Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population. There is a strong association between the severity of NAFLD and the components of the metabolic syndrome. NAFLD is also independently associated with cardiovascular disease and type 2 diabetes mellitus (T2DM). The progressive potential of non-alcoholic fatty liver disease (NAFLD) is indisputable today, and the histological spectrum of NAFLD ranges from isolated steatosis to nonalcoholic steatohepatitis (NASH), with risk of developing fibrosis and subsequent cirrhosis and hepatocellular carcinoma. There is a substantial inter-patient variation in disease progression, therefore, this review will focus on potential modifiers of fibrosis progression, development of liver cirrhosis, decompensation and liver-related mortality. The potential drivers of disease progression that is discussed are; T2DM and Insulin Resistance, body weight, alcohol consumption, genetics (including HFE and alfa-1-antitrypsin) as well as histological features predictive of disease progression.
Keywords: End-stage liver disease, HCC, fibrosis, alcohol, fibrosis progression, NAFLD.
[http://dx.doi.org/10.1053/j.gastro.2014.11.039] [PMID: 25461851]
[http://dx.doi.org/10.1016/j.jhep.2016.07.033] [PMID: 27486010]
[http://dx.doi.org/10.1016/S0140-6736(17)32129-3] [PMID: 29029897]
[http://dx.doi.org/10.1002/hep.28431] [PMID: 26707365]
[http://dx.doi.org/10.1016/S0016-5085(99)70506-8] [PMID: 10348825]
[http://dx.doi.org/10.1053/gast.2002.36572] [PMID: 12404245]
[http://dx.doi.org/10.1016/j.jhep.2014.12.012] [PMID: 25920090]
[http://dx.doi.org/10.1042/CS20080253] [PMID: 19243311]
[http://dx.doi.org/10.1016/S2213-8587(14)70032-4] [PMID: 24731669]
[http://dx.doi.org/10.1038/srep33386] [PMID: 27633274]
[http://dx.doi.org/10.1056/NEJMra0912063] [PMID: 20879883]
[http://dx.doi.org/10.1016/j.jhep.2016.05.013] [PMID: 27212244]
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.01.016] [PMID: 26803429]
[http://dx.doi.org/10.1002/hep.28785] [PMID: 27543837]
[http://dx.doi.org/10.1038/nrgastro.2013.171] [PMID: 24042449]
[http://dx.doi.org/10.1016/S0168-8278(18)30221-6]
[http://dx.doi.org/10.1002/hep.29477] [PMID: 28833331]
[http://dx.doi.org/10.1016/j.jhep.2017.11.012] [PMID: 29154966]
[http://dx.doi.org/10.1053/j.gastro.2005.03.084] [PMID: 15940625]
[http://dx.doi.org/10.1016/j.cgh.2008.12.015] [PMID: 19162235]
[http://dx.doi.org/10.1007/s11695-007-9041-2] [PMID: 17476865]
[PMID: 9647594]
[http://dx.doi.org/10.1016/j.cgh.2007.06.005] [PMID: 17702661]
[http://dx.doi.org/10.1002/hep.21346] [PMID: 17006934]
[http://dx.doi.org/10.5812/hepatmon.15167] [PMID: 24497882]
[http://dx.doi.org/10.4132/jptm.2016.03.01] [PMID: 27086596]
[http://dx.doi.org/10.1002/hep.20701] [PMID: 15915461]
[http://dx.doi.org/10.1002/hep.27173] [PMID: 24753132]
[http://dx.doi.org/10.3109/07853890.2010.518623] [PMID: 21039302]
[http://dx.doi.org/10.1038/nrgastro.2013.41] [PMID: 23507799]
[http://dx.doi.org/10.1002/hep.29085] [PMID: 28130788]
[http://dx.doi.org/10.1016/j.jhep.2017.07.027] [PMID: 28803953]
[http://dx.doi.org/10.1053/j.gastro.2015.04.043] [PMID: 25935633]
[http://dx.doi.org/10.1016/j.jhep.2015.02.041] [PMID: 25920092]
[http://dx.doi.org/10.1016/j.jhep.2011.06.010] [PMID: 21723839]
[http://dx.doi.org/10.1016/j.jhep.2017.05.016] [PMID: 28545937]
[http://dx.doi.org/10.1016/S0140-6736(16)00618-8] [PMID: 27061677]
[http://dx.doi.org/10.1053/j.gastro.2010.09.038] [PMID: 20858492]
[http://dx.doi.org/10.1016/j.cgh.2017.04.040] [PMID: 28479500]
[http://dx.doi.org/10.1002/hep.26183] [PMID: 23213066]
[http://dx.doi.org/10.1016/j.dld.2015.08.004] [PMID: 26454786]
[http://dx.doi.org/10.1016/j.jhep.2019.06.021] [PMID: 31279902]
[http://dx.doi.org/10.1016/j.jhep.2016.09.022] [PMID: 27729222]
[http://dx.doi.org/10.1371/journal.pone.0174291] [PMID: 28350839]
[http://dx.doi.org/10.1111/jgh.13264] [PMID: 26667191]
[http://dx.doi.org/10.1038/s41598-017-04631-7] [PMID: 28680048]
[http://dx.doi.org/10.1002/hep.21327] [PMID: 17006923]
[http://dx.doi.org/10.1002/hep4.1134] [PMID: 29404527]
[http://dx.doi.org/10.1016/j.jhep.2014.11.034] [PMID: 25477264]
[http://dx.doi.org/10.1016/0046-8177(89)90249-9] [PMID: 2656500]
[http://dx.doi.org/10.1002/hep.1840110114] [PMID: 2295475]
[http://dx.doi.org/10.1002/hep.1840220616] [PMID: 7489979]
[http://dx.doi.org/10.1136/jcp.55.9.689] [PMID: 12195000]
[http://dx.doi.org/10.1016/S0016-5085(00)70364-7] [PMID: 10833486]
[http://dx.doi.org/10.1111/j.1572-0241.2003.07659.x] [PMID: 14499785]
[http://dx.doi.org/10.1002/hep.20410] [PMID: 15382171]
[http://dx.doi.org/10.1016/j.jhep.2004.09.012] [PMID: 15629518]
[http://dx.doi.org/10.1111/j.1365-2036.2005.02334.x] [PMID: 15709991]
[http://dx.doi.org/10.1136/gut.2009.205088] [PMID: 20581244]
[http://dx.doi.org/10.1016/j.jhep.2013.04.027] [PMID: 23665288]
[http://dx.doi.org/10.1002/hep.30664] [PMID: 30993748]
[http://dx.doi.org/10.1007/s10620-013-2743-5] [PMID: 23775317]
[http://dx.doi.org/10.1038/ajg.2010.18] [PMID: 20145609]
[http://dx.doi.org/10.1371/journal.pone.0128774] [PMID: 26083565]
[http://dx.doi.org/10.1053/j.gastro.2018.04.034] [PMID: 29733831]
[http://dx.doi.org/10.1016/j.diabres.2018.02.023] [PMID: 29496507]
[http://dx.doi.org/10.1056/NEJMoa1008862] [PMID: 21366474]
[http://dx.doi.org/10.1007/BF00400637] [PMID: 7758879]
[http://dx.doi.org/10.1016/S0895-4356(01)00342-0] [PMID: 11470389]
[http://dx.doi.org/10.1038/ajg.2014.132]
[http://dx.doi.org/10.2337/dc12-0002] [PMID: 22699290]
[http://dx.doi.org/10.1093/jnci/89.18.1360] [PMID: 9308706]
[http://dx.doi.org/10.1093/jnci/83.24.1820] [PMID: 1660542]
[http://dx.doi.org/10.1016/0016-5085(84)90544-4] [PMID: 6086443]
[http://dx.doi.org/10.1016/j.jhep.2013.08.011] [PMID: 23978719]
[http://dx.doi.org/10.1053/j.gastro.2003.10.065] [PMID: 14762783]
[http://dx.doi.org/10.1136/gut.2004.052167] [PMID: 15753540]
[http://dx.doi.org/10.1016/j.cgh.2012.10.001] [PMID: 23041539]
[http://dx.doi.org/10.1002/dmrr.1291] [PMID: 21898753]
[http://dx.doi.org/10.1053/gast.2002.34168] [PMID: 12105842]
[http://dx.doi.org/10.1002/hep.1840360609] [PMID: 12447858]
[http://dx.doi.org/10.1002/lt.20033] [PMID: 14762843]
[http://dx.doi.org/10.1016/S0140-6736(09)60318-4] [PMID: 19299006]
[http://dx.doi.org/10.1056/NEJMoa1000367] [PMID: 21121834]
[http://dx.doi.org/10.1001/jama.2012.113905] [PMID: 23280227]
[http://dx.doi.org/10.1111/obr.12407] [PMID: 27020692]
[http://dx.doi.org/10.1093/aje/kws448] [PMID: 23703888]
[http://dx.doi.org/10.1002/jmri.22580] [PMID: 22025886]
[http://dx.doi.org/10.1152/ajpendo.00064.2004] [PMID: 15339742]
[http://dx.doi.org/10.1002/hep.27647] [PMID: 25482832]
[http://dx.doi.org/10.1002/hep.20466] [PMID: 15565570]
[http://dx.doi.org/10.1148/radiol.12120896] [PMID: 23382291]
[http://dx.doi.org/10.1148/radiol.14140754] [PMID: 25247408]
[http://dx.doi.org/10.1007/s00261-019-02079-z] [PMID: 31172210]
[http://dx.doi.org/10.1007/s00330-015-3724-1] [PMID: 25916386]
[http://dx.doi.org/10.1053/j.gastro.2017.03.005] [PMID: 28286210]
[http://dx.doi.org/10.1038/ajg.2013.104] [PMID: 23567356]
[http://dx.doi.org/10.1038/s41598-018-25641-z] [PMID: 29765064]
[http://dx.doi.org/10.1111/liv.13603] [PMID: 28963767]
[http://dx.doi.org/10.1159/000282101] [PMID: 20460922]
[http://dx.doi.org/10.1016/j.jhep.2011.12.011] [PMID: 22245895]
[http://dx.doi.org/10.1053/j.gastro.2006.02.024] [PMID: 16697725]
[http://dx.doi.org/10.1053/j.gastro.2009.04.052] [PMID: 19409898]
[http://dx.doi.org/10.1055/s-0032-1306428] [PMID: 22418890]
[http://dx.doi.org/10.1053/j.gastro.2015.04.005] [PMID: 25865049]
[http://dx.doi.org/10.1016/j.jhep.2016.03.019] [PMID: 27321729]
[http://dx.doi.org/10.1136/bmj.c912] [PMID: 20223875]
[http://dx.doi.org/10.1016/S0016-5085(03)01200-9] [PMID: 14517789]
[http://dx.doi.org/10.1056/NEJMoa021423] [PMID: 12711737]
[http://dx.doi.org/10.1136/gutjnl-2016-313622] [PMID: 28320770]
[http://dx.doi.org/10.1016/S0140-6736(14)61838-9] [PMID: 25433429]
[http://dx.doi.org/10.1016/j.jhep.2015.11.004]
[http://dx.doi.org/10.1002/hep.510230513] [PMID: 8621128]
[http://dx.doi.org/10.1136/gutjnl-2017-313884] [PMID: 28314735]
[PMID: 25805864]
[http://dx.doi.org/10.1016/j.jhep.2018.03.018] [PMID: 29628280]
[http://dx.doi.org/10.1111/j.1360-0443.1993.tb02093.x] [PMID: 8329970]
[http://dx.doi.org/10.1093/alcalc/agv038] [PMID: 25882743]
[http://dx.doi.org/10.7717/peerj.2633] [PMID: 27812428]
[http://dx.doi.org/10.1016/j.jhep.2014.11.025] [PMID: 25433160]
[http://dx.doi.org/10.3109/07853890.2011.588246] [PMID: 21599573]
[http://dx.doi.org/10.1002/hep.30170] [PMID: 30019340]
[http://dx.doi.org/10.1002/hep.27368] [PMID: 25125077]
[http://dx.doi.org/10.1016/j.jhep.2012.03.024] [PMID: 22521357]
[http://dx.doi.org/10.1080/00365521.2016.1239759] [PMID: 27650916]
[http://dx.doi.org/10.1080/00365520802555991] [PMID: 19016382]
[http://dx.doi.org/10.1016/j.cgh.2018.01.026] [PMID: 29378307]
[http://dx.doi.org/10.1159/000447279] [PMID: 27548267]
[http://dx.doi.org/10.3748/wjg.v24.i13.1440] [PMID: 29632425]
[http://dx.doi.org/10.1002/hep.30226] [PMID: 30125379]
[http://dx.doi.org/10.1136/bmj.d671] [PMID: 21343207]
[http://dx.doi.org/10.1038/ng.257] [PMID: 18820647]
[http://dx.doi.org/10.1002/hep.23768] [PMID: 20648472]
[http://dx.doi.org/10.1038/ng.2901] [PMID: 24531328]
[http://dx.doi.org/10.1371/journal.pone.0038322] [PMID: 22719876]
[http://dx.doi.org/10.1002/hep.25518] [PMID: 22162034]
[http://dx.doi.org/10.1002/hep.26767] [PMID: 24114809]
[http://dx.doi.org/10.1016/j.jhep.2014.02.030] [PMID: 24607626]
[http://dx.doi.org/10.1002/hep.30350] [PMID: 30415504]
[http://dx.doi.org/10.1056/NEJMoa1712191] [PMID: 29562163]
[http://dx.doi.org/10.1053/j.gastro.2016.01.032] [PMID: 26850495]
[http://dx.doi.org/10.1038/s41598-018-23453-9] [PMID: 29572551]
[http://dx.doi.org/10.1371/journal.pgen.1001324] [PMID: 21423719]
[http://dx.doi.org/10.1038/ng.970] [PMID: 22001757]
[http://dx.doi.org/10.1016/0016-5085(94)90235-6] [PMID: 7523217]
[http://dx.doi.org/10.1002/hep.24038] [PMID: 21274866]
[http://dx.doi.org/10.1111/j.1572-0241.2001.04052.x] [PMID: 11513189]
[http://dx.doi.org/10.1016/S0168-8278(99)80032-4] [PMID: 10488699]
[http://dx.doi.org/10.1016/S0016-5085(98)70482-2] [PMID: 9453491]
[http://dx.doi.org/10.1002/hep.20023] [PMID: 14752836]
[http://dx.doi.org/10.1111/j.1478-3231.2011.02488.x] [PMID: 21457446]
[http://dx.doi.org/10.1016/j.jhep.2010.09.037] [PMID: 21145841]
[http://dx.doi.org/10.1002/hep.24706] [PMID: 21953442]
[http://dx.doi.org/10.1111/liv.13144] [PMID: 27064133]
[http://dx.doi.org/10.1016/j.cgh.2013.11.035] [PMID: 24342745]
[http://dx.doi.org/10.1111/j.1572-0241.2007.01192.x] [PMID: 17391316]
[http://dx.doi.org/10.3748/wjg.v20.i11.3002] [PMID: 24659891]
[http://dx.doi.org/10.1016/j.hepres.2006.08.003] [PMID: 16971174]
[http://dx.doi.org/10.1111/apt.12255] [PMID: 23441892]
[http://dx.doi.org/10.1002/hep.27662] [PMID: 25524401]
[http://dx.doi.org/10.1002/hep.26238] [PMID: 23325576]
[http://dx.doi.org/10.1053/j.gastro.2009.11.013] [PMID: 19931264]
[http://dx.doi.org/10.1002/jmri.26601] [PMID: 30637926]
[http://dx.doi.org/10.1038/nrdp.2016.51] [PMID: 27465791]
[http://dx.doi.org/10.1056/NEJMcp0900449] [PMID: 19553648]
[http://dx.doi.org/10.2147/COPD.S125389] [PMID: 28243076]
[http://dx.doi.org/10.1056/NEJM197606102942404] [PMID: 1083485]
[http://dx.doi.org/10.1164/ajrccm/140.4.961] [PMID: 2679271]
[http://dx.doi.org/10.1002/hep.21329] [PMID: 17006922]
[http://dx.doi.org/10.1007/s00428-014-1633-3] [PMID: 25070245]
[http://dx.doi.org/10.1002/lt.25057] [PMID: 29573137]
[http://dx.doi.org/10.1016/S0168-8278(00)80119-1] [PMID: 11131449]
[http://dx.doi.org/10.1097/01.mpg.0000226387.56612.1e] [PMID: 16819398]
[http://dx.doi.org/10.1097/MEG.0000000000001056] [PMID: 29324588]
[http://dx.doi.org/10.1136/gutjnl-2018-316228] [PMID: 30068662]
[http://dx.doi.org/10.1016/j.cgh.2014.04.014] [PMID: 24768810]
[http://dx.doi.org/10.1111/apt.15219] [PMID: 30882933]
[http://dx.doi.org/10.1016/j.cgh.2018.11.030] [PMID: 30471458]
[http://dx.doi.org/10.1053/j.gastro.2013.06.057] [PMID: 23860502]
[http://dx.doi.org/10.1111/j.1572-0241.1999.01377.x] [PMID: 10484010]
[http://dx.doi.org/10.1002/hep.510370203] [PMID: 12540771]
[http://dx.doi.org/10.1002/hep.24268] [PMID: 21360720]
[http://dx.doi.org/10.1002/hep.24376] [PMID: 21520200]
[http://dx.doi.org/10.1080/00365521.2016.1230779] [PMID: 27616339]
[http://dx.doi.org/10.1016/j.metabol.2015.12.012] [PMID: 26823198]
[http://dx.doi.org/10.1002/cphy.c120035] [PMID: 24265236]
[http://dx.doi.org/10.1016/j.jhep.2009.03.019] [PMID: 19501928]
[http://dx.doi.org/10.1016/S0168-8278(17)31613-6]
[http://dx.doi.org/10.1053/j.gastro.2018.04.014] [PMID: 29660324]
[http://dx.doi.org/10.1002/hep.21655] [PMID: 17476695]
[http://dx.doi.org/10.1016/j.jhep.2017.11.014] [PMID: 29154964]
[http://dx.doi.org/10.1016/j.jhep.2019.08.027] [PMID: 31518646]
[http://dx.doi.org/10.1136/bmjopen-2016-015659] [PMID: 28679676]
[http://dx.doi.org/10.1053/gast.2001.25540] [PMID: 11438497]
[http://dx.doi.org/10.1097/MEG.0b013e328328f3ec] [PMID: 19194305]
[http://dx.doi.org/10.1002/hep.23527] [PMID: 20209604]
[http://dx.doi.org/10.1111/liv.12230] [PMID: 23809459]
[http://dx.doi.org/10.1111/apt.13828] [PMID: 27778410]
[http://dx.doi.org/10.1371/journal.pone.0191026] [PMID: 29342182]
[http://dx.doi.org/10.1038/s41395-018-0133-5] [PMID: 29899440]