Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis

Abstract

Alcoholic hepatitis (AH) is a severe condition developed in patients with underlying alcoholic liver disease. Ductular reaction has been associated with chronic alcohol consumption but there is no information regarding the extent of liver progenitor cell (LPC) proliferation in AH. The aim of this study was to investigate LPC markers in AH and its correlation with disease severity. Fifty-nine patients with clinical and histological diagnosis of AH were included in the study. LPC markers were assessed by real-time polymerase chain reaction (PCR) and immunohistochemistry. Standard logistic regression analysis and classification and regression trees (CART) analysis were used for statistical analysis. A microarray analysis showed an upregulation of LPC markers in patients with AH. Real-time PCR demonstrated that epithelial cell adhesion molecule (EpCAM), Prominin-1, and Keratin7 were significantly increased in patients with AH compared with normal livers (P 0.01), chronic hepatitis C (P 0.01), and HCV-induced cirrhosis (P 0.01). Immunohistochemistry scores generated for Keratin7 and EpCAM demonstrated a good correlation with gene expression. Keratin7 gene expression correlated with liver failure as assessed by model for endstage liver disease score (r 5 0.41, P 5 0.006) and Maddrey's discriminant function (r 5 0.43, P 5 0.004). Moreover, Keratin7 (OR1.14, P 5 0.004) and Prominin-1 (OR1.14, P 5 0.002), but not EpCAM (OR1.16, P 5 0.06), were identified as independent predictors of 90-day mortality. CART analysis generated an algorithm based on the combination of Keratin7 and EpCAM gene expression that stratified three groups of patients with high, intermediate, and low short-term mortality (89%, 33%, and 6%, respectively; area under the receiver operating curve 0.73, 95% confidence interval 0.60-0.87). Keratin7 expression provided additional discrimination potential to the age, bilirubin, international normalization ratio, creatinine (ABIC) score. Conclusion: LPC markers correlate positively with severity of liver disease and short-term mortality in AH patients. This study suggests that LPC proliferation may be an important feature of AH pathophysiology. (HEPATOLOGY 2012;55:1931-1941

Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis

“…Our histological results are in line with previous data in alcoholic [18,35,36], metabolic [36][37][38] or viral [34] liver disease, which demonstrated that high liver total K7 expression parallel disease severity as assessed by the MELD score. Indeed, LPC are known to expand from the ductular reaction, the intrahepatic stem cell compartment, into the liver lobule when mature hepatocytes are not able to bring full regeneration following severe injury [52], particularly in the setting of ACLF [12].…”

“…Other baseline and dynamic models are currently under investigation [46]. When applying another more restrictive criterion (90-day mortality) as evaluated in another study [18], we also found a significant increase in proliferative LPC and hepatocyte number in patients alive compared to patients who died during this 3-month follow-up (Supplementary table 5). Hepatic gene expression profile also differentiates improvers from non-improvers.…”

“…in previous studies [18,34,37,38]. The presence of infiltrating macrophages in an injured liver is not an unexpected finding in an inflammatory microenvironment, as macrophages participates both to the pro-inflammatory response and the repair mechanisms [53].…”

“…The plasticity of hepatocytes and their possible dedifferentiation into LPC is also described [17]. Nevertheless, in humans, while LPC expansion is known as a marker of disease severity [18], the putative role of these cells in liver function improvement and better clinical outcome remains at present unclear [19]. The proliferative response of this intrahepatic stem cell population [20] and its interactions with other cell types of the hepatic microenvironment, such as macrophages [21] is a focus of major interest and a potential target for new treatment strategies including cytokine [22,23], macrophage [24] or stem cell [25] therapy.…”

Alcohol, Diet and Drug Use Preceding Alcoholic Hepatitis

“…Given that AH is associated with marked dysregulation of progenitor cells and impaired liver regeneration [18, 19], this provides a biologically plausible hypothesis where alcohol cessation may conceivably cause short-term deterioration in liver function. This is consistent with our data that confirm that a proportion of patients have cut down or stopped drinking before coming unwell.…”