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Auxiliary liver transplantation in children
38.2 History of auxiliary liver transplantation
38.3 Auxiliary liver transplantation for alf: Early results
38.8 Auxiliary liver transplantation for metabolic disease
38.10 Auxiliary liver transplantation for alf: Late outcomes
Acute liver failure (ALF) in children is a life-threatening event with a mortality rate as high as 90% in the absence of liver transplantation, particularly for those with developing hepatic encephalopathy [1,2]. It is a relatively rare event and accounts for approximately 10%–15% of all liver transplants (orthotopic liver transplantation [OLT]) in children, with the greatest burden being in the 11–18 years age group. With current intensive medical management and liver transplantation for patients meeting established transplant criteria, survival rates have improved to greater than 80% at 1 year posttransplant and beyond.
Although there are clinical indicators which help stratify those patients at highest risk of death without transplantation and those who are likely to recover with supportive care alone, these are not sufficiently developed in children 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 orthotopic liver replacement. The risks of orthotopic liver replacement, followed by a lifetime of immunosuppression (IS), are a significant and potentially unnecessary burden.
38.2 HISTORY OF AUXILIARY LIVER TRANSPLANTATION
Auxiliary liver transplantation (ALT) is the heterotopic or orthotopic implantation of a donor liver allograft, either partial or whole, without fully removing the native liver. OLT following removal of the native liver was first described in dogs by Staudacher in 1952 and in humans by Starzl in 1963 [3,4]. Heterotopic ALT (HALT) was initially performed in dogs by Welch in 1955 and in humans by Absolon in 1964 [5,6]. Initial expectations were that ALT would be easier to perform and better tolerated than OLT. In reality, ALT proved more technically demanding, and early results using HALT for chronic liver disease (CLD) were poor and the cirrhotic liver remnant was a risk for the subsequent development of hepatocellular carcinoma [7,8]. The first case report of successful ALT for subacute liver failure was published in 1990 by Metselaar et al., with radiologic and histologic recovery of the native liver sufficient to allow tapering of IS [9]. Gubernatis et al. reported successful ALT for ALF in 1991 with native liver recovery and withdrawal from IS and a further description of ALT for acute Wilson’s disease with successful liver regeneration [10,11]. These case reports signalled a potential change in approach to liver transplantation in the ALF population.
38.3 AUXILIARY LIVER TRANSPLANTATION FOR ALF: EARLY RESULTS
In 1996, Chenard-Neu et al. published a multicentre European study of ALT in 30 adult and paediatric recipients with ALF in 1996 [12]. Only 63% (n = 19) of the recipients survived, with 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 three more (overall 53% of survivors) outside of the study period. of note, the relatively early withdrawal of IS may be attributed to the fact that 9 (69%) of the 13 patients weaned off IS (n = 9) had surgical excision of the allograft. The paediatric cohort in this series included seven patients, of whom five survived. Biopsy of the native liver in these patients showed complete regeneration in six and regeneration with fibrosis in only one. of the surviving patients, four were able to withdraw from IS completely and one was being tapered at the time of publication.
Several years later, Van Hoek et al. published the results of an overlapping (including some previously reported patients) multicentre European cohort comparing 47 adult and paediatric patients who underwent ALT with 384 patients who underwent OLT for ALF, respectively [13]. 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 OLT group (23% vs. 1.8%, p < 0.01). There was also an increased incidence of portal vein thrombosis in the ALT group (21.3%) compared with the OLT group (0.5%). Among the ALT group, there were two distinct subsets: HALT, in which a graft (generally partial) is positioned below the intact native liver, and auxiliary partial OLT (APOLT), in which part of the native liver is resected and replaced by an appropriately sized partial graft. One-year survival for APOLT (71%) was not statistically different from that for OLT (61%), but both were superior to HALT (33%, p < 0.05). 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 not retransplanted, the graft was resected in 15 patients, with discontinuation of IS in 14 of those 15 patients. In a further 25 patients, the graft was left in situ with cessation of IS in 6. Nine of the patients with the graft left in situ died within the first year, as did six of those who had 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 ALT patient who was retransplanted by APOLT and was able to be weaned off IS. Overall, of the 26 surviving patients, 16 (62%) had IS withdrawal at 1 year. There was no separate analysis of paediatric outcome, although in the ALT cohort there were four patients in the 0–10 years age group and 13 in the 11–20 years age group. It was recognised that an age of <40 years, hyperacute liver failure and children were predictors of survival and withdrawal from IS. An age of >40 years and subacute liver failure identified patients less likely to regenerate.
Further small case series also provide evidence that ALT is a viable option for ALF. Boudjema et al reported eight patients with ALF receiving APOLT, of whom four were children [14]. 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% overall and 67% of surviving patients. A single-centre American publication from 1997 of 7 cases of APOLT and 11 of OLT for ALF with follow-up ranging from 2.5 to >5 years [15] in children (<18 years) reported 30-day, 1-year and 3-year patient survivals for the APOLT group of 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 anaemia and one child underwent retransplantation. The other three children had their grafts left in situ and IS was weaned and withdrawn between 15 months and 3 years.
These early results indicated that APOLT was a viable alternative to OLT for ALF and that IS withdrawal was of benefit to two-thirds of survivors. However, they also highlighted that technical complications were more common (Chapter 40). In addition, it was recognised that HALT outcomes were inferior to APOLT, possibly due to inadequate portal perfusion or secondary to higher caval pressures due to the infrahepatic graft placement. Finally, there is a subgroup of patients with ‘toxic liver syndrome’ in whom the liver is releasing ‘toxins’ into the bloodstream and who remain haemodynamically unstable and encephalopathic; ALT is more difficult in this group and may not be appropriate.
Other important aspects are recipient and donor selection. These have to take into account optimising patient survival, the impact of postoperative complications and the likelihood of liver regeneration and IS withdrawal. In addition, the protocol for identifying liver regeneration and the initiation of IS withdrawal is key to ensuring safe IS tapering and withdrawal with the graft remaining in situ and needs to be carefully supervised.
All children with ALF should be considered for ALT. Children who are haemodynamically unstable, requiring high levels of vasopressors, or have evidence of significant cerebral oedema are not suitable for ALT, as the perioperative morbidity and mortality risk is higher [16]. The aetiology of the ALF (viral, seronegative, paracetamol overdose, etc.) does not appear to strongly influence outcome in children, in contrast to adults older than 40 years, and particularly those with subacute liver failure who appear less likely to regenerate. The presence of bone marrow impairment in association with seronegative hepatitis in children should not be considered a contraindication, although it may portend a more complex postoperative recovery.
Biopsy of the native liver at the time of transplantation should be performed. Macroscopic and microscopic evidence of significant fibrosis may be a relative contraindication. Successful ALT with eventual native liver (NL) recovery has been noted even in cases where intraoperative NL biopsy demonstrated massive hepatocyte necrosis or significant fibrosis [14,15]. A publication from our group examined peri- and postoperative liver biopsies of 49 patients (17 of them children) who underwent ALT over a 10-year period [17]. The majority had evidence of liver regeneration (62%) at the time of transplantation. Acetaminophen (paracetamol) toxicity produced diffuse, uniform hepatocyte loss but not complete necrosis, and invariable recovery of NL function. Failure of regeneration was associated with massive hepatocyte necrosis with little or no evidence of surviving hepatocytes or ‘map-like’ regions of architectural collapse that outnumber areas of regeneration associated with seronegative ALF. More recent data from our group examining molecular changes associated with liver regeneration in patients undergoing ALT for ALF noted differential patterns of expression of microRNA (miRNA) that are associated with cellular proliferation, innate immunity and angiogenesis [18].
This data suggests that pre- or perioperative analysis of the native liver may eventually allow insight into which patients may not regenerate. Histopathological examination of the patterns of hepatocyte loss may also help predict likelihood of liver regeneration. The identification of predictable molecular signatures associated with the failure of NL regeneration may help identify those patients unlikely to benefit from ALT.
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