What Triggers ‘Indeterminate’ Acute Liver Failure in Children?

By Mike Leonis, MD, PhD

Pediatric acute liver failure is a rare but potentially catastrophic condition that occurs in previously healthy children. Most children will spontaneously recover with medical support, but, unfortunately, up to 20% will undergo liver transplantation, and up to 10% may die before making it to liver transplantation.

Symptoms may be misleading

Symptoms that typically lead parents to bring their child to the hospital for evaluation include the sudden onset of jaundice, abdominal pain and/or vomiting, and possibly disorientation, confusion or severe lethargy. Often, these symptoms overlap with other milder illnesses, such as common viral syndromes. Therefore, first-line caregivers will often get screening labs to assess for biochemical signs of liver injury to aid in their assessment of the patient.

The diagnostic cause isn’t always clear

If the patient is diagnosed with acute liver failure about 60% of the time, doctors can establish a diagnostic cause for their acute liver failure. Unfortunately, this means that 40% of the time, we are unable to establish a firm diagnosis, leading to an “indeterminate” diagnosis. For decades, clinical researchers have wondered what triggers acute liver failure in those patients with an “indeterminate” diagnosis.

Study investigates immune-based biomarkers

As part of the NIH-sponsored Pediatric Acute Liver Failure Study Group, we were able to study a cohort of children with acute liver failure, regardless of triggering etiology, who presented over an 8-year period of time.

All patients were assessed intensively during their initial hospital stay and were followed for up to one year after presentation. During the first part of this study, 47 children with acute liver failure had blood available at the time of initial presentation to study 15 immune cell activation markers by flow cytometry. This cytometric technique allows one to characterize the nature of the immune cells circulating in the child's blood at the onset of their disease and to determine whether the immune cell markers are elevated or not compared to established reference ranges.

When we analyzed these 15 immune cell markers in the "derivation cohort," we identified three groups of patients with various degrees of immune cell activation (i.e. low, medium and high immune cell activation groups) that were distinctly separate from each other.

Interestingly, four immune cell activation markers were sufficient to describe these three groups of patients, and three of these four markers (perforin+ CD8, granzyme+ CD8 and % CD8 cells) all related to the activation of a certain type of immune cell called CD8+ T cells (Figure 1).

High-immune activation cohort linked to 'indeterminate' diagnosis

When we went back and looked at the flow cytometric results for a larger cohort of 71 PALF patients enrolled in a prior era of the study (i.e. the "validation cohort"), we found identical immune activation marker patterns in three distinct groups of patients. Of significant interest to clinicians, the majority of patients in the low-immune activation group had metabolic, acetaminophen or other drug-induced causes for their acute liver failure, whereas the high-immune activation group comprised the patients predominantly with an autoimmune, immune dysregulation or 'indeterminate' diagnosis for their acute liver failure.

This finding was the first solid evidence that the underlying explanation for an “indeterminate” diagnosis in pediatric acute liver failure patients was the presence of a high-immune activation state.

…and worse clinical outcomes

Further analysis showed that patients in the high-immune activation group had worse clinical outcomes than those in the low- and/or medium-immune activation groups, whether we looked at survival with their native liver, days before undergoing liver transplant or combining both of these suboptimal outcomes (Figure 2).

Follow-up studies validate findings

Follow-up studies were performed by coinvestigators and others that showed CD8+ T-cell activation within liver tissue specimens from children with indeterminate PALF, which validated the notion that most children with indeterminate acute liver failure have a high-immune activation state. This has led to coinage of the term "activated T-cell hepatitis" to describe the subset of “indeterminate” patients with a high-immune activation state and has led to research proposals to target those with features of an activated T-cell hepatitis on presentation with novel immunosuppressive therapeutic approaches.

Multicenter study to evaluate immunosuppressive therapy

In fact, the NIH is currently sponsoring a multicenter study underway across 20 pediatric centers in the United States, including Cleveland Clinic Children's, to test the hypothesis of whether immunosuppressive therapy helps those with an "indeterminate" etiology for their pediatric acute liver failure.

Key takeaway

The majority of children with acute liver failure previously diagnosed as “indeterminate” actually have an “activated T cell hepatitis” associated with poorer outcomes compared to those with a low-immune cell activation state. Further research is necessary to determine if immune suppression is the appropriate next best step for this patient population.

References

Leonis, M. A., Miethke, A. G., Fei, L., Maynor, S., Bleesing, J., Squires, R. H., Pediatric Acute Liver Failure Study Group. (2020) “Four biomarkers linked to activation of cluster of differentiation 8-positive lymphocytes predict clinical outcomes in pediatric acute liver failure.” Hepatology 73:233-246. PMID 32294261.

Chapin, C., Melin-Aldana, H., Kreiger, P. A., Burn, T., Neighbors, K., Taylor, S. A., Ostilla, L., Wechsler, J. B., Horslen, S. P., Leonis, M. A., Loomes, K. M., Behrens, E. M., Squires, R. H., Alonso, E. M., Pediatric Acute Liver Failure Study Group. (2020) “Activated CD8 T-cell hepatitis in children with indeterminate acute liver failure: results from a multicenter cohort”. J. Pediatr. Gastroenterol. Nutr. 71:713-719. PMID: 32796431.

Li, R., Belle, S. H., Horslen, S., Chen, L. W., Zhang, S., Squires, R. H., Pediatric Acute Liver Failure Study Group (2016). “Clinical course among cases of acute liver failure of indeterminate diagnosis”. J. Pediatr. 171:163-70. PMID: 26831743

Bucuvalas J, Filipovich L, Yazigi N, Narkewicz MR, Ng V, Belle SH, et al. Immunophenotype predicts outcome in pediatric acute liver failure. J Pediatr Gastroenterol Nutr 2013;56:311–315. [PubMed: 23111765]

About the author: Dr. Leonis is the Medical Director of Pediatric Liver Transplantation at Cleveland Clinic Children’s.