Journal of Hepatology
Volume 46, Issue 4 , Pages 578-582, April 2007

(C) I take the whole liver only

Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery Vanderbilt University Medical Center, 801 Oxford House, Nashville, TN 37232-4753, USA

published online 05 February 2007.

Article Outline

Abbreviations: ALF, acute liver failure, OLT, orthotopic liver transplantation, APOLT, auxiliary partial liver transplantation

 

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1. Introduction 

Acute liver failure (ALF) is classically defined as onset of encephalopathy within 8 weeks of the onset of jaundice in a patient with no history of liver disease [1]. The term was redefined in 1993 as the time course of disease may have important biologic and prognostic implications [2]. There are numerous causes for the disease and this may have important prognostic information as well. For instance, spontaneous recovery rates for acetaminophen toxicity [3] and hepatitis A [4] are high when compared with those of other causes [5] (see article by Renner in this Forum). There are few medical interventions for patients with ALF and artificial biosupport systems have not uniformly demonstrated efficacy although advances in critical care medicine have led to some improvement in outcomes [6] (see article by Singhal and Neuberger in this Forum).

Whole-organ orthotopic liver transplantation (OLT) has emerged as the treatment of choice for ALF in patients for whom spontaneous recovery is not likely [7]. Approximately 5% of patients awaiting an organ in the United States have ALF and are listed as Status 1. In a review of Status 1 patients from 1994 to 2003, 49% received an organ within 15 days of listing [8]. One-year survival for recipients with ALF was 81% with 83% and 75% three-month and one-year graft survival rates, respectively. Similar results were found in the European liver transplant registry (ELTR) [9]. Several other modalities have been studied or are currently under investigation such as auxiliary transplantation [10], bioartificial livers and living related donation [11], but cadaveric OLT remains the gold standard for treatment of irreversible ALF [12].

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2. Why I take the whole organ 

The acutely failing liver creates tremendous metabolic demand and multiorgan dysfunction that must be reversed in order to produce the best outcome in patients for whom spontaneous recovery is deemed unlikely. Moreover, the tolerance of post-transplant complications in this group of acutely ill recipients is lower than that of elective transplant recipients leading to lower overall survival rates in the immediate post-transplant period. Farmer et al. reported 16 (22%) of 95 deaths following liver transplantation for ALF were due to neurologic complications with 13 directly attributable to ALF. Data from the Hospital Paul Brousse indicate that transplantation with high risk (split, steatotic, or ABO incompatible) grafts results in poorer 1-year survival [13]. Of 116 patients who underwent OLT, 1-year survival was 81% vs. 51% in high and low risk grafts, respectively. Multivariate analysis revealed that reduced sized or partial grafts (RR=3.76; 95% CI=1.57–8.94) and steatotic (RR=2.41; 95% CI=1.18–4.92) were predictive of lower 1-year patient survival. It is therefore key to provide an appropriately sized graft with adequate hepatocellular volume while minimizing the risk of technical complications. A balance must be struck between the risk of delaying transplantation while awaiting an appropriate graft and the risk attendant to the use of sub-optimal grafts Table 1.

Table 1. Comparison of techniques used to treat acute hepatic failure
ModalityStudyOne-year survival (%)Complication rateBenefitsDetractors
Whole-organ OLTAzoulay et al. [26]66Biliary – 4%
(1)Sufficient liver mass

(2)Lower complication rates


(1)Organ availability

(2)Need for lifelong immunosuppression

PNF – 0%
Vascular – 8.3%
Total/recipienta – 0.3
van Hoek et al. [25]61Vascular – 1.8%
PNF – 5.5%

ALTAzoulay et al. [26]66Biliary – 42%
(1)Cessation of immunosuppression


(1)Higher complication rates

(2)Rare achievement of overall goals

(3)Selection bias in studies

PNF – 8.3%
Vascular – 25%
Total/recipienta – 1.0
van Hoek et al. [25]62Vascular – 23%
PNF – 12.8%

Living donorUemoto et al. [15]5932%
(1)Immediate organ availability


(1)Insufficient liver mass

(2)Higher complication rates

(3)Donor morbidity and high potential for coercion

(4)Need for lifelong immunosuppression

Nishizaki et al. [17]7787%

OLT, orthotopic liver transplant; ALT, Auxiliary Liver Transplant; PNF, Primary non-function.

aTechnical complications per recipient.

The volume of liver necessary for reversal of the metabolic derangements that result from ALF remains unknown, however a graft size roughly 50% of standard liver volume is necessary for favorable outcome following transplantation although this is still a matter of debate [14]. In one study delayed function occurred more frequently in cirrhotic recipients of small grafts when compared to noncirrhotics [15]. The translation of this to patients with ALF is unknown, but it seems that necessary graft volume is directly related to the severity of the recipient’s disease [12]. A graft unable to meet the metabolic demands of patients with ALF will result in inadequate reversal of the sequela of liver failure and consequently in ongoing coagulopathy, pulmonary, renal and/or neurologic insult. The greatest likelihood of providing a graft to meet these metabolic demands can most reliably be obtained through the utilization of the whole organ.

The greatest shortcoming in utilization of whole organ grafts for ALF lies in donor organ availability. During 2003 and 2004, 52% of patients listed as Status 1 in the United States received an organ within 15 days and only 5% remained listed as Status 1 [16]. Fourteen percent were either downgraded or inactivated, 12% had died, 5% were considered too sick, and 11% had recovered. In western centers the majority of patients receive an organ within a suitable amount of time and a significant amount (25%) recover or are downgraded thus allowing for allocation of grafts to more urgent candidates. Some outcome selection takes place through time spent awaiting an organ, i.e. sicker patients with attendant likelihood of poorer outcomes either die or are inactivated due to advancing disease. The fact that 11% recover cannot be overlooked as these patients are spared the risks of transplantation and lifelong immunosuppression. Moreover, in the case of living donation, two lives could be unnecessarily placed at risk. Ideally, better predictors of spontaneous recovery would identify these patients prior to listing, however highly reliable indices remain elusive [17].

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3. Considerations against living donation 

Due to difficulty in urgently obtaining whole organ grafts, especially in eastern centers, many have advocated the use of living donation [18], [19], [20]. The application of living donor liver transplantation is controversial in itself, and there are several issues specific to its application to ALF. First, although success has been reported, it appears that right hemi-liver grafts are necessary in order to provide adequate liver volume in ALF. Higher rates of complications have been reported in those donating a right hemi-liver graft than those donating the left liver with complication rates ranging from 0% to 67% [21], [22]. The effects of increased donor morbidity come at high cost in this recipient population with reduced patient and graft survival when compared to non-urgent indications for transplantation [23], [24]. No defined level of “acceptable” donor morbidity exists, however if one were to conceive of a donor morbidity to recipient survivor ratio, the denominator would be lower for transplantation in the acute setting. In turn, more donor morbidity would be experienced for each recipient that survives and the effect of living donation on the size of the donor pool is minimal at this time [25]. Moreover, there is no standardized process for evaluating potential organ donors and a certification process for centers performing adult living donor liver transplant as suggested by Busuttil has not been accepted world wide, though one has recently been put in place in the US [26].

Due to the risk for donor morbidity and lack of standardization, serious ethical concerns have arisen regarding the validity of informed consent in urgent cases. Crisis may eliminate the ability to make decisions in a deliberate way and limit the ability of donor candidates to objectively weigh risks and benefits [27]. The central principle of informed consent is to maintain donor autonomy and avoidance of coercion. Arguably, no greater potential for coercion by family, the recipient’s medical team or auto-coercion in combination with significant donor risk exists than in living donor liver transplantation for urgent indications. Although there is likely a role for adult-to-adult living donor OLT, due to the ethical issues and the effects of graft size on recipient outcome this technique is likely best reserved for non-emergent transplantation in centers where cadaveric grafts can reliably be obtained.

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4. Considerations against auxiliary liver transplantation 

Auxiliary partial liver transplantation (APOLT) has the theoretical advantage over whole-organ OLT in that if the native organ recovers and regenerates, the morbidity and cost associated with immunosuppression can be avoided (see article by Jaeck, Pessaux, Wolf in this Forum). This rationale has become obsolete due to the advent of newer immunosuppressive agents and strategies such as early steroid cessation. Regeneration and organ recovery seems to most reliably occur in young patients with hyperacute presentation of ALF due to either acetaminophen toxicity or viral etiology [3]. It is in this group that spontaneous survival is most likely to occur. Outcomes similar to OLT have been reported by the EURALT study group with a 1-year survival of 61% and 62% for APOLT and OLT, respectively, although there were significantly more complications with APOLT [28]. These results must be interpreted with some reservation due to selection bias as the trial is non-randomized and minimal comparison of the group’s baseline characteristics. Moreover, at 1-year only 16/47 (34%) of patients who underwent APOLT were alive and off immunosuppression, including those who underwent graft removal.

To definitively establish APOLT as an acceptable treatment modality, one must establish that a substantial portion of patients can have cessation of immunosuppression in addition to no difference in survival. A case-control study from the Hospital Paul Brousse with excellent matching of two whole-liver OLT controls to each APOLT case suggests that APOLT is associated with significantly more complications than OLT [29]. Patients undergoing APOLT had higher rates of technical complications, infectious complications, and need for re-transplantation than those undergoing OLT. Interestingly, 3 of 12 patients undergoing APOLT had persistent neurologic sequela suggesting that in some cases the partial grafts may be unable to meet the metabolic demands and rapidly reverse brain edema. Only one patient had complete success of APOLT, i.e. survival, regeneration, rapid cessation of immunosuppression and return to independent function. Although survival was similar in the Hospital Paul Brousse study, the European Transplant Registry demonstrated inferior results with 69% vs. 52% 1-year patient survival (p=0.03) for OLT and APOLT, respectively [30]. Thus, although APOLT has seen a recurrence in popularity over the past decade, no definitive evidence exists to indicate its superiority over standard OLT. Evidence does exist, however, that it may be associated with lower 1-year survival, higher complication rates, insufficient withdrawal of immunosuppression and inferior neurologic outcomes.

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5. Other modalities are also of limited value in the setting of ALF 

In addition to the determination of highly accurate predictors of organ recovery, development of a reliable artificial or bioartificial device to supplant liver function would represent the most significant advance in the treatment of ALF since the application of OLT (see article by Singhal and Neuberger in this Forum). Several devices have been introduced however with varying reports of success [31], [32]. Ideally such a device will reverse the multi-organ dysfunction which characterizes liver failure allowing for either native organ recovery or the availability of a suitable cadaveric graft. Several other modalities for bridging to transplantation such as xenotransplantation and hepatocyte transplantation have been investigated, however neither of these modalities is applicable outside of clinical trials.

In conclusion, despite the absence of clinical trials comparing medical therapy alone with OLT, whole-organ grafting is widely accepted as the gold-standard therapy for ALF for which native organ recovery is deemed unlikely; obviously, improving selection parameters to identify these patients is paramount. Providing adequate hepatocellular mass to reverse the effects of the failed liver is crucial to optimize outcomes when transplantation is implemented and using whole-organ grafts is the most effective way to accomplish this. Other modalities such as auxiliary and living-donor transplantation have been described, however neither of these offers conclusive advantage to cadaveric whole-organ OLT in centers where cadaveric organ allocation is common. Moreover, these modalities may pose increased risk to the recipient as is the case with APOLT or risk the life of two people and have ill-defined roles in the non-urgent setting as with living donation. Rapid application of these techniques in an era where highly reliable predictors of native recovery do not exist may subject more patients (and donors) to unnecessary risk inherent to transplantation and immunosuppression. For these reasons, the application of these techniques should remain confined to clinical trials or centers with very low levels or no option for cadaveric organ donation. Outside of these circumstances, whole-organ OLT should remain the metric by which all other therapies are measured as despite theoretical advantages, none have clearly demonstrated superiority.

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References 

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PII: S0168-8278(07)00055-4

doi:10.1016/j.jhep.2007.01.014

Journal of Hepatology
Volume 46, Issue 4 , Pages 578-582, April 2007

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