Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients

Omid A. Shaye, Michael Yadegari, Maria T Abreu, Fred Poordad, Karen Simon, Paul Martin, Konstantinos A. Papadakis, Andrew Ippoliti, Eric Vasiliauskas, Tram T. Tran

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 × 108 RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 × 108 RBC versus 3,452 pmol/8 × 108 RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4% vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 × 108 RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.

Original languageEnglish
Pages (from-to)2488-2494
Number of pages7
JournalAmerican Journal of Gastroenterology
Volume102
Issue number11
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

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6-Mercaptopurine
Azathioprine
Transaminases
Cholestasis
6-methylthiopurine ribonucleoside-5'-phosphate
Bilirubin
Pharmaceutical Preparations
Pediatrics
Sensitivity and Specificity

ASJC Scopus subject areas

  • Gastroenterology

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Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients. / Shaye, Omid A.; Yadegari, Michael; Abreu, Maria T; Poordad, Fred; Simon, Karen; Martin, Paul; Papadakis, Konstantinos A.; Ippoliti, Andrew; Vasiliauskas, Eric; Tran, Tram T.

In: American Journal of Gastroenterology, Vol. 102, No. 11, 01.11.2007, p. 2488-2494.

Research output: Contribution to journalArticle

Shaye, OA, Yadegari, M, Abreu, MT, Poordad, F, Simon, K, Martin, P, Papadakis, KA, Ippoliti, A, Vasiliauskas, E & Tran, TT 2007, 'Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients', American Journal of Gastroenterology, vol. 102, no. 11, pp. 2488-2494. https://doi.org/10.1111/j.1572-0241.2007.01515.x
Shaye, Omid A. ; Yadegari, Michael ; Abreu, Maria T ; Poordad, Fred ; Simon, Karen ; Martin, Paul ; Papadakis, Konstantinos A. ; Ippoliti, Andrew ; Vasiliauskas, Eric ; Tran, Tram T. / Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients. In: American Journal of Gastroenterology. 2007 ; Vol. 102, No. 11. pp. 2488-2494.
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title = "Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients",
abstract = "OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15{\%} of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 × 108 RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6{\%}) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 × 108 RBC versus 3,452 pmol/8 × 108 RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4{\%} vs 2.3{\%}, P < 0.05); however, nearly 90{\%} of all patients with 6-MMPR > 5,300 pmol/8 × 108 RBC had no hepatotoxicity, while almost 40{\%} of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.",
author = "Shaye, {Omid A.} and Michael Yadegari and Abreu, {Maria T} and Fred Poordad and Karen Simon and Paul Martin and Papadakis, {Konstantinos A.} and Andrew Ippoliti and Eric Vasiliauskas and Tran, {Tram T.}",
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T1 - Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients

AU - Shaye, Omid A.

AU - Yadegari, Michael

AU - Abreu, Maria T

AU - Poordad, Fred

AU - Simon, Karen

AU - Martin, Paul

AU - Papadakis, Konstantinos A.

AU - Ippoliti, Andrew

AU - Vasiliauskas, Eric

AU - Tran, Tram T.

PY - 2007/11/1

Y1 - 2007/11/1

N2 - OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 × 108 RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 × 108 RBC versus 3,452 pmol/8 × 108 RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4% vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 × 108 RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.

AB - OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 × 108 RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 × 108 RBC versus 3,452 pmol/8 × 108 RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4% vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 × 108 RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.

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