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L iver fibrosis is characterized by an increase in the synthesis and deposition of extracellular matrix proteins, including type I collagen. The activated hepatic stellate cell (HSC) is responsible for increased type I collagen synthesis during liver fibrosis. After a fibrogenic stimulus, the HSC undergoes a complex phenotypic change from a quiescent vitamin A-storing cell to that of an activated, myofibroblast-like cell (reviewed in Friedman 1 and Eng et al. 2 ). Numerous changes occur during HSC activation, including the loss of retinoid stores, the appearance of smooth muscle ␣-actin, and a dramatic increase in the synthesis of type I collagen.Type I collagen is the product of 2 genes, the ␣1(I) and the ␣2(I) genes. Although located on different chromosomes, these genes are coordinately regulated in a developmental, tissue-specific, and inducible manner. [3][4][5][6] Previous studies have shown that ␣1(I) collagen gene expression is increased during HSC activation at both the transcriptional and posttranscriptional levels. 7-9 Transcriptional regulatory elements have been identified in the 5Ј-flanking region, the promoter region, first intron, and 3Ј-flanking region of both type I collagen genes in several species. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] Several deoxyribonuclease (DNase) I-hypersensitive sites (HSs) have been identified in the 5Ј-flanking region of the murine ␣1(I) collagen gene that are present in collagen-producing, but not in non-collagenproducing cells, suggesting that these elements are in-

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Summary Background Limited data exist on the burden and features of non‐cirrhotic hepatocellular carcinoma (HCC) in the United States. Aim To evaluate characteristics, aetiologies, trends and outcomes of non‐cirrhotic HCC from 2000 to 2014 at five large US centres Methods Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. Results Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non‐cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non‐cirrhotic patients, non‐alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non‐cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non‐cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004). Conclusions Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non‐cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non‐cirrhotic patients presented with more advanced HCC, their survival was better.

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