Pediatric acute liver failure of undetermined cause: A research workshop

Abstract

Pediatric Acute liver failure (PALF) is a potentially devastating condition which occurs in previously healthy children of all ages and frequently leads to a rapid clinical deterioration. An identified cause for liver injury is lacking in approximately 30% of cases. Children with undetermined diagnosis have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. A single day workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together clinicians and basic scientists to integrate aligned research findings and develop a foundation for new mechanistic studies and future treatment trials. The clinical phenotype of indeterminate PALF shares important similarities to the hyperinflammatory state characteristic of Hemophagocytic lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS). A failure of cytotoxic T cells to limit or contract inflammatory responses may propagate injury and lead to a local and systemic milieu that does not support normal hepatic regeneration. Evidence was presented that bone marrow (BM) derived Sinusoidal endothelial cell PROgenitor Cells (sprocs) play a vital role in hepatic regeneration. Overwhelming systemic inflammatory responses may suppress mobilization of BM sprocs and dampen hepatic recovery. Conclusion: Thus, experience gained through treatment trials of HLH and MAS in childhood may inform study design for therapy of PALF. Successful approaches to limiting neuro-inflammation through reduction of systemic inflammation and standardized neuroprotection protocols that limit glial injury could significantly improve intact survival. Finally, since PALF is a rare disease, investigative efforts must include broad multi-center collaboration and careful stewardship of biorepository specimens.

Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+CD8+ T‐cell infiltrate

“…Patients in this group, called indeterminate PALF (iPALF), have worse outcomes and are more likely to undergo liver transplantation (LT) than those with known diagnosis (dPALF) . To date, little is known about the pathophysiology of iPALF, but growing evidence supports the hypothesis that the liver injury is immune‐mediated, resulting from an imbalance between proinflammatory and anti‐inflammatory factors . iPALF patients frequently exhibit signs of immune activation and dysregulation including cytopenias, elevated soluble interleukin‐2 receptor levels, natural killer cell dysfunction, and development of aplastic anemia (AA) either shortly before or after their liver injury.…”

“…(2,5) To date, little is known about the pathophysiology of iPALF, but growing evidence supports the hypothesis that the liver injury is immune-mediated, resulting from an imbalance between proinflammatory and anti-inflammatory factors. (6)(7)(8)(9)(10)(11) iPALF patients frequently exhibit signs of immune activation and dysregulation including cytopenias, elevated soluble interleukin-2 receptor levels, natural killer cell dysfunction, and development of aplastic anemia (AA) either shortly before or after their liver injury. It is now accepted that immune dysregulation plays a key role in propagating liver injury in the majority of iPALF cases.…”

Successful rescue of acute liver failure and hemophagocytic lymphohistiocytosis following varicella infection: A case report and review of literature

“…Recent studies have suggested that patients with ALF have an immune dysregulation pattern similar to observations in HLH[ 11 , 19 ]. Some patients with ALF present with elevated ferritin and sIL-2R levels, low fibrinogen, and numerous infiltrating CD8+ T cells on liver biopsy, which are compatible with those found in HLH[ 19 , 20 ].…”

“…Indeterminate ALF necessitates a broad evaluation for underlying etiologies; both infectious and noninfectious are included. Although screening for common forms of viral hepatitis, including hepatitis A to E is nearly universal, testing for viruses less frequently considered hepatropic may not always be complete[ 10 , 11 ]. For example, some cases of herpes virus-associated fulminant hepatitis were only confirmed by postmortem liver biopsy[ 12 ].…”

Advances in the diagnosis and management of Haemophagocytic Lymphohistiocytosis: A review of literature

“…Acute liver failure (ALF) and secondary HLH Some cases of acute liver failure are associated with HLH. The condition has been described in both adults and children (Giard et al 2016;Lin et al 2016;Alonso et al 2017). The presence of rampant immune activation and dysregulation with associated ALF makes the diagnosis of HLH difficult.…”