Outcomes and Prognosis of Acute Liver Failure: Insights from a Busy Liver Centre at Max Healthcare

Introduction

Hepatitis A virus (HAV) infection stands as the leading cause of acute liver failure (ALF) in developing nations.1-3 Advances in critical care and protocol-based management have improved both native liver survival and overall ALF outcomes.4-7 Patients with a significantly elevated INR and/or advanced hepatic encephalopathy (HE) with intracranial hypertension often require LT for survival. An INR > 6.5 is a pivotal criterion as per King’s College Hospital Criteria (KCHC) for ALF not caused by acetaminophen toxicity.8 Severe HE (grade-3 and grade-4) and intracranial hypertension carry a particularly bleak prognosis. Despite multiple transplant criteria for ALF, none reliably predict outcomes, complicating the timing of transplantation in living donor scenarios.8-12 Continuous clinical and biochemical monitoring remains crucial for well-informed liver transplantation decisions in ALF. While the liver’s regenerative capability is impressive post-injury, its potential for recovery is hard to predict, underscoring the need for vigilant monitoring for decision-making. We aim to present our experience from a single centre in treating ALF.

Materials and methods

This was a retrospective single-centre study conducted from June 2017 to February 2024 at the Centre for Liver and Biliary Sciences, Max Hospital, Saket, New Delhi, involving 70 cases of ALF. The data was retrospectively collected and analysed including baseline clinical parameters, biochemical characteristics, LT listing scores, surgical procedures, post-LT immunosuppression, immediate post-surgical complications, post-LT survival and native liver survival (SNL). ALF or fulminant hepatic failure, is defined by sudden and severe liver injury leading to significant dysfunction and HE in individuals without pre-existing liver disease.¹³ Paediatric ALF is defined as coagulopathy with PT ≥ 15 and INR ≥ 1.5 that is uncorrected by Vitamin K, accompanied by HE, or a PT ≥ 20 or INR ≥ 2 with/ without HE in the absence of underlying chronic liver disease.¹⁴

Optic nerve sheath diameter (ONSD), pupillary size, transcranial doppler, deep tendon reflexes and Cushing triad of respiratory difficulty, bradycardia and hypertension were used to diagnose and monitor cerebral oedema or intracranial hypertension.¹⁵ Elective intubation and mechanical ventilation, along with sedation using propofol infusion are standard approaches for neuroprotection in patients with severe hepatic encephalopathy and intracranial hypertension. It was ensured that if the patient’s condition worsened despite medical management, they could quickly be taken up for transplantation. At our LDLT centre as soon as the patient arrived in our ICU, a potential donor was identified, worked up and legal and ethical clearance was done. With this approach it allowed us to wait until the last possible moment before considering transplantation, giving these patients a chance to recover with their native liver. The key indicators for proceeding with LT in ALF patients included worsening INR, lactate levels, worsening of cerebral oedema, increased inotropic requirements and/or deterioration in pulmonary or renal functions. The decision to proceed with LT was based on clinical judgment rather than relying on severity scores. “Too sick to transplant” cases were defined by meeting the following criteria: a Pao2/FiO2 ratio <150 mm Hg, a norepinephrine dose >1 μg/kg per minute, and a serum lactate level >9 mmol/L.¹⁶

All LTs were conducted following approval from the institutional review committee and following national guidelines, adhering to both the Declarations of Helsinki and Istanbul. Owing to the retrospective nature of this study, the requirement for written informed consent was waived. The surgical procedure for LT followed the previously published institute’s protocol8. Intraoperatively, methylprednisolone at 10mg/kg was infused during the anhepatic phase. ALF cases are extubated on post-operative day 2-5 following the surgery depending on the neurological status.

Triple immunosuppression consisting of Tacrolimus, Mycophenolate mofetil (MMF), and steroids was started on the day of liver transplantation (LT). Tacrolimus trough levels were targeted between 8 and 12 ng/mL for the initial 3 months post-transplant, then adjusted to 6-8 ng/mL for the remainder of the first year. Long-term Tacrolimus levels were kept between 3-5 ng/mL. MMF was administered at a dose of 20-40 mg/ kg/day (up to a maximum of 2 grams daily) divided into two doses. Steroids were gradually tapered and stopped after 3 months of surgery.

Statistical analysis

Statistical analysis was conducted using SPSS version 26.0 for Windows. Data are presented as mean ± standard deviation (SD), median with interquartile range for non-normally distributed data, or proportions (%). Proportions were compared using Chi-square or Fisher’s exact test, and continuous variables were analysed using independent sample t-tests or Mann-Whitney U tests. Binary logistic regression was employed for multivariate analysis. A p-value of less than 0.05 was considered statistically significant.

Results

Seventy ALF patients were included in the study, of whom 26 were females (37%) with a median age of 24.5 years (IQR: 13-35). The dataset includes 28 (40%) pediatric patients. The leading cause of ALF in our group was HAV infection in 55.7% of cases, followed by indeterminate causes at 20%, Dengue and AIH at 8.6% each, Hepatitis E virus at 4.3% and Others at 2.9%. The etiological distribution based on outcomes has been mentioned in Figure 1.

The overall cohort was divided into three categories: LT group (n=34), survivors with their native liver (SNL group, n=28) and death group (n=8, not transplanted) as mentioned in Figure 2. The SNL group included 12 paediatric ALF cases at a median age of 22 (13-28) years. Thirteen of these patients met the KCHC for LT listing, however, survived with native liver. The median PELD/MELD score was 40 (36-46). Operative and post-operative complications have been depicted in Table 1. All the recipients in LT group underwent ABO-compatible living donor liver transplantation based on clinical indications as mentioned in methodology. The majority of related donors were first-degree relatives, with parents accounting for 35.3%, siblings at 29.4%, spouses at 14.7%, and others making up the remaining percentage. There was no major complication or mortality in donor group. Most patients in this group were extubated by the second postoperative day (POD, 53%) followed by 26.5% on POD 3, 8.8% on POD 1, 8.8% on POD 4 and 2.9% on POD 5. None of these patients were extubated on table as a part of neuroprotection.

Nine patients required re-exploration post-transplantation for various complications: intraabdominal hematoma (n=1), biliary fistula (n=1), middle hepatic vein thrombosis (MHV, n=1), hepatic artery thrombosis (HAT, n=3), burst abdomen (n=1), and purulent surgical drain (n=2). Post-operative interventions included percutaneous transhepatic biliary drainage in 2 patients, endoscopic retrograde cholangiopancreaticography in 1, MHV stenting in 1, and ultrasound-guided graft liver biopsy in 4. One patient required re-transplantation due to primary graft failure and unfortunately still did not survive. Out of the 34 transplant patients, 10 died postoperatively from various causes: persistent intracranial hypertension leading to brain death (n=5), biliary leak and sepsis (n=2), portal vein thrombosis and multiorgan failure (n=1), primary non-function followed by re-transplant and subsequent sepsis (n=1), and primary non-function alone (n=1). The LT recipients were followed up for a median period of 33 months with survival rate of 70%. In the death group (n=8), three patients had resolving ALF but experienced worsening multiorgan dysfunction, while the remaining five were candidates for LT but were too sick to undergo the procedure (as defined in methodology).

In univariate analysis as shown in table 2, the factors predicting the need for LT, were admission serum international normalized ratio (INR), arterial blood lactate level, jaundice-to-encephalopathy (J-E) interval, and advanced HE. On binary logistic regression analysis (Table 3) using Forward Wald method we entered arterial blood lactate value, Serum INR, HE grade and J-E interval (>7 days) into the predictive model and found that presence of arterial lactate [Exp(B) 2.662, 95% CI 1.42, 4.99, p=0.002] and prolonged J-E interval [Exp(B) 1.635, 95% CI 1.14, 2.35, p=0.008] were the only two significant predictors of LT.

Table 1: Operative details and post operative complications in LT recipients (n=34):

Abbreviations: CIT- Cold ischemia time; GRWR- Graft to recipient weight ratio; HAT- Hepatic artery thrombosis; ICU- Intensive care unit; LL- Left lobe, MRL- Modified right lobe, PVT- Portal vein thrombosis

*Many of the patients have overlapping complications, hence total number of complications are overestimating the proportion of complicated cases.

Table 2: Predictors of liver transplant in patients with ALF (Univariate analysis)

Abbreviations: HAV- Hepatitis A virus, HE- Hepatic encephalopathy, INR- International normalised ratio, J-E - Jaundice to Encephalopathy, LT- Liver transplant, SNL- Survivors with native liver

Table 3: Predictors of LT on multivariate binary logistic regression analysis

Abbreviations: HE- Hepatic encephalopathy, INR- International normalised ratio, J-E - Jaundice to Encephalopathy

Discussion

In developed nations, ALF is from a variety of causes such as paracetamol toxicity (most commonly), autoimmune hepatitis, drug induced liver injury and other metabolic disorders. However, in India, hepatitis viruses account for majority of the ALF cases with hepatitis A virus being the most common cause, followed by drug-induced liver failure (especially anti-tubercular therapy). This difference in aetiology impacts the clinical features and outcomes of ALF.1-3 In our cohort, HAV constituted 55% of cases, and the aetiology did not influence the outcomes. Perhaps, it is time to look at universal vaccination for hepatitis A virus as seroconversion by the age of 2 as has been reported in the past may no longer be valid.

The J-E interval is a prognostic indicator, with intervals greater than 7 days indicating a poor prognosis as evident by the studies done in the western world. Based on this, ALF is subclassified into hyperacute (≤ 7 days), acute (> 7 days to ≤ 4 weeks), and subacute (5 to ≤ 12 weeks) presentations. Hyperacute cases typically have the most favourable prognosis.4 The use of extracorporeal liver assist devices such as therapeutic plasma exchange and continuous renal replacement therapy remains controversial.17-18 Based on our experience, their application is not well-established and may even lead to complications and poorer outcomes. One of the major prognostic indicators for survival of native liver is the improvement of Prothrombin time and this value is altered by plasmapheresis.

Studies have indicated an increased likelihood of native liver survival in conditions such as paracetamol toxicity, hepatitis A, and ischemic hepatitis, whereas the chances are lower in cases of indeterminate and other non-viral causes of ALF like drug induced liver failure. Despite the severity of illness in many patients, medical management has resulted in spontaneous liver regeneration in the majority of cases with ALF. Hepatitis A has been extensively studied in India and has demonstrated favourable outcomes.2,3,6 However, in our cohort HAV etiology did not show significantly improved outcomes as compared to other etiologies.

A recently published paediatric study from another Indian centre examined 61 ALF patients who underwent liver transplantation (LT). Their median MELD score was 37, comparable to our cohort’s median MELD score of 40. Like our group, viral hepatitis was the most frequent cause in their study. They reported a survival without LT (SNL) of 22.8% for KCHC-eligible patients, whereas our cohort showed a higher SNL of 46.4%. This disparity highlights the limitations and potential over-reliance on prognostic scores for transplantation decisions. Post-LT survival rate was 65%.¹⁹

LDLT remains the primary mode of LT in India and other Asian countries where cadaveric donation is not well established. ALF cases in these countries often fail to receive LT if there is no suitable donor or due to financial and logistics constraints. The discussed cases with SNL demonstrate the importance of continuing medical therapy even in presence of poor prognostic scores.

Several criteria are used to list cases with ALF for LT; however, none of them is specific enough to describe when to actually proceed with LT.8-12 While the timing of LT in deceased donor LT (DDLT) setting depends on organ availability, the onus to accurately time the LT lies on the team of hepatologist, intensivists and liver transplant surgeons in the LDLT program. Timing the LT in a LDLT setting is crucial, as an overzealous, early LT may devoid the patient of chances of NLS, while a delay may make the patient non-transplantable if the patient goes on to develop sepsis, irreversible neurological injury or multi-organ failure. The ALF early dynamic model was proposed and validated in adults based on sequential monitoring of arterial ammonia, INR, serum bilirubin and HE.10 Other less commonly used scores are PELD/MELD12, aLIU (admission liver injury unit score) and CHALF score.11 Therefore, treating physicians should exercise caution, prioritize clinical parameters and biochemical trends, and refrain from solely relying on these scores when determining whether to proceed with liver transplantation.

Indeed, it’s crucial to emphasize that patients with ALF, especially those presenting with poor prognostic markers, should be managed at a medical centre equipped with a transplant facility. This ensures that if the condition deteriorates despite medical management, the patient can be promptly taken up for transplantation. This approach at LDLT centres, having a donor on standby, enabled us to wait until it was quite evident that transplantation alone could salvage the patient. This approach provided an opportunity for recovery of the native liver.

The timing of when to consider transplantation in such cases remains a topic of debate. The key indicators, worsening clinical status such as advancing hepatic encephalopathy, escalating intracranial hypertension, involvement of extrahepatic organs, heightened inotropic requirements, and increasing biochemical parameters like INR, bilirubin, and ammonia levels all signify the need to proceed with liver transplantation. It’s important to acknowledge that other Indian centres may have different approaches and protocols tailored to their unique circumstances and patient populations.

From our series, we have reported the first successful living donor liver transplant for dengue related acute liver failure.20 The mortality from transplant in our series was 29.4% and is much higher than our mortality after transplant for chronic liver disease. Perhaps, this figure would be better if we chose to transplant them before clinical deterioration, but in that case, we would not have been able to achieve 40% survival of native liver. Overall, we were able to achieve 74.3% survival in patients with ALF.

In conclusion, HAV infection emerged as the predominant cause of ALF. Elevated arterial blood lactate levels and an extended J-E interval were identified as significant indicators of poor outcomes, often necessitating liver transplantation. While LT offers a life-saving option for many, deciding between medical and surgical management remains complex. This decision is influenced by the postoperative risks associated with LT and the potential for recovery with the native liver, making it a challenging clinical choice.