Role of inflammation and infection in the pathogenesis of human acute liver failure: Clinical implications for monitoring and therapy

Table 1 Cell types and proteins involved in immune pathogenesis of acute liver failure

Ref.	Cell type/protein study population	Finding in ALF
Taylor et al[12]	Neutrophils	Significant reduction in neutrophil surface expression of CD16 (causing reduced binding capacity) and neutrophil phagocytic activity compared with healthy controls. Impaired phagocytic activity predictive of death without transplantation
	ALF
Manakkat Vijay et al[13]	Neutrophils	Toll-like receptors sense pathogens and induce inflammatory responses. Neutrophil toll-like receptor 9 expression increased on day 1 compared with healthy controls, and correlated with severity of HE and SIRS
	APAP-ALF
Srungaram et al[14]	Osteopontin (activates neutrophils and macrophages)	Median osteopontin levels significantly elevated in the ALF group compared with comparator cohorts; median osteopontin levels were highest in patients with APAP-ALF and ischaemic hepatitis (conditions associated with a hyperacute course and better outcomes - osteopontin may have a central role to play in the resolution of ALF)
ALFSG	ALF
Lawson et al[15]	Neutrophils	Neutrophils accumulate in liver parallel to or slightly after liver injury; number of neutrophils in liver substantial compared with baseline, with increased levels of TNF-α, KC and MIP-2 chemokines
	APAP-ALF
Sehgal et al[16]	Monocyte-macrophages	Functionality of monocytes and macrophages impaired in pregnant patients developing ALF compared with those with ALI.
	Hepatitis E in Pregnancy
Wigmore et al[17]	Monocytes	Peripheral blood mononuclear cells from patients with ALF show reduced potential to produce IL-6 and TNF and elicit an acute phase response in vitro
	ALF
Leifeld et al[18]	Macrophages	CC-chemokines recruit and activate macrophages and T-cells. Elevated levels of serum and intrahepatic chemokines in ALF compared with controls, correlating with extent of infiltration by macrophages and T-cells.
	ALF
dos Santos et al[19]	Eosinophils	High number of intrahepatic eosinophils in ALF, associated with increased expression of IL-6.
	ALF
Wyke et al[20]	Complement system	Defective opsonisation due to complement deficiency. Complement factors reduced to below 40% of the activity of control serum
	ALF

ALF: Acute liver failure; APAP: Acetaminophen; SIRS: Systemic inflammatory response.

Table 2 Proposed biomarkers in acute liver failure with an immune basis

Ref.	Biomarker study population	Relevance	Finding in ALF
Antoniades et al[75]	Monocyte HLA-DR expression	Monocytes are key in the immune dysregulation of ALF	Percentage of monocyte HLA-DR expression significantly lower in ALF patients compared with healthy controls, correlating with poor prognosis
	APAP-ALI
Koch et al[76]	Soluble urokinase plasminogen activator receptor (suPAR)	suPAR related to immune activation in systemic inflammation	suPAR levels significantly increased in ALF patients, correlating with parameters reflecting hepatocyte injury
	ALF (all aetiologies)
Craig et al[77]	Pentraxin-3	Pentraxins are soluble pattern recognition receptors forming part of the humoral innate immune system	Admission levels of pentraxin-3 significantly higher in patients with APAP-ALI than those with non-APAP ALI. Pentraxin-3 levels significantly higher in APAP-ALI patients who died/required transplantation vs spontaneous survivors.
	APAP-ALI
Rule et al[78]	Procalcitonin	Biomarker of bacterial infection studied in other clinical conditions	No difference in procalcitonin levels in pre-defined severity groups, non-SIRS and SIRS groups with no documented infection and no correlation with presence of infection
ALFSG	ALF (all aetiologies)
Antoniades et al[79]	Secretory Leukocyte Protease Inhibitor	Stimulates epithelial cell proliferation and modulates macrophage function	Higher SLPI levels were associated with a greater liver injury, infection and adverse outcome
	APAP-ALI
Craig et al[80]	Neopterin and soluble CD163 (sCD163)	Markers of macrophage activation	Levels of both markers significantly higher in APAP-ALI compared with CLD and healthy controls. No association between biomarker level and presence of infection.
	APAP-ALI

ALF: Acute liver failure; APAP: Acetaminophen.