Pediatric acute liver failure of undetermined cause: A research workshop

Abstract

Pediatric acute liver failure (PALF) is a potentially devastating condition that 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: Experience gained through treatment trials of HLH and MAS in childhood may inform study design for therapy of PALF. Successful approaches to limiting neuroinflammation through reduction of systemic inflammation and standardized neuroprotection protocols that limit glial injury could significantly improve intact survival. Finally, given that PALF is a rare disease, investigative efforts must include broad multicenter collaboration and careful stewardship of biorepository specimens. (Hepatology 2017;65:1026-1037).

Figure 1. Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes

Hemophagocytic syndromes are characterized by an uncontrolled expansion of activated CD8 cells that secrete pro-inflammatory cytokines such as interferon gamma and granulocyte-macrophage colony-stimulating factor. These cytokines cause monocytes to differentiate into macrophages, which then release pro-inflammatory cytokines, thus causing an exaggerated, cyclical cascade. Persistent activation of macrophages leads to massive increase in pro-inflammatory cytokines. The mechanism leading to expansion of activated macrophages is not clear. One possible hypothesis for uncontrolled expansion of T cells is a defect in cytolytic function. Footnote for Figure 1: Granulocyte-macrophage colony-stimulating factor (GM-CSF), soluble interleukin 2 receptor (sIL-2r), macrophage colony-stimulating factor (M-CSF). Figure courtesy of Dr Alexie Gromm.

Figure 2

Proposed model of liver injury progression in indeterminate pediatric acute liver failure. Systemic inflammatory insults may lead to local liver inflammation in conjunction with exogenous local triggers such as viruses that contain PAMPs, and endogenous local triggers in the form of DAMPS generated from liver injury itself. The release of DAMPS from liver injury may promote a feed forward cycle of inflammation. This liver injury ultimately results in the production of sdf1 to promote the recruitment of sprocs and subsequent liver regenerative programs including HGF. As sprocs arise from the bone marrow, systemic inflammation may inhibit this process via suppression of bone marrow stem cells. Altered metabolic state in the form serum glucose may also provide additional signals to promote hepatic regeneration. Brain injury may result from systemic inflammation itself, compounded by toxic metabolite build up from liver injury and altered metabolic state. Together this network of events may lead to the liver, bone marrow, and brain injury often seen in iPALF. Footnote for Figure 2: pathogen associated molecular patterns (PAMPs), damage associated molecular patterns (DAMPs), sinusoidal endothelial cell PROgenitor cells (sprocs); stromal cell-derived factor 1 (sdf1), hepatocyte growth factor (HGF), indeterminate Pediatric Acute Liver Failure (iPALF), cytokeratin 7 positive (CK7⁺), cytokeratin 19 positive (CK19⁺), hepatic progenitor cell (HPC).