ONLINE ONLY CASE REPORTS Onset of Ulcerative after Helicobacter pylori Eradication Therapy: A Case Report

Mitsuro Chiba, MD, PhD; Tsuyotoshi Tsuji, MD, PhD; Kenichi Takahashi, MD; Masafumi Komatsu, MD, PhD; Takeshi Sugawara, MD; Iwao Ono, MD, PhD Perm J 2016 Spring;20(2):e115-e118 http://dx.doi.org/10.7812/TPP/15-085

population of Japan are identified as ABSTRACT possible candidates for H pylori eradica- In Japan, Helicobacter pylori eradication has been approved since 2013 for treat- tion.14,15 Along with the development of ment of H pylori-induced chronic , in an attempt to reduce the prevalence evaluating cancer risk by combined assay of gastric cancer, a leading cancer in Japan. H pylori affects more than for H pylori infection and serum pepsino- 50% of the world’s population. H pylori eradication therapy is generally safe. To our gen levels, namely the ABC method,16 knowledge, no case of newly diagnosed occurring immediately H pylori eradication therapy will prevail after H pylori eradication therapy has previously been reported. more than ever. A 63-year-old man received a diagnosis of chronic gastritis and H pylori infection. H pylori eradication therapy is gen- In early March 2014, primary H pylori eradication therapy was initiated; lansoprazole, erally safe.2,17 For the primary triple , and clarithromycin were administered for 1 week. Beginning on the therapy, lansoprazole-amoxicillin-clar- fourth day, he had watery twice a day. From the 11th day, bloody stools and ithromycin, the main adverse effects watery diarrhea increased to 6 times a day. , performed on the 40th day reported are diarrhea and soft stools, after termination of drug therapy, revealed diffuse in the distal aspect of with frequencies of 7% and 12%, the colon, with histologic findings consistent with ulcerative colitis. He was admitted respectively.11 Only 1 of 271 patients to the hospital and was provided with a semivegetarian diet and . He was withdrawn from eradication treat- noticed a gradual decrease in the amount of blood in his feces then a disappearance ment because of adverse effect (skin of the blood. A fecal occult blood test on the 11th hospital day recorded 337 ng/mL. eruption).11 However, there are reports Fecal occult blood test is not indicated during macroscopic bloody stool but is indi- of Clostridium difficilecolitis or pseu- cated after disappearance of bloody stool. Therefore, he achieved clinical remission domembranous colitis associated with by the 11th hospital day. He was in remission on discharge. H pylori eradication therapy.18-20 There is New onset of ulcerative colitis should be added to a list of adverse events of also a report of relapse of ulcerative coli- H pylori eradication therapy. tis during the therapy, which eventually required subtotal .21 To our INTRODUCTION cancer, one of the leading cancers not knowledge, no case of newly diagnosed With the growing knowledge of the only in the Asia-Pacific region including ulcerative colitis occurring immediately etiopathogenetic role of Helicobacter Japan but also in the world, the critical after H pylori eradication therapy has pylori in gastrointestinal and systemic role of H pylori in the development of been reported. diseases, attempts to eradicate H pylori gastric cancer has been established.9-12 have been expanding in the treatment of Consequently, in Japan in 2010, H pylori CASE PRESENTATION peptic (gastroduodenal) ,1,2 gastric eradication was approved for patients A 63-year-old man, 165 cm in height mucosa-associated lymphoid tissue lym- after endoscopic resection of early-stage and 55 kg in body weight, was referred phoma,3,4 iron-deficiency anemia,5,6 idio- gastric cancer. Three years later, eradica- to our division in May 2014. He was pathic thrombocytopenic purpura,7,8 and tion of H pylori was drastically expanded previously admitted because of vertigo 2 to include H pylori-induced chronic in 2012. Since that time, he received vitamin B12 deficiency. In Japan, H pylori eradication therapy was approved for gastritis.2,13 Namely, in February 2013, medications for treatment of vertigo peptic treatment in 2000, and for H pylori eradication was approved for and hypertension: betahistine mesylate, mucosa-associated lymphoid tissue lym- H pylori-induced chronic gastritis in an mecobalamin, adenosine triphosphate phoma and idiopathic thrombocytopenic attempt to reduce gastric cancer.2,13 This disodium hydrate, clotiazepam, and purpura in 2010. With regard to gastric means that more than half of the adult amlodipine besilate. His family history

Mitsuro Chiba, MD, PhD, is the head of the Inflammatory Bowel Disease Section at Akita City Hospital in Japan. E-mail: [email protected]. Tsuyotoshi Tsuji, MD, PhD, is the head of the GI Endoscopy Section at Akita City Hospital in Japan. E-mail: [email protected]. Kenichi Takahashi, MD, is a Gastroenterologist at Akita City Hospital in Japan. E-mail: [email protected]. Masafumi Komatsu, MD, PhD, is a Gastroenterologist and the Director of Akita City Hospital in Japan. E-mail: [email protected]. Takeshi Sugawara, MD, is a Gastroenterologist at Nakadori General Hospital in Akita, Japan. E-mail: [email protected]. Iwao Ono, MD, PhD, is the head of Division of Pathology at Nakadori General Hospital in Akita, Japan. E-mail: [email protected].

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Colonoscopy, performed on the 40th admitted to the hospital, where he day after the termination of the drugs, stayed for 24 days, a typical period of revealed diffuse inflammation in the time for a patient with these symptoms distal aspect of the colon (Figure 2A). of this severity in our hospital. Routine The histologic findings from the laboratory data, including hematologic were consistent with ulcerative colitis: studies, liver and kidney function tests, crypt abscess, goblet cell depletion, and and C-reactive protein, were normal. marked infiltration by inflammatory C difficile antigen and toxin were not cells (Figure 3). The urea breath test was detected by TECHLAB C Diff Quik positive for H pylori infection.2 Chek Complete (TECHLAB Inc, The patient was referred to Akita Blacksburg, VA). Stool culture did City Hospital in Akita, Japan, for treat- not reveal any pathogen, including ment of ulcerative colitis. His chief enterohemorrhagic , complaint was bloody, soft stool twice Campylobacter jejuni, Salmonella spe- a day. His appetite was good, and he cies, , and Klebsi- reported no . Results ella oxytoca. A double-contrast barium of physical examination, including study showed microspicula and the abdomen, were normal. He was fine barium flakes in the sigmoid colon

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.

did not include inflammatory bowel disease (IBD). He reported that he had a daily bowel movement. In early Janu- Figure 2. Photographs of the distal colon during colonoscopy before (A) and after (B) treatment. ary 2014, he was screened for gastric Diffuse inflammation was markedly improved after treatment. cancer: a blood test for pepsinogen and esophagogastroduodenoscopy. Chronic gastritis and H pylori infection were di- agnosed (Figure 1). 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 clar- ithromycin, 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 be- cause administration of the eradication Figure 3. Photomicrograph of biopsy specimen of the rectum. Crypt abscess (center), goblet cell therapy drugs had already been termi- depletion, and marked inflammatory cell infiltration are observed (hematoxylin and eosin stain, 20x nated. However, bloody stool persisted. maginfication).

e116 The Permanente Journal/ Spring 2016/ Volume 20 No. 2 CASE REPORTS Onset of Ulcerative Colitis after Helicobacter pylori Eradication Therapy: A Case Report

and irregularity of the wall in the rectum The association between antibiotic (Figure 4). use and subsequent diagnosis of IBD Finally, a proctosigmoiditis type of two to five years later is well document- ulcerative colitis of mild severity was ed.25 The mechanism of this association diagnosed. The patient was provided is not known. Long-term effects of with a semivegetarian diet designed for antibiotics on gut microflora might be patients with IBD.22 Metronidazole, related to a subsequent onset of IBD.26,27 750 mg/day, was administered orally Alternatively, a genetically altered in- during the hospitalization. He noticed flammatory response to pathogens may a gradual decrease of blood in his feces, lead to both IBD and that then a disappearance of the blood. A fe- require antibiotics, without the former cal occult blood test on the 11th hospital being etiologically related to the latter.28 day recorded 337 ng/mL, and this test In the present case, ulcerative colitis result became negative (< 50 ng/mL) on developed immediately after H pylori the 18th hospital day. Colonoscopy on eradication therapy. This indicates an the 23rd day showed a marked improve- immediate effect of antibiotics on gut A ment (Figure 2B). microflora, resulting in imbalance (dys- The patient and his wife were pro- biosis) leading to IBD. vided a dietary guidance for a semiveg- Gut microflora is a critical environ- etarian diet from a registered dietitian mental factor in IBD.29 Westernized before discharge. The urea breath test diet-induced of gut microflora yielded normal results one month after can explain the high frequency of IBD discharge. The patient has remained in developed countries.22 A semivegetar- in remission without medication until ian diet has been designed to combat time of this publication (Figure 1). In dietary westernization.22 We recom- 2015, he again participated in the Tokyo mend that all IBD-diagnosed patients Marathon. are prescribed a semivegetarian diet, with counseling and education to sup- DISCUSSION port the patient’s compliance. In our Because antibiotics are prescribed hospital, this recommendation includes for H pylori eradication, various ad- admission to the hospital for treatment verse events of antibiotics can occur to experience and familiarize patients in patients undergoing eradication of with a semivegetarian diet to ensure H pylori. Patients are informed of the compliance at least initially. We treat B possible adverse events of the medi- moderate or severe cases of ulcerative cation, including rash, diarrhea, and colitis with drugs specific for IBD in- bloody diarrhea. In this case, diarrhea cluding 5-aminosalicylic acid, steroid appeared on the fourth day of treatment, hormones, and biologics together with but it was mild enough to allow contin- a semivegetarian diet, but we treat mild ued administration of the medication. cases initially only with a semivegetarian After termination of treatment with the diet. This case is an example showing the medication, diarrhea increased to six induction and maintenance of remission times a day and was mixed with blood. without medication specific for IBD Generally, antibiotic-associated diarrhea such as 5-aminosalicylic acid.30 In our or colitis subsides spontaneously within practice, oral metronidazole is initially a few days after withdrawal of antibiot- used for about 1 month in treatment ics.23 In this case, symptoms lasted for of active IBD, with the expectation of more than a month. C difficile toxin, eliminating any potentially pathogenic ,24 or other pathogen bacteria.22,31 Metronidazole is the sec- was not identified. Pseudomembrane ond-line drug for H pylori eradication in C was not observed by endoscopy. Dif- Japan.1 In this case, metronidazole that fuse inflammation in the distal aspect of was prescribed to treat ulcerative colitis Figure 4. Radiograph of double-contrast barium the colon and the histologic findings of seemed to induce H pylori eradication. enema study. Shown are the rectosigmoid portion (A), magnification of rectangle in Figure crypt abscess and goblet cell depletion H pylori affects more than 50% 2,15 4A of the sigmoid colon (B) with microspicula were consistent with ulcerative colitis. of the world’s population. Cases and fine barium flakes observed (arrows), and of IBD similar to the present case are irregularity of the wall (arrows) in the rectum (C).

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anticipated to appear more frequently Feb;38(1):43-53. DOI: http://dx.doi.org/10.1016/j. 19. Rai R, Rai S. Pseudomembranous colitis bcmd.2006.09.006. requiring surgical intervention following triple along with an expanding requirement 6. Qu XH, Huang XL, Xiong P, et al. Does therapy for Helicobacter pylori eradication. ANZ J for H pylori eradication. It is recom- Helicobacter pylori infection play a role in iron Surg 2002 Dec;72(12):917-9. DOI: http://dx.doi. mended that practitioners keep in mind deficiency anemia? A meta-analysis. World J org/10.1046/j.1445-2197.2002.02593.x. Gastroenterol 2010 Feb 21;16(7):886-96. 20. Trifan A, Girleanu I, Cojocariu C, et al. that IBD might develop immediately 7. Fujimura K, Kuwana M, Kurata Y, et al. 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