We would like to thank Dr. Aspinall for the comments regarding our article. This article gives insight into the origin of the macrophage population and their potential in tissue repair processes subsequent to acetaminophen-induced liver failure (AALF). It demonstrates that hepatic macrophages are derived from the recruitment of circulating monocytes and through proliferation of the resident Kupffer cell population during AALF. These findings are in agreement with experimental models of acetaminophen-induced liver injury.[1, 2] This is largely an observational study, but we do point toward the fact that an influx of circulatory-derived monocytes occurs at an earlier time point in the evolution of acute liver injury (ALI) after acetaminophen ingestion (Supporting Table 1). We were only able to examine hepatic macrophages at the time of liver transplantation. We concur that this is a potential limitation of the study, highlighting the inherent difficulties in studying this rapidly evolving disease in humans.
We and others have published that the magnitude of the systemic inflammatory response, characterized by elevations in both pro- and anti-inflammatory cytokines, in AALF correlates very strongly with severity of acute hepatic injury and extrahepatic organ dysfunction.[4, 5] Cytokine profiling data are provided as additional means of stratifying the patient cohort, rather than highlighting novel insights into disease pathogenesis. No patients were in receipt of extracorporeal liver support other than renal replacement therapy.
Subsequent to initial reports,[6, 7] the presence of microbiologically confirmed infection in acute liver failure has recently been described as occurring at a median of 5-10 days after admission to a tertiary liver unit. Administration of prophylactic/preemptive antibiotics is an established standard of care for all patients with evidence of severe ALI necessitating referral to our center with multiple organ failure and thus these patients were not specifically excluded from the study. Nevertheless, the effect of superimposed infection after ALI warrants further investigation in experimental models.
Our data indicate that hepatic macrophages are attempting to resolve inflammation within a reparatory/regenerative microenvironment where levels of proinflammatory mediators (e.g., TNF-α, IFN-γ, and IL-12) were not significantly elevated, compared to pathological control tissue (Supporting Table 2). In view of its postulated role in promoting macrophage/microglial proinflammatory-mediator secretion, the raised circulating levels of ammonia in AALF may be of pathogenic significance earlier in the disease process at the initiation/propagation phases of liver injury.
The limitations of this study would not allow one to draw any conclusions on the effect of ammonia on the functional phenotype of hepatic macrophages during AALF. This question should be explored in vitro and in experimental models of liver injury.
CHARALAMBOS G. ANTONIADES, B.SC., M.B.B.S., M.D., M.R.C.P.1 JULIAWENDON, M.B.CH.B., F.R.C.P.2
1Section of Hepatology, Imperial College London & Institute of Liver Sciences, King's College Hospital, London, UK
2King's College Hospital, Institute of Liver Studies, London, UK