Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation.
Acute liver failure (ALF) is associated with massive short-term cell death, whereas chronic liver injury is accompanied by continuous cell death. Hepatic stellate cells (HSCs) contribute to tissue repair and liver fibrosis in chronic liver injury, although their role in ALF remains unexplained. Twenty-nine patients (median age = 43 years, 17 females and 12 males) with ALF according to the Acute Liver Failure Study Group criteria were included. Upon the diagnosis of ALF and after 7 days, we determined liver stiffness (LS) with FibroScan, standard laboratory parameters, and serum levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, hyaluronic acid, and markers of overall cell death (M65) and apoptosis (M30). Stellate cell activation and progenitor response were analyzed immunohistochemically in biopsy samples of 12 patients with alpha-smooth muscle actin (alpha-SMA), keratin-17, and keratin-19 staining, respectively. Cell death markers (M30 level = 2243 +/- 559.6 U/L, M65 level = 3732 +/- 839.9 U/L) and fibrosis markers (TIMP-1 level = 629.9 +/- 69.4 U/mL, MMP-2 level = 264 +/- 32.5 U/mL, hyaluronic acid level = 438.5 +/- 69.3 microg/mL) were significantly increased in patients versus healthy controls. This was paralleled by collagen deposition, elevated alpha-SMA expression, and higher LS (25.6 +/- 3.0 kPa). ALF was associated with ductular progenitor proliferation.


CONCLUSIONS
Our results demonstrate HSC activation and a progenitor response in ALF. Positive correlations between LS, the degree of liver cell damage, and the intensity of HSC activation suggest that fibrosis is a response to ALF in an attempt to repair damaged tissue.
Dechêne
Alexander
A
Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
Sowa
Jan-Peter
JP
Gieseler
Robert K
RK
Jochum
Christoph
C
Bechmann
Lars P
LP
El Fouly
Amr
A
Schlattjan
Martin
M
Saner
Fuat
F
Baba
Hideo A
HA
Paul
Andreas
A
Dries
Volker
V
Odenthal
Margarethe
M
Gerken
Guido
G
Friedman
Scott L
SL
Canbay
Ali
A
D000328:Adult; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016923:Cell Death; D004548:Elasticity / Q000502:physiology*; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D055166:Hepatic Stellate Cells / Q000473:pathology*; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D017114:Liver Failure, Acute / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood; D008875:Middle Aged; D012189:Retrospective Studies; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood
D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D006820:Hyaluronic Acid; D020782:Matrix Metalloproteinases