Mechanisms of Hepatocyte Injury, Multiorgan Failure, and Prognostic Criteria in Acute Liver Failure

• ABSTRACT
• MECHANISMS OF LIVER CELL DEATH IN ALF
• Activation of Cell Membrane “Death Receptors”
• TNF-α AND TNF-R1 PATHWAYS
• FAS RECEPTOR/FAS-LIGAND PATHWAY
• Intracellular Stress
• Nitric Oxide
• Other Cytokines and Chemokines
• Relationship to Multiorgan Failure
• MECHANISMS WITH AN IMPACT ON HEPATOCELLULAR REGENERATION IN ALF
• PROGNOSTIC CRITERIA
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Acute liver failure (ALF) occurs when the rate and extent of liver cell death are not adequately balanced by regenerative activity. Two forms of liver cell death are recognized: apoptosis and necrosis. A number of causes of ALF have been shown, predominantly in experimental animal models, to induce one or the other form of liver cell death. Nonetheless, an insult capable of inducing apoptosis may cause cell death by necrosis, particularly if the degree of mitochondrial damage is sufficient to exhaust stores of adenosine triphosphate. Here we consider mechanisms of liver cell injury in ALF, including evolving knowledge of signaling pathways leading to hepatocellular apoptosis and necrosis. Factors that have an impact on the adequacy of hepatic regeneration along with the pathophysiology of complicating multiorgan failure are also reviewed. Prognostic criteria are discussed, especially in relation to current concepts of mechanisms of liver cell death and multiorgan dysfunction.

A critical degree of liver cell death, not adequately compensated for by hepatocellular regenerative activity, is fundamental to the development of ALF. Two pathways of liver cell death exist: apoptosis and necrosis. Apoptosis is manifest by nuclear and cytoplasmic shrinkage without disturbance of cell membrane integrity or liberation of intracellular content. Consequently, secondary inflammation is not a feature. Necrosis involves depletion of adenosine triphosphate (ATP) with resultant cell swelling and lysis leading to release of cellular content and secondary inflammation.[1]

At a molecular level, apoptosis occurs as a result of the sequential activation of a series of cysteine proteases known as caspases. Apoptosis can be triggered by extrinsic or intrinsic mechanisms, the former involving activation of death receptors located on cell membranes and the latter involving oxidative stress of mitochondria and the endoplasmic reticulum.[1] [2] [3] [4] [5] The specific caspases involved vary according to the type of proapoptotic stimulus. For example, caspase 8 mediates proapoptotic signal transduction downstream of activated cell surface death receptors; caspase 9 mediates signals that follow oxidative mitochondrial damage. These latter signals augment cell death initiated by activation of death receptors, illustrating important interactions between extrinsic and intrinsic pathways of cell death, as discussed later (Fig. [1]).[1]

A number of causes of ALF have been shown, predominantly in experimental animal models, to induce one or the other form of liver cell death, such as necrosis in the case of severe acetaminophen overdose and apoptosis in the case of ischemia-reperfusion injury and fulminant Wilson's disease.[1] [6] [7] [8] [9] Nonetheless, an insult capable of inducing apoptosis may cause cell death by necrosis, particularly if the degree of mitochondrial damage is sufficient to exhaust ATP stores. Processes leading to marked oxidative stress typically cause cell death by necrosis rather than by apoptosis as a consequence of not only the severity of mitochondrial damage but also the inhibition of the proapoptotic caspase cascade (Fig. [1]).[1] [10] [11] [12] The cellular contents of the antioxidant glutathione and nitric oxide (NO), in addition to the osmolarity and an increasingly recognized number of tyrosine kinases, adapter molecules, transcription factors, cytokines, and chemokines, act as important factors modulating pathways of liver cell death.

Here we consider mechanisms of liver cell injury in ALF, including evolving knowledge of signaling pathways leading to hepatocellular apoptosis and necrosis. Factors having an impact on the adequacy of hepatic regeneration along with the pathophysiology of complicating multiorgan failure are also reviewed. Prognostic criteria are discussed, especially in relation to current concepts of mechanisms of liver cell death and multiorgan dysfunction.

MECHANISMS OF LIVER CELL DEATH IN ALF

Activation of Cell Membrane “Death Receptors”

The pleiotropic cytokine, tumor necrosis factor (TNF)-α, and the Fas ligand mediate hepatocellular death through interaction with structurally related cell membrane receptors belonging to the TNF and nerve growth factor superfamily, namely TNF-receptor 1 (TNF-R1) and Fas receptor, respectively.[13] [14] TNF-R1 and Fas receptor are connected to a cytoplasmic region called “death domain” that activates the caspase cascade (Fig. [1]).[15]

TNF-α AND TNF-R1 PATHWAYS

TNF-R1 is highly expressed on hepatocytes. After ligand binding, TNF-R1 recruits the adapter protein TNF-R- associated protein with death domain (TRADD) to its intracellular domain, leading to activation of not only the caspase cascade but also the transcription factor nuclear factor kappa B (NF-κB) and c-Jun-N-terminal kinase (JNK).

TNF-α induces liver cell death through the caspase cascade after activation of Fas-associated proteins with death domain (FADD).[16] [17] Activation of FADD, in turn, triggers two different proapoptotic cascades.[18] After proteolytic cleavage of caspase 8, the active molecule may activate caspase 3 either directly or indirectly, the latter via a process involving mitochondrial damage with release of cytochrome c and apoptosis-inducing factor (AIF) into the cytosol (Fig. [1]).[18] [19] [20] [21]

Nonetheless, hepatocytes are normally resistant to the harmful effects of TNF-α.[22] Susceptibility to cell death occurs in the settings of global transcription or translational arrest[23] or selective inhibition of NF-κB[21] [24] or c-Myc.[25] Studies using NF-κB and TNF-R1 knockout mice have demonstrated that TNF-α-dependent activation of NF-κB plays a critical role in protecting hepatocytes from apoptosis.[26] Inhibition of NF-κB activation after partial hepatectomy results in both apoptosis and blockade of regeneration, indicating that this component of the TNF-α/TNF-R1 signaling cascade controls both antiapoptotic and cell proliferation pathways in hepatocytes.[27] [28] Studies performed in a rat hepatocyte cell line suggest that NF-κB exerts its protective effect against TNF-α-induced cell death by downregulation of JNK and activating protein-1 (AP-1). Sustained JNK activation resulting from NF-κB inactivation resulted in cell death via c-Jun-dependent AP-1 activation.[29] These findings suggest that the critical function of activation of NF-κB in hepatocytes is to terminate the induction of JNK by TNF-α.

A number of other factors that protect against TNF-α-related apoptosis have recently been identified. Activation of extracellular signal-regulated kinase and P38 mitogen-activated protein kinase has been shown to suppress TNF-α-related apoptosis of rat hepatocytes.[30] Similarly, studies performed in galactosamine-sensitized mice treated with lipopolysaccharide (LPS) indicate that the TNF-inducible protein A20, a NF-κB-dependent gene product, protects hepatocytes from TNF-α-related apoptosis, notably, and in contradistinction to NF-κB inhibition, without interfering with cell signaling pathways leading to regeneration.[31] Conversely, studies performed in galactosamine- and LPS-treated mice lacking the tyrosine kinase domain of the Ron receptor, a transmembrane glycoprotein involved in modulation of inflammatory responses,[32] in which animals were protected from TNF-α-mediated apoptosis, indicate that this tyrosine kinase contributes to proapoptotic signaling related to TNF-α.[33]

In addition, TNF-α-induced cell death has been shown to play an important role in the pathogenesis of carbon tetrachloride-related ALF in experimental animals.[1] TNF-α is also an important mediator of ALF in hepatic ischemia-reperfusion injury, a phenomenon in which cellular damage in an ischemic organ is accentuated after the re-establishment of oxygen flow. Serum levels of TNF-α are increased; anti-TNF-α serum reduces serum transaminase levels in this setting.[34] A central role for TNF-α in inducing hepatocellular apoptosis in ischemia-reperfusion injury has recently been described in mice. Both TNF-R1 knockout animals and wild-type mice treated with pentoxifylline, an inhibitor of TNF-α production, displayed resistance to apoptosis and increased survival after prolonged periods of ischemia.[9] These findings, along with other experiences with antiapoptotic strategies in experimental animals, including inhibition of caspases[35] and overexpression of Bcl-2,[36] indicate that apoptosis rather than necrosis is the predominant mechanism of cell death in the ischemic liver.[9] A brief period of hepatic ischemia, approximately 5 to 10 minutes in duration, has been shown to protect the livers of experimental animals against subsequent ischemia- reperfusion injury.[37] Studies performed in mice indicate that activation of NF-κB and p38 stress-activated protein kinase contribute at least in part to this phenomenon.[38] Other studies performed in rats suggest that NO, as discussed below, may also play a protective role in this circumstance.[39]

Accumulating evidence suggests that some degree of oxidative stress is necessary for TNF-α-related apoptosis and resultant ALF due to ischemia/reperfusion injury.[40] The antioxidant N-acetylcysteine has been shown to reduce TNF-α toxicity in rats,[41] whereas depletion of the natural antioxidant glutathione is associated with increased mortality in a murine model of TNF-α cytotoxicity.[22] Taken together, these findings suggest that oxidative stress may sensitize the ischemic liver to TNF-α, leading to potentially massive apoptosis. Oxidative stress may not then be directly toxic to the ischemic liver but rather act as a facilitator of TNF-α-mediated apoptotic cell death. Nonetheless, marked oxidative stress inhibits the proapoptotic caspase cascade and depletes mitochondrial ATP, favoring necrosis,[1] as discussed earlier. Indeed, studies of cultured mouse hepatocytes and of mice in vivo indicate that oxidative stress due to acetaminophen results in necrosis, rather than apoptosis.[6] [7] Furthermore, acetaminophen-related liver damage did not differ significantly in acetaminophen-exposed TNF-α knockout mice and wild-type animals.[42] Similarly, treatment with anti-TNF-α antibodies did not protect wild-type mice from acetaminophen-related liver damage.[43] Taken together, these latter findings suggest that signaling via the TNF-α pathway does not contribute substantially to acetaminophen-related ALF.

The overall effect of TNF-α on hepatocytes is influenced not only by the underlying physiological state of the cell, including the degree of any oxidant stress, but also by the cytokine milieu generated in response to a toxic insult. Examples include protection against TNF-α-induced liver injury in mice lacking interferon (IFN)-γ, interleukin (IL)-12, or IL-18.[44] [45] [46] In addition to direct toxic effects on hepatocytes, IFN-γ may sensitize these cells to the cytotoxic effects of TNF-α.[46] [47] [48] IL-10, IL-1β, and NO donors have each been shown to protect against TNF-α- and galactosamine-induced hepatocyte apoptosis in mice.[49] [50] [51]

FAS RECEPTOR/FAS-LIGAND PATHWAY

The Fas receptor is constitutively expressed on hepatocytes,[52] and these cells are very sensitive to Fas ligand- induced apoptosis, as shown by studies in which mice treated with an agonistic anti-Fas antibody died from hepatic failure.[53] Hepatocytes express lower constitutive levels of Bcl-2 and Bcl-x_L than do the cells of other organs, a finding that may explain their particular sensitivity to Fas-mediated apoptosis.[54] Expression of a Bcl-2 or a Bcl-x_L transgene in hepatocytes protects mice from anti-Fas-induced ALF.[55] Exposure of hepatocytes to a moderate hyperosmotic environment has been shown to result in a rapid increase in trafficking of Fas receptor from an intracellular location to the cell membrane followed by activation of caspase 3 and 8, thereby facilitating Fas-ligand-induced apoptosis. Hyperosmotic Fas receptor trafficking is due at least in part to activation of JNK.[56] These findings provide a molecular basis for the earlier observations that there is a link between cell volume and apoptosis[57] [58] and that the hydration state of the hepatocyte is an important determinant of its susceptibility to various forms of stress.[57] [59]

Interaction between Fas receptor and Fas ligand plays a major role in hepatocyte injury occurring early in the course of fulminant viral hepatitis B.[60] Cytotoxic T lymphocytes recognize viral antigens expressed on Fas receptor-positive hepatocytes and kill virus-infected hepatocytes at least in part through Fas-induced activation of caspases.[61] Activation of the Fas receptor/Fas ligand pathway leads to cell death either through direct activation of the caspase cascade or through mitochondrial disruption, as discussed below.[18] [62] Recent findings in mice treated with an agonistic anti-Fas Ab, a representative model of viral-induced ALF clinically, indicate a pivotal role for mitochondrial injury in Fas-mediated hepatocyte apoptosis and suggest, as with TNF-α- mediated cell death, a key role for reactive oxygen species in this process.[63] Increased survival and reduced hepatic necroinflammatory activity, as reflected both by circulating transaminase levels and by liver histology, were documented in mice with anti-Fas Ab-induced ALF that were treated with a superoxide dismutase mimic with catalase-like activity.[63] Such therapy substantially reduced the overproduction of reactive oxygen species in hepatocytes after exposure to anti-Fas Ab, resulting in inhibition of mitochondrial damage, cytochrome c release, and caspase-3 activation.[62]

In addition to fulminant viral hepatitis B, signaling by the Fas receptor-Fas ligand pathway plays an important role in the pathogenesis of fulminant Wilson's disease.[8] In contrast, recent data suggest that this pathway does not contribute to liver injury occurring after reperfusion of the ischemic liver,[9] despite the fact that mitochondrial production of reactive oxygen metabolites is increased in this setting and that hepatocellular expression of both Fas receptor and Fas-ligand is upregulated by oxidative stress.[1] Despite this upregulation, murine studies indicate that Fas receptor-mediated proapoptotic signaling is inhibited in the setting of oxidative stress due to acetaminophen overdose, with this inhibition viewed as the consequence of acetaminophen-induced mitochondrial damage rather than of the initial glutathione depletion.[64]

Intracellular Stress

Oxidative mitochondrial injury plays an important role in the development of liver cell death consequent to opening of the mitochondrial permeability transition (MPT) located at the points of junction of the inner and outer membranes.[65] [66] Opening of MPT pores leads to release of cytochrome c and AIF into the cytosol, events that, as discussed earlier, trigger the apoptotic cascade.[65] A number of factors promote mitochondrial oxidative stress by enhancing the production of reactive oxygen metabolites, including TNF-α, ceramide, bile acids, the microsomal cytochrome P450 enzyme system, and ischemia/ reperfusion.[1] Depletion of hepatic glutathione stores promotes oxidative stress as a result of a reduced capacity to detoxify reactive oxygen metabolites.[1]

Early studies suggested that mitochondrial injury is required to initiate apoptosis occurring in response to intracellular stress.[67] [68] However, recent evidence indicates that some apoptotic signals resulting from intracellular stress bypass mitochondria to directly activate caspases. Mitochondria may be secondarily damaged by activated caspases in this schema, leading to further caspase activation. Oxidative stress of the endoplasmic reticulum, an organelle that plays a critical role in protein biosynthesis and intracellular calcium homeostasis, is one such process that can trigger apoptosis without involvement of mitochondria.[69] [70] Caspase 12 and disturbed calcium homeostasis at least contribute to this process (Fig. [1]).[69] As discussed earlier, necrosis rather than apoptosis occurs when sufficient mitochondrial injury is sustained to result in critical depletion of cellular ATP, especially in the setting of inhibition of caspase activity by marked oxidative stress.[1]

Nitric Oxide

Low concentrations of NO are produced constitutively in the liver by the action of endothelial NO synthase on L-arginine. Protective effects of NO on hepatocytes have been described in several models of liver injury, including endotoxin- or thioacetamide-induced, hemorrhagic shock-related, and ischemia-reperfusion injury.[71] [72] [73] [74] [75] NO may protect the liver by improving the microcirculation through vasodilatation and antiplatelet effects, inhibiting neutrophil activation, neutralizing toxic free radicals, and inhibiting apoptosis.[75] The latter occurs as a result of the S-nitrosylation of caspases, rendering them inactive.[1] Conversely, production of excessive quantities of NO as a consequence of upregulated expression of inducible NO synthase (iNOS) by LPS and proinflammatory cytokines such as TNF-α[76] [77] may be toxic. In particular, a role for iNOS in acetaminophen-induced ALF has recently been proposed.[78] [79] [80] The cytotoxic properties of iNOS are at least in part attributable to the formation of peroxynitrite after a reaction of excess NO with superoxide in the setting of marked oxidative stress, leading to cell necrosis.[1] [79] [80] [81] Notably, iNOS plays an important cytoprotective role in the regenerating liver in the post-partial hepatectomy setting, in which marked oxidative stress is not a feature, providing further evidence that whether a particular stimulus is harmful or beneficial to hepatocytes depends to a large extent on the cells' physiological status.[82] [83]

Other Cytokines and Chemokines

In addition to TNF-α, as discussed earlier, the possible role of a number of other proinflammatory and anti-inflammatory cytokines in the pathogenesis of acute liver injury of various etiologies has been investigated, both experimentally and clinically. Thus, a pivotal role for IFN-γ, a proinflammatory cytokine that plays a central role in the activation of macrophages and T lymphocytes, in the pathogenesis of ALF due to hepatitis B virus has been suggested by findings in a transgenic mouse model of fulminant hepatitis induced by transfer of hepatitis B surface antigen (HBsAg)-specific cytotoxic T lymphocytes. Following initial signaling via the Fas receptor/Fas ligand pathway leading to apoptosis of hepatocytes, as discussed earlier, the cytotoxic T cells secreted IFN-γ, resulting in macrophage activation and a delayed-type hypersensitivity response that destroyed the liver.[60] The importance of IFN-γ has also been demonstrated in murine ALF because of concanavalin A and low-dose LPS exposure.[84] [85]

IL-12 has been shown in experimental animals to cause Kupffer cell hypertrophy and proliferation, accumulation of activated macrophages and lymphocytes in liver parenchyma, increased lytic activity of intrahepatic natural killer cells, and hepatocellular necrosis.[86] [87] [88] Prior administration of IL-12 exacerbates liver damage in concanavalin A-induced ALF; anti-IL-12 antibodies reduce it.[89] The latter also protect against low-dose LPS-induced ALF in Propionibacterium acnes-sensitive mice.[90] The effects of IL-12 in these models of liver injury are likely to be mediated by IFN-;gg. Recent investigations also document an important role of IL-5 derived from natural killer kills in the pathogenesis of murine concanavalinA-induced hepatitis.[91]

Several cytokines have also been shown to reduce acute liver injury in experimental animal models. The anti-inflammatory cytokine IL-10 protects against concanavalin A-, galactosamine/LPS-, and acetaminophen-induced ALF in mice.[92] [93] The anti-inflammatory properties of this cytokine include reduction in antigen-presenting capacity of monocytes and dendritic cells[94] and downregulation of synthesis of potentially proinflammatory molecules such as TNF-α, IL-1, IL-8, IL-12, NO, and reactive oxygen species.[94] [95] [96] IL-11 has been shown to inhibit concanavalin- and acetaminophen-related liver injury in mice.[97] [98] IL-4 and IL-13 have been implicated in protecting the liver against experimental ischemia-reperfusion injury,[99] whereas mice lacking IL-6 are at increased susceptibility to carbon tetrachloride- induced hepatotoxicity.[100] Monocyte chemoattractant protein 1 and its receptor C-C chemokine receptor 2 likely represent a protective chemokine pathway by facilitating the heptatic recruitment of a subset of macrophages that may promote resolution of liver injury. Substantially increased intrahepatic expression of these molecules has been demonstrated in mice after administration of toxic doses of acetaminophen.[101] [102]

In the clinical setting, intrahepatic expression of IFN-γ, IL-12, and IL-10 has recently been assessed in the explants of 11 patients transplanted for fulminant hepatitis B.[103] A marked induction of the proinflammatory mediators IFN-γ and IL-12 was apparent at both the protein and the mRNA levels and not counterbalanced by the anti-inflammatory IL-10. A similar pattern was found in 5 patients with ALF because of other etiologies, including autoimmune hepatitis, ecstasy-related hepatotoxicity, and cryptogenic, implying that the imbalance between proinflammatory and anti-inflammatory cytokine mediators may contribute to the pathogenesis of ALF due to of a range of etiologies. Increased circulating levels of IL-6 and IL-8,[104] along with TNF-α, soluble TNF-R1, and IL-10[105] have also been reported.

Relationship to Multiorgan Failure

Accumulation of toxins such as ammonia and lactate and the deleterious effects of vasoactive cytokines produced in response to the initiating cause of liver injury or complicating sepsis, or both, contribute to the development of multiorgan dysfunction in ALF. Thus, there are recent clinical data suggesting that elevated levels of IL-6 and IL-8 contribute to the splanchnic and systemic vasodilatation and systemic hypotension often evident in this syndrome.[104] The possible importance of gut-derived LPS in mediating this overproduction of vasoactive cytokines has recently been called into question by studies in which no significant correlations with circulating cytokine levels were found.[104] Adrenal insufficiency may contribute to the propensity for systemic hypotension,[106] as has been demonstrated in severe sepsis.[107] Microcirculatory plugging due to formation of microthrombi as a consequence of activation and consumption of platelets, together with increased adhesion of leukocytes to endothelium, may exacerbate the potential for tissue hypoxia.[108] Nonetheless, the recent finding of a normal hepatic venous pyruvate to lactate ratio suggests that accelerated glycolysis, rather than tissue hypoxia, accounts for accumulation of lactate,[109] [110] which has been implicated in the pathogenesis of cerebral edema in ALF.[111] Increased glycolysis is a known consequence of the systemic inflammatory response syndrome (SIRS) and may be the mechanism underlying the recent observation of a significant association between the severity of the SIRS and grade of hepatic encephalopathy in ALF.[112]

Sepsis is a major cause of the SIRS in ALF[112] and sepsis-related oxidative stress[113] has been shown in rodents to both promote hepatocellular necrosis and inhibit liver cell regeneration,[114] on which spontaneous recovery ultimately depends. Complicating sepsis also exacerbates the already increased energy requirements of ALF.[115] Rapid deterioration in nutritional status with depletion of muscle and fat stores is often seen. Along with accelerated glycolysis, impairment of glycogen storage and reduced capacity for gluconeogenesis result in both hypoglycemia and increased breakdown of adipose tissue and muscle consequent to the use of fat and protein as alternative fuel sources.[115] Reduced hepatic synthesis of insulin-like growth factor-1 exacerbates protein degradation.[116] Impaired peripheral uptake of glucose consequent to insulin resistance has been documented early in the course of ALF, with insulin sensitivity typically being restored by 2 weeks in patients who survive.[117]

MECHANISMS WITH AN IMPACT ON HEPATOCELLULAR REGENERATION IN ALF

A variable degree of liver regeneration is evident histologically in most cases of ALF, with the extent of regenerative activity typically more pronounced in hyperacute than in subacute categories. Factors responsible for the adequacy or with otherwise regeneration in the setting of such severe liver cell loss remain incompletely understood.

Increased circulating levels of TNF-α and IL-6 have been described.[104] [105] These cytokines are key initiators of liver regeneration following partial hepatectomy, although TNF-α-related cell death rather than regeneration predominates in the presence of oxidative stress,[83] as discussed earlier. Plasma levels of stimulatory hepatocyte growth factor (HGF) and inhibitory transforming growth factor-β (TGF-β) are also elevated, presumably due to release from damaged extracellular matrix.[118] [119] Increased activity of the fibrinolytic system, responsible for activation of both HGF and TGF-β,[120] [121] is also evident.[122] Nonetheless, toxins that impair HGF-induced DNA synthesis by hepatocytes have been described in plasma of ALF patients.[123] Despite this, increased regeneration has been observed in rats with carbon tetrachloride- related ALF treated with exogenous human recombinant HGF.[124] Regeneration was also augmented following treatment with anti-TGF-β antibody in such a model.[125] The antimicrobial agent ciprofloxacin also significantly enhanced hepatic regenerative activity in a rat model of ALF, most likely by blocking hepatocyte membrane receptors for inhibitory γ-aminobutyric acid.[126] [127]

Impaired regeneration following partial hepatectomy along with increased susceptibility to acetaminophen-related hepatotoxicity have recently been documented in peroxisome proliferator-activated receptor-α null mice, possibly as a consequence of altered expression of genes responsible for cell cycle control, cytokine signaling, and fat metabolism.[128] [129] The latter may be particularly important, because replicating hepatocytes require β-oxidation of fatty acids in mitochondria for energy.[130] Supplementation with free fatty acids and carnitine, the carrier responsible for transport of fatty acids into mitochondria, augments the rate of regeneration after partial hepatectomy in the rat.[131] The role of such supplementation in the ALF setting, where mitochondria may be profoundly damaged and unable to oxidize fatty acid supplements, has not been assessed but is of potential importance because rapid depletion of fat stores is often seen in this condition, as discussed earlier.

Studies performed in experimental animals following partial hepatectomy demonstrate that hepatic regeneration is also a phosphate-consuming process. Several processes contribute to this, including protein phosphorylation,[132] a rapid turnover of intracellular high energy phosphate,[133] and a requirement for increased synthesis of phospholipids.[134] A substantial fall in serum phosphate values is often seen clinically in patients following partial hepatectomy, presumably as a result of substrate utilization because of a high degree of regenerative activity.[135] Hypophosphatemia is also seen in a substantial proportion of ALF patients and correlates with a favorable outcome. Conversely, hyperphosphatemia, possibly reflecting impaired hepatocellular regenerative activity, has been identified as a poor prognostic marker.[136]

PROGNOSTIC CRITERIA

A number of prognostic criteria in ALF have been proposed. Those formulated at King's College Hospital are the most widely applied (Table [1]).[137] In the original assessment of these indicators, positive predictive values for death (the proportions of those patients fulfilling criteria who died) in acetaminophen and nonacetaminophen etiologies of ALF were 84% and 98%, respectively, whereas negative predictive values (the proportions of those patients not fulfilling criteria who survived) were 86 and 82%, respectively.[137] Predictive accuracies (the proportions of all patients in whom outcome was correctly predicted) were 85 and 94%, respectively. Several subsequent reports from other centers using the King's College criteria have indicated that, although fulfillment of criteria carries a poor prognosis for spontaneous survival, lack of fulfillment carries a less favorable outlook than originally suggested,[138] [139] leading to much uncertainty as to which patients can be managed without listing for urgent transplantation (Table [2]).

These criteria were recently reevaluated in another cohort of patients with ALF due to acetaminophen managed at King's College.[140] The positive predictive value was 80% compared with 84% in the original series, whereas the negative predictive value was 94%, even higher than the 86% found in the original series and in keeping with the figure of 93% in a recent series from Denmark.[136] With additional consideration of blood lactate levels (a postresuscitation arterial blood lactate level > 3.0 mmol/L or either this parameter or an “early” value > 3.5 mmol/L), negative predictive values were 97 and 99%, respectively. Positive predictive values fell to 79 and 74%, respectively. Additional consideration of blood lactate levels modestly improved the negative predictive value, but positive predictive value remained higher with the initial King's College criteria alone (Table [2]). Nonetheless, patients with a poor outcome were identified earlier when blood lactate levels were taken into consideration.[140]

In the Clichy criteria proposed by Bernuau et al,[141] the presence of coma or confusion in association with reduced factor V levels carried positive and negative predictive values for death in patients with viral hepatitis, mostly due to hepatitis B virus of 82 and 98%, respectively. However, in a French study subsequently reporting on encephalopathic patients with non-acetaminophen-related ALF, mostly due to acute viral hepatitis B as in the Clichy series, the Clichy criteria were found to have a substantially lower ability to correctly identify which patients would survive without transplantation.[141] Furthermore, the Clichy criteria performed less well in this regard than did the King's College criteria when both sets of indicators were applied to the same non-acetaminophen study population.[142] By contrast, positive predictive values of the two sets of criteria were comparably high, in keeping with a subsequent report on 17 patients from London.[143] A Belgian series of patients with non- acetaminophen-related ALF found that overall predictive accuracy was modestly increased when both the King's College and the Clichy criteria were considered in combination, although the ability to identify patients who will recover spontaneously remained low, even in this circumstance.[144] In the only reported comparative assessment of the two sets of criteria in acetaminophen-related ALF, Izumi et al[143] found that the Clichy criteria performed less well, with lower positive predictive value (49 versus 92%) and predictive accuracy (56 versus 83%).

Factor VIII and factor V ratios[145]; serial prothrombin times[146]; assessment of liver size on computerized tomography scanning[147]; liver histology[148]; the Acute Physiology and Chronic Health Evaluation (APACHE) score[149]; sensory evoked potentials[150]; serum levels of Gc-globulin (vitamin D-binding protein), which is an important liver-derived component of the extracellular actin-scavenging system[151]; and the severity of the SIRS[112] have alternatively been proposed as possible prognostic indices in FHF, with varying degrees of applicability and reports of efficacy. In India, where the hepatitis E virus is endemic and the most common cause of ALF, older age, a non-hepatitis E virus-related etiology, advanced encephalopathy grade, cerebral edema, and degree of prolongation of prothrombin time have been identified as factors indicative of poor prognosis.[152] [153]

The possible prognostic value of circulating and intrahepatic cytokine levels has been the subject of several recent reports. In a report from the United Kingdom, circulating levels of both IL-6 and IL-8, but not TNF-α, were found to be significantly higher in patients who subsequently died than in those who survived.[104] Lack of correlation with the degree of liver failure, as reflected by prothrombin time, serum bilirubin level, or degree of hepatic encephalopathy, suggested that these parameters reflected not the severity of ALF per se but rather complications such as circulatory disturbance and resultant extrahepatic multiorgan failure, as discussed earlier. The value of incorporating such indices in prognostic modeling with the aim of selecting patients for transplantation is limited because the hemodynamic instability that they reflect otherwise precludes such intervention. A Japanese study found that circulating levels at hospital admission of TNF-α and IL-10, but not IL-6, were significantly higher in patients who died than in those who survived. In keeping with the United Kingdom experience, levels did not correlate significantly with degree of liver injury as reflected by serum transminase values.[105] A German series found no significant correlations between intrahepatic levels of IL-12, IFN-γ, or IL-10, at either protein or mRNA levels, and jaundice to encephalopathy time, encephalopathy grade, requirement for inotrope support, serum bilirubin level, prothrombin time, or APACHE II score.[103]

Hyperphosphatemia, possibly as a consequence of renal impairment and lack of substrate utilization due to blunted hepatic regenerative activity, as discussed earlier, has recently been reported to be an early predictor of poor outcome in severe acetaminophen-related liver injury.[136] In a series of 125 patients, including 30 with hepatic encephalopathy, a threshold phosphate concentration of 1.2 mmol/L or above at 48 to 96 hours after overdose had higher sensitivity, predictive accuracy, and positive and negative predictive values for death than did the King's College criteria (89 versus 67%, 98 versus 92%, 100 versus 80%, and 98 versus 93%, respectively). Specificity was 100%. Consideration of the King's College criteria in combination with the phosphate level led to improvement in sensitivity to 94%. As with consideration of blood lactate levels,[140] patients with a poor outcome were identified substantially earlier using the phosphate criteria (median 1 hour after referral) than they were with the King's College guidelines (median 12 hours).[135]

Finally, the association between adrenal insufficiency and outcome has recently been assessed. Patients who did not survive to discharge from the intensive care unit or who underwent liver transplantation had significantly lower increment and peak cortisol levels after stimulation with synacthen than did patients who survived. Higher incidences of subnormal increment and peak cortisol levels were found in nonsurvivors (55%) than they were in survivors (21%).[106] Nonetheless, the relative lack of both sensitivity and specificity limits the usefulness of these parameters for prognostic modeling in individual patients, at least when considered in isolation.

ABBREVIATIONS

A20a TNF-inducible protein

AIFapoptosis-inducing factor

ALFacute liver failure

AP-1activating protein-1

APACHEacute physiology and chronic health evaluation

ATPadenosine triphosphate

Bid, Bax, Bcl2, Bcl-X_Lmembers of the Bcl protein family

FADDFas-associated proteins with death domain

FasLFas ligand

HBsAghepatitis B surface antigen

HGFhepatocyte growth factor

IFN-γinterferon gamma

ILinterleukin

iNOSinducible nitric oxide synthase

JNKc-Jun-N-terminal kinase

LPSlipopolysaccharide

MPTmitochondrial permeability transition

NF-κBnuclear factor kappa B

NOnitric oxide

SIRSsystemic inflammatory response syndrome

TGF-βtransforming growth factor-beta

TNF-αtumor necrosis factor-alpha

TNF-R1tumor necrosis factor receptor 1

TRADDTNF-R-associated protein with death domain

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