acute liver failure ( alf ) can occur as a result of various etiologies including hepatic injury by drugs and poison , viral hepatitis , ischemia , or other causes .
the mechanisms by which liver cells are destroyed as well as the processes mediating liver regeneration , remain largely unknown .
it has become evident that liver cell death can occur via distinct biochemical pathways and morphological alterations , including apoptosis , autophagic cell death , and necrosis .
apoptosis is defined by chromatin condensation , nuclear fragmentation , cell shrinkage , blebbing of the plasma membrane , and formation of apoptotic bodies that contain nuclear or cytoplasmic material ( kerr et al . , 1972 ;
autophagic cell death , on the other hand , is characterized by a massive accumulation of double - membrane containing vacuoles , called autophagosomes , that subsequently fuse with lysosomes .
necrotic cell death is often negatively defined as a form of cell death that lacks signs of apoptosis or autophagy .
typically , necrotic cells show cytoplasmic swelling , dilation of organelles , and mechanical rupture of the plasma membrane .
although necrosis has been deemed to be a mainly passive process , the initiation , and modulation of necrotic cell death are currently under intense investigation at the molecular level .
the relative contribution of apoptosis or necrosis to organ dysfunction in alf remains controversial ( schulze - osthoff and bantel , 2011 ) .
necrosis is typically the consequence of acute metabolic perturbation with atp depletion , whereas apoptosis represents an atp - dependent cell death program .
furthermore , in several cases , the nature and duration of cellular injury determine if cells die by apoptosis , necrosis , or other mechanisms . at low doses ,
a variety of injurious stimuli often induce apoptosis , but the same stimuli can result in necrosis at higher doses . therefore , in many situations cell death might be not executed as a clear - cut form of cell death , but as a continuum with intermediate features of both apoptosis and necrosis .
a distinction of different cell death forms is therefore not only relevant for semantical reasons , but has important clinical implications when considering the therapeutic targeting of cell death processes .
thus , an understanding of the cell death processes is most important for development of effective interventions to prevent hepatocellular death in acute liver damage ( fischer and schulze - osthoff , 2005 ) .
apoptosis represents a programmed form of cell death that is required for the maintenance of tissue homeostasis by counterbalancing cell proliferation and eliminating damaged , infected , or transformed cells .
this process is particularly important in the liver as an organ that is naturally exposed to toxins , drugs , and viruses .
apoptosis results from a collapse of cellular infrastructure through internal proteolytic digestion , which leads to cytoskeletal disintegration , metabolic derangement , and genomic fragmentation .
members of the caspase family of proteases form the core engine of apoptosis and are involved in initiation , execution , and regulatory phases of the pathway .
caspases are cysteine proteases that cleave substrates after aspartate residues within specific peptide recognition sequences .
to preclude unwarranted cell death , caspases are expressed as inactive zymogens consisting of a prodomain followed by two subunits with the catalytic domain .
caspases operate in hierarchical cascades that serve to amplify the apoptotic signal ( los et al . , 1999 ) . based on their structure and order in cell death pathways
effector caspases such as caspase-3 , -6 , and -7 cleave diverse cellular substrates including structural proteins such as cytokeratin-18 and many others ( fischer et al . ,
in contrast , initiator caspases , such as caspase-8 , -9 , and -10 , exert regulatory roles by activating downstream effector caspases .
caspases are activated by two major signaling routes , namely the extrinsic death receptor and the intrinsic mitochondrial pathway , that both depend on the formation of large multi - protein complexes ( schulze - osthoff et al . , 1998 ;
initiator caspase-8 is the key mediator of the extrinsic pathway . in a simplified model , binding of death ligands such as trail or cd95l or
this event then results in the recruitment of the adapter protein fadd and the initiator caspase-8 into a death - inducing signaling complex ( disc ) , wherein caspase-8 becomes activated by dimerization and autoproteolytic cleavage ( figure 1 ) .
subsequently , caspase-8 cleaves and activates the effector caspase-3 , culminating in the demise of so - called type i cells . in most cells including hepatocytes , however , only low amounts of initiator caspases are activated at the disc , which is insufficient for cell death . in those type ii cells ,
the extrinsic receptor pathway must be amplified by the intrinsic mitochondrial apoptotic pathway through the caspase-8-mediated cleavage of bid , a pro - apoptotic bcl-2 family protein , which subsequently initiates together with the bcl-2 family members bak and bax the release of mitochondrial pro - apoptotic mediators ( schwerk and schulze - osthoff , 2005 ) .
interestingly , cd95-induced hepatocyte apoptosis is delayed but not inhibited in bak / bax - deficient mice indicating that hepatocytes can act as type i cells in the absence of pro - apoptotic bcl-2 proteins ( hikita et al . ,
activation of nf-b is mediated by traf-2 , rip-1 , and other signaling molecules that lead to activation of ib kinase and subsequent activation of nf-b target genes .
fadd and caspase-8 are the essential adapter proteins involved in apoptosis , which in hepatocytes requires a mitochondrial amplification loop through caspase-8-mediated cleavage of bid .
the subsequent translocation of bax and bak results in mitochondrial outer membrane permeabilization , cytochrome c release , and effector caspase-3 activation . under conditions of impaired apoptosis ,
tnf receptor-1 can induce necroptosis , which involves rip-1 and rip-3 kinases . among other effects
, rip-3 can increase the production of reactive oxygen species ( ros ) due to increased oxidative phosphorylation , resulting in intracellular calcium overload , mitochondrial membrane permeability transition ( mpt ) , depletion of atp , and necrosis .
apap - induced necrosis is essentially mediated by a toxic metabolite , which depletes glutathione and forms apap protein adducts , triggering oxidative stress , compromised respiratory function , and atp depletion .
although apap treatment can instigate the mitochondrial pathway of apoptosis , high doses of apap will ultimately mediate liver cell death by necrosis .
this has been impressively demonstrated in mice that died rapidly of liver failure with massive hepatocyte apoptosis when agonistic anti - cd95 antibody was injected ( ogasawara et al . , 1993 ) .
similarly , treatment of mice with tnf- in combination with a transcription - blocking agent , such as d - galactosamine ( d - galn ) or actinomycin d , induces lethal hepatitis ( leist et al . , 1994 , 1995 ;
another well established mouse model of alf consists of a combined treatment with d - galn and lipopolysaccharide ( lps ) , which induces tnf- expression and an inflammatory response that is predominantly directed toward the liver ( galanos et al . , 1979 ) .
it has been suggested that the toxicity in the murine tnf- and anti - cd95 models resembles viral forms of acute hepatic failure in patients ( keppler et al . , 1968 ; el - mofty et al . , 1975 ) .
cd95/cd95l expression has been shown to be upregulated in viral hepatitis and to correlate with disease activity and hepatocyte apoptosis ( hiramatsu et al .
, 1994 ; mita et al . , 1994 ; pianko et al . , 2001 ; lee et al . ,
we have recently demonstrated that diseased , e.g. , hcv - infected , livers show an upregulation of trail receptors and increased susceptibility toward trail - induced apoptosis ( volkmann et al . , 2007 ) .
these data implicate that viral forms of alf are associated with death receptor - induced cell death .
recent data show that the cd95 system is involved in human alf caused not only by viral hepatitis but also by wilson s disease ( strand et al . , 1998 ;
increased levels of death ligands or receptors such as cd95l , tnf- , or tnf receptors ( tnf - r ) were found in blood of patients with alf ( ryo et al .
particularly , high serum levels of soluble death receptor cd95 have also been found in drug - induced alf ( tagami et al .
, 2003 ; rutherford et al . , 2007 ) . silencing of cd95 or caspase-8 protected mice from alf or fulminant hepatitis induced by agonistic cd95 antibody or concanavalin a , respectively ( song et al .
however , cd95 and caspase-8 also promotes liver regeneration by inducing differentiation of stellate cells and possibly of other non - parenchymal liver cells ( desbarats and newell , 2000 ; canbay et al .
, 2003 ; ben moshe et al . , 2007 ) . additionally , tnf- plays a pivotal role in liver regeneration by activation of transcription factors such as nf-b , which induces the transcription of a huge number of cytokines and growth - promoting target genes ( wullaert et al . , 2007 ) .
the activation of nf-b by tnf- is mediated by distinct adapter proteins that are recruited to tnf - r-1 upon ligand binding ( figure 1 ) .
whether increased levels of circulating death receptors or ligands in human alf mirror apoptotic cell death or liver regeneration and whether death receptor - induced cell death depends on special alf etiologies remains unknown .
in contrast to viral infection , drug - induced liver injury is mainly associated with signaling pathways triggered by mitochondrial damage ( chan et al . , 2005 ) .
in the intrinsic pathway , apoptosis is mediated by translocation of pro - apoptotic bcl-2 molecules , such as bax and bak , from the cytosol to mitochondria to form pores in the outer mitochondrial membrane ( los et al . , 1999 ) .
this process is followed by the mitochondrial release of cytochrome c and other pro - apoptotic factors .
cytochrome c normally functions in electron transport processes of the respiratory chain to generate atp . in the cytosol of apoptotic cells
, however , it serves as a cofactor for the adapter protein apaf-1 . upon binding of cytochrome c and datp , apaf-1 oligomerizes , and recruits the initiator caspase-9 to trigger the formation of the apoptosome
thus , similar to the disc , the apoptosome is a high - molecular weight complex that serves as a caspase activation platform . once assembled in the apoptosome , caspase-9 becomes activated and subsequently triggers the caspase cascade ( schulze - osthoff et al .
as mentioned above , there is also considerable crosstalk between the extrinsic and intrinsic pathways .
for example , during death receptor - mediated apoptosis caspase-8 can proteolytically activate the bcl-2 protein bid , which facilitates cytochrome c release and amplifies the apoptotic signal following death receptor activation .
in contrast to apoptosis , necrosis is mediated by opening of the mitochondrial membrane permeability transition ( mpt ) pore , which triggers the collapse of the membrane potential and cessation of atp formation .
the resulting mitochondrial swelling leads to the rupture of the outer mitochondrial membrane with the release of intermembrane proteins and subsequent nuclear dna fragmentation .
other prominent features include massive energy depletion , formation of reactive oxygen species ( ros ) , and activation of non - apoptotic proteases .
the elevated calcium levels in the cytosol trigger mitochondrial calcium overload , leading to depolarization of the inner mitochondrial membrane and a shut - down of atp production .
while depletion of atp impedes the function of membrane channels , increased calcium activates calcium - dependent proteases , such as calpains .
calcium fluxes , atp depletion , and oxidative stress involve complex and interactive feedback loops , which self - amplify and potentiate each other leading to exaggerated cell death
. the relative amount of atp might be an important factor that determines whether hepatocytes die by apoptosis or necrosis ( ferrari et al .
when the necrotic cell ruptures , an inflammatory response follows due to the release of intracellular contents .
in contrast , inflammation is not typical of apoptosis , because phagocytic cells rapidly engulf apoptotic cells and thereby prevent the release of noxious intracellular compounds .
acetaminophen ( paracetamol , n - acetyl - p - aminophenol ; apap ) overdose represents one of the most common causes of alf in developed countries ( larson et al . , 2005 ) .
apap - induced hepatotoxicity is due to the formation of the toxic metabolite n - acetyl - p - benzoquinone imine by the cytochrome p450 system , which causes glutathione depletion , oxidative stress , alterations of calcium homeostasis , resulting in mpt , loss of mitochondrial membrane potential , and atp depletion ( hinson et al . , 2010 ) .
although necrosis has been thought to be the predominant mode of cell death in apap - induced liver injury , conflicting in vitro and animal data have emerged suggesting a potential role of apoptosis in acetaminophen - induced hepatotoxicity ( el - hassan et al .
mice treated with a toxic dose of acetaminophen showed 40% apoptotic and 60% necrotic hepatocytes ( ray et al . , 1996 ) .
it was demonstrated that mice with defective cd95 receptor ( lpr mice ) or cd95 ligand ( gld mice ) were partially protected from apap - induced liver injury ( liu et al . , 2004 ) .
moreover , increased circulating levels of cd95 have been found in humans with apap intoxication ( tagami et al . , 2003 ) .
it has been recently suggested that apap hepatotoxicity is caused by the mitochondrial apoptosis pathway and facilitated by chemokine ( c - x - c motif ) receptor 2 ( cxcr2 ) signaling . in this study caspase inhibition
prevented dna fragmentation , although the authors did not investigate whether caspase inhibition was also associated with cell survival ( hu and colletti , 2010 ; schulze - osthoff and bantel , 2011 ) .
in contrast , in another study no caspase activation was observed and , accordingly , caspase inhibition did not protect from liver injury in apap - treated mice ( jaeschke et al . , 2006 ) .
further data from animal models revealed also no evidence that apoptotic cell death contributes to apap - induced liver injury .
for instance , following the application of an apap overdose in mice , less than 1% of the parenchymal cells revealed an apoptotic morphology ( gujral et al . , 2002 ) .
another study in mice showed that knockdown of the cd95 receptor protected against 300  mg / kg apap overdose but not against 700  mg / kg overdose ( zhang et al . , 2000 ) , indicating that the mode of cell death might at least partially depend on the apap dose .
indeed , several studies demonstrated that apap induces mitochondrial dysfunction with atp depletion which even interrupts initial cd95-induced mitochondrial signaling pathways ( lawson et al .
on the other hand , subliminal cd95 activation can also increase apap - induced liver injury ( tinel et al . , 2004 ) , indicating that death receptor signaling might influence the extent of apap - induced necrotic liver injury .
conflicting data exist also about the role of tnf- in apap - induced liver injury .
increased tnf- expression in liver and circulating tnf- levels have been observed after apap poisoning ( blazka et al .
. however , the role of tnf- in apap - induced necrosis remains controversial , as tnf- inhibitors exerted either protection or no effect ( blazka et al . , 1995 ; simpson et al .
in addition , tnf- knockout mice showed similar sensitivity to acetaminophen compared to wildtype mice ( boess et al . , 1998 ) .
it has been recently shown that inhibition of c - jun n - terminal kinase ( jnk ) , a member of the mitogen - activated protein kinase family , reduced paracetamol - induced toxicity in mice by inhibiting hepatic tnf- production ( henderson et al . , 2007 ) .
furthermore , apap - induced jnk activation has been linked to activation of the pro - apoptotic bcl-2 protein bim . in line ,
apap - induced necrotic liver injury was shown to be reduced in bim knockout mice ( badmann et al . ,
however , neither jnk1 nor jnk2 knockdown did protect mice from apap - induced liver toxicity , raising concerns about a major role of jnk in apap - induced liver injury ( gunawan et al .
, 2006 ; henderson et al . , 2007 ; bourdi et al . , 2008 ) . altogether ,
although apoptotic alterations can occur , profound energy depletion , and mitochondrial failure presumably divert cell death to necrosis as the principal mode of apap - induced liver toxicity .
autophagy represents another process that might influence the outcome of apap - induced liver toxicity .
autophagy is a catabolic mechanism by which long - lived proteins and organelles are recycled in order to maintain energy and protein synthesis .
it is characterized by the appearance of numerous cytosolic vacuole - like structures , called autophagosomes , which encapsulate cytosolic materials and fuse with lysosomes .
although the role of the autophagy in protection during nutrient starvation is accepted , its function in programmed cell death remains controversial . under normal physiological conditions autophagy
occurs at low basal levels , contributing to the turnover of cytoplasmic components and promoting cell survival during stress conditions .
interestingly , it has been recently demonstrated that apap induces autophagy in mouse liver and primary human hepatocytes and that activation of autophagy protects against apap - induced hepatotoxicity ( ni et al . ,
it was suggested that the induction of oxidative stress might play an important role in apap - induced autophagy .
moreover , it was shown that pharmacological inhibition of autophagy increased apap - induced liver injury .
clearly , more work is needed to elucidate the role of autophagy in apap - induced hepatotoxicity and the complex crosstalk with other cell death pathways .
in addition to measuring death ligands , several other cell death biomarkers have been proposed for monitoring the clinical outcome of alf and other liver diseases ( volkmann et al . , 2006 ; rutherford et al .
caspases cleave the intermediate filament protein cytokeratin ( ck)-18 into specific fragments that are released into circulating blood and can be detected by the m30 elisa ( bantel et al . , 2001b , 2004 ; seidel et al . , 2005
) . moreover , when this assay is combined with a second elisa that detects the total release of caspase - cleaved and uncleaved ck-18 ( m65 elisa ) , even different forms of cell death , such as necrosis and apoptosis , can be discriminated . using these serological assays
, it has been recently demonstrated that the predictive sensitivity of total ck-18 for lethal outcome was comparable to the model for end - stage liver disease ( meld ) score at time of admission of alf patients ( bechmann et al . , 2010 ) .
moreover , modification of the meld score by substitution of bilirubin for total ck-18 significantly increased the prediction of alf outcome .
interestingly , we have demonstrated that alf patients display considerable caspase activity and high levels of caspase - cleaved ck-18 in the serum , which was unexpectedly higher in spontaneous survivors than in patients that required transplantation or died ( volkmann et al . , 2008 ) . nevertheless , despite a weaker activation of caspases , liver biopsies of patients without spontaneous recovery revealed extensive tunel reactivity , which detects both apoptotic and necrotic cell death .
moreover , sera from those patients contained increased levels of total ck-18 , but reduced levels of its caspase - generated fragments as compared to patients with spontaneous recovery .
these findings therefore indicate that necrosis but not apoptosis is the predominant cell death in those critically ill alf patients , whereas in alf patients with spontaneous recovery apoptotic cell death predominates .
in contrast , in another study , detection of caspase - cleaved ck-18 could not adequately predict alf outcome ( rutherford et al .
however , unlike in our study in which apap - induced alf only played a minor role , in this study a relevant number of patients with apap - induced alf was included .
as mentioned above , in those patients necrotic cell death might predominate irrespective of the outcome . in line with this observation
, patients with apap - induced alf showed higher levels of total ck-18 compared to caspase - cleaved ck-18 levels ( bechmann et al .
2008 ; craig et al . , 2011 ; bantel and schulze - osthoff , 2012 ) .
caspase activation might also play a role in liver regeneration and this might explain our observation of higher caspase activity in spontaneous survivors .
caspases can cleave different cytokine precursors to generate active cytokines and thus create an environment that could be essential for liver regeneration .
experiments in mice showed that caspase activation is associated with chemokine production and inflammation in the liver , whereas caspase-3 inhibition strongly reduced activity of pro - inflammatory transcription factors and chemokines ( faouzi et al . , 2001 ) .
a role of caspases in liver regeneration is best exemplified by a recent report showing that a hepatocyte - specific knockout of caspase-8 attenuates hepatocyte proliferation after partial hepatectomy ( ben moshe et al . , 2007 ) .
in addition to cell death biomarkers , circulating levels of nucleosomes and high - mobility group box 1 ( hmbg1 ) protein , both of which are released during hepatocyte death , have been shown to be elevated in patients with alf
2011 ) . however , those biomarkers were not able to predict alf outcome , and no significant differences in hmbg1 or nucleosome levels between paracetamol- and non - paracetamol - induced liver injury were found ( craig et al . , 2011 ) .
one explanation for the lacking correlation of those biomarkers with alf outcome might be that the release of hmbg1 and nucleosomes are not strictly related to necrotic cell death , but also occur during apoptosis ( bell et al .
certainly , further larger cohort studies are required to evaluate the predictive value of cell death markers in patients with paracetamol- or non - paracetamol - induced alf .
an admixture of necrosis and apoptosis occurs in alf and might therefore open up novel strategies for therapeutic intervention ( fischer and schulze - osthoff , 2005 ) .
more extreme injury leads to necrotic killing , whereas milder injury may result in apoptosis .
whether inhibition of apoptosis using available pharmacological caspase inhibitors can indeed prevent liver cell death or will just simply shift the mode of cell death to necrosis , remains to be shown ( los et al . , 2002 ) . as caspases not only play a role in apoptosis but also in processes of liver regeneration , the possibility of adverse effects should not be ignored when considering the therapeutic use of caspase inhibitors in alf treatment .
death receptor - blocking agents , such as cd95-fc or trail - r - fc proteins , might be promising candidates in virus - induced alf ( bantel and schulze - osthoff , 2003 ) . micrornas ( mirnas ) are non - coding rnas which have been implicated in the posttranscriptional regulation of various cellular pathways .
it was recently demonstrated that overexpression of mirna-221 delays cd95-induced fulminant liver failure in mice ( sharma et al . , 2011 ) .
thus , mirnas involved in cell death signaling pathways might serve as potential therapeutic targets in alf . due to the pleiotropic effects of tnf- , inhibitors of this cytokine might not only influence liver cell death but also immune response and liver regeneration .
treatment of apap intoxicated mice with anti - tnf- partially prevented hepatotoxicity ( blazka et al . ,
other studies showed no alterations of apap toxicity in mice treated either with anti - tnf- antibody or soluble tnf receptor ( simpson et al .
whether the observed discrepancy is due to the variant experimental conditions , such as different mouse strains , remains to be elucidated ( jaeschke et al . ,
there is increasing evidence suggesting that tnf- triggers cell death not only by apoptosis , but also by a necrosis - like process , which has been recently called necroptosis ( schulze - osthoff et al .
whereas tnf--induced apoptosis involves caspase-8 , tnf--induced necroptosis is essentially mediated by the kinases rip-1 and rip-3 that are recruited to tnf - r1 ( figure 1 ) .
interestingly , specific inhibitors of rip-1 , called necrostatins , have been recently designed as novel cytoprotective agents that might be a promising tool to positively influence alf outcome , at least in conditions in which death receptor - mediated necrosis predominates .
therapeutic targets to improve apap - induced alf outcome might be jnk or other members of the mitogen - activated protein kinase family , such as p38 .
jnk inhibition by sp600125 , a small - molecule reversible atp - competitive inhibitor , or by d - jnkii , a peptide inhibitor that inhibits the interaction of jnk with substrates , markedly reduced mortality in murine paracetamol - induced hepatotoxicity , with a significant reduction of hepatic apoptosis and necrosis ( bennett et al .
, 2001 ; borsello et al . , 2003 ; henderson et al . , 2007 ) .
since glutathione depletion and subsequent oxidative stress formation are key pathogenic mechanisms of apap - induced hepatocyte death , application of n - acetylcysteine , a pro - drug for glutathione synthesis , which has been shown to reduce apap - induced liver necrosis , is the current standard therapy in apap - induced alf ( corcoran et al . , 1985 ; saito et al . , 2010 )
in addition , other drugs with anti - oxidant effects might improve alf outcome . in this respect ,
application of cyclooxygenase inhibitors exerted protective effects in an experimental alf mouse model with decreased oxidative stress formation and marked reduction of hepatic necrosis ( chang et al .
a novel therapeutic target in alf that connects the immune system with cell death might be cyclophilin a. this intracellular protein exerts pro - inflammatory and hepatotoxic activity when released from necrotic liver cells in apap - induced liver injury .
conversely , inhibition of cyclophilin reduced inflammatory response to necrotic liver ( dear et al . , 2011 ) .
thus , targeting of cyclophilin might represent an opportunity for a novel therapeutic approach in acetaminophen poisoning . as mentioned above , pharmacological inhibition of autophagy exacerbated apap - induced liver toxicity .
vice versa , induction of autophagy by rapamycin was shown to inhibit apap - induced hepatotoxicity ( ni et al . , 2012 ) .
thus , autophagy induction might be a further strategy to improve alf outcome in apap intoxicated patients .
taken together , there are many promising therapeutic approaches for inhibition of apap- and non - apap - induced alf .
however , it should be kept in mind that most of the described targets exert a pleiotropic role and might interfere not only with cell death but also with survival pathways .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 acute liver failure ( alf ) can be the consequence of various etiologies , that might vary between different geographic regions . 
 most frequent are intoxications with acetaminophen , viral hepatitis , or liver damage of unknown origin . 
 alf occurs when the extent of hepatocyte death exceeds the regenerative capacity of the liver . 
 the mode of liver cell death that is predominantly induced in alf , i.e. , apoptosis or necrosis , is still controversial and presumably determined by the etiology , duration , and magnitude of liver injury . 
 severe liver damage involves oxidative stress and depletion of atp resulting in necrosis . in contrast , maintenance of atp stores is required for the execution of apoptosis . 
 recent data suggest that necrosis resulting from severe liver damage is associated with poor outcome of alf patients . 
 discrimination between apoptosis and necrosis might be therefore useful for the identification of alf patients requiring liver transplantation . 
 identification of the molecular cell death mechanisms remains an important issue not only for early prediction of alf outcome , but also for therapeutic interventions . in view of the pleiotropic functions of critical mediators of cell death and tissue regeneration , 
 a particular challenge will be to reduce hepatocellular death without inhibiting the regenerative capacity of the liver . here , we review the molecular mechanisms of hepatocyte injury and the pathways leading to apoptosis and necrosis , which might represent potential diagnostic and therapeutic targets in alf . 
Introduction
Death Receptor Signaling in Acute Liver Failure
Role of Mitochondrial Damage in Acute Liver Failure
Cell Death Mechanisms Involved in Acetaminophen-Induced Acute Liver Failure
Cell Death Biomarkers for Monitoring Acute Liver Failure
Possible Therapeutic Strategies for Cell Death Inhibition in Acute Liver Failure
Conflict of Interest Statement