OVERVIEW: What every practitioner needs to know

Are you sure your patient has Peptic Ulcer Disease? What are the typical findings for this disease?

A peptic ulcer is a mucosal break or erosion in the stomach or duodenum, usually measuring 5mm or larger. Depending on the underlying pathology, peptic ulcer disease can be classified as either primary or secondary. Primary peptic ulcers occur most often in the duodenum, while secondary ulcers can occur in the stomach or duodenum, and occur more often in younger children.

Primary peptic ulcer disease is caused most commonly by Helicobacter pylori infection, but can also be caused by gastric acid hypersecretion syndromes such as in the Zollinger-Ellison syndrome, G-cell hyperplasia, systemic mastocytosis, short bowel syndrome, and hyperparathyroidism. Secondary peptic ulcers are caused by medications or by physical stressors such as systemic illness, head trauma, burns, sickle cell disease, type I diabetes, systemic lupus erythematosus.

Peptic ulcer disease is rare in children, accounting for 1 in 3000 hospital admissions.

Children and adolescents with ulcers usually complain of epigastric abdominal pain and vomiting. They may also present with hematemesis. Melena may be present when there is significant and brisk upper GI tract bleeding.

What other disease/condition shares some of these symptoms?

Esophagitis

Eosinophilic esophagitis

Eosinophilic gastritis

Crohn’s disease

Gall bladder disease

Pneumonia

Pancreatitis

Functional dyspepsia

What caused this disease to develop at this time?

Primary PUD can be caused by:

Helicobacter pylori infection

Zollinger-ellison syndrome

G-cell hyperplasia

systemic mastocytosis

short bowel syndrome

hyperparathyroidism
Secondary PUD can be caused by:

exposures to medications such as NSAIDS, corticosteroids, sodium valproate, theophylline

systemic illness or sepsis

burns

other illnesses such as sickle cell disease, type I diabetes, systemic lupus erythematosus

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies should be selected based on findings on physical exam and presenting symptoms.
CBC with differential may reveal anemia from chronic blood loss, but may also be normal in patients with peptic ulcer disease. A reticulocyte count will often be elevated with blood loss and anemia due to a bleeding ulcer.
Serum electrolytes, liver function tests, pancreatic enzymes may be necessary to evaluate for other causes of abdominal pain if suspected from the history and/or exam.
Urinalysis and urine culture may be necessary to rule out urinary tract infection. Cystitis can present with abdominal pain, and pylonephritis involves pain and vomiting, which are presenting symptoms similar to PUD. Young children are often unable to communicate UTI symptoms of dysuria and urgency.
Stool for occult blood, may be suggestive of upper gastrointestinal bleeding.
Screening tests for H pylori:

urease breath test (UBT): The UBT is a highly reliable, non-invasive test with excellent specificity and sensitivity in children over 6 years of age. It does require cooperation from the child, and is easier to administer to older children.

H pylori antigen in stool. Even more convenient, obtaining a stool sample allows for another non-invasive yet reliable test for H pylori. Enzyme immunoassays (EIA) look for H pylori antigen in stool. This test can be used in any age group (doesn’t require cooperation) and usually costs less than UBT.
Serum based tests for antibodies to H. pylori (IgA, IgM) are not reliable in children and should not be used to test for H pylori in the clinical setting.

Would imaging studies be helpful? If so, which ones?

Upper GI endoscopy is the best approach to diagnosing peptic ulcer disease. Barium radiograpy has been replaced by endoscopy as the study of choice to confirm ulcer disease.

Although radiography can identify complications of ulcer disease, such as gastric deformities or scarring, the trend toward decreasing use of barium radiography in this setting has led to fewer pediatric radiologists with expertise in interpreting these studies, further lessening their value as a diagnostic tool.

Confirming the diagnosis

There are no pediatric clinical decision algorithms for suspected peptic ulcer disease. Endoscopic evaluation should be pursued for the investigation of patients with signs and symptoms suggestive of peptic ulcer disease.

A joint position statement from the North American and European Societies of Pediatric Gastroenterology addresses the evaluation and management of infection with H. pylori (discussed below).

Testing for H. pylori is not recommended in children with functional abdominal pain. The quality of evidence for this last recommendation was graded as high.

If you are able to confirm that the patient has Peptic Ulcer Disease, what treatment should be initiated?

H2-blockers (Cimetidine, Famotidine, Ranitidine) or proton pump inhibitors (Lansoprazole, Omeprazole) are first line therapies for peptic ulcer disease. Randomized controlled trials have demonstrated that Proton pump inhibitors (PPIs) produce superior relief from symptoms, ulcer healing, and acid suppression when compared to H2-blockers.

Cytoprotective agents such as Sucralfate can be helpful if mucosal lesions are seen at endoscopy.

If H pylori is present, treatment should include a 7-14 day regimen of: PPI + Amoxicillin + Imidazole, or PPI + Amoxicillin + Clarithromycin, or Bismuth salts + Amoxicillin + Imidazole. Selection of regimen should be based on H pylori resistance patterns in the community.

There are reports of increasing Clarithromycin resistance in several countries. At this time, testing for antibiotic susceptibility prior to initiation of treatment is recommended in regions where there >20% of H pylori strains are Clarithromycin resistant. Yet, for most hospitals, H pylori antibiotic susceptibility data is not available. Therefore, in this situation it is reasonable to initiate treatment with any of the first-line regimens, followed by a non-invasive test for H pylori eradication after 4-8 weeks of therapy.

If eradication of the organism has not been achieved, both the North American and European Society for Pediatric Gastroenterology (NASPGHAN and ESPGHAN) recommend pursuing further treatment using a different antibiotic regimen, or alternatively, using an even longer duration of treatment. Second-line antibiotic regimens can be tried empirically, but other options include endoscopy with biopsies for culture and antibiotic susceptibility testing to guide therapy, or performing flourescence in situ hybridation for Clarithromycin susceptibility on previously obtained biopsies.

When H pylori is detected by endoscopic biopsy, in the absence of peptic ulcer disease, the NASPGHAN and ESPGHAN consensus is to treat the infection, although the grade of evidence for this is low. The dilemma faced by the endoscopist is that there is not sufficient evidence to prove that the presence of H pylori alone (without ulcer formation) causes gastrointestinal symptoms. Thus eradication of the organism may not improve symptoms. However, the consensus to treat H. pylori infection was based on evidence that the presence of H pylori is associated with gastric malignancies, although this risk varies based on host and strain-specific factors.

What are the adverse effects associated with each treatment option?

Cimetidine can cause diarrhea, rash, myalgias, confusion, neutropenia, gynecomastia, elevated liver function tests, and dizziness.

Ranitidine can cause headache, gastrointestinal discomfort, malaise, insomnia, sedation, arthralgia, hepatotoxicity.

Famotidine can cause headache, dizziness, constipation, diarrhea, drowsiness.

Omeprazole can cause headache, diarrhea, nausea, vomiting.

Lansoprazole can cause headache and diarrhea.

Sucralfate can cause constipation and headache. It also can cause aluminum accumulation, and therefore sucralfate should not be used in children with renal failure.

What are the possible outcomes of Peptic Ulcer Disease?

Acute gastrointestinal hemorrhage, with hypotension and shock may occur as a complication of PUD. Perforation is the second most common complication of PUD.

The risks of untreated ulcer disease far outweigh the risk of available treatments, regardless of the etiology. The prognosis depends largely on the underlying cause. Addressing ulcerogenic causes such as NSAIDS or systemic illness are critical to treatment of ulcer disease. H. pylori, on the other hand, has been associated with treatment failure, antibiotic resistance and recurrence of ulcer disease.

What causes this disease and how frequent is it?

Helicobacter pylori infection is the most common cause of peptic ulcer disease in children.

Mode of transmission is not completely known but is thought to be fecal-oral.

Risk factors include low socioeconomic status.

There may be a genetic component to Pediatric peptic ulcer disease: 1/4 to 1/3 of children with PUD have a first-degree relative who also has PUD.

This may be in part due to H. pylori clustering in families.
Hypersecretory states causing primary PUD are extremely rare.
The incidence of stress-related PUD in children is not known.

How do these pathogens/genes/exposures cause the disease?

Gastric and duodenal epithelial cells have a number of defenses against acid and pepsin. These include a protective layer of mucous over the epithelial lining, secretion of bicarbonate to buffer acid close to the cell surface, and ion pumps at the basolateral cell surface, which help regulate intracellular hydrogen ion levels. When defense mechanisms are interrupted, such as in the face of infection or states of physiologic stress, mucosal injury occurs. A peptic ulcer is a defect in the stomach or duodenum, extending into the muscularis mucosa layer.

The exact mechanism by which H. pylori causes gastric irritation is not known, but it is thought that the urease present in the bacteria plays a role. It hydrolyzes to bicarbonate and ammonia, increasing the gastric surface pH, which may interfere with production of protective mucous. Ammonia itself is toxic to gastric epithelial cells.

How can Peptic Ulcer Disease be prevented?

Peptic ulcer disease can be reduced by increased prescriber vigilance in the population taking NSAIDS regularly. Counseling to avoid unnecessary use of these medications as their gastrointestinal toxicity may be significant and unpredictable. If NSAID use is unavoidable, concomitant use of a proton pump inhibitor is recommended.

In regards to H. pylori, it is estimated that approximately 40-50% of the world’s population is colonized with this organism. A decrease in transmission of this bacteria is seen with use of clean water supply, refrigerated food, improved nutrition (diet containing ample fruits and vegetables) and improved hygiene and sanitation.

What is the evidence?

Chelimsky, G, Czinn, S. “Peptic ulcer disease in children”. Pediatr Rev. vol. 22. 2001. pp. 349

Koletzko, S, Jones, N, Goodman, K. “Evidence based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children”. J Pediatr Gastroenterol Nutr. vol. 53. 2011. pp. 230-43.

Ongoing controversies regarding etiology, diagnosis, treatment

It is still unclear whether H. pylori causes pain in those patients without ulcer. The decision to treat H pylori gastritis in the absence of PUD has been controversial. The most recent recommendations by the North American and European society for pediatric gastroenterology are to treat H pylori infection detected by biopsy, even if ulcer disease is absent, because this may decrease the carcinogenic risk posed by certain strains of this organism.

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