Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring

Hani Shamseddeen, Eduardo Vilar-Gomez, Naga Chalasani, Robert P. Myers, G. Mani Subramanian, Harold H. Shlevin, Adam E. Allgood, Eric S. Orman

Research output: Contribution to journalArticle

Abstract

Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy’s law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34–299) and 56 U/L (47–85)] than for those with normal baseline values [median 26.5 U/L (range 18–33) and 29 U/L (25.5–30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Original languageEnglish (US)
JournalDrug Safety
DOIs
StateAccepted/In press - Jan 1 2020

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Biochemistry
Drug Monitoring
Liver
Alanine Transaminase
Fibrosis
Monitoring
Pharmaceutical Preparations
Aspartate Aminotransferases
Chemical and Drug Induced Liver Injury
Bilirubin
Alkaline Phosphatase
Enzymes
Clinical Trials
Non-alcoholic Fatty Liver Disease
Placebos
Reference Values

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis : Implications for Drug Hepatotoxicity Monitoring. / Shamseddeen, Hani; Vilar-Gomez, Eduardo; Chalasani, Naga; Myers, Robert P.; Subramanian, G. Mani; Shlevin, Harold H.; Allgood, Adam E.; Orman, Eric S.

In: Drug Safety, 01.01.2020.

Research output: Contribution to journalArticle

Shamseddeen, Hani ; Vilar-Gomez, Eduardo ; Chalasani, Naga ; Myers, Robert P. ; Subramanian, G. Mani ; Shlevin, Harold H. ; Allgood, Adam E. ; Orman, Eric S. / Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis : Implications for Drug Hepatotoxicity Monitoring. In: Drug Safety. 2020.
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abstract = "Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53{\%} and 49{\%} of participants, aspartate aminotransferase (AST) was > ULN in 49{\%} and 59{\%}, alkaline phosphatase was > ULN in 36{\%} and 27{\%}, and bilirubin was >ULN in 13{\%} and 19{\%}. During follow-up, ALT increased to 2× baseline in 8{\%} and 15{\%}, AST increased to 2× baseline in 6{\%} and 21{\%}, and bilirubin increased to 2× baseline in 9{\%} and 18{\%}. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9{\%} and 12{\%}. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy’s law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34–299) and 56 U/L (47–85)] than for those with normal baseline values [median 26.5 U/L (range 18–33) and 29 U/L (25.5–30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.",
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T2 - Implications for Drug Hepatotoxicity Monitoring

AU - Shamseddeen, Hani

AU - Vilar-Gomez, Eduardo

AU - Chalasani, Naga

AU - Myers, Robert P.

AU - Subramanian, G. Mani

AU - Shlevin, Harold H.

AU - Allgood, Adam E.

AU - Orman, Eric S.

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N2 - Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy’s law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34–299) and 56 U/L (47–85)] than for those with normal baseline values [median 26.5 U/L (range 18–33) and 29 U/L (25.5–30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

AB - Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy’s law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34–299) and 56 U/L (47–85)] than for those with normal baseline values [median 26.5 U/L (range 18–33) and 29 U/L (25.5–30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

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