Onset of Ulcerative Colitis after Helicobacter pylori Eradication Therapy: A Case Report

Abstract

In Japan, Helicobacter pylori eradication has been approved since 2013 for treatment of H pylori-induced chronic gastritis, in an attempt to reduce the prevalence of gastric cancer, a leading cancer in Japan. H pylori infection affects more than 50% of the world’s population. H pylori eradication therapy is generally safe. To our knowledge, no case of newly diagnosed ulcerative colitis occurring immediately after H pylori eradication therapy has previously been reported.

A 63-year-old man received a diagnosis of chronic gastritis and H pylori infection. In early March 2014, primary H pylori eradication therapy was initiated; lansoprazole, amoxicillin, and clarithromycin were administered for 1 week. Beginning on the fourth day, he had watery diarrhea twice a day. From the 11th day, bloody stools and watery diarrhea increased to 6 times a day. Colonoscopy, performed on the 40th day after termination of drug therapy, revealed diffuse inflammation in the distal aspect of the colon, with histologic findings consistent with ulcerative colitis. He was admitted to the hospital and was provided with a semivegetarian diet and metronidazole. He noticed a gradual decrease in the amount of blood in his feces then a disappearance of the blood. A fecal occult blood test on the 11th hospital day recorded 337 ng/mL. Fecal occult blood test is not indicated during macroscopic bloody stool but is indicated after disappearance of bloody stool. Therefore, he achieved clinical remission by the 11th hospital day. He was in remission on discharge.

New onset of ulcerative colitis should be added to a list of adverse events of H pylori eradication therapy.

INTRODUCTION

With the growing knowledge of the etiopathogenetic role of Helicobacter pylori in gastrointestinal and systemic diseases, attempts to eradicate H pylori have been expanding in the treatment of peptic (gastroduodenal) ulcers,^1,2 gastric mucosa-associated lymphoid tissue lymphoma,^3,4 iron-deficiency anemia,^5,6 idiopathic thrombocytopenic purpura,^7,8 and vitamin B₁₂ deficiency.² In Japan, H pylori eradication therapy was approved for peptic ulcer treatment in 2000, and for mucosa-associated lymphoid tissue lymphoma and idiopathic thrombocytopenic purpura in 2010. With regard to gastric cancer, one of the leading cancers not only in the Asia-Pacific region including Japan but also in the world, the critical role of H pylori in the development of gastric cancer has been established.^9–12 Consequently, in Japan in 2010, H pylori eradication was approved for patients after endoscopic resection of early-stage gastric cancer. Three years later, eradication of H pylori was drastically expanded to include H pylori-induced chronic gastritis.^2,13 Namely, in February 2013, H pylori eradication was approved for H pylori-induced chronic gastritis in an attempt to reduce gastric cancer.^2,13 This means that more than half of the adult population of Japan are identified as possible candidates for H pylori eradication.^14,15 Along with the development of evaluating cancer risk by combined assay for H pylori infection and serum pepsinogen levels, namely the ABC method,¹⁶ H pylori eradication therapy will prevail more than ever.

H pylori eradication therapy is generally safe.^2,17 For the primary triple therapy, lansoprazole-amoxicillin-clarithromycin, the main adverse effects reported are diarrhea and soft stools, with frequencies of 7% and 12%, respectively.¹¹ Only 1 of 271 patients was withdrawn from eradication treatment because of adverse effect (skin eruption).¹¹ However, there are reports of Clostridium difficile colitis or pseudomembranous colitis associated with H pylori eradication therapy.^18–20 There is also a report of relapse of ulcerative colitis during the therapy, which eventually required subtotal colectomy.²¹ To our knowledge, no case of newly diagnosed ulcerative colitis occurring immediately after H pylori eradication therapy has been reported.

CASE PRESENTATION

A 63-year-old man, 165 cm in height and 55 kg in body weight, was referred to our division in May 2014. He was previously admitted because of vertigo in 2012. Since that time, he received medications for treatment of vertigo and hypertension: betahistine mesylate, mecobalamin, adenosine triphosphate disodium hydrate, clotiazepam, and amlodipine besilate. His family history did not include inflammatory bowel disease (IBD). He reported that he had a daily bowel movement. In early January 2014, he was screened for gastric cancer: a blood test for pepsinogen and esophagogastroduodenoscopy. Chronic gastritis and H pylori infection were diagnosed (Figure 1).

Figure 1.

Timeline of case.

Apr = April; d = day; Feb = February; HP = Helicobacter pylori; Jan = January; Jun = June; Jul = July; Mar = March; SVD = semivegetarian diet; UBT = urea breath test result; UC = ulcerative colitis.

The following month he participated in the 2014 Tokyo Marathon. In early March, primary H pylori eradication therapy was initiated: lansoprazole, 30 mg; amoxicillin, 750 mg; and clarithromycin, 200 mg, twice daily for 1 week.¹ From Day 4 of treatment, he had watery diarrhea twice a day. The symptoms were not so severe as to halt administration of the medication. From the 11th day, 3 days after termination of the eradication therapy, bloody stools and watery diarrhea increased to 6 times a day. Antibiotic-associated colitis or hemorrhagic colitis was suspected, and he was expected to recover quickly because administration of the eradication therapy drugs had already been terminated. However, bloody stool persisted. Colonoscopy, performed on the 40th day after the termination of the drugs, revealed diffuse inflammation in the distal aspect of the colon (Figure 2A). The histologic findings from the rectum were consistent with ulcerative colitis: crypt abscess, goblet cell depletion, and marked infiltration by inflammatory cells (Figure 3). The urea breath test was positive for H pylori infection.²

Figure 2.

Photographs of the distal colon during colonoscopy before (A) and after (B) treatment. Diffuse inflammation was markedly improved after treatment.

Figure 3.

Photomicrograph of biopsy specimen of the rectum. Crypt abscess (center), goblet cell depletion, and marked inflammatory cell infiltration are observed (hematoxylin and eosin stain, 20x maginfication).

The patient was referred to Akita City Hospital in Akita, Japan, for treatment of ulcerative colitis. His chief complaint was bloody, soft stool twice a day. His appetite was good, and he reported no abdominal pain. Results of physical examination, including the abdomen, were normal. He was admitted to the hospital, where he stayed for 24 days, a typical period of time for a patient with these symptoms of this severity in our hospital. Routine laboratory data, including hematologic studies, liver and kidney function tests, and C-reactive protein, were normal. C difficile antigen and toxin were not detected by TECHLAB C Diff Quik Chek Complete (TECHLAB Inc, Blacksburg, VA). Stool culture did not reveal any pathogen, including enterohemorrhagic Escherichia coli, Campylobacter jejuni, Salmonella species, Staphylococcus aureus, and Klebsiella oxytoca. A double-contrast barium enema study showed microspicula and fine barium flakes in the sigmoid colon and irregularity of the wall in the rectum (Figure 4).

Figure 4.

Radiograph of double-contrast barium enema study. Shown are the rectosigmoid portion (A), magnification of rectangle in Figure 4A of the sigmoid colon (B) with microspicula and fine barium flakes observed (arrows), and irregularity of the wall (arrows) in the rectum (C).

Finally, a proctosigmoiditis type of ulcerative colitis of mild severity was diagnosed. The patient was provided with a semivegetarian diet designed for patients with IBD.²² Metronidazole, 750 mg/day, was administered orally during the hospitalization. He noticed a gradual decrease of blood in his feces, then a disappearance of the blood. A fecal occult blood test on the 11th hospital day recorded 337 ng/mL, and this test result became negative (< 50 ng/mL) on the 18th hospital day. Colonoscopy on the 23rd day showed a marked improvement (Figure 2B).

The patient and his wife were provided a dietary guidance for a semivegetarian diet from a registered dietitian before discharge. The urea breath test yielded normal results one month after discharge. The patient has remained in remission without medication until time of this publication (Figure 1). In 2015, he again participated in the Tokyo Marathon.

DISCUSSION

Because antibiotics are prescribed for H pylori eradication, various adverse events of antibiotics can occur in patients undergoing eradication of H pylori. Patients are informed of the possible adverse events of the medication, including rash, diarrhea, and bloody diarrhea. In this case, diarrhea appeared on the fourth day of treatment, but it was mild enough to allow continued administration of the medication. After termination of treatment with the medication, diarrhea increased to six times a day and was mixed with blood. Generally, antibiotic-associated diarrhea or colitis subsides spontaneously within a few days after withdrawal of antibiotics.²³ In this case, symptoms lasted for more than a month. C difficile toxin, Klebsiella oxytoca,²⁴ or other pathogen was not identified. Pseudomembrane was not observed by endoscopy. Diffuse inflammation in the distal aspect of the colon and the histologic findings of crypt abscess and goblet cell depletion were consistent with ulcerative colitis.

The association between antibiotic use and subsequent diagnosis of IBD two to five years later is well documented.²⁵ The mechanism of this association is not known. Long-term effects of antibiotics on gut microflora might be related to a subsequent onset of IBD.^26,27 Alternatively, a genetically altered inflammatory response to pathogens may lead to both IBD and infections that require antibiotics, without the former being etiologically related to the latter.²⁸ In the present case, ulcerative colitis developed immediately after H pylori eradication therapy. This indicates an immediate effect of antibiotics on gut microflora, resulting in imbalance (dysbiosis) leading to IBD.

Gut microflora is a critical environmental factor in IBD.²⁹ Westernized diet-induced dysbiosis of gut microflora can explain the high frequency of IBD in developed countries.²² A semivegetarian diet has been designed to combat dietary westernization.²² We recommend that all IBD-diagnosed patients are prescribed a semivegetarian diet, with counseling and education to support the patient’s compliance. In our hospital, this recommendation includes admission to the hospital for treatment to experience and familiarize patients with a semivegetarian diet to ensure compliance at least initially. We treat moderate or severe cases of ulcerative colitis with drugs specific for IBD including 5-aminosalicylic acid, steroid hormones, and biologics together with a semivegetarian diet, but we treat mild cases initially only with a semivegetarian diet. This case is an example showing the induction and maintenance of remission without medication specific for IBD such as 5-aminosalicylic acid.³⁰ In our practice, oral metronidazole is initially used for about 1 month in treatment of active IBD, with the expectation of eliminating any potentially pathogenic bacteria.^22,31 Metronidazole is the second-line drug for H pylori eradication in Japan.¹ In this case, metronidazole that was prescribed to treat ulcerative colitis seemed to induce H pylori eradication.

H pylori affects more than 50% of the world’s population.^2,15 Cases of IBD similar to the present case are anticipated to appear more frequently along with an expanding requirement for H pylori eradication. It is recommended that practitioners keep in mind that IBD might develop immediately after H pylori eradication therapy.

CONCLUSION

We encountered a case in which ulcerative colitis developed immediately after H pylori eradication therapy. Therapy was indicated for the prevention of gastric cancer. More than half of the world’s population is affected with H pylori. The indication of H pylori eradication therapy has been expanding along with the growing knowledge of the etiopathogenetic role of H pylori in gastrointestinal and systemic diseases. Onset of ulcerative colitis should to be added to a list of adverse events of H pylori eradication therapy.