Auxiliary Transplantation

Background

The liver retains the ability to regenerate completely even after severe ALF. For many patients with ALF there is insufficient time to allow for effective liver regeneration, and in these circumstances death is inevitable in the absence of LT. Orthotopic LT has proved to be the most effective way of restoring liver function in patients with end-stage ALF, with reported 1-year patient survival of greater than 70%. The majority of patients transplanted for ALF are young and are therefore at greatest risk for exposure to the long-term complications of immunosuppression after transplantation, which include nephropathy and renal failure, hypertension, malignancy, and graft failure. With whole-liver replacement, loss of the native liver precludes the possibility of liver regeneration, and this led to renewed interest in ALT for ALF in the early 1990s.

The mortality of ALF before the introduction of LT ranged between 80% and 95%. In the United States between 1997 and 2004 the 1-year and 5-year patient and graft survival rates for LT for ALF were 82%, 70%, 76%, and 61%, respectively. Over a similar time frame the European Liver Transplant Registry database recorded lower 1-year patient and graft survival of 74% and 66%, respectively, and broadly similar 5-year patient and graft survival of 69% and 60%, respectively. Outcomes have improved in recent years (patient survival at 1, 3, and 5 years between 2004 and 2009 was 79%, 75%, and 72%, respectively). The concept of ALT for ALF is to transplant sufficient liver mass to support the patient while the native liver recovers and to have patient survival outcomes that are comparable to whole-liver replacement. Anecdotal reports of ALT from several centers were published together as a European experience (van Hoek et al), which was helpful in identifying that patients under 40 years of age and particularly children were most likely to survive with subsequent liver regeneration and withdrawal from immunosuppression. In addition, patients with hyperacute liver failure seemed to be more likely to regenerate than those with subacute liver failure and that orthotopic rather than heterotopic engraftment had a better outcome.

Auxiliary transplants have included the use of whole liver, right lobe, left lobe, or left lateral segment grafts. Graft selection depends on the quality of the donor liver, size discrepancy between donor and recipient, severity of liver failure (and the degree of “toxic liver syndrome”), and the likelihood of recovery of the native liver. The selection of appropriate recipients for this procedure remains a challenge.

Selection Criteria

The present selection criteria for performing LT for ALF identify patients with a predicted mortality of 85% to 90% in the absence of transplantation. The window for transplantation in these patients before death from multiorgan failure, cerebral edema, or sepsis can be short, and a liver may not become available for transplantation. Patients with ALF can be differentiated by their clinical course into two groups: hyperacute and subacute liver failure. Hyperacute liver failure (e.g., caused by acetaminophen toxicity) has a rapid onset and is associated with encephalopathy and progression of liver failure. It is associated with a toxic liver syndrome with hemodynamic instability, cerebral edema, severe coagulopathy, and renal failure. However, if these patients survive, regeneration occurs rapidly with restoration of normal liver architecture. In contrast, subacute liver failure is associated with a more indolent course, with severe jaundice, moderate coagulopathy, and preservation of renal function. Encephalopathy occurs late and is often associated with the onset of sepsis. Even though these patients have regenerative nodules at the time of transplantation, liver regeneration is often slow and may be ineffective with a higher risk for progression to fibrosis. ALT has been performed successfully in both groups of patients, particularly in children.

When considering ALT, it is important to have a graft of good quality to ensure that sufficient liver mass is transplanted to provide early good graft function. Marginal livers are difficult to use as partial grafts and provide inferior function and should be avoided. If a marginal liver is being considered, it should be used as a whole graft replacement.

Technical Considerations

ALT is technically more demanding than whole-liver replacement, and careful consideration needs to be given to the condition of the recipient at the time of transplantation. Patients with hemodynamic instability or raised intracranial pressure may not tolerate surgery, and whole-liver replacement is more appropriate. Patients with hyperacute liver failure may have toxic liver syndrome secondary to liver necrosis and can temporarily improve with hepatectomy and portocaval shunt. Therefore there is a need to resect the majority of the native liver in these patients to reduce the severity of this systemic insult. If a significant volume of necrotic liver is left in situ, the patient may continue to experience cerebral edema and hemodynamic instability following transplantation, and neurological injury has been reported on several occasions in this group. In our experience an extended right hepatectomy provides the best protection against these effects in adult recipients and also creates space for a right lobe graft with the larger liver mass providing better early graft function.

Poor-quality or small-for-size grafts should not be used in these circumstances because of the likelihood of a poor outcome. Evidence from living donation suggests that the graft-to-recipient body weight ratio should be greater than 0.8% for satisfactory graft and patient survival. Small or poor-quality grafts are at risk for small-for-size syndrome, with the development of cholestasis, ascites, and gastrointestinal hemorrhage with persistence of portal hypertension and death from recurrent sepsis 4 to 6 weeks after LT.

Patients with subacute liver failure invariably have evidence of some regeneration at the time of transplantation. Selection of patients who are suitable for ALT is more difficult because not all will regenerate. Factors predicting native liver regeneration include age younger than 40 years, the absence of significant fibrosis, and the presence of some surviving hepatocytes on liver biopsy at the time of transplantation. Children invariably regenerate regardless of the cause of their liver disease. Patients with subacute liver failure seldom have toxic liver syndrome, and it may be possible to leave a larger mass of native liver behind for regeneration. In addition, their clinical condition tends to be more stable, and they will tolerate more protracted surgery and can be considered for either right or left lobe APOLT. Even though the patient’s recovery after a right lobe graft may be more rapid, liver regeneration occurs more slowly and may be delayed by larger functioning grafts.

Auxiliary Liver Transplantation for Acute Liver Failure in Children

ALF in children is a relatively common indication for LT and accounts for 6.92% (0 to 2 years), 17.93% (3 to 10 years), and 18.67% (11 to 18 years) of patients ( Table 68-1 ). The key problem in children is getting a graft of the appropriate size to use as an auxiliary graft. Farmer et al reported the largest single-center series of LT for ALF in children (159 LT on 122 recipients); however, ALT was not used. In a series from our center from 1990 to 2009, 128 liver transplants were performed on children with ALF, of which 20 were APOLT. Patient survival was 85% at 1, 5, and 10 years. There were 3 deaths at a median of 9 days after APOLT. There were no biliary or vascular complications. Most important is the fact that of 17 survivors, 14 (82%) had successful regeneration of their native livers and the majority had withdrawn from all immunosuppression. The likelihood of obtaining a size-matched graft for children with ALF is uncommon. A right APOLT can seldom be performed because of the problems of size discrepancy; however, the left lateral segment of an adult liver usually provides a satisfactory liver mass for successful APOLT. All the small children in our series of APOLT and the majority reported by others have received left lateral segment grafts.

Results of Auxiliary Liver Transplantation for Acute Liver Failure Worldwide

Reported outcomes of ALT are listed in Table 68-2 . Following early occasional case reports, later series included larger numbers of adults and children with outcomes equivalent to those obtained by whole-liver replacement. Immunosuppression withdrawal is possible in approximately 80% of survivors. The majority of groups use orthotopic rather than heterotopic ALT with formal right or left hepatectomy with the equivalent graft in adult patients. Greater variation has been reported in children, although left hepatectomy and left lateral segment APOLT is the most practical approach and overcomes the problems posed by size discrepancy. All series report high rates of immunosuppression withdrawal, often starting within a few weeks of ALT. Operative and cold ischemia times are longer than with standard LT, reemphasizing that the procedure is technically more demanding.

Background

LT has been used successfully to treat inborn errors of metabolism that produce structural and functional impairment of the liver. Liver replacement not only corrects the underlying metabolic defect but also treats underlying cirrhosis and portal hypertension. Some liver-based metabolic disorders do not cause cirrhosis but are associated with severe or life-threatening extrahepatic complications. LT has been used to replace the defective enzyme or receptor site in such disorders, with a reported long-term survival in children of 78% and 68% at 5 and 10 years, respectively. APOLT has been used as a treatment for noncirrhotic metabolic diseases based in the liver where there is a missing gene product or protein; the rationale is to provide sufficient liver mass to correct the underlying metabolic disorder while retaining a part of the native liver. Should the donor graft fail, it can be removed with the native liver acting as a safety net. In addition, gene therapy remains a possibility in the long term and would avoid the need for lifelong immunosuppression. Contraindications to APOLT include any metabolic disease in which the liver is the site of production of an abnormal protein or enzyme that damages other target organs, such as familial amyloid polyneuropathy and primary hyperoxaluria type 1. These require removal of the entire liver; otherwise any remnant continues to produce the abnormal protein with disease progression. Some of these conditions that have been treated by APOLT are described later.