the paper entitled ' prolonged treatment with n - acetylcysteine delays liver recovery from acetaminophen hepatotoxicity ' by yang and colleagues , published in the previous issue of critical care , demonstrates that prolonged administration of n - acetylcysteine ( nac ) at 100 mg / kg in acetaminophen ( apap)-induced liver failure in mice potentially limits hepatocellular regeneration . activation of a transcription factor , nuclear factor - kappa - b ( nf-b ) , strongly linked to impairment of liver regeneration , is a putative mechanism for this . furthermore , the paper postulates that high doses of nac may interfere with normal metabolic processes of the liver , leading to impairment of its regenerative capacity . nac has been used since the 1970s , and it effectively manages apap poisoning by glutathione repletion if administered within 8 to 10 hours of ingestion of the overdose . in later years , clinical use of nac was extended to patients who present more than 10 hours after ingestion and to those with apap - induced acute liver failure ( alf ) , and patients in such categories are routinely on nac infusions for many days , even weeks . the putative protective mechanisms of nac in late - apap poisoning and apap - induced liver failure remain poorly characterised but include free - radical scavenging , hemodynamic , and cytokine effects . concern has been expressed relating to its extended use in late presenters with apap poisoning and apap - induced liver failure because of the possibility of changed kinetics of nac in liver injury , reduced efficacy , and adverse hemodynamic changes ( vasodilatation and increased cardiac index ) . this new study raises the issue of whether impairment of regeneration is also a clinical concern for extended nac use . a key issue in liver recovery after any acute injury is tissue repair and regeneration . such liver regeneration involves replication of mature parenchyma and non - parenchyma liver cells , which requires multiple cytokine and growth factor signalling pathways , including tumour necrosis factor - alpha , interleukin-6 , hepatocyte growth factor ( hgf ) , and transforming growth factor - alpha . inhibition of the transcription factor nf-b was shown to be associated with impaired liver regeneration and apoptosis of hepatocytes . nf-b is also demonstrated to be responsible for regulation of transcription of a cell cycle regulator cyclin d1 . this new study in a mouse model demonstrates that nac , in doses similar to those used therapeutically to treat apap poisoning in humans , impairs liver regenerative capacity and that the effect is more pronounced when administered for a longer duration ( that is , 72 versus 24 hours ) . the histopathological evidence of this effect was supported by the reduced nf-b dna binding in liver and decreased expression of cyclin d1 . it is noteworthy that nac acting on apap - treated human hepatoma - derived cell hepg2 cell cultures was shown to have a protective effect against apap - induced oxidative damage but not from apoptosis . this evidence does support the findings of yang and colleagues , despite the species differences that could contribute to apap and nac metabolic pathways . the current clinical literature recommends the prolonged administration of nac in patients with apap - induced alf and in those who present late for medical care until evidence of improvement of the international normalised ratio or transplantation takes place . in this backdrop , the evidence by yang and colleagues raises two issues with respect to prolonged use of nac : first , whether prolonged nac use is potentially harmful by reducing liver regeneration in patients presenting late with apap poisoning , especially in those with apap - induced alf , and second , the issue of appropriate dosing and duration of nac treatment . the concept of tailor - making nac therapy to the apap - poisoned patient has been raised recently in the literature , and differing protocols of nac infusion are starting to be evaluated , albeit with study limitations . future research on apap - induced alf patients could be in the direction of monitoring for biomarkers ( for example , sfas and hgf )   for liver regeneration or apoptosis in order to establish whether there is a ' tipping point ' of risk / benefit after which nac infusion might be stopped . further research is also required to fully evaluate the impact of nac on cytokine systems controlling hepatocellular recovery . in the management of late presenters with apap poisoning and apap - induced liver failure , clinicians may have to consider individual case scenarios in tailor - making duration and dose of nac therapy . alf : acute liver failure ; apap : acetaminophen ; hgf : hepatocyte growth factor ; nac : n - acetylcysteine ; nf-b : nuclear factor - kappa - b .