Acute liver failure (ALF) is defined as the acute onset of severe hepatitis with loss of hepatic function in patients with no known underlying liver disease. ALF can result from various hepatic insults including viral infections, drug-induced liver injury, toxin exposures, and autoimmune diseases ( Fig. 37.1 ). Non-A, non-B hepatitis, an unexplained cause for ALF, remains the most common scenario.
ALF in children is a life-threatening event with a mortality rate as high as 90% in the absence of liver transplantation (LT), particularly for those with severe hepatic encephalopathy. It is relatively rare and accounts for approximately 10% to 15% of all LTs in children. The incidence varies by age: 6.9% for 0 to 2 years and 17.9% for 3 to 10 years, with the greatest burden coming in the 11-18-year age group (18.7%). With current intensive medical management and LT for patients meeting established transplant criteria, survival rates have improved to greater than 85% at 1 year and beyond.
In 1974, Karvountzis et al. showed that if patients survive the initial phase of ALF, native liver (NL) function could recover without long-term sequelae. However, for those patients who do not recover hepatic function, orthotopic LT (OLT) became the treatment of choice.
Although general clinical indicators help stratify which patients face the highest mortality risk without transplantation and also those who are likely to recover with supportive care only, there are not yet sufficiently accurate predictors in pediatric ALF to determine who will survive in the absence of transplantation. As such, there is a significant subset of children who have the potential for spontaneous recovery of liver function yet who still undergo standard OLT. The risks of OLT followed by a lifetime on immunosuppressants (IS) are a significant and unnecessary burden.
Current Guide to Listing Criteria for Liver Transplant in Acute Liver Failure in Children
In pediatric patients with ALF, listing criteria focus on acute metabolic and synthetic liver dysfunction, including the following indications, presented in Table 37.1 .
|Acute liver failure
|Metabolic, with cirrhosis
|Alpha 1-antitrypsin deficiency
Glycogenosis type IV
Primary bile acid synthesis defect
|Metabolic, without cirrhosis
|Hyperoxaluria type i
Urea cycle disorders
Familial hypercholesterolemia type IIA
Glycogenosis type IA
Hemophilia type A and B
Protein C deficiency
Hepatitis non A-E
Cryptogenic liver cirrhosis
Infantile copper overload
An international normalized ratio (INR) over 4 and total bilirubin greater than 300 μmol/L (17.6 mg/dL), irrespective of hepatic encephalopathy. Disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis (HLH), must be excluded.
Unresponsive and dilated pupils
Severe respiratory failure/acute respiratory distress syndrome – consider extracorporeal membrane oxygenation
Increasing inotropic requirements
Infection unresponsive to treatment
History of severe progressive neurological problems in which the ultimate neurological outcome may not be acceptable
Systemic disorders such as HLH where LT is not curative
Outcomes of LT for ALF have improved over the past 30 years but are still worse than those for chronic liver disease (CLD) because the children are sicker and invariably transplanted from an intensive care setting. Following liver replacement, these children will have to remain on lifelong immunosuppression with its associated risks of malignancy, renal impairment, hypertension, and infection. The likelihood of liver regeneration in ALF depends on the etiology of liver failure, whether there is a persistent insult, as in patients with sub-ALF, or a single insult, as in mushroom poisoning or acetaminophen overdose; hyper-ALF patients are more likely to regenerate than subacute; age when children (and adults < 40 years of age) are more likely to regenerate compared with adults; and pattern of hepatocyte loss, where there is a complete loss of the hepatocyte population regeneration is unlikely. The best treatment option for ALF is to temporarily support liver function until the NL has sufficiently regenerated. Unlike acute kidney injury where hemodialysis can completely replace renal function until the kidneys recover, there are no effective artificial means available for replacing liver function. Although existing liver support devices can carry out some functions like detoxification, none can cover the numerous functions of the liver long enough for the liver regeneration to occur predictably. These devices could serve as a bridge to LT, providing some stability while awaiting emergency LT. Auxiliary LT (ALT) is the only treatment option available at present that can act as a reliable bridge to liver regeneration so that patients are spared lifelong immunosuppression.
Auxiliary Partial Orthotopic Liver Transplant
Auxiliary partial orthotopic liver transplant (APOLT) was proposed as an alternative surgical approach to treat ALF and to allow recovery of NL function. APOLT is a unique surgical procedure in which a portion of the native damaged liver is removed (usually left lobectomy in children), and a partial or whole liver graft is implanted and used as a bridge to NL recovery. The goal of the procedure is to provide support for the liver function of these children while allowing NL to recover.
When the recovery is achieved, immunosuppression is weaned, causing the transplanted liver to involute. This procedure is most beneficial in children and young adults because of the potential to avoid lifelong immunosuppression and its side effects. However, the transplant criteria remain the same for the full liver replacement and ALT. A key consideration is that early patient survival should be the same for both procedures. Our experience suggests that long-term survival seems to be better for the APOLT group than for whole liver replacement group.
Initially considered technically challenging, APOLT has become refined as a surgical procedure, and outcomes are good for selected indications and should be considered to be the gold standard of care for children with ALF.
History of Auxiliary Liver Transplantation
ALT is the heterotopic or orthotopic implantation of a donor liver allograft, either partial or whole, without fully removing the NL. OLT following removal of the NL was first described in dogs by Staudacher in 1952 and humans by Starzl et al. in 1963. Heterotopic ALT was initially performed in dogs by Welch in 1955 and in humans by Absolon et al. in 1964. Initial expectations were that ALT for CLD would be easier to perform and better tolerated than OLT. In reality, ALT proved more technically demanding, and the early results using heterotopic ALT for CLD were poor; if patients did survive, the cirrhotic liver remnant was at risk of developing hepatocellular carcinoma. The first case report of successful ALT for sub-ALF was published in 1990 by Metselaar et al. with radiological and histological recovery of the NL sufficient to allow tapering of IS. Gubernatis et al. reported successful ALT for ALF in 1991, describing NL regeneration with the possibility of withdrawal from IS. These case reports signaled a potential change in the approach to LT in ALF.
Heterotopic Auxiliary Transplantation for Acute Liver Failure
Heterotopic auxiliary transplantation (HALT) involves implanting the new liver graft in a nonanatomical location with minimal or no handling of the NL. Stampfl et al. published the first report of HALT for ALF in 1990. A 15-year-old girl with acute Wilson disease with impending cerebral herniation was planned for emergency ABO-incompatible LT. At surgery, manipulation of the NL caused significant elevations in intracranial pressure (ICP). An intraoperative decision was taken to avoid recipient hepatectomy and to proceed with HALT using the right lobe. The patient did well postoperatively with improved neurological status. She subsequently developed antibody-mediated rejection and underwent orthotopic replacement with a blood group–compatible liver graft after 27 days and made a good recovery. The authors suggested that HALT in the ALF setting was technically feasible and could be used when manipulation of the NL causes significant hemodynamic and ICP shifts. Metselaar et al. were the first to demonstrate that the NL can regenerate after HALT for ALF after reporting HALT in a 35-year-old woman with subacute hepatic failure with predominant function in the NL at 6 months.
Auxiliary Liver Transplantation for Acute Liver Failure: Early Results
In 1996, Chenard-Neu et al. published a multicenter European study of ALT in 30 adult and pediatric recipients with ALF. Only 63% ( n = 19) of the recipients survived at a mean follow-up of 18 months. Of the survivors, 68% ( n = 13) were able to withdraw from IS within the timeframe of the study, with an additional 3 (53% of survivors) doing so outside of the study period. Of note, the relatively early withdrawal of IS may be attributed to the fact that 69% of the 13 patients weaned off IS ( n = 9) had surgical excision of the allograft. Of 30 recipients, 7 were children, 5 of whom survived. Biopsy of the NL in these patients demonstrated complete regeneration in six and regeneration with fibrosis in one. Of the five surviving patients, four were able to withdraw IS completely, and one was being tapered at the time of publication.
In 1999, van Hoek et al. published results from an overlapping multicenter European cohort comparing 47 adult and pediatric patients who underwent ALT for ALF to a further 384 patients who underwent OLT for ALF. There were no differences in patient survival at 1 year (61% for OLT and 62% for ALT), but there was a significantly increased risk of vascular complications in the ALT versus the OLT group (23% vs. 1.8%; P <.01). This was primarily because of an increased risk of portal vein thrombosis in the ALT group (21.3%) as compared with the OLT group (0.5%). Among the ALT group, there were two distinct subsets: heterotopic ALT (HALT), in which a graft (generally partial) is positioned below the intact NL, and partial orthotopic ALT (APOLT), in which part of the NL is resected and replaced by a partial graft. One-year survival for APOLT (71%) was not statistically different from OLT (61%), but both were superior to HALT (33%; P <.05). Seven of the ALT patients required retransplantation, but there were no differences in the 1-year retransplant-free survival between OLT and ALT recipients. Of the 40 ALT patients surviving without retransplantation, the graft was resected in 15 patients, with discontinuation of IS in 14 of those 15 patients, and left in situ in 25 patients with cessation of IS in 6. Nine of the patients with the graft left in situ died within 1 year, as did six of those following allograft hepatectomies. At the end of 1 year, six patients in the ALT group with the graft left in situ and nine patients who had removal of the graft were alive and off IS. Therefore, 15 of 40 ALT patients (38%) who did not require retransplantation were off IS and alive at 1 year. There was one additional patient who was retransplanted by APOLT and was able to be weaned off IS. Therefore, of the 26 surviving patients, 16 (62%) had IS withdrawal at 1 year. There was no separate analysis of outcome in children, although in the ALT cohort there were four patients in the 0-10 year age group and 13 in the 11-20 year age group.
Further small case series also provided evidence that ALT was a viable option for ALF. Boudjema et al. reported eight patients with ALF receiving APOLT, of whom four were children. Of these, six survived (three children), with follow-up ranging from 1 to 17 months. Three patients underwent removal of their graft with cessation of IS; one had the graft left in situ with cessation of IS, one was being tapered, and two remained on full IS at the time of publication. As such, the overall IS rate was 50%, with 67% of patients surviving. A single-center American study from 1997 reported 7 cases of APOLT and 11 OLT for ALF, with follow-up ranging from 2.5 to more than 5 years. All seven were younger than 18 years of age. For the APOLT group, the 30-day, 1-year, and 3-year patient survivals were 100%, 57%, and 57%, respectively, with no statistically significant differences in survival between APOLT and OLT. Four APOLT patients had resection of their allograft, two for biliary complications, one for aplastic anemia, and one underwent retransplantation. The other three had their grafts left in situ , and IS was weaned between 15 months and 3 years after the operation.
These results showed that APOLT was a feasible alternative to OLT for ALF and that IS withdrawal was of benefit to a significant proportion of patients. Evidence had accumulated that HALT was an inferior procedure to APOLT, probably because of inadequate venous inflow or higher caval pressures attributed to the infrahepatic graft placement. The increased risk of vascular complications, including portal vein thrombosis, suggested implantation technique needed refinement to account for portal flow competition between the NL and allograft. However, in the context of ALF this is not a common problem. problem. Initially, portal blood flow is preferential to the graft because of high resistance in the diseased NL. As the NL recovers, portal venous flow shifts from the graft to favor the NL. The presence of the transplanted liver allows for the recovery of NL function over an extended period.
Key aspects to the success of APOLT for ALF are the criteria for recipient and donor selection and identifying any clear contraindications for either recipient or donor livers. Following regeneration of the NL, it does not appear necessary to resect the allograft provided IS is withdrawn slowly and in a controlled manner.
Patient selection is critical for successful APOLT because of the expected regenerative capacity of the NL and the clinical condition of the patient at the time of transplant. The capacity of the NL to regenerate depends on multiple factors. Children and younger adults have better regeneration as compared with older adults, with a threshold set by many units at 40 years of age. Etiology of ALF is important, with hyper-ALF resulting from acetaminophen overdose, viral hepatitis and mushroom poisoning having the best regenerative potential. These insults, although causing massive hepatocyte damage, have the underlying liver architecture preserved, which provides the scaffolding for the surviving hepatocytes to quickly repopulate the liver. With ongoing improvements in pediatric intensive care, it is possible to support patients with ALF for a longer duration, allowing the liver to regenerate. Patients who develop subacute hepatitis have a much lower ability to regenerate. Because of the protracted nature of the liver insult, there is a collapse of the reticulin framework within the liver with a pattern of nodular regeneration, which is slow and less efficient. Quaglia et al. investigated the relationship between explant histology and liver regeneration in a series of 40 patients who underwent APOLT for ALF. Three main types of liver injury were described: “diffuse,” with uniformly distributed hepatocyte loss of a varying degree commonly seen in acetaminophen overdose; “map-like,” with areas of complete liver cell loss with adjacent areas of hyperplastic parenchyma, as seen in seronegative hepatitis; and “complete” loss, with total absence of any recognizable hepatocytes. They reported excellent regeneration after “diffuse” injury and minimal regeneration in cases with “complete” injury.
APOLT is more technically demanding and takes longer than a standard OLT; therefore the condition of the patient at the time of transplantation has to be carefully considered. A number of technical issues, such as longer operative time, handling of the NL, which may worsen “toxic liver” syndrome, causing intraoperative hemodynamic instability and requiring multiorgan support of these patients, has to be borne in mind. Multiorgan failure by itself is not a contraindication for transplantation: patients with ALF are usually on organ support, including artificial ventilation and renal replacement therapy. In the majority of cases, these conditions are reversible once liver function is restored. Patients who are hemodynamically unstable on high doses of inotropes, with severe systemic inflammatory response syndrome, or with high ICP may not tolerate a prolonged procedure and are best treated by liver replacement with early hepatic artery ligation and a temporary portocaval shunt.
Children who are hemodynamically unstable, require high levels of vasopressors, and/or have evidence of cerebral edema are not suitable for ALT because the perioperative morbidity and mortality risk is higher. All children with ALF who meet transplant criteria should be considered for APOLT. The presence of bone marrow suppression in association with seronegative hepatitis should not be considered a contraindication, although it may be associated with a more complex postoperative recovery.
Biopsy of the NL at the time of transplantation should be performed in all patients. Macroscopic and microscopic evidence regarding the likelihood of regeneration and the absence of significant fibrosis are helpful. However, successful ALT with NL recovery has been noted even in cases where intraoperative NL biopsy demonstrated massive hepatocyte necrosis or significant fibrosis.
In the future, beyond histopathological examination of the patterns of hepatocyte loss, the identification of molecular signatures associated with success or failure of NL regeneration may help identify those patients unlikely to benefit from ALT. In 2013, Salehi et al. demonstrated coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity, and angiogenesis. Failed regeneration after ALT was associated with distinct miRNA that enforces cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro and triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663, and 503, whose downregulation was associated with successful regeneration and induced cell proliferation, which is a key determinant of successful outcome. The data suggested that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes, including hepatocyte proliferation.
Criteria used for selection of appropriate grafts both in LT and ALT serve to ensure that function is reliable from early post transplant (see Box 37.1 ). These include donor age younger than 50 years (preferably < 40 years), normal appearance on laparotomy with no gross evidence of steatosis or a less than 10% steatosis on biopsy, and modest elevation of liver function tests. Because partial grafts are most commonly used, recipients are at increased risk of small-for-size syndrome (SFSS) if there is insufficient functional liver mass (i.e., quality and quantity). The clinical features of SFSS include cholestasis, prolonged coagulopathy, portal hypertension, and ascites. To avoid SFSS, the graft weight-to-recipient weight ratio should be at least 0.8% and preferably greater than 1%, as with living donor LT (LDLT).