Acute liver failure: individualization of care and minimizing the need for liver transplantation

Acute liver failure (ALF) is a challenging condition that requires a rapid transfer and management in a specialized intensive care unit affiliated to a transplant center. The outcome depends mainly on patient’s age, etiology of ALF, severity of the neurological damage at time of presentation, systemic and brain hemodynamic status and the possibility of a rapid access to liver transplantation (LT). Nevertheless, in recent years, the global survival rate improved and the number of patients with ALF who do not require LT have significantly increased. Between 1998 and 2013, the gap of improvement was respectively 12% and 25% (1). During the same period, the number of emergency listings and the number of transplanted patients significantly decreased (P<0.001). Recent data from the European Liver Transplant Registry (ELTR) showed that the 1- and 5-year survival rate of ALF patients transplanted in recent years [2015–2022] significantly improved compared to previous years, reaching respectively 80% and 70% (2). Currently, the main challenge is to improve transplant free survival.

Recently, a group of experts in ALF established, under the auspices of the American College of Gastroenterology, guidelines based on existing data from the literature for diagnosis and management of ALF (3). In recent years, several major factors, as described by Shingina et al., have contributed to the drastic improvement in outcome. Early contact with a LT center is a crucial aspect of the management (3). Bismuth, Samuel et al. had shown that the survival rate of patients with hepatic encephalopathy stage IV and hepatic coma grade 3 at admission, was significantly lower than that of patients with stage 3 or 4 encephalopathy and coma grade 2 (4). Therefore, early transfer patients with paracetamol-induced or non-paracetamol-induced ALF to transplant centers has been well established, as during the waiting time on the emergency list for transplant, patients’ clinical status continues to deteriorate (5). Overall, the appearance of acidosis, oliguria or increased creatinine, altered consciousness, hypoglycemia, increased lactate despite vascular filling, marked increase of international normalized ratio (INR) and of total bilirubin, must be considered for transfer to a liver transplant center. The main causes of ALF are paracetamol, other toxic drugs, hepatitis viruses (A, B, E), autoimmune hepatitis and others. The etiological treatment should not delay the patient transfer and the transplantation if LT criteria are fulfilled. N-acetyl cysteine should be initiated early in cases of paracetamol intoxication (intentional or unintentional) as well as in cases of severe liver failure not related to paracetamol in patients with a low-grade hepatic encephalopathy (6). Other specific treatments should be initiated and/or continued in the expert center with access to transplantation.

One key point highlighted in the guidelines by Shingina et al. is the role of transjugular liver biopsy in patients with ALF (3). Its indication must be carefully considered due to the high-risk of complications in these patients with severe hemostasis disorders. The main indication for transjugular liver biopsy is to rule out contraindications to LT when the cause of ALF has not been found in order not to miss a tumoral liver etiology (hepatic infiltration of an extrahepatic disease). In the series by Hunyady et al., liver biopsy was contraindicated in 7.5% of cases and was used to eliminate contraindications in 12% of patients suspected of having an extrahepatic disease (7).

The King’s College Hospital (KCH) score has been reassessed and validated multiple times for ALF caused by acetaminophen and non-acetaminophen-related cases, considering the advances in the management of ALF. It remains the most widely used score worldwide mainly in patients with acetaminophen related ALF. A meta-analysis showed that the criteria for KCH score for ALF caused by acetaminophen and non-acetaminophen had a high specificity (95% and 81% respectively). However, the sensitivity was relatively low in both groups (58% and 69% respectively) (8). More recently, the same team validated a dynamic predictive model for ALF caused by acetaminophen. Seven variables at day 1 were identified (age, cardiovascular failure, Glasgow coma scale, arterial pH, creatinine, INR, and arterial lactate), and two at day 2 (lowest arterial lactate and INR). In the validation set of this model, the area under the curve (AUC) for 30-day survival was 0.91 (0.87–0.94) using the day 1 model and 0.91 (0.88–0.95) using the day 2 model (9).

Once listed, ALF patients require a very quick access to LT. In most countries, only patients with ALF, once they develop the criteria for LT, are granted priority access to the LT. Meanwhile, this is not the case for those patients with acute on chronic liver failure (ACLF), despite that the MELD score attribution rules allow, to those with a high MELD score, a quick access to transplantation.

The main specific complication of ALF is the occurrence of cerebral edema and a rapid progressive intracranial hypertension. Before the year 2000s, brain death was the first cause of mortality. It became currently the third cause of mortality after sepsis and multiorgan failure (10). Several factors have contributed to this result, including the control of secondary brain insults of systemic origin, hyperosmolar therapy, mechanical ventilation in cases of severe hepatic encephalopathy, sedation of patients with medications that reduce cerebral blood flow, continuous veno-venous hemodialysis and the use of non-invasive intracranial pressure monitoring using transcranial doppler of the middle cerebral artery. The management of other organ failures (cardiovascular, pulmonary, renal, metabolic, infectious) is essential but not specific to ALF.

The expert’s guidelines reported by Shingina et al. for patients with ALF rigorously described all steps for management using the GRADE process (3). Specific liver aspects worth to be developed. In the past, the therapeutic strategy focused on the management of hepatic encephalopathy and cerebral oedema by clearance of ammonia with either continuous or intermittent hemodialysis. In most of the situation continuous renal replacement therapy (CRRT) was performed in patients with AKI or metabolic acidosis and showed in a sub-group analysis, that renal replacement therapy (RRT) use on day 1 and not IRRT was significantly associated with lower 21-day post study admission transplant-free all-cause mortality (11). The development of liver support as a bridge to LT or in anticipation of liver regeneration has been a major challenge. In a controlled, randomized study, involving 102 patients with ALF and meeting criteria for LT, albumin dialysis using the Molecular Adsorbent Recirculating System (MARS) was evaluated. The study did not show significant difference in overall survival at 6 and 12 months between the MARS treatment group and the standard treatment group. Improvement in 6-month survival was observed in the paracetamol induced ALF. The main limitation of this study was the short delay between randomization and LT (median of 16.2 hours), which did not allow for conclusions about the actual efficacy of the MARS system (12). Thus, the MARS might have its place mainly in paracetamol-ALF and as a bridge to transplant (13).

Therapeutic plasma exchange (PE) has been commonly used in the east in patients with decompensated cirrhosis or with ACLF, but only two controlled, randomized studies have shown the efficacy of PE in the treatment of ALF. In the study of Larsen et al. (182 patients with ALF, 58% paracetamol etiology), survival to hospital discharge was 58.7% for patients treated with high-volume PE (10–12 L/day) compared to 47.8% for the control group [hazard ratio (HR) 0.56, 95% confidence interval (CI): 0.36–0.86; P=0.008]. The survival was significantly higher in those patients with poor prognosis but contraindicated for LT in the high-volume PE treatment group compared to the standard medical treatment group (14). More recently, a study including 40 patients showed that survival without transplantation at 21 days was higher in patients treated with standard PE than in the standard treatment group (75% vs. 45%; P=0.04, HR 0.30, 95% CI: 0.01–0.88) (15). Improvement of systemic inflammatory response syndrome (SIRS), sequential organ failure assessment (SOFA) score, reduction in ammonia levels, and lactate clearance were also observed in the PE arms in both studies. These studies have some limitations, no benefit of PE was observed in the group of patients who underwent LT, the liver regeneration process serial monitoring is masked by the amount of coagulation factors administered during the procedure, thus disrupting the decision to accept the graft, efficacy on non-paracetamol ALF etiologies… Despite the limitations of these studies, these techniques could be incorporated into the strategy for managing ALF patients, mainly in critically ill patients, in those contraindicated to LT and in countries where access to transplantation is not readily available.

Other liver support devices, mainly used in eastern countries in patients with ALF and ACLF due to hepatitis B virus (HBV) infection or reactivation, combined two or three different dialysis system that included continuous veno-venous hemodiafiltration (CVV-HDF), PE, MARS, plasma bilirubin adsorption and other devices has been reported, but never evaluated in prospective trials in the context of ALF (13).

Conclusions

Early transfer to a liver transplant center at time of diagnosis and initiation of hepatic encephalopathy is mandatory to optimize management and outcome. The etiology of ALF must be determined rapidly as it affects outcome. Despite improvement in recent years of transplant free survival, LT remains the optimal treatment mainly in non-paracetamol etiologies. In the long wait for further clinical development of new artificial liver support devices, bioartificial liver devices, hepatocyte transplantation using mesenchymal, embryonic, or stem cells therapies, high-volume PE, extra-corporeal albumin dialysis (ECAD) with MARS™ device, could help in the management of critically ill patients with ALF awaiting or have a contraindication to LT. Liver support therapy should be reserved to centers experienced in the management of advanced liver disease either listed for transplant or with a transplant project, and/or to clinical trials. The choice of the support relies mostly on the expertise of the center and the availability of the devices.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-381/coif). F.S. serves as an unpaid editorial board member of HepatoBiliary Surgery and Nutrition. The other author has no conflicts of interest to declare.

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