Clinical Case Study
LeAnne Vitito, MS, RN, CGRN, APRN Department Editor
6-MERCAPTOPURINE-INDUCED HEPATOTOXICITY DURING THE TREATMENT OF ULCERATIVE COLITIS: A CASE STUDY Jingtao Chen, MS, NP-C Patrick Brady, MD Yasser Saloum, MD Shanil Lara, MD
6
-mercaptopurine (6-MP), a purine analog, functions as an antimetabolite substituting for the purine base guanine in RNA and DNA halting DNA synthesis. It is most active in the S-phase the cell cycle of rapidly proliferating cells such as lymphocytes (Bradford, & Shih, 2011). Lymphocytes are the center of the inflammatory process in many autoimmune disorders. 6-mercaptopurine and its prodrug azathioprine have been implemented as an effective and safe adjunct or substitute for corticosteroids in a number of autoimmune disorders such as inflammatory bowel disease. Major adverse effects of these drugs include bone marrow suppression (myelotoxicity) and liver damage (hepatotoxicity) (Shaye et al., 2007). Although hepatotoxicity is rare, it can lead to liver failure. These immunomodulators are metabolized into their active form and other metabolites via several enzymatic pathways (Figure 1). Although commercial assays are available to measure some of these enzymatic activities, it appears these tests alone cannot predict drug toxicity in the individual patient. The following case illustrates the importance of close patient follow-up while on the treatment for ulceration colitis, the utility of thiopurine metabolite levels, and importance of drug interactions. About the authors: Jingtao Chen, MS, NP-C, is Nurse Practitioner, University of South Florida, Tampa, Florida. THE OFFICIAL JOURNAL OF THE SOCIETY
Patrick Brady, MD, is Professor, University of South Florida, Tampa, Florida.
OF GASTROENTEROLOGY NURSES AND
Yasser Saloum, MD, is Assistant Professor, University of South Florida, Tampa, Florida.
ASSOCIATES, INC. AND THE CANADIAN SOCIETY OF GASTROENTEROLOGY
Shanil Lara, MD, is Gastroenterology Fellow, University of South Florida, Tampa, Florida. All identifying information has been removed in this study.
NURSES AND ASSOCIATES
The authors declare no conflict of interest. DEDICATED TO THE SAFE AND EFFECTIVE PRACTICE OF GASTROENTEROLOGY AND
Correspondence to: Jingtao Chen, MS, NP-C, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612 ([email protected]).
ENDOSCOPY NURSING
DOI: 10.1097/SGA.0000000000000091
VOLUME 38
|
NUMBER 1
|
JANUARY/FEBRUARY 2015
65
Copyright © 2015 Society of Gastroenterology Nurses and Associates. Unauthorized reproduction of this article is prohibited
GNJ-D-14-00007.indd 65
20/01/15 6:23 PM
Clinical Case Study
FIGURE 1. Azathioprine is converted to mercaptopurine (6-MP) during the first pass through of the liver. 6-MP is then metabolized through multiple steps (solid and dashed arrow) to its active metabolite 6-thioguane (6-TGN). 6-MP is also inactivated by 2 different pathways: an early metabolism by xanthine oxide (XO) and a later one by thiopurine methyltransferase (TPMT). XO metabolizes 6-MP to the inactive thiouric acid (6-TU). As a xanthine oxidase inhibitor, allopurinol may affect 6-thioguanine nucleotide (6-TGN) levels by decreasing 6-TU production. After this initial inactivation by XO, TPMT will further inactivate 6-MP by converting it to another metabolite 6-MMPN, which is also hepatotoxic. The TPMT activity not only is genetically determined but also may be inhibited by drugs such as aminosalicylates. Note: AZA = azathioprine; HGRPT = hypoxanthine-guanine phosphoribosyltransferase; 6-MMPN = 6-methylmercaptopurine; XO = xantHine oxidase.
Case Study This 29-year-old man with ulcerative colitis presented to our clinic for evaluation of uncontrolled abdominal pain, diarrhea, and rectal bleeding for the previous 2 weeks. His abdominal pain was in his lower abdomen, constant, 4-7out of a possible score of 10 in severity, and worse after meals. He was having three to eight looseto-watery bowel movements per day and complained of rectal bleeding with most of his bowel movements. He had no family history of inflammatory bowel disease or colon cancer. He had no prior surgical history. The patient was diagnosed with ulcerative colitis in January 2007 during colonoscopy, which showed diffuse colitis from the rectum to the cecum. The terminal ileum was normal. Colonic biopsies revealed acute active colitis. Initially, he was treated with oral mesalamine (Asacol) 400 mg three times daily. Unfortunately, the patient was lost to follow-up and he presented to the clinic in March 2008 for disease flare-up. Subsequently, he had repeat colonoscopy showing a much less extensive disease with colitis only extending from the rectum to 45 cm with worse disease in the distal 25 cm of the colon. Mesalamine was increased to 800 mg three times daily. Again, the patient did not follow up in our clinic until February 2011 when he presented for evaluation of recurrent symptoms. In the past one and a half years, the patient had a total of four flareups, each manifested by abdominal pain, diarrhea, and rectal bleeding. Those events were successfully treated with a tapering dose of prednisone starting at 30 mg daily that resulted in good symptomatic relief. Because the patient required prednisone treatment more than 3 times, we considered starting immunomodulators for long-term management of ulcerative colitis. To determine his candidacy for that treatment, thiopurine methyltransferase (TPMT) activity was measured and
that was normal. Weight-based 6-MP at 1 mg/kg (total of 100 mg) once daily was initiated in March 2011. The patient returned to clinic in September 2012 for fecal urgency and rectal bleeding with loose bowel movements for duration of 10 days. Before this office visit, he went to a local hospital emergency room because of disease flare-up and was given prednisone 30 mg daily for 7 days. His laboratory results showed that he was not anemic, but his white blood count was slightly elevated to 12,400 μl. The patient was taking 6-MP sporadically and was not compliant with follow-up visits or our recommendations regarding complete blood cell count and comprehensive metabolic profile monitoring. The patient was counseled to take 6-MP daily and to comply with the necessary blood work. To simplify his regimen further, he was given once daily mesalamine preparation (Lialda) and Asacol was discontinued. One month later, his liver function results revealed an alanine aminotransferase (ALT) of 206 IU/L (
LeAnne Vitito, MS, RN, CGRN, APRN Department Editor
6-MERCAPTOPURINE-INDUCED HEPATOTOXICITY DURING THE TREATMENT OF ULCERATIVE COLITIS: A CASE STUDY Jingtao Chen, MS, NP-C Patrick Brady, MD Yasser Saloum, MD Shanil Lara, MD
6
-mercaptopurine (6-MP), a purine analog, functions as an antimetabolite substituting for the purine base guanine in RNA and DNA halting DNA synthesis. It is most active in the S-phase the cell cycle of rapidly proliferating cells such as lymphocytes (Bradford, & Shih, 2011). Lymphocytes are the center of the inflammatory process in many autoimmune disorders. 6-mercaptopurine and its prodrug azathioprine have been implemented as an effective and safe adjunct or substitute for corticosteroids in a number of autoimmune disorders such as inflammatory bowel disease. Major adverse effects of these drugs include bone marrow suppression (myelotoxicity) and liver damage (hepatotoxicity) (Shaye et al., 2007). Although hepatotoxicity is rare, it can lead to liver failure. These immunomodulators are metabolized into their active form and other metabolites via several enzymatic pathways (Figure 1). Although commercial assays are available to measure some of these enzymatic activities, it appears these tests alone cannot predict drug toxicity in the individual patient. The following case illustrates the importance of close patient follow-up while on the treatment for ulceration colitis, the utility of thiopurine metabolite levels, and importance of drug interactions. About the authors: Jingtao Chen, MS, NP-C, is Nurse Practitioner, University of South Florida, Tampa, Florida. THE OFFICIAL JOURNAL OF THE SOCIETY
Patrick Brady, MD, is Professor, University of South Florida, Tampa, Florida.
OF GASTROENTEROLOGY NURSES AND
Yasser Saloum, MD, is Assistant Professor, University of South Florida, Tampa, Florida.
ASSOCIATES, INC. AND THE CANADIAN SOCIETY OF GASTROENTEROLOGY
Shanil Lara, MD, is Gastroenterology Fellow, University of South Florida, Tampa, Florida. All identifying information has been removed in this study.
NURSES AND ASSOCIATES
The authors declare no conflict of interest. DEDICATED TO THE SAFE AND EFFECTIVE PRACTICE OF GASTROENTEROLOGY AND
Correspondence to: Jingtao Chen, MS, NP-C, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612 ([email protected]).
ENDOSCOPY NURSING
DOI: 10.1097/SGA.0000000000000091
VOLUME 38
|
NUMBER 1
|
JANUARY/FEBRUARY 2015
65
Copyright © 2015 Society of Gastroenterology Nurses and Associates. Unauthorized reproduction of this article is prohibited
GNJ-D-14-00007.indd 65
20/01/15 6:23 PM
Clinical Case Study
FIGURE 1. Azathioprine is converted to mercaptopurine (6-MP) during the first pass through of the liver. 6-MP is then metabolized through multiple steps (solid and dashed arrow) to its active metabolite 6-thioguane (6-TGN). 6-MP is also inactivated by 2 different pathways: an early metabolism by xanthine oxide (XO) and a later one by thiopurine methyltransferase (TPMT). XO metabolizes 6-MP to the inactive thiouric acid (6-TU). As a xanthine oxidase inhibitor, allopurinol may affect 6-thioguanine nucleotide (6-TGN) levels by decreasing 6-TU production. After this initial inactivation by XO, TPMT will further inactivate 6-MP by converting it to another metabolite 6-MMPN, which is also hepatotoxic. The TPMT activity not only is genetically determined but also may be inhibited by drugs such as aminosalicylates. Note: AZA = azathioprine; HGRPT = hypoxanthine-guanine phosphoribosyltransferase; 6-MMPN = 6-methylmercaptopurine; XO = xantHine oxidase.
Case Study This 29-year-old man with ulcerative colitis presented to our clinic for evaluation of uncontrolled abdominal pain, diarrhea, and rectal bleeding for the previous 2 weeks. His abdominal pain was in his lower abdomen, constant, 4-7out of a possible score of 10 in severity, and worse after meals. He was having three to eight looseto-watery bowel movements per day and complained of rectal bleeding with most of his bowel movements. He had no family history of inflammatory bowel disease or colon cancer. He had no prior surgical history. The patient was diagnosed with ulcerative colitis in January 2007 during colonoscopy, which showed diffuse colitis from the rectum to the cecum. The terminal ileum was normal. Colonic biopsies revealed acute active colitis. Initially, he was treated with oral mesalamine (Asacol) 400 mg three times daily. Unfortunately, the patient was lost to follow-up and he presented to the clinic in March 2008 for disease flare-up. Subsequently, he had repeat colonoscopy showing a much less extensive disease with colitis only extending from the rectum to 45 cm with worse disease in the distal 25 cm of the colon. Mesalamine was increased to 800 mg three times daily. Again, the patient did not follow up in our clinic until February 2011 when he presented for evaluation of recurrent symptoms. In the past one and a half years, the patient had a total of four flareups, each manifested by abdominal pain, diarrhea, and rectal bleeding. Those events were successfully treated with a tapering dose of prednisone starting at 30 mg daily that resulted in good symptomatic relief. Because the patient required prednisone treatment more than 3 times, we considered starting immunomodulators for long-term management of ulcerative colitis. To determine his candidacy for that treatment, thiopurine methyltransferase (TPMT) activity was measured and
that was normal. Weight-based 6-MP at 1 mg/kg (total of 100 mg) once daily was initiated in March 2011. The patient returned to clinic in September 2012 for fecal urgency and rectal bleeding with loose bowel movements for duration of 10 days. Before this office visit, he went to a local hospital emergency room because of disease flare-up and was given prednisone 30 mg daily for 7 days. His laboratory results showed that he was not anemic, but his white blood count was slightly elevated to 12,400 μl. The patient was taking 6-MP sporadically and was not compliant with follow-up visits or our recommendations regarding complete blood cell count and comprehensive metabolic profile monitoring. The patient was counseled to take 6-MP daily and to comply with the necessary blood work. To simplify his regimen further, he was given once daily mesalamine preparation (Lialda) and Asacol was discontinued. One month later, his liver function results revealed an alanine aminotransferase (ALT) of 206 IU/L (
