Subscribe to RSS
DOI: 10.1055/s-0035-1550054
Liver Fibrosis in Alcoholic Liver Disease
Publication History
Publication Date:
14 May 2015 (online)
Abstract
Excessive alcohol consumption causes a wide spectrum of liver disease, ranging from simple steatosis to severe forms of liver injury such as steatohepatitis, liver fibrosis, cirrhosis, and liver cancer. Moreover, alcohol consumption also accelerates liver fibrosis in patients with other types of liver diseases such as viral hepatitis and nonalcoholic fatty liver disease. Virtually all clinical complications of alcoholic liver disease occur in patients with established fibrosis and cirrhosis, thus making fibrosis a key parameter for treatment and prognosis of patients. Here, the authors review diagnosis, management, and antifibrotic therapy of alcoholic liver fibrosis. They discuss both the unique features of alcoholic liver fibrosis and the similarities to liver fibrosis from other etiologies, and review molecular pathogenesis and animal models. Finally, future directions for basic and clinical research on alcoholic liver fibrosis are proposed.
-
References
- 1 Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009; 360 (26) 2758-2769
- 2 Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141 (5) 1572-1585
- 3 Ueno A, Lazaro R, Wang PY, Higashiyama R, Machida K, Tsukamoto H. Mouse intragastric infusion (iG) model. Nat Protoc 2012; 7 (4) 771-781
- 4 Bertola A, Mathews S, Ki SH, Wang H, Gao B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc 2013; 8 (3) 627-637
- 5 Chen CM, Yoon YH, Yi HY, Lucas DL. Alcohol and hepatitis C mortality among males and females in the United States: a life table analysis. Alcohol Clin Exp Res 2007; 31 (2) 285-292
- 6 Roulot D, Costes JL, Buyck JF , et al. Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. Gut 2011; 60 (7) 977-984
- 7 Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liver Dis 2005; 9 (1) 37-53
- 8 Adachi M, Brenner DA. Clinical syndromes of alcoholic liver disease. Dig Dis 2005; 23 (3-4) 255-263
- 9 Altamirano J, Miquel R, Katoonizadeh A , et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014; 146 (5) 1231-9.e1 , 6
- 10 Tiniakos DG. Liver biopsy in alcoholic and non-alcoholic steatohepatitis patients. Gastroenterol Clin Biol 2009; 33 (10-11) 930-939
- 11 Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004; 127 (5) (Suppl. 01) S87-S96
- 12 Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003; 37 (3) 493-503
- 13 Altamirano J, Bataller R. Cigarette smoking and chronic liver diseases. Gut 2010; 59 (9) 1159-1162
- 14 Naveau S, Dobrin AS, Balian A , et al. Body fat distribution and risk factors for fibrosis in patients with alcoholic liver disease. Alcohol Clin Exp Res 2013; 37 (2) 332-338
- 15 Ruhl CE, Everhart JE. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 2005; 129 (6) 1928-1936
- 16 Dranoff JA, Feld JJ, Lavoie EG, Fausther M. How does coffee prevent liver fibrosis? Biological plausibility for recent epidemiological observations. Hepatology 2014; 60 (2) 464-467
- 17 Goh GB, Chow WC, Wang R, Yuan JM, Koh WP. Coffee, alcohol and other beverages in relation to cirrhosis mortality: the Singapore Chinese Health Study. Hepatology 2014; 60 (2) 661-669
- 18 Askgaard G, Grønbæk M, Kjær MS, Tjønneland A, Tolstrup JS. Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study. J Hepatol 2015;
- 19 Corrao G, Bagnardi V, Zambon A, Torchio P. Meta-analysis of alcohol intake in relation to risk of liver cirrhosis. Alcohol Alcohol 1998; 33 (4) 381-392
- 20 Day CP. Who gets alcoholic liver disease: nature or nurture? (extended abstract). Acta Gastroenterol Belg 2003; 66 (4) 290-291 , discussion 292–293
- 21 Stickel F, Osterreicher CH. The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol 2006; 41 (3) 209-224
- 22 Hrubec Z, Omenn GS. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans. Alcohol Clin Exp Res 1981; 5 (2) 207-215
- 23 Druesne-Pecollo N, Tehard B, Mallet Y , et al. Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol 2009; 10 (2) 173-180
- 24 Zintzaras E, Stefanidis I, Santos M, Vidal F. Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?. Hepatology 2006; 43 (2) 352-361
- 25 Li D, Zhao H, Gelernter J. Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet 2012; 131 (5) 725-737
- 26 Chen P, Schnabl B. Host-microbiome interactions in alcoholic liver disease. Gut Liver 2014; 8 (3) 237-241
- 27 Leclercq S, Matamoros S, Cani PD , et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A 2014; 111 (42) E4485-E4493
- 28 Marcos M, Pastor I, González-Sarmiento R, Laso FJ. Common polymorphisms in interleukin genes (IL4, IL6, IL8 and IL12) are not associated with alcoholic liver disease or alcoholism in Spanish men. Cytokine 2009; 45 (3) 158-161
- 29 Wang Y, Hu Y, Chao C , et al. Role of IRAK-M in alcohol induced liver injury. PLoS ONE 2013; 8 (2) e57085
- 30 Roy N, Mukhopadhyay I, Das K , et al. Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population. Gene 2012; 509 (1) 178-188
- 31 Zeng T, Zhang CL, Han XY, Zhao S, Xie KQ. Association between CD14-159C>T polymorphisms and the risk for alcoholic liver disease: a meta-analysis. Eur J Gastroenterol Hepatol 2013; 25 (10) 1183-1189
- 32 Nahon P, Sutton A, Pessayre D , et al. Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death. Clin Gastroenterol Hepatol 2005; 3 (3) 292-298
- 33 Marcos M, Pastor I, Chamorro AJ, Ciria-Abad S, González-Sarmiento R, Laso FJ. Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease. Aliment Pharmacol Ther 2011; 34 (10) 1159-1172
- 34 Trépo E, Nahon P, Bontempi G , et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology 2014; 59 (6) 2170-2177
- 35 Friedrich K, Rupp C, Hov JR , et al. A frequent PNPLA3 variant is a sex specific disease modifier in PSC patients with bile duct stenosis. PLoS ONE 2013; 8 (3) e58734
- 36 Dongiovanni P, Donati B, Fares R , et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013; 19 (41) 6969-6978
- 37 Stickel F, Buch S, Lau K , et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians. Hepatology 2011; 53 (1) 86-95
- 38 Lin CW, Lin CC, Mo LR , et al. Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis. J Hepatol 2013; 58 (4) 730-735
- 39 Innes HA, Hutchinson SJ, Barclay S , et al; Hepatitis C Clinical Database Monitoring Committee. Quantifying the fraction of cirrhosis attributable to alcohol among chronic hepatitis C virus patients: implications for treatment cost-effectiveness. Hepatology 2013; 57 (2) 451-460
- 40 Greenfield JR, Samaras K, Hayward CS, Chisholm DJ, Campbell LV. Beneficial postprandial effect of a small amount of alcohol on diabetes and cardiovascular risk factors: modification by insulin resistance. J Clin Endocrinol Metab 2005; 90 (2) 661-672
- 41 Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25 (1) 108-111
- 42 Bataller R, Rombouts K, Altamirano J, Marra F. Fibrosis in alcoholic and nonalcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2011; 25 (2) 231-244
- 43 Wood MJ, Powell LW, Ramm GA. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008; 111 (9) 4456-4462
- 44 Sorrentino P, Terracciano L, D'Angelo S , et al. Oxidative stress and steatosis are cofactors of liver injury in primary biliary cirrhosis. J Gastroenterol 2010; 45 (10) 1053-1062
- 45 Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity. Clin Liver Dis 2013; 17 (4) 587-607 , viii
- 46 Lieber CS, DeCarli LM, Mak KM, Kim CI, Leo MA. Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin. Hepatology 1990; 12 (6) 1390-1398
- 47 Kisseleva T, Cong M, Paik Y , et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A 2012; 109 (24) 9448-9453
- 48 Lazaro R, Wu R, Lee S , et al. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 2015; 61 (1) 129-140
- 49 Jeong WI, Park O, Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology 2008; 134 (1) 248-258
- 50 Chiang DJ, Roychowdhury S, Bush K , et al. Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis. PLoS ONE 2013; 8 (7) e69114
- 51 Karaca G, Xie G, Moylan C , et al. Role of Fn14 in acute alcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 2015; 308 (4) G325-G334
- 52 Li JP, Gao Y, Chu SF , et al. Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis. Acta Pharmacol Sin 2014; 35 (8) 1031-1044
- 53 Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425-456
- 54 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115 (2) 209-218
- 55 Chedid A, Arain S, Snyder A, Mathurin P, Capron F, Naveau S. The immunology of fibrogenesis in alcoholic liver disease. Arch Pathol Lab Med 2004; 128 (11) 1230-1238
- 56 Sakhuja P. Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis?. World J Gastroenterol 2014; 20 (44) 16474-16479
- 57 Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88 (1) 125-172
- 58 Mederacke I, Hsu CC, Troeger JS , et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
- 59 Seki E, Schwabe RF. Hepatic inflammation and fibrosis: Functional links and key pathways. Hepatology 2015; 61 (3) 1066-1079
- 60 Kwon HJ, Won YS, Park O , et al. Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice. Hepatology 2014; 60 (1) 146-157
- 61 Setshedi M, Wands JR, Monte SM. Acetaldehyde adducts in alcoholic liver disease. Oxid Med Cell Longev 2010; 3 (3) 178-185
- 62 Mello T, Ceni E, Surrenti C, Galli A. Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol Aspects Med 2008; 29 (1-2) 17-21
- 63 Tilg H, Gao B. Dietary saturated lipids in alcoholic liver disease: new microbiota-targeting bullets?. Gastroenterology 2015; 148 (1) 16-19
- 64 Chen P, Torralba M, Tan J , et al. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 2015; 148 (1) 203-214.e16
- 65 Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006; 130 (2) 435-452
- 66 Melhem A, Muhanna N, Bishara A , et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006; 45 (1) 60-71
- 67 Cohen-Naftaly M, Friedman SL. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol 2011; 4 (6) 391-417
- 68 J Torok N, Dranoff JA, Schuppan D, Friedman SL. Strategies and endpoints of antifibrotic drug trials: summary and recommendations from the AASLD Emerging Trends Conference, Chicago, June 2014. Hepatology 2015; [In press]
- 69 Kong X, Feng D, Wang H , et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012; 56 (3) 1150-1159
- 70 Feng D, Kong X, Weng H , et al. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. Gastroenterology 2012; 143 (1) 188-98.e7
- 71 Ki SH, Park O, Zheng M , et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010; 52 (4) 1291-1300
- 72 European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57 (2) 399-420
- 73 Hock B, Schwarz M, Domke I , et al. Validity of carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin. Addiction 2005; 100 (10) 1477-1486
- 74 Alatalo P, Koivisto H, Puukka K , et al. Biomarkers of liver status in heavy drinkers, moderate drinkers and abstainers. Alcohol Alcohol 2009; 44 (2) 199-203
- 75 Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol 2014; 20 (33) 11684-11699
- 76 MacSween RN, Burt AD. Histologic spectrum of alcoholic liver disease. Semin Liver Dis 1986; 6 (3) 221-232
- 77 Singh DK, Rastogi A, Sakhuja P, Gondal R, Sarin SK. Comparison of clinical, biochemical and histological features of alcoholic steatohepatitis and non-alcoholic steatohepatitis in Asian Indian patients. Indian J Pathol Microbiol 2010; 53 (3) 408-413
- 78 Mueller S, Seitz HK, Rausch V. Non-invasive diagnosis of alcoholic liver disease. World J Gastroenterol 2014; 20 (40) 14626-14641
- 79 Chrostek L, Panasiuk A. Liver fibrosis markers in alcoholic liver disease. World J Gastroenterol 2014; 20 (25) 8018-8023
- 80 Mueller S, Millonig G, Sarovska L , et al. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol 2010; 16 (8) 966-972
- 81 Gelsi E, Dainese R, Truchi R , et al. Effect of detoxification on liver stiffness assessed by Fibroscan® in alcoholic patients. Alcohol Clin Exp Res 2011; 35 (3) 566-570
- 82 Penny SM. Alcoholic liver disease. Radiol Technol 2013; 84 (6) 577-592 , quiz 593–595
- 83 d'Assignies G, Fontés G, Kauffmann C , et al. Early detection of liver steatosis by magnetic resonance imaging in rats infused with glucose and intralipid solutions and correlation to insulin levels. Metabolism 2013; 62 (12) 1850-1857
- 84 Mookerjee RP, Lackner C, Stauber R , et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011; 55 (5) 1103-1111
- 85 Murray KF, Carithers Jr RL ; AASLD. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 2005; 41 (6) 1407-1432
- 86 O'Shea RS, Dasarathy S, McCullough AJ ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51 (1) 307-328
- 87 Rincon D, Lo Iacono O, Ripoll C , et al. Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients with severe acute alcoholic hepatitis. Aliment Pharmacol Ther 2007; 25 (7) 841-848
- 88 Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 2014; 146 (2) 349-356
- 89 Colmenero J, Bataller R, Sancho-Bru P , et al. Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology 2007; 132 (2) 687-697
- 90 Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S ; Veterans Affairs Cooperative Study 391 Group. II. Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease. Alcohol Clin Exp Res 2003; 27 (11) 1765-1772
- 91 Verrill C, Markham H, Templeton A, Carr NJ, Sheron N. Alcohol-related cirrhosis—early abstinence is a key factor in prognosis, even in the most severe cases. Addiction 2009; 104 (5) 768-774
- 92 Vuittonet CL, Halse M, Leggio L , et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm 2014; 71 (15) 1265-1276
- 93 Masson S, Emmerson I, Henderson E , et al. Clinical but not histological factors predict long-term prognosis in patients with histologically advanced non-decompensated alcoholic liver disease. Liver Int 2014; 34 (2) 235-242
- 94 Takahashi H, Shigefuku R, Maeyama S , et al. Cirrhosis improvement to alcoholic liver fibrosis after passive abstinence. BMJ Case Rep 2014;
- 95 Thompson KJ, McKillop IH, Schrum LW. Targeting collagen expression in alcoholic liver disease. World J Gastroenterol 2011; 17 (20) 2473-2481
- 96 Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 2012; 92 (4) 1515-1542
- 97 Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev 2006; (2) CD002235
- 98 Kim MY, Cho MY, Baik SK , et al. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study. Liver Int 2012; 32 (6) 977-987
- 99 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 2013; 58 (5) 1814-1823
- 100 National Institute on Alcohol Abuse and Alcoholism. Translational Research in Alcoholic Hepatitis. Available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-AA-12-007.html . Accessed March 20, 2015