DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20191591

A prospective study of N-acetylcysteine treatment in drug-induced fulminant hepatic failure

Tauseef Nabi, Nadeema Rafiq, Quratul Ain Arifa

Abstract


Background: Acute liver failure (ALF) is a rare but severe, life-threatening, complex, multisystemic gastroenterological emergency. Its rapid progression and high mortality demand early diagnosis and expert management. Drug-induced ALF (DI-ALF) remains the uncommon cause of ALF in India. To date, there is no established treatment for DI-ALF other than liver transplantation and little is known about the use of N-acetylcysteine (NAC) in DI-ALF. A prospective case-control study was carried with the aim to determine the effect of NAC on mortality of DI-FHF patients and also to evaluate the safety and efficacy of NAC use.

Methods: A total of 18 patients with a diagnosis of DI-FHF were included in the study. 10 patients received NAC infusion for 72 hours whereas the control group received placebo. The variables evaluated were demographic, signs and symptoms, biochemical parameters, outcome and length of hospital stay.

Results: Out of 18 DI-FHF patients, 13 (72.2%) had anti-tuberculosis therapy (ATT) induced FHF and 5 (27.8%) patients had ayurvedic induced FHF. The two groups were comparable for the various baseline characteristics (age, INR, alanine aminotransferase, creatinine, albumin, grade of encephalopathy, etc.). The mortality decreased to 20% with the use of NAC versus 75% in the control group (P=0.023). Use of NAC was associated with a shorter length of hospital stay of survived patients (P=0.043). Moreover, the overall survival was improved by NAC (P=0.023) in DI-FHF. ATT induced FHF showed better outcome as compared to ayurvedic induced FHF use (P=0.019).

Conclusions: Author recommended the use of NAC along with conventional treatments in patients with DI-FHF in non-transplant centers while awaiting referrals. ATT induced FHF showed better outcome as compared to ayurvedic induced FHF with NAC administration and its use was safe.


Keywords


Acute liver failure, Anti-tuberculosis therapy, Drug-induced ALF, Drug-induced fulminant hepatic failure, N-acetylcysteine

Full Text:

PDF

References


Wendon J, Cordoba J, Dhawan A, Larsen FS, Manns M, Nevens F, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047-81.

Hoofnagle JH, Carithers RL, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatol. 1995;21(1):240-52.

Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation. Rockville, Maryland; 2007.

Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Internal Med. 2002;137(12):947-54.

Acharya SK, Dasarathy S, Kumer TL, Sushma S, Prasanna KS, Tandon A, et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. Hepatol. 1996;23(6):1448-55.

Bernal W, Wendon J. Acute liver failure. New Eng J Med. 2013;369(26):2525-34.

Lee WM. Acute liver failure in the United States. Seminars Liver Dis. 2003;23(3):217-26.

Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterol. 2015;148(7):1340-52.

Reuben A, Koch DG, Lee WM. Drug‐induced acute liver failure: results of a US multicenter, prospective study. Hepatol. 2010;52(6):2065-76.

Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterol. 2005;129(2):512-21.

Wai CT, Tan BH, Chan CL, Sutedja DS, Lee YM, Khor C, et al. Drug‐induced liver injury at an Asian center: a prospective study. Liver Int. 2007;27(4):465-74.

Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731-9.

Schiødt FV, Atillasoy E, Shakil AO, Schiff ER, Caldwell C, Kowdley KV, et al. Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transplantation Surg. 1999;5(1):29-34.

European Association for the Study of the Liver. Randomized trial of steroid therapy in acute liver failure. Gut. 1979;20:620-3.

Karkhanis J, Verna EC, Chang MS, Stravitz RT, Schilsky M, Lee WM, et al. Acute Liver Failure Study Group. Steroid use in acute liver failure. Hepatol. 2014;59(2):612-21.

Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatol. 2005;41(5):1179-97.

Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterol. 2009;137(3):856-64.

Nabi T, Nabi S, Rafiq N, Shah A. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: a prospective study. Saudi J Gastroenterol Off J Saudi Gastroenterol Assoc. 2017;23(3):169.

Nakamura M, Nagamine T. The effect of carnitine supplementation on hyperammonemia and carnitine deficiency treated with valproic acid in a psychiatric setting. Innovations Clin Neurosci. 2015;12(9-10):18.

Sevilla-Mantilla C, Ortega L, Agúndez JA, Fernandez-Gutierrez B, Ladero JM, Dı́az-Rubio M. Leflunomide-induced acute hepatitis. Dig Liver Dis. 2004;36(1):82-4.

Giordano C, Rivas J, Zervos X. An update on treatment of drug-induced liver injury. J Clin Translational Hepatol. 2014;2(2):74.

Cotgreave IA. N-Acetylcystei ne: Pharmacological Considerations and Experimental and Clinical Applications. Adv Pharmacol. 1996;38:205-227.

Harrison P, Wendon J, Williams R. Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure. Hepatol. 1996;23(5):1067-72.

Rank N, Michel C, Haertel C, Lenhart A, Welte M, Meier-Hellmann A, et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study. Crit Care Med. 2000;28(12):3799-807.

Bémeur C, Vaquero J, Desjardins P, Butterworth RF. N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis. 2010;25(2):241-9.

Rodriguez TS, Miles M, McLeod M. A23 a case of acute liver dysfunction due to trimethoprim-sulfamethoxazole treated with n-acetylcysteine. J Can Assoc Gastroenterol. 2018;1(2):39.

Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323-30.

Lee WM, Larson AM, Stravitz RT. AASLD position paper: the management of acute liver failure: update 2011. Hepatol. 2011;55(55):965-7.

Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transplantation. 2004;10(8):1018-23.

Mindikoglu AL, Magder LS, Regev A. Outcome of liver transplantation for drug‐induced acute liver failure in the United States: analysis of the United Network for Organ Sharing database. Liver Transplantation. 2009;15(7):719-29.

Chughlay MF, Kramer N, Spearman CW, Werfalli M, Cohen K. N‐acetylcysteine for non‐paracetamol drug‐induced liver injury: a systematic review. Brit J Clin Pharmacol. 2016;81(6):1021-9.

Mudalel ML, Dave KP, Hummel JP, Solga SF. N-acetylcysteine treats intravenous amiodarone induced liver injury. WJG. 2015;21(9):2816.

Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010;105:2396-404.

Devarbhavi H. Acute liver failure induced by anti-infectious drugs: causes and management. Current Hepatol Rep. 2017;16(4):276-85.

Devarbhavi H, Patil M, Reddy VV, Singh R, Joseph T, Ganga D. Drug‐induced acute liver failure in children and adults: Results of a single‐centre study of 128 patients. Liver Int. 2018;38(7):1322-9.

Rathi C, Pipaliya N, Patel R, Ingle M, Phadke A, Sawant P. Drug induced liver injury at a tertiary hospital in india: etiology, clinical features and predictors of mortality. Ann Hepatol. 2017;16(3):442-50.

Kumar R, Bhatia V, Khanal S, Sreenivas V, Gupta SD, Panda SK, et al. Antituberculosis therapy–induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome. Hepatol. 2010;51(5):1665-74.

Devarbhavi H, Dierkhising R, Kremers WK. Anti-tuberculosis therapy drug‐induced liver injury and acute liver failure. Hepatol. 2010;52(2):798-9.

Cheng SL. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur Respir J. 2016;48(60):2716.

Darweesh SK, Ibrahim MF, El-Tahawy MA. Effect of N-Acetylcysteine on mortality and liver transplantation rate in non-acetaminophen-induced acute liver failure: a multicenter study. Clin Drug Investigation. 2017;37(5):473-82.