High‐volume Plasmapheresis in Children With Acute Liver Failure

Field: Medicine (Health Sciences)

See "Safety of High-Volume Plasmapheresis in Children With Acute Liver Failure" by Jørgensen et al on page 815. Pediatric acute liver failure (PALF) is a rare but devastating condition with a transplant-free survival between 10% and 40% depending on etiology (1–3). Significant advances in standard medical treatment (SMT) has seen more patients with ALF recover without the need for liver transplantation. In some cases, however, mortality remains high without liver transplantation because of the sepsis, cerebral edema, and multiple organ failure that follows abrupt loss of hepatic function. In recent years, we have seen the emergence of extracorporeal liver support systems (ELSS) with the aim of supporting patients with ALF or acute on chronic liver failure (AoLF) as a bridge to spontaneous recovery or successful liver transplantation (4,5). Although various ELSS including albumin dialysis (namely Molecular Adsorbent Recirculating System; MARS), plasmapheresis, and high-volume continuous renal replacement therapy (CRRT) have demonstrated an improvement in biochemical and clinical parameters in patients with ALF, no significant effect on patient survival has been shown (6,7). A recent prospective multicenter randomized controlled trial of 182 adult patients with ALF has shown that high volume plasma exchange (PE) with SMT as compared with SMT alone improved transplant-free survival and was able to modulate the proinflammatory response though removal of damage-associated molecular patterns (DAMPs) (8). Current experience of PE in children are limited to small case series in children with ALF using exchange of plasma volume corresponding to 1.3 to 4 times their estimated plasma volume (9–13). In this issue of the Journal, Jørgensen et al (14) describe the use of high-volume PE in a group of children presenting with ALF. Between 2012 and 2019, 16 children with ALF and elevated bilirubin >200 μmol/l or toxic hepatitis were treated with 3 consecutive daily sessions of high-volume PE, replacing 10% of body weight with fresh frozen plasma. Among these 16 children, 8 survived without liver transplantation, 2 survived after liver transplantation, and 6 children died. High-volume PE was well tolerated without major side effects. Furthermore, transaminases, bilirubin, and international normalized ratio all decreased during the 3 days of high-volume PE. Because of the broad criteria used for the initiation of high-volume PE, there was significant heterogeneity in the severity of illness between the group of children who survived with their native liver and the group of children who died or required liver transplantation. The children who survived with their native liver had significantly lower liver injury scores, were not listed for transplantation, and a majority of them had no signs of encephalopathy or multiple organ dysfunction at the time of PE treatment. Although it is possible that high-volume PE may have contributed to transplantation-free survival in this group of patients, it may be argued that these children might have recovered with SMT alone. An ideal ELSS should be able to perform both the synthetic and detoxification function of the liver by removing toxins preventing further aggravation of liver injury, providing a favorable environment for liver regeneration and preventing the development of irreversible neurological damage, multiple organ failure, and uncontrolled infection. The reason for the lack of consistent survival benefit among the different ELSS may be explained by differences in the detoxification function of these systems. It may also be because of the methodological limitations of numerous studies that included heterogenous patient groups with different etiologies and natural histories, as well as the lack of patient stratification according to severity. Currently, the only definitive treatment for patients with ALF who meet poor prognostic criteria is liver transplantation. Unfortunately, many patients die before a suitable organ is found or are too sick to be on the transplant list. Therefore, the important question for the clinician is to decide, which patient may benefit the most from extracorporeal liver support system as a bridge to recovery or liver transplantation. A first group of patients who may benefit from ELSS are patients with potential liver regeneration capacity. Spontaneous recovery of liver function with supportive management has been reported in 33% to 55% of children with ALF (1–3) depending on etiology of liver failure (drug-induced ALF, autoimmune hepatitis, viral hepatis, and acute on chronic liver failure). Among the 8 children who survived without liver transplantation in the Jørgensen et al study (14), 2 patients presented with autoimmune hepatitis, 1 with viral hepatitis, and 3 patients with mushroom poisoning. Early initiation of an intensive therapy with high-volume PE in these patients may have contributed to creating optimal conditions for liver regeneration by the removal of proinflammatory cytokines and damage-associated molecular patterns (DAMPs) released by dying hepatocytes. Interestingly, current evidence from animal models of drug-induced ALF are suggesting that proinflammatory cytokines and DAMPs contribute to liver injury during the early phase of drug hepatotoxicity but promote liver regeneration at later phases (15–19). Among the proinflammatory cytokines, TNF-α appears to be particularly interesting because of its combined effect on the liver by contributing both to hepatic tissue injury during the early proinflammatory phase and promoting late phase liver regeneration by priming quiescent hepatocytes to become more responsive to growth factors (17–19). Therefore, during the initial proinflammatory phase of ALF, high-volume PE may be beneficial for the patients by dampening the systemic inflammatory response syndrome and improving neurological complications and multiple organ failure. The immunomodulatory effect of high-volume PE may also be, however, potentially deleterious during the late phase of ALF by preventing liver regeneration. As the use of high-volume PE can be associated with its own side-effects (volume overload, hypocalcemia), this poses an important question to us as liver intensivists: which patients should be selected for PE and at what point in the trajectory of their illness? This is in fact true for any ELSS. In countries with short waiting time for liver transplantation and in patients without liver regeneration potential, this effect of PE and other ELSS may be of no consequence, while it may be very important for patients with high chance of liver recovery or long waiting time for liver transplantation. Future studies will be required to help the clinician to individualize the extracorporeal liver support therapy to the patient's clinical course in order to bridge them efficiently to liver recovery or transplantation.