Alcoholic liver disease: mechanisms of injury and targeted treatment

Nature Reviews Gastroenterology and Hepatology - Tập 12 Số 4 - Trang 231-242 - 2015
Alexandre Louvet1, Philippe Mathurin1
1Service des Maladies de L'appareil Digestif et Unité INSERM 995, Hôpital Huriez, Rue Polonovski, 59037 Lille Cedex, France.

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European Association for the Study of the Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J. Hepatol. 57, 399–420 (2012).

Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141, 1572–1585 (2011).

Lucey, M. R., Mathurin, P. & Morgan, T. R. Alcoholic hepatitis. N. Engl. J. Med. 360, 2758–2769 (2009).

Mathurin, P. et al. Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features. Aliment. Pharmacol. Ther. 25, 1047–1054 (2007).

Pessione, F. et al. Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence. Liver Int. 23, 45–53 (2003).

Verrill, C., Markham, H., Templeton, A., Carr, N. J. & Sheron, N. Alcohol-related cirrhosis—early abstinence is a key factor in prognosis, even in the most severe cases. Addiction 104, 768–774 (2009).

Mendenhall, C. L. Anabolic steroid therapy as an adjunct to diet in alcoholic hepatic steatosis. Am. J. Dig. Dis. 13, 783–791 (1968).

Galambos, J. T. Natural history of alcoholic hepatitis. 3. Histological changes. Gastroenterology 63, 1026–1035 (1972).

Pares, A., Caballeria, J., Bruguera, M., Torres, M. & Rodes, J. Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage. J. Hepatol. 2, 33–42 (1986).

Norberg, A., Jones, A. W., Hahn, R. G. & Gabrielsson, J. L. Role of variability in explaining ethanol pharmacokinetics: research and forensic applications. Clin. Pharmacokinet. 42, 1–31 (2003).

Cederbaum, A. I. Alcohol metabolism. Clin. Liver Dis. 16, 667–685 (2012).

Lieber, C. S. ALCOHOL: its metabolism and interaction with nutrients. Ann. Rev. Nutr. 20, 395–430 (2000).

Lieber, C. S. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol 34, 9–19 (2004).

Lu, Y. & Cederbaum, A. I. CYP2E1 and oxidative liver injury by alcohol. Free Radic. Biol. Med. 44, 723–738 (2008).

Lieber, C. S. Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968–1998)—a review. Alcohol. Clin. Exp. Res. 23, 991–1007 (1999).

Cederbaum, A. I. Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells. J. Gastroenterol. Hepatol. 21 (Suppl. 3), S22–S25 (2006).

Wheeler, M. D. et al. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic. Biol. Med. 31, 1544–1549 (2001).

Philippe, M. A., Ruddell, R. G. & Ramm, G. A. Role of iron in hepatic fibrosis: one piece in the puzzle. World J. Gastroenterol. 13, 4746–4754 (2007).

Tsukamoto, H. et al. Experimental liver cirrhosis induced by alcohol and iron. J. Clin. Invest. 96, 620–630 (1995).

Luedde, T., Kaplowitz, N. & Schwabe, R. F. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147, 765–783 (2014).

Brenner, C., Galluzzi, L., Kepp, O. & Kroemer, G. Decoding cell death signals in liver inflammation. J. Hepatol. 59, 583–594 (2013).

Dolganiuc, A., Thomes, P. G., Ding, W. X., Lemasters, J. J. & Donohue, T. M. Jr. Autophagy in alcohol-induced liver diseases. Alcohol. Clin. Exp. Res. 36, 1301–1308 (2012).

Fernandez-Checa, J. C., Garcia-Ruiz, C., Ookhtens, M. & Kaplowitz, N. Impaired uptake of glutathione by hepatic mitochondria from chronic ethanol-fed rats. Tracer kinetic studies in vitro and in vivo and susceptibility to oxidant stress. J. Clin. Invest. 87, 397–405 (1991).

Fernandez-Checa, J. C., Ookhtens, M. & Kaplowitz, N. Effects of chronic ethanol feeding on rat hepatocytic glutathione. Relationship of cytosolic glutathione to efflux and mitochondrial sequestration. J. Clin. Invest. 83, 1247–1252 (1989).

Hirano, T., Kaplowitz, N., Tsukamoto, H., Kamimura, S. & Fernandez-Checa, J. C. Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats. Hepatology 16, 1423–1427 (1992).

Wheeler, M. D. et al. Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J. Biol. Chem. 276, 36664–36672 (2001).

Fernandez-Checa, J. C., Kaplowitz, N., Garcia-Ruiz, C. & Colell, A. Mitochondrial glutathione: importance and transport. Semin. Liver Dis. 18, 389–401 (1998).

Fernandez-Checa, J. C., Hirano, T., Tsukamoto, H. & Kaplowitz, N. Mitochondrial glutathione depletion in alcoholic liver disease. Alcohol 10, 469–475 (1993).

Gong, P., Cederbaum, A. I. & Nieto, N. Heme oxygenase-1 protects HepG2 cells against cytochrome P450 2E1-dependent toxicity. Free Radic. Biol. Med. 36, 307–318 (2004).

Imrie, D. & Sadler, K. C. Stress management: how the unfolded protein response impacts fatty liver disease. J. Hepatol. 57, 1147–1151 (2012).

Malhi, H. & Kaufman, R. J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 54, 795–809 (2011).

Ji, C., Deng, Q. & Kaplowitz, N. Role of TNF-α in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 40, 442–451 (2004).

Petrasek, J. et al. STING–IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc. Natl Acad. Sci. USA 110, 16544–16549 (2013).

Esfandiari, F., Villanueva, J. A., Wong, D. H., French, S. W. & Halsted, C. H. Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am. J. Physiol. 289, G54–G63 (2005).

Ji, C. Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. J. Gastroenterol. Hepatol. 23 (Suppl. 1), S16–S24 (2008).

Crabb, D. W. & Liangpunsakul, S. Alcohol and lipid metabolism. J. Gastroenterol. Hepatol. 21 (Suppl. 3), S56–S60 (2006).

Ji, C. & Kaplowitz, N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124, 1488–1499 (2003).

Hernandez-Gea, V. et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J. Hepatol. 59, 98–104 (2013).

You, M., Fischer, M., Deeg, M. A. & Crabb, D. W. Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP). J. Biol. Chem. 277, 29342–29347 (2002).

Endo, M., Masaki, T., Seike, M. & Yoshimatsu, H. TNF-α induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp. Biol. Med (Maywood) 232, 614–621 (2007).

Lawler, J. F. Jr, Yin, M., Diehl, A. M., Roberts, E. & Chatterjee, S. Tumor necrosis factor-α stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase. J. Biol. Chem. 273, 5053–5059 (1998).

Nakajima, T. et al. Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage. Hepatology 40, 972–980 (2004).

Galli, A., Pinaire, J., Fischer, M., Dorris, R. & Crabb, D. W. The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor α is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J. Biol. Chem. 276, 68–75 (2001).

Fischer, M., You, M., Matsumoto, M. & Crabb, D. W. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. J. Biol. Chem. 278, 27997–28004 (2003).

Molina, P. E. Alcohol–intoxicating roadblocks and bottlenecks in hepatic protein and lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 295, E1–E2 (2008).

Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

Garcia-Villafranca, J., Guillen, A. & Castro, J. Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver. Biochimie 90, 460–466 (2008).

You, M. & Crabb, D. W. Recent advances in alcoholic liver disease. I. Minireview: molecular mechanisms of alcoholic fatty liver. Am. J. Physiol. 287, G1–G6 (2004).

Yin, H. et al. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 146, 801–811 (2014).

You, M., Liang, X., Ajmo, J. M. & Ness, G. C. Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am. J. Physiol. 294, G892–G898 (2008).

Jeong, W. I. et al. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell. Metab. 7, 227–235 (2008).

Louvet, A. et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology 54, 1217–1226 (2011).

Bykov, I. et al. Hepatic gene expression and lipid parameters in complement C3−/− mice that do not develop ethanol-induced steatosis. J. Hepatol. 46, 907–914 (2007).

Cohen, J. I., Roychowdhury, S., McMullen, M. R., Stavitsky, A. B. & Nagy, L. E. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice. Gastroenterology 139, 664–674. (2010).

Pritchard, M. T. et al. Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice. Gastroenterology 132, 1117–1126 (2007).

Tomita, K. et al. Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met. Gastroenterology 126, 873–885 (2004).

Naveau, S. et al. Harmful effect of adipose tissue on liver lesions in patients with alcoholic liver disease. J. Hepatol. 52, 895–902 (2010).

Naveau, S. Excess weight risk factor for alcoholic liver disease. Hepatology 25, 108–111 (1997).

Raynard, B. et al. Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 35, 635–638 (2002).

Dunn, W. et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J. Hepatol. 57, 384–391 (2012).

Kang, L. et al. Chronic ethanol-induced insulin resistance is associated with macrophage infiltration into adipose tissue and altered expression of adipocytokines. Alcohol. Clin. Exp. Res. 31, 1581–1588 (2007).

Xu, A. et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Invest. 112, 91–100 (2003).

Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).

You, M., Considine, R. V., Leone, T. C., Kelly, D. P. & Crabb, D. W. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 42, 568–577 (2005).

Song, Z., Zhou, Z., Deaciuc, I., Chen, T. & McClain, C. J. Inhibition of adiponectin production by homocysteine: a potential mechanism for alcoholic liver disease. Hepatology 47, 867–879 (2008).

Mathurin, P. et al. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 32, 1008–1017 (2000).

Parlesak, A., Schafer, C., Schutz, T., Bode, J. C. & Bode, C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J. Hepatol. 32, 742–747 (2000).

Tamai, H., Horie, Y., Kato, S., Yokoyama, H. & Ishii, H. Long-term ethanol feeding enhances susceptibility of the liver to orally administered lipopolysaccharides in rats. Alcohol. Clin. Exp. Res. 26 (8 Suppl.) 75S–80S (2002).

Fujimoto, M. et al. Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance. Alcohol. Clin. Exp. Res. 24 (4 Suppl.) 48S–54S (2000).

Hanck, C., Rossol, S., Bocker, U., Tokus, M. & Singer, M. V. Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis. Alcohol Alcohol. 33, 606–608 (1998).

Bhagwandeen, B. S., Apte, M., Manwarring, L. & Dickeson, J. Endotoxin induced hepatic necrosis in rats on an alcohol diet. J. Pathol. 152, 47–53 (1987).

Adachi, Y., Moore, L. E., Bradford, B. U., Gao, W. & Thurman, R. G. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108, 218–224 (1995).

Nanji, A. A., Khettry, U. & Sadrzadeh, S. M. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc. Soc. Exp. Biol Med. 205, 243–247 (1994).

Gustot, T. et al. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology 43, 989–1000 (2006).

Oak, S., Mandrekar, P., Catalano, D., Kodys, K. & Szabo, G. TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. J. Immunol. 176, 7628–7635 (2006).

Guha, M. & Mackman, N. LPS induction of gene expression in human monocytes. Cell. Signal. 13, 85–94 (2001).

Wheeler, M. D. & Thurman, R. G. Up-regulation of CD14 in liver caused by acute ethanol involves oxidant-dependent AP-1 pathway. J. Biol. Chem. 278, 8435–8441 (2003).

Hritz, I. et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 48, 1224–1231 (2008).

Zima, T. & Kalousova, M. Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcohol. Clin. Exp. Res. 29 (11 Suppl.) 110S–115S (2005).

De Minicis, S. & Brenner, D. A. Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. J. Gastroenterol. Hepatol. 23 (Suppl. 1) S98–S103 (2008).

Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U. & Thurman, R. G. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34, 101–108 (2001).

Xiong, S. et al. Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis. Am. J. Physiol. 295, G512–G521 (2008).

Lin, M., Rippe, R. A., Niemela, O., Brittenham, G. & Tsukamoto, H. Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages. Am. J. Physiol. 272, G1355–G1364 (1997).

She, H. et al. Iron activates NF-kappaB in Kupffer cells. Am. J. Physiol. 283, G719–G726 (2002).

Tsukamoto, H. et al. Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am. J. Physiol. 277, G1240–G1250 (1999).

Afford, S. C. et al. Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J. Pathol. 186, 82–89 (1998).

Colmenero, J. et al. Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology 132, 687–697 (2007).

Maltby, J., Wright, S., Bird, G. & Sheron, N. Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis. Hepatology 24, 1156–1160 (1996).

Taieb, J. et al. Blood neutrophil functions and cytokine release in severe alcoholic hepatitis: effect of corticosteroids. J. Hepatol. 32, 579–586 (2000).

Barnes, M. A. et al. Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis. Hepatology 57, 1980–1991 (2013).

Mandrekar, P., Ambade, A., Lim, A., Szabo, G. & Catalano, D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 54, 2185–2197 (2011).

Wan, J. et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59, 130–142 (2014).

Byun, J. S., Suh, Y. G., Yi, H. S., Lee, Y. S. & Jeong, W. I. Activation of Toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. J. Hepatol. 58, 342–349 (2013).

Minagawa, M., Deng, Q., Liu, Z. X., Tsukamoto, H. & Dennert, G. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology 126, 1387–1399 (2004).

Szabo, G. & Mandrekar, P. A recent perspective on alcohol, immunity, and host defense. Alcohol. Clin. Exp. Res. 33, 220–232 (2009).

Brun, P., Castagliuolo, I., Pinzani, M., Palu, G. & Martines, D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am. J. Physiol. 289, G571–G578 (2005).

Paik, Y. H. et al. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37, 1043–1055 (2003).

Thirunavukkarasu, C., Uemura, T., Wang, L. F., Watkins, S. C. & Gandhi, C. R. Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes. J. Cell. Physiol. 204, 654–665 (2005).

Yan, A. W. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53, 96–105 (2011).

Mutlu, E. et al. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol. Clin. Exp. Res. 33, 1836–1846 (2009).

Chen, P., Starkel, P., Turner, J. R., Ho, S. B. & Schnabl, B. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor I and mediates alcoholic liver disease in mice. Hepatology http://dx.doi.org/10.1002/hep.27489 .

Schnabl, B. & Brenner, D. A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 (2014).

Chen, P. et al. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 148, 203–214 (2014).

Mutlu, E. A. et al. Colonic microbiome is altered in alcoholism. Am. J. Physiol. 302, G966–G978 (2012).

Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014).

Forsyth, C. B. et al. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol 43, 163–172 (2009).

Stadlbauer, V. et al. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J. Hepatol. 48, 945–951 (2008).

Kirpich, I. A. et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 42, 675–682 (2008).

Delzenne, N. M., Neyrinck, A. M., Backhed, F. & Cani, P. D. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat. Rev. Endocrinol. 7, 639–646 (2011).

Malaguarnera, G., Giordano, M., Nunnari, G., Bertino, G. & Malaguarnera, M. Gut microbiota in alcoholic liver disease: pathogenetic role and therapeutic perspectives. World J. Gastroenterol. 20, 16639–16648 (2014).

Diehl, A. M. Recent events in alcoholic liver disease, V. effects of ethanol on liver regeneration. Am. J. Physiol. 288, G1–G6 (2005).

Michalopoulos, G. K. Liver regeneration: alternative epithelial pathways. Int. J. Biochem. Cell Biol. 43, 173–179 (2011).

Cosgrove, B. D. et al. An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha. Hepatology 48, 276–288 (2008).

Freimuth, J. et al. Loss of caspase-8 in hepatocytes accelerates the onset of liver regeneration in mice through premature nuclear factor kappa B activation. Hepatology 58, 1779–1789 (2013).

Wang, H. et al. Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity. Hepatology 51, 1354–1362 (2010).

Webber, E. M., Bruix, J., Pierce, R. H. & Fausto, N. Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 28, 1226–1234 (1998).

Xu, M. J. et al. Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy: a critical role for IL-6/STAT3. Hepatology 61, 692–702 (2015).

Roskams, T. et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am. J. Physiol. 163, 1301–1311 (2003).

Koteish, A., Yang, S., Lin, H., Huang, X. & Diehl, A. M. Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. J. Biol. Chem. 277, 13037–13044 (2002).

Dippold, R. P., Vadigepalli, R., Gonye, G. E., Patra, B. & Hoek, J. B. Chronic ethanol feeding alters miRNA expression dynamics during liver regeneration. Alcohol. Clin. Exp. Res. 37 (Suppl. 1) E59–E69 (2013).

Jung, Y. et al. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 134, 1532–1543 (2008).

Sancho-Bru, P. et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology 55, 1931–1941 (2012).

Dubuquoy, L. et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut (in press).

Tsuchiya, M. et al. Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice. Hepatology 56, 130–139 (2012).

Lieber, C. S., Jones, D. P. & Decarli, L. M. Effects of prolonged ethanol intake: production of fatty liver despite adequate diets. J. Clin. Invest. 44, 1009–1021 (1965).

Lieber, C. S., DeCarli, L. M. & Sorrell, M. F. Experimental methods of ethanol administration. Hepatology 10, 501–510 (1989).

Tsukamoto, H. et al. Severe and progressive steatosis and focal necrosis in rat liver induced by continuous intragastric infusion of ethanol and low fat diet. Hepatology 5, 224–232 (1985).

Tsukamoto, H., Reidelberger, R. D., French, S. W. & Largman, C. Long-term cannulation model for blood sampling and intragastric infusion in the rat. Am. J. Physiol. 247, R595–R599 (1984).

von Montfort, C., Beier, J. I., Guo, L., Kaiser, J. P. & Arteel, G. E. Contribution of the sympathetic hormone epinephrine to the sensitizing effect of ethanol on LPS-induced liver damage in mice. Am. J. Physiol. 294, G1227–G1234 (2008).

Bertola, A., Park, O. & Gao, B. Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin. Hepatology 58, 1814–1823 (2013).

Mathews, S., Xu, M., Wang, H., Bertola, A. & Gao, B. Animals models of gastrointestinal and liver diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges. Am. J. Physiol. 306, G819–G823 (2014).

Affo, S. et al. Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis. Gut 62, 452–460 (2013).

Altamirano, J. et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 146, 1231–1239 (2014).

Affo, S. et al. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut 63, 1782–1792 (2014).

Dominguez, M. et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 136, 1639–1650 (2009).

Morales-Ibanez, O. et al. Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. Hepatology 58, 1742–1756 (2013).

Yong, K. J. et al. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N. Engl. J. Med. 368, 2266–2276 (2013).

O'Shea, R. S., Dasarathy, S. & McCullough, A. J. Alcoholic liver disease. Am. J. Gastroenterol. 105, 14–32 (2010).

Mathurin, P. et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J. Hepatol. 36, 480–487 (2002).

Mathurin, P. et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 60, 255–260 (2011).

Forrest, E. H. et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut 54, 1174–1179 (2005).

Dominguez, M. et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am. J. Gastroenterol. 103, 2747–2756 (2008).

Louvet, A. et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 45, 1348–1354 (2007).

Centre Hospitalier Regional, Universitaire de Lille. Lille Model. LilleModel.com [online] , (2015).

Mathurin, P. et al. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology 38, 1363–1369 (2003).

Iimuro, Y., Gallucci, R. M., Luster, M. I., Kono, H. & Thurman, R. G. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26, 1530–1537 (1997).

Yin, M. et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117, 942–952 (1999).

Naveau, S. et al. Plasma levels of soluble tumor necrosis factor receptors p55 and p75 in patients with alcoholic liver disease of increasing severity. J. Hepatol. 28, 778–784 (1998).

Spahr, L. et al. Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis. J. Hepatol. 41, 229–234 (2004).

Kendrick, S. F., Henderson, E., Palmer, J., Jones, D. E. & Day, C. P. Theophylline improves steroid sensitivity in acute alcoholic hepatitis. Hepatology 52, 126–131 (2010).

di Mambro, A. J. et al. In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis. Hepatology 53, 1316–1322 (2011).

Dhanda, A. D. et al. Long-term outcome in patients with severe alcoholic hepatitis can be reliably determined using an in vitro measure of steroid sensitivity. Hepatology http://dx.doi.org/10.1002/hep.27211 .

Kendrick, S. F. et al. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology 51, 1988–1997 (2010).

Hamdi, H. et al. Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis. Hepatology 46, 1986–1992 (2007).

Mookerjee, R. P. et al. Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. Gut 52, 1182–1187 (2003).

Spahr, L. et al. Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study. J. Hepatol. 37, 448–455 (2002).

Tilg, H. et al. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J. Hepatol. 38, 419–425 (2003).

Sharma, P., Kumar, A., Sharma, B. C. & Sarin, S. K. Infliximab monotherapy for severe alcoholic hepatitis and predictors of survival: an open label trial. J. Hepatol. 50, 584–591 (2009).

Naveau, S. et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 39, 1390–1397 (2004).

Boetticher, N. C., et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 135, 1953–1960 (2008).

Brenndorfer, E. D. et al. Anti-tumor necrosis factor alpha treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C. Hepatology 52, 1553–1563 (2010).

Akriviadis, E. et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 119, 1637–1648 (2000).

Sidhu, S. S. et al. Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis (COPE trial). Dig. Dis. Sci. 57, 1664–1671 (2012).

De, B. K. et al. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J. Gastroenterol. 15, 1613–1619 (2009).

Doherty, G. M., Jensen, J. C., Alexander, H. R., Buresh, C. M. & Norton, J. A. Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 110, 192–198 (1991).

Han, J., Thompson, P. & Beutler, B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J. Exp. Med. 172, 391–394 (1990).

Louvet, A. et al. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J. Hepatol. 48, 465–470 (2008).

Mathurin, P. et al. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA 310, 1033–1041 (2013).

Park, S. H. et al. Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: a randomised, non-inferiority, open trial. J. Hepatol. 61, 792–798 (2014).

Thursz, M. et al. Steroids or Pentoxifylline for Alcoholic Hepatitis: Results of the STOPAH Trial. Hepatology 60, LB1 (2014).

Lebrec, D. et al. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology 138, 1755–1762 (2010).

Lieber, C. S. S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings. Alcohol 27, 173–177 (2002).

Colell, A. et al. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine. Hepatology 26, 699–708 (1997).

Garcia-Ruiz, C. Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J. Clin. Invest. 94, 193–201 (1994).

Phillips, M. et al. Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis--a randomised clinical trial. J. Hepatol. 44, 784–790 (2006).

Moreno, C. et al. Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. J. Hepatol. 53, 1117–1122 (2010).

Stewart, S. et al. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J. Hepatol. 47, 277–283 (2007).

Nguyen-Khac, E. et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N. Engl. J. Med. 365, 1781–1789 (2011).

Gustot, T., Durand, F., Lebrec, D., Vincent, J. L. & Moreau, R. Severe sepsis in cirrhosis. Hepatology 50, 2022–2033 (2009).

Louvet, A. et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology 137, 541–548 (2009).

Wasmuth, H. E. et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J. Hepatol. 42, 195–201 (2005).

Leon, C. G., Tory, R., Jia, J., Sivak, O. & Wasan, K. M. Discovery and development of toll-like receptor 4 (TLR4) antagonists: a new paradigm for treating sepsis and other diseases. Pharm. Res. 25, 1751–1761 (2008).

Imperiale, T. F. & McCullough, A. J. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann. Intern. Med. 113, 299–307 (1990).

Maddrey, W. C. et al. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 75, 193–199 (1978).

Hardy, T. et al. White cell count and platelet count associate with histological alcoholic hepatitis in jaundiced harmful drinkers. BMC Gastroenterol. 13, 55. (2013).

Mookerjee, R. P. et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J. Hepatol. 55, 1103–1111 (2011).

US National Library of Medicine, ClinicalTrials.gov [online] , (2015).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2013).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2013).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2013).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US National Library of Medicine, ClinicalTrials.gov [online] , (2014).

US Department of Health and Human Services. NIH Research Portfolio Online Report Tools (RePORT) [online] , (2015).