30%, with up to 40% of cases remaining and prone to silent progression or complications. NSAIDs preferentially induce gastric s over duodenal ones, with gastric lesions occurring approximately 4 times more frequently due to direct topical and greater impairment of gastric mucosal defenses. The risk shows synergy with H. pylori , where co-occurrence can increase odds by 3- to 6-fold compared to either factor alone.

Other risk factors

Dietary factors, such as consumption of spicy foods or acidic foods including citrus fruits (e.g., lemons), do not cause peptic ulcer disease but may irritate the gastric mucosa and exacerbate symptoms in some individuals with existing ulcers, though individual tolerance varies. Evidence on the effects of acidic foods is mixed, with no strong consensus for universal avoidance; major health organizations indicate that diet does not play a significant role in causing or treating ulcers, and specific foods like citrus should only be limited if they personally worsen symptoms. is a significant modifiable for peptic ulcer disease, approximately doubling the risk by impairing mucosal blood flow, inhibiting , and delaying ulcer healing, with relative risks typically ranging from 1.5 to 2.0 across studies. Current smokers also experience higher rates of ulcer complications and recurrence compared to nonsmokers. Excessive alcohol consumption irritates the gastric and duodenal mucosa, promoting production and , though it is not considered a primary cause of peptic ulcer disease. A dose-response relationship exists, with daily intake exceeding 40 g associated with elevated risk, and heavy drinking (more than 42 drinks per week) conferring a fourfold increase in ulcers. Stress contributes to peptic ulcer development, particularly physiological stress in critical illnesses like burns or severe trauma, which stimulates vagal activity and acid hypersecretion. shows a weaker but positive association, increasing ulcer risk independently of Helicobacter pylori infection or use. Zollinger-Ellison syndrome, a rare condition caused by gastrin-secreting tumors (gastrinomas) in the or , leads to marked hypersecretion and often multiple, refractory peptic ulcers. Diagnosis typically involves elevated fasting serum levels alongside a basal acid output exceeding 15 mEq/h.00789-0/fulltext) Genetic predisposition influences peptic ulcer susceptibility, with first-degree family history conferring a 2- to 3-fold increased risk, likely due to inherited variations in acid secretion or mucosal defense. Rare genetic conditions, such as , are also linked, potentially through hypercalcemia-induced release and acid overproduction. Certain comorbidities elevate the risk of peptic ulcer disease, including (COPD) and , with odds ratios generally between 1.5 and 2.5 after adjusting for confounders. In , and impaired platelet function contribute to higher ulcer bleeding rates, while COPD may exacerbate risk via chronic inflammation and interactions. These factors can synergize with primary etiologies like use to amplify overall vulnerability.

Pathophysiology

Mucosal defense mechanisms

The gastroduodenal mucosa maintains integrity through a multifaceted system of defense mechanisms that counteract luminal aggressors such as and under normal physiological conditions. These protective strategies operate at pre-epithelial, epithelial, and subepithelial levels, ensuring a delicate balance that prevents tissue damage. Physical barriers form the first line of defense. The layer, secreted by goblet cells, consists of glycoproteins that create a viscoelastic approximately 0.2-0.6 mm thick, which shields the from direct contact with and enzymes. Tight junctions between epithelial cells further reinforce this barrier, preventing back-diffusion of ions and maintaining epithelial permeability. Chemical defenses neutralize potential threats. ions are secreted by surface epithelial cells into the gel, creating a pH gradient that maintains near-neutral conditions (approximately 7) at the epithelial surface despite acidic luminal contents. Prostaglandins, particularly PGE2, enhance these protections by stimulating and while increasing mucosal blood flow to support nutrient delivery and waste removal. Cellular and circulatory factors contribute to ongoing resilience. The gastric epithelium undergoes rapid renewal, with surface mucous cells turning over every 3-5 days through proliferation of stem cells in the gastric isthmus, allowing quick replacement of damaged cells. Mucosal blood flow, regulated locally, delivers oxygen and nutrients while facilitating the removal of excess acid and toxic metabolites. Neural and hormonal regulation fine-tunes these defenses. , released from D cells in the , acts as a paracrine inhibitor of acid secretion by suppressing and release from nearby cells. (EGF), produced by mucosal cells and salivary glands, promotes epithelial proliferation and repair, enhancing overall mucosal integrity. This equilibrium between defensive mechanisms and controlled aggressive factors like and is essential for mucosal ; disruptions, such as those induced by or nonsteroidal anti-inflammatory drug use, can impair synthesis or other components, tipping the balance toward injury.

Ulcer formation processes

Peptic ulcer formation begins with initial mucosal injury, where and erode the epithelial layer, particularly when protective mechanisms are compromised. This starts superficially in the mucosa but progresses due to ongoing exposure to luminal contents, leading to breaches in the epithelial barrier. The inflammatory response follows, characterized by infiltration into the damaged site, which amplifies tissue injury through the release of and proteases. Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) are upregulated in this phase, promoting further and inhibiting secretion, thereby exacerbating epithelial damage and delaying repair. In the chronic phase, persistent injury leads to a mucosal defect 5 mm or greater in diameter, extending through the and forming a discrete ulcer crater with elevated, edges. Healing attempts involve for formation and to restore blood supply, but continued aggressors like acid exposure hinder complete resolution, resulting in chronic ulceration. Ulcer formation varies by location: duodenal ulcers typically develop in the due to high post-pyloric load and alkaline duodenal contents, often linked to hypergastrinemia, while gastric ulcers predominate in the antrum or body, influenced by regional differences in mucosal blood flow and H. pylori distribution. Healing dynamics under suppression therapy, such as inhibitors, achieve resolution in approximately 80% of cases within 4-8 weeks by reducing acid-mediated erosion. However, factors like continued can delay this process by up to 50% through impaired mucosal blood flow and reduced expression.

Diagnosis

Clinical assessment

The clinical assessment of peptic ulcer disease (PUD) begins with a detailed history to identify symptom patterns and risk factors that raise suspicion for the condition. Patients often describe epigastric pain that may vary in relation to meals: duodenal ulcers typically cause pain that is relieved by eating or antacids, occurring 1-3 hours after meals or at night, while gastric ulcers may worsen with food intake shortly after meals. A thorough inquiry into medication history, including nonsteroidal anti-inflammatory drug (NSAID) use, and potential exposure to Helicobacter pylori through family or environmental factors is essential, as these are key contributors. Family history of ulcers or gastrointestinal malignancy should also be elicited, as it increases the likelihood of PUD. Alarm features in the history warrant heightened concern and prompt further evaluation to exclude complications or alternative diagnoses. These include unintentional , progressive , persistent vomiting, evidence of such as or , , and early satiety suggesting obstruction. To differentiate PUD from functional dyspepsia, the Rome IV criteria are applied: functional dyspepsia requires bothersome postprandial fullness, early satiety, epigastric pain, or burning for at least 3 months, with no evidence of structural disease, whereas PUD symptoms often align more closely with meal-related patterns and risk factors. The focuses on abdominal findings and systemic signs. Epigastric tenderness is a common localized finding upon , reflecting mucosal inflammation. may indicate chronic from occult blood loss, while or could signal acute . In cases of suspected , signs such as , rebound tenderness, and a rigid board-like are critical. The exam also assesses for from or general nutritional status. Risk stratification during assessment helps prioritize patients for urgent intervention. Factors such as age ≥60 years, current , and a history of prior ulcers significantly elevate suspicion for PUD and influence the need for expedited evaluation, as impairs healing and increases recurrence risk. PUD can occur, particularly in high-risk groups, and assessment should include screening considerations for long-term NSAID users, where ulcers may be incidentally discovered without preceding symptoms. In such cases, history focuses on exposure risks rather than overt complaints to identify silent disease.

Endoscopic evaluation

Upper gastrointestinal endoscopy (EGD), also known as , serves as the gold standard for diagnosing peptic ulcer disease by providing direct visualization of the mucosal lining in the , , and . It is particularly indicated for patients ≥60 years with new-onset dyspepsia or those of any age presenting with alarm symptoms such as unexplained , , recurrent , , or evidence of , as these features raise suspicion for ulcers or complications. In cases of acute , early EGD within 24 hours of presentation is recommended to confirm the diagnosis, assess severity, and facilitate immediate intervention, correlating with symptom urgency to reduce risks like rebleeding. During EGD, ulcers are identified by their characteristic mucosal breaks exceeding 5 mm in diameter, with location typically in the or . Endoscopic findings distinguish between clean-based ulcers, which indicate low rebleeding risk, and those with active bleeding or high-risk . The Forrest classification stratifies bleeding peptic ulcers based on endoscopic appearance to guide therapy:
  • Ia: Active spurting hemorrhage, indicating ongoing severe .
  • Ib: Active oozing hemorrhage from the base.
  • IIa: Nonbleeding visible vessel, a precursor to rebleeding.
  • IIb: Adherent clot over the .
  • IIc: Flat pigmented spot or hematin-covered base.
  • III: Clean base without , signifying recent hemorrhage resolution.
High-risk lesions (Ia, Ib, IIa) warrant immediate endoscopic , while IIb may require clot removal for reassessment. Biopsy protocols are essential during EGD to exclude and detect . For gastric , multiple (typically 6-8 samples from the ulcer margin and base) are obtained to rule out gastric cancer, particularly if the ulcer appears irregular or fails to heal; duodenal ulcers rarely require routine unless atypical features are present. All patients with peptic ulcers undergo testing for H. pylori via from the antrum and corpus, processed for (assessing bacterial density and inflammation) or (detecting for immediate results). Therapeutic endoscopy is integrated when high-risk bleeding is identified, employing hemostasis techniques such as epinephrine injection combined with (e.g., bipolar electrocoagulation or heater ), mechanical clipping, or topical agents like hemostatic powders for active or impending hemorrhage. These interventions reduce rebleeding rates from 10-20% in untreated high-risk ulcers to under 10%. EGD carries low overall risks, with perforation occurring in 0.03-0.1% of diagnostic procedures and slightly higher (up to 0.3%) in therapeutic cases involving or ; esophageal perforations account for most incidents. Sedation-related complications, such as hypoxia or cardiovascular events, affect less than 0.3% of patients, minimized by monitoring and appropriate dosing. Follow-up EGD is recommended 8-12 weeks after initial for gastric ulcers to confirm healing and repeat biopsies if incomplete resolution or persistent symptoms occur, ensuring exclusion of underlying ; routine is not needed for duodenal ulcers that heal appropriately.

Laboratory investigations

Laboratory investigations play a crucial role in supporting the of peptic ulcer disease (PUD) by identifying underlying causes such as infection and assessing for complications like . These tests include non-invasive methods for detecting H. pylori, blood analyses for , and targeted assays for rare etiologies, helping to guide management without relying solely on invasive procedures. Non-invasive tests for H. pylori are preferred for initial evaluation and post-eradication confirmation in patients with PUD. The (UBT) involves ingestion of labeled with or , followed by breath sample analysis; it demonstrates high sensitivity of approximately 97% and specificity of 96% for active . UBT is particularly reliable for confirming eradication, recommended at least four weeks after completing antibiotic therapy and two weeks after discontinuing inhibitors (PPIs). The stool antigen test (SAT) detects H. pylori antigens in , offering sensitivity of 81-98% and comparable specificity, making it a cost-effective alternative suitable for both and follow-up. Serologic testing for anti-H. pylori IgG antibodies is not recommended for diagnosing active in PUD due to its inability to distinguish current from past exposure, as antibodies persist long after eradication; it is better suited for epidemiological studies. Blood tests aid in evaluating PUD complications, particularly chronic . A (CBC) can reveal , often iron-deficiency type, resulting from occult gastrointestinal blood loss in up to 15-20% of chronic PUD cases. The test (FOBT), using guaiac-based or fecal immunochemical (FIT) methods, screens for hidden in stool. FIT has higher sensitivity than guaiac-based tests for detecting (around 50-92% depending on site and type), though both have limitations for occult upper GI due to degradation. Additional laboratory assessments target specific etiologies or comorbidities. Serum levels are measured if Zollinger-Ellison is suspected in patients with or multiple ulcers, where elevated levels (>1000 pg/mL) indicate hypergastrinemia due to ; levels between 200-1000 pg/mL may require stimulation testing for confirmation. Liver and renal function tests, including serum and liver enzymes, are routinely evaluated to identify comorbidities that may influence PUD management or mimic symptoms. Antibiotic resistance testing is increasingly important given rising H. pylori resistance patterns. Culture and susceptibility testing from gastric samples is recommended when initial eradication fails, revealing clarithromycin resistance rates exceeding 15% in many regions, prompting avoidance of -based triple therapy unless susceptibility is confirmed. In low-risk patients with dyspepsia, non-invasive H. pylori testing followed by treatment (test-and-treat strategy) is cost-effective, reducing needs and preventing ulcer progression in H. pylori-positive cases by up to 90%. This approach prioritizes UBT or SAT for their high accuracy and minimal invasiveness.

Differential diagnosis

Peptic ulcer disease (PUD) often presents with epigastric pain, bloating, or dyspepsia, necessitating differentiation from other gastrointestinal and non-gastrointestinal conditions to ensure accurate diagnosis. Functional dyspepsia is a common mimic, characterized by postprandial distress, early satiety, or epigastric pain without identifiable structural lesions on endoscopy, contrasting with PUD's visible ulcers. It is diagnosed by exclusion after negative endoscopic evaluation and lacks association with H. pylori infection or NSAID use in most cases. Gastroesophageal reflux disease (GERD) typically features predominant symptoms of and regurgitation, often exacerbated by lying down or bending, and responds to proton pump inhibitors (PPIs), but reveals no peptic ulcers, instead showing possible . Unlike PUD, pain is not usually meal-related, and H. pylori testing may help identify overlaps with . Biliary colic or pancreatitis can imitate PUD with upper abdominal pain, but involves episodic right upper quadrant discomfort triggered by fatty meals, while presents with severe, persistent epigastric pain radiating to the back, often worsened by . Differentiation relies on elevated serum amylase or levels in pancreatitis and ultrasonographic evidence of gallstones in biliary colic, with normal excluding PUD. Gastric cancer must be ruled out in cases of persistent or non-healing ulcers, particularly with alarm features like unexplained , anorexia, or . with is essential, as malignant ulcers fail to heal on repeat evaluation, unlike benign PUD lesions. Cardiovascular conditions, such as or , may cause epigastric discomfort mimicking PUD, especially if exertional or accompanied by and diaphoresis, but pain is unrelated to meals and is normal. (ECG) and cardiac biomarkers distinguish these from gastrointestinal origins. is the primary discriminator, confirming PUD through direct visualization of ulcers while excluding most mimics, with H. pylori testing further aiding differentiation of infectious versus non-infectious etiologies.

Management

Lifestyle and pharmacological interventions

Lifestyle modifications play a crucial role in managing peptic ulcer disease by promoting healing and reducing symptom exacerbation. is particularly important, as continued impairs ulcer healing, with studies showing that nonsmokers achieve healing rates of approximately 95% compared to 63% in smokers after treatment; quitting can thus improve healing outcomes by roughly 50% relative to persistent smoking. Moderation of alcohol intake is recommended, as excessive consumption can damage the and delay recovery, though moderate levels do not appear to significantly affect ulcer incidence or healing. Consuming small, frequent meals helps alleviate discomfort by minimizing fluctuations, while avoiding potential irritants such as spicy foods, , fatty foods, and acidic foods (such as citrus fruits) can further reduce symptoms in some patients, particularly if these foods personally exacerbate discomfort. Dietary factors do not cause peptic ulcers but can influence symptom severity in active cases, with recommendations tailored to individual tolerance. Stress reduction techniques, such as or integrated programs, show limited but promising evidence for improving ulcer healing rates, potentially by mitigating psychological factors that exacerbate the condition. Pharmacological interventions primarily focus on acid suppression and mucosal protection to facilitate ulcer healing. Proton pump inhibitors (PPIs), such as omeprazole at doses of 20-40 mg daily, are the cornerstone of therapy, achieving healing rates of 80-90% within 4 weeks for most peptic ulcers. H2-receptor antagonists, like , offer an alternative for acid reduction but are less potent, with healing rates ranging from 77-92% at 4 weeks, making them suitable for milder cases or when PPIs are contraindicated. For symptom relief in mild disease, antacids provide rapid neutralization of , while acts as a mucosal protectant by forming a barrier over the ulcer site, demonstrating rates of 60-70% in healing at 4-6 weeks. Initial treatment typically lasts 4-8 weeks to promote complete , followed by tapering to doses if needed to prevent , particularly in non-H. pylori cases. Long-term PPI use, however, carries risks including increased susceptibility to Clostridioides difficile infection and bone fractures due to potential impacts on calcium absorption; current guidelines, including those updated through 2024, emphasize using the shortest effective course and lowest dose to minimize these adverse effects. These interventions often serve as adjuncts to etiology-specific therapies, such as H. pylori eradication, to optimize overall outcomes.

Eradication of H. pylori

Eradication of Helicobacter pylori (H. pylori) is a cornerstone of managing peptic ulcer disease caused by this infection, involving combination antibiotic regimens alongside acid suppression to achieve high cure rates. For duodenal ulcers associated with H. pylori, standard regimens include triple or quadruple therapy for 10-14 days: a proton pump inhibitor (PPI) such as omeprazole, pantoprazole, or lansoprazole twice daily, plus two antibiotics (e.g., amoxicillin 1 g twice daily with clarithromycin 500 mg twice daily, or in quadruple therapy incorporating metronidazole). The preferred first-line therapy for treatment-naïve patients is 14-day bismuth quadruple therapy, consisting of a proton pump inhibitor (PPI) twice daily, bismuth subcitrate or subsalicylate four times daily, metronidazole 500 mg three times daily, and tetracycline 500 mg four times daily, which demonstrates eradication efficacy exceeding 90% even in areas with high antibiotic resistance. Alternatively, per the 2024 American College of Gastroenterology (ACG) guidelines, dual therapy with a potassium-competitive acid blocker (PCAB, such as vonoprazan) and amoxicillin for 14 days is suggested as a conditional first-line option, achieving eradication rates of 85-95% in susceptible populations. This bismuth quadruple regimen is recommended by the 2024 ACG guidelines as the optimal choice due to rising resistance patterns, particularly in regions where clarithromycin resistance surpasses 15%. In settings with confirmed low clarithromycin resistance (less than 15%), an alternative first-line option is -based triple therapy: a PPI twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily for 14 days, achieving eradication rates of 70-85%. However, global clarithromycin resistance has escalated to 20-30% by 2025, with rates exceeding 15% in most countries, necessitating avoidance of this regimen in high-prevalence areas to prevent treatment failure. For patients experiencing treatment failure, salvage regimens include levofloxacin-based triple therapy (PPI twice daily, levofloxacin 500 mg once daily, and amoxicillin 1 g twice daily for 14 days) or rifabutin-based triple therapy (PPI twice daily, rifabutin 150 mg twice daily, and amoxicillin 1 g twice daily for 10-14 days), both yielding approximately 85% eradication success in cases. These options are selected based on prior exposure and local resistance profiles, as outlined in ACG recommendations. Following completion of the eradication regimen, PPI therapy is continued for 4-8 weeks to promote full ulcer healing. Successful eradication must be confirmed at least 4 weeks after completing therapy using non-invasive tests such as the or fecal antigen test to ensure cure and guide further management if needed. Adjunctive use of , such as at 250-500 mg daily during therapy, can mitigate common side effects like , which occurs in approximately 30% of patients on regimens, thereby improving adherence without compromising efficacy. Successful H. pylori eradication significantly reduces the risk of peptic ulcer recurrence, altering the long-term disease course.

Treatment of NSAID-induced ulcers

The primary treatment strategy for NSAID-induced ulcers involves discontinuing the NSAID to promote and prevent recurrence, as cessation significantly improves ulcer resolution rates compared to continued use. If NSAID cannot be stopped due to clinical necessity, co- with a (PPI) such as omeprazole 20 mg daily is recommended, reducing the incidence of endoscopic gastric s by 74% relative to NSAID monotherapy. For patients requiring ongoing anti-inflammatory therapy, selective (COX-2) inhibitors like celecoxib offer a lower-risk alternative to non-selective NSAIDs, associated with approximately a 50% reduction in the risk of developing endoscopic ulcers. This benefit is particularly relevant for moderate-risk individuals but may be attenuated in those also taking low-dose aspirin. For NSAID-induced duodenal ulcers confirmed negative for H. pylori, treatment involves stopping or reducing NSAID use under medical guidance and administering proton pump inhibitor (PPI) monotherapy for 4-8 weeks to promote healing. Healing of established NSAID-induced ulcers typically requires acid suppression with high-dose PPI therapy, such as omeprazole 40 mg twice daily for 8 weeks, which achieves ulcer resolution in approximately 90% of cases. Continued NSAID use during this period lowers healing rates to around 61%, underscoring the preference for discontinuation. In high-risk patients—those with a history of prior ulcers, age greater than 65 years, or concurrent use of corticosteroids—additional gastroprotective measures are essential; at 200 mcg four times daily serves as an effective alternative protectant, reducing serious gastrointestinal complications by 40%. As of 2025, vonoprazan, a potassium-competitive acid blocker, has emerged as a non-inferior option to traditional PPIs for healing NSAID-induced ulcers, demonstrating comparable efficacy in clinical studies. Before resuming NSAID therapy, testing for H. pylori co-infection is advised to address any contributing factors.

Management of complications

The management of complications in peptic ulcer disease focuses on addressing life-threatening events such as , , and , often requiring urgent , endoscopic, or surgical interventions across etiologies including infection and NSAID use. Initial stabilization is critical for all patients, involving hemodynamic with intravenous fluids to maintain ≥65 mmHg, blood product transfusion if <7 g/dL in hemodynamically stable patients, and broad-spectrum antibiotics to cover potential peritonitis or sepsis. For upper gastrointestinal bleeding from peptic ulcers, which accounts for a significant portion of emergency endoscopies, initial resuscitation prioritizes volume replacement with crystalloids or colloids followed by packed red blood cell transfusion targeting hemoglobin 7-9 g/dL to avoid overtransfusion risks. Endoscopy within 24 hours is recommended for risk stratification and hemostasis, achieving initial success in approximately 90% of cases through techniques such as epinephrine injection, thermal coagulation, or mechanical clipping, with rebleeding rates reduced by over 50% when combined with pharmacotherapy. High-dose proton pump inhibitor (PPI) therapy is administered intravenously as an 80 mg bolus followed by 8 mg/hour continuous infusion for 72 hours post-hemostasis to promote clot stability and lower rebleeding incidence to under 10%. In cases of refractory bleeding despite endoscopic attempts (occurring in 5-10% of patients), surgical options such as oversewing the ulcer or angiographic embolization are pursued, particularly if hemodynamic instability persists. Perforated peptic ulcers demand rapid surgical intervention in most hemodynamically unstable patients, with the omental patch repair (Graham patch) serving as the standard procedure to close the defect and prevent ongoing contamination of the peritoneal cavity. Preoperative preparation includes nasogastric tube decompression to reduce gastric distension, intravenous broad-spectrum antibiotics targeting enteric flora (e.g., piperacillin-tazobactam), and fluid resuscitation, which improve outcomes by mitigating sepsis in up to 80% of cases when initiated promptly. Laparoscopic approaches are preferred in stable patients for faster recovery, though open surgery remains essential for extensive contamination or posterior duodenal perforations. Gastric outlet obstruction secondary to peptic scarring is managed conservatively initially with nasogastric decompression, PPI therapy, and H. pylori eradication if applicable, but persistent cases require endoscopic balloon dilation, which achieves symptom relief in 70-90% of benign etiologies without immediate surgery. For failures or recurrent strictures, surgical interventions like vagotomy with pyloroplasty restore patency and acid control, with success rates exceeding 85% in selected patients. Refractory peptic ulcers, defined as failure to heal after 8-12 weeks of optimal medical therapy and now rare (<5% of cases due to advances in antisecretory agents and eradication regimens), necessitate surgical evaluation for procedures such as truncal vagotomy or partial gastrectomy to address persistent hyperacidity or incomplete healing. These interventions are reserved for complications like recurrent bleeding or obstruction unresponsive to endoscopy. Post-intervention care for all complications includes intensive care unit monitoring for high-risk patients to detect early rebleeding or sepsis, with long-term recurrence prevention centered on H. pylori eradication (achieving cure rates >90% with quadruple therapy) and discontinuation of contributing factors like NSAIDs. Multidisciplinary follow-up with repeat ensures healing and reduces readmission rates by 40-60%.

Prevention

Primary prevention strategies

Primary prevention of peptic ulcer disease focuses on reducing exposure to key risk factors such as infection and nonsteroidal anti-inflammatory drugs (NSAIDs), alongside modifiable lifestyle behaviors, particularly in at-risk populations. Strategies emphasize measures, targeted pharmacoprophylaxis, and behavioral interventions to avert the initial onset of ulcers, which can lead to complications like or if untreated. These approaches are supported by clinical guidelines from organizations like the American College of Gastroenterology (ACG) and the (WHO), prioritizing cost-effective, evidence-based actions over routine population screening. Avoiding H. pylori infection, a primary cause of peptic ulcers, relies on and practices, especially in endemic areas with high prevalence rates exceeding 50% in developing regions. Access to clean water, proper sewage systems, and measures significantly lowers transmission via fecal-oral or oral-oral routes. Hand , including thorough washing with before meals and after using the , has been associated with significant reductions in risk in children in high-burden settings, as shown in studies in . Routine population screening for H. pylori is not recommended due to cost and lack of proven benefit in low-prevalence areas, but testing is advised for close family members of infected individuals in high-prevalence regions (>20%), where intrafamilial spread is common, followed by eradication if positive. For NSAID users, who face a 15-20% lifetime risk of ulcer development, prevention involves using the lowest effective dose for the shortest duration to minimize mucosal damage. Selective (COX-2) inhibitors are preferred over nonselective NSAIDs in patients without cardiovascular contraindications, as they reduce ulcer risk by approximately 50% compared to traditional NSAIDs. Co-prescription of inhibitors (PPIs) is strongly recommended for high-risk individuals, such as those over 65, with a history of ulcers, or concurrent use; meta-analyses show PPIs decrease endoscopic ulcer incidence by 70-80% in these groups. Guidelines from the ACG and National Institute for Health and Care Excellence () endorse this strategy, with alternatives like considered only if PPIs are unsuitable. Lifestyle modifications play a supportive role in reducing ulcer risk, though they are not standalone preventives. is critical, as use doubles the odds of H. pylori-associated ulcers and impairs mucosal healing; structured programs, including replacement and counseling, achieve quit rates of 20-30% at one year, per WHO data. Limiting alcohol intake to less than 20 grams per day (about one ) helps avoid gastric irritation, with excessive consumption (>40 g/day) linked to a 2-3-fold increased risk in cohort studies. A balanced diet emphasizing fruits, vegetables, and whole grains while limiting irritants like spicy foods, , and carbonated beverages supports mucosal integrity, though no specific diet eliminates risk entirely. Public health efforts include ongoing research into H. pylori , with -based subunit in preclinical trials as of 2025 showing promising and bacterial load reduction in animal models, but none are commercially available yet. As of October 2025, a novel demonstrated excellent protective and therapeutic efficacy in animal models at the United European Gastroenterology Week. These candidates, targeting subunit B (UreB), aim to induce mucosal immunity and could prevent up to 70% of infections if successful in larger trials. In targeted settings like intensive care units (ICUs), stress ulcer prophylaxis with PPIs is standard for mechanically ventilated patients at high risk (e.g., those with or ), reducing clinically significant bleeding incidence by about 50% (from 4-6% to 2-3%) without increasing mortality, according to randomized controlled trials and meta-analyses. The Society of Critical Care Medicine recommends PPIs over H2-receptor antagonists for this purpose due to superior acid suppression.

Secondary prevention

Secondary prevention of peptic ulcer disease focuses on strategies to reduce the risk of ulcer recurrence following initial healing, particularly in patients with a history of infection or (NSAID) use. After successful initial treatment, recurrence rates can remain elevated without targeted interventions, emphasizing the need for confirmatory testing and ongoing management. Confirmation of H. pylori eradication is essential to prevent recurrence, as persistent infection leads to high relapse rates of 50-60% within one year, compared to 0-2% after successful eradication. The 2024 American College of Gastroenterology (ACG) guidelines recommend re-testing all treated patients at least four weeks after completing using noninvasive methods such as the or fecal antigen test, or gastric if is indicated. If re-testing is positive, re-treatment with an alternative regimen is advised, tailored to local resistance patterns—such as bismuth-based quadruple for clarithromycin-resistant strains—to achieve eradication rates exceeding 90%. Emerging 2025 consensus statements highlight the role of , such as Lactobacillus and Bifidobacterium strains, as adjuncts post-antibiotics to restore gut balance and potentially lower reinfection risk by 10-15% through immune modulation and bacterial competition. For patients continuing NSAIDs due to underlying conditions like , long-term (PPI) therapy is recommended to suppress and prevent re-ulceration. A standard dose of 20 mg daily omeprazole or equivalent reduces the incidence of recurrent ulcers by approximately 70-90% compared to over 6-12 months, even when NSAIDs are maintained. However, prolonged PPI use requires monitoring for potential adverse effects, including dependency, bone density loss, and increased infection risk, with periodic attempts at dose reduction or deprescribing once the ulcer has healed for at least six months. Surveillance endoscopy is advised for high-risk gastric ulcers, particularly those with incomplete healing or suspicious features on initial evaluation, to confirm resolution and exclude malignancy. Guidelines from the American Society for Gastrointestinal Endoscopy recommend repeat endoscopy 8-12 weeks after initial therapy for benign-appearing gastric ulcers, with annual surveillance in select cases of persistent risk factors like ongoing NSAID use or prior incomplete healing to detect early recurrence. Sustained lifestyle modifications play a critical role in minimizing relapse. Continued doubles the risk of ulcer recurrence by impairing mucosal and increasing secretion, while excessive alcohol intake (>2 s/day) similarly elevates risk through direct gastric irritation. Reinforcement of and alcohol moderation—ideally limited to one per day—can reduce recurrence by up to 50% in post- patients. These measures integrate with primary prevention approaches by addressing modifiable risk factors long-term.

Epidemiology and history

Epidemiology

Peptic ulcer disease (PUD) affects a significant portion of the global population, with a lifetime estimated at 5% to 10%. The global point stood at approximately 8.09 million cases in 2019, reflecting an increase in absolute numbers due to but a decline in age-standardized rates. In developed countries, prevalence rates have decreased substantially, dropping by 32.9% from to 2021, primarily driven by widespread eradication and improved sanitation. As of 2025, age-standardized rates continue to decline, though absolute cases have increased slightly due to global . Regional disparities in PUD burden are pronounced, with higher rates in low- and middle-income areas such as and compared to high-income regions like . In , the pooled prevalence is 15.2%, predominantly duodenal ulcers at 10.2%. For instance, India's point prevalence for peptic ulcers is about 4.7% (with duodenal ulcers historically higher at up to 12 per 1,000 in some cohorts), contrasting with the where annual incidence is 0.1% to 0.3%. These differences correlate closely with H. pylori seroprevalence, which is approximately 43.9% worldwide among adults. Demographically, PUD exhibits a predominance, with rates of 6.2% in men versus 2.8% in women, yielding a male-to-female ratio of about 2:1. Incidence peaks between ages 40 and 60, though rates rise again in older adults due to comorbidities and use. Many older adults with peptic ulcers are , increasing the risk of undetected complications. Trends indicate a shift in PUD etiology, with H. pylori-associated cases declining in high-income settings due to eradication programs and reduced infection rates. In contrast, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers are rising, comprising 10% to 30% of cases among users and now accounting for about 25% of overall PUD in developed countries by 2025. PUD imposes considerable morbidity, contributing to hundreds of thousands to over 1 million hospitalizations annually worldwide, though complication rates have stabilized at 5% to 10% mortality for events. , the direct economic cost is approximately $777 million as of 2015, encompassing treatment, hospitalizations (which account for over 40% of expenses), and lost productivity.

Historical aspects

Peptic ulcer disease has been recognized since ancient times, with early descriptions attributed to around 400 BCE, who referred to "corrosions of the stomach" as a condition involving painful gastric erosions linked to digestive processes. By the , advancements in allowed for more systematic identification through autopsies, where uncomplicated acute and chronic ulcers were frequently observed and correlated with premortem symptoms such as epigastric pain, establishing the disease as a distinct pathological entity rather than mere digestive upset. A major paradigm shift occurred in 1982 when Australian pathologists J. Robin Warren and Barry J. Marshall identified as a spiral bacterium associated with gastric epithelium in patients with active chronic , challenging prevailing theories that attributed ulcers primarily to stress, diet, or excessive acid production. Their discovery, initially met with skepticism in the medical community, was validated over time and earned them the in or in 2005 for demonstrating the bacterial etiology of peptic ulcers and related conditions. This revelation shifted focus from symptomatic acid suppression to addressing the underlying infection. Treatment evolved from supportive measures in the mid-20th century, where antacids were routinely used in the to neutralize and alleviate symptoms, often combined with dietary restrictions. The introduction of H2-receptor antagonists, beginning with in 1976, marked a breakthrough by inhibiting histamine-mediated acid secretion, promoting ulcer healing in over 70% of cases and reducing the need for . In the , proton pump inhibitors (PPIs) like omeprazole, launched in 1989, further enhanced acid suppression efficacy, achieving healing rates exceeding 90% in duodenal ulcers within eight weeks. By the 1990s, H. pylori eradication therapy emerged as standard, with bismuth-based triple regimens incorporating antibiotics like and , yielding cure rates of 80-95% and preventing recurrence. Prior to the 1980s, surgical interventions dominated refractory cases, with procedures like (severing branches to reduce acid secretion) and partial performed in up to 100,000 cases annually in the U.S., accounting for the majority of elective surgeries. Post-1980s, the advent of effective led to a dramatic decline, with elective surgeries dropping 80-97% by the and now comprising less than 10% of peptic ulcer management, reserved mainly for complications like . The bacterial hypothesis faced significant controversy, including initial rejection by peers who viewed H. pylori as a harmless commensal; to prove causation, Marshall conducted a self-ingestion experiment in 1985, deliberately infecting himself with the bacterium, developing acute , and subsequently curing it with antibiotics, which helped sway scientific opinion. From a 2025 perspective, rising antibiotic resistance in H. pylori—with global clarithromycin resistance exceeding 20% and multidrug resistance patterns complicating eradication—poses ongoing challenges, necessitating tailored regimens and susceptibility testing to maintain treatment success rates above 90%.

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