Antoniades et al. are to be congratulated on their extensive study of intrahepatic and circulating macrophage populations in patients with acetaminophen-induced acute liver failure (ALF). However, their important findings deserve clarification.
The authors hypothesize two phases of macrophage involvement during ALF with an influx of bone marrow-derived monocytes being followed by expansion of Kupffer cell-derived macrophages. They compare patients according to clinical outcomes (spontaneous survival, liver transplantation, or death) and describe differing macrophage populations and associated cytokines in each group.
However, there are unstated variables that may have influenced their findings. As a tertiary referral center, the authors' patients may receive initial management elsewhere, which could have included empirical antimicrobials. This data should be included, specifically referencing time from overdosage to inclusion in the study rather than timing from admission at the tertiary unit.
Furthermore, despite many ALF patients having a documented episode of microbial infection during their illness, this group was specifically excluded. This makes it harder to extrapolate the authors' findings to unselected patients with ALF.
Most surprisingly, no data are presented regarding ammonia levels in the different outcome scenarios. The authors' group previously reported significant associations between severity of hyperammonemia and progression of encephalopathy in ALF. In the current study, both the transplanted patients and those who died displayed more encephalopathy, acidosis, coagulopathy, and elevated proinflammatory cytokines than survivors and are likely to have had hyperammonemia.
If so, this has major implications for macrophage functioning in ALF. Clinically relevant concentrations of ammonia sensitize macrophages to activating stimuli, increasing the secretion of proinflammatory cytokines in response to lipopolysaccharide and/or interferon gamma. Therefore, it would be valuable to know whether the patient groups studied by Antoniades et al. had different degrees of hyperammonemia.
Finally, it should be stated whether patients received extracorporeal liver support or albumin dialysis, as this influences cytokine profiling.
In summary, Antoniades et al. provide a comprehensive description of macrophage populations in ALF but the clinical relevance of their findings would be enhanced by clarifying patient phenotypes.
RICHARD J. ASPINALL, MBCHB, PH.D.
Gastroenterology & Hepatology, Queen Alexandra Hospital, Portsmouth, U.K.