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We aimed to assess in subjects with NAFLD the impact of the (cholestatic) C pattern on the likelihood of developing major liver\u2010related outcomes (MALO).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Five hundred and eighty\u2010two consecutive patients with biopsy\u2010proven NAFLD or a clinical diagnosis of NAFLD\u2010related compensated cirrhosis were classified as hepatocellular (H), C and mixed (M) patterns, by using the formula (ALT\/ALT Upper Limit of Normal\u2010ULN)\/(ALP\/ALP ULN). MALO were recorded during follow\u2010up. An external cohort of 1281 biopsy\u2010proven NAFLD patients was enrolled as validation set.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>H, M and C patterns were found in 153 (26.3%), 272 (46.7%) and 157 (27%) patients respectively. During a median follow\u2010up of 78\u00a0months, only 1 (0.6%) patient with H pattern experienced MALO, whilst 15 (5.5%) and 38 (24.2%) patients in M and C groups had MALO. At multivariate Cox regression analysis, age &gt;55\u00a0years (HR 2.55, 95% CI 1.17\u20135.54;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.01), platelets &lt;150\u2009000\/mmc (HR 0.14, 95% CI 0.06\u20130.32;<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001), albumin &lt;4\u00a0g\/L(HR 0.62, 95% CI 0.35\u20131.08;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.09), C versus M pattern (HR 7.86, 95% CI 1.03\u201360.1;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.04), C versus H pattern(HR 12.1, 95% CI 1.61\u201390.9;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.01) and fibrosis F3\u2013F4(HR 35.8, 95% CI 4.65\u2013275.2;<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001) were independent risk factors for MALO occurrence. C versus M pattern(HR 14.3, 95% CI 1.90\u2013105.6;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.008) and C versus H pattern (HR 15.6, 95% CI 2.10\u2013115.1;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.0068) were confirmed independently associated with MALO occurrence in the validation set. The immunohistochemical analysis found a significantly higher prevalence of moderate\u2010high\u2010grade ductular metaplasia combined with low\u2010grade ductular proliferation in C pattern when compared with the biochemical H pattern. Gene expression analysis showed a lower expression of<jats:italic>NR1H3, RXR\u03b1 and VCAM1<\/jats:italic>in patients with the C pattern.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The presence of a cholestatic pattern in patients with NAFLD predicts a higher risk of MALO independently from other features of liver disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15232","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T03:24:01Z","timestamp":1646450641000},"page":"1037-1048","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A cholestatic pattern predicts major liver\u2010related outcomes in patients with non\u2010alcoholic fatty liver 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