Character and temporal evolution of apoptosis in acetaminophen-induced acute liver failure*.
OBJECTIVE
To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of acetaminophen-induced acute liver failure.


METHODS
A prospective observational study in two tertiary liver transplant units.


METHODS
Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11).


METHODS
Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed.


RESULTS
Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis.


CONCLUSIONS
Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.
1Department of Hepatology, Imperial College London, London, UK. 2Institute of Liver Studies at King's College School of Medicine at King's College Hospital, London, UK. 3Institute of Human Health and Performance, University College London, London, UK. 4Department of Asthma Allergy and Lung Biology, King's College London, London, UK. 5Division of Critical Care Medicine, University of Alberta, Edmonton, Canada.
Lucia A
LA
Possamai
Mark J W
MJ
McPhail
Alberto
A
Quaglia
Valentina
V
Zingarelli
R Daniel
RD
Abeles
Robert
R
Tidswell
Zudin
Z
Puthucheary
Jakirty
J
Rawal
Constantine J
CJ
Karvellas
Elaine M
EM
Leslie
Robin D
RD
Hughes
Yun
Y
Ma
Wayel
W
Jassem
Debbie L
DL
Shawcross
William
W
Bernal
Anil
A
Dharwan
Nigel D
ND
Heaton
Mark
M
Thursz
Julia A
JA
Wendon
Ragai R
RR
Mitry
Charalambos G
CG
Antoniades
D018806:APACHE; D000082:Acetaminophen / Q000633:toxicity*; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D016638:Critical Illness; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000097:blood; D008099:Liver; D017114:Liver Failure, Acute / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000503:physiopathology; D010446:Peptide Fragments / Q000097:blood; D011446:Prospective Studies; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D053538:Keratin-18; C561463:M30 cytokeratin-18 peptide, human; C577325:M65 antigen, human; D010446:Peptide Fragments; D000082:Acetaminophen