Review
Copyright ©The Author(s) 2022.
World J Gastroenterol. Jan 21, 2022; 28(3): 310-331
Published online Jan 21, 2022. doi: 10.3748/wjg.v28.i3.310
Table 1 Epidemiology of non-alcoholic fatty liver disease-related hepatocellular carcinoma based on studies published in the last decade (2011-2020)
Ref.
Year/Country
Study design
HCC patients, n
HCC caused by NAFLD, n (%)
Non-cirrhotics among HCC-related NAFLD, n (%)
Fibrosis stage of NAFLD-HCC patients, n (%)
Tumor size
Yang et al[26]2011/United StatesRetrospective 46061 (13.27)NANANA
Schütte et al[27]2014/GermanyRetrospective66443 (6.5)6 (13.95)NANA
Chun et al[28]2014/United StatesRetrospective2713 (48.1)NANANA
Edenvik et al[29]2015/SwedenRetrospective61669 (11.2)15 (21.7)NANA
Younossi et al[30]2015/United StatesRetrospective4979701 (14.1)NANANA
Weinmann et al[31]2015/GermanyRetrospective111945 (4)10 (22.2)NATrend towards ↑ tumor size in NASH-HCC (6 cm) vs non-NASH-HCC (4.8 cm) (P = 0.18)
Mittal et al[23]2016/United StatesRetrospective1500107 (8)37 (34.6)NAΝΑ
Wong et al[32]2017/United StatesRetrospective17.6645898 (33.4)3326 (56.4%)NA↑ proportion of tumors > 5 cm in NAFLD-HCC vs non-NAFLD-HCC (P < 0.001)
Huang et al[33]2017/AustraliaProspective27038 (14)9 (23.7)NAΝΑ
Koh et al[34]2019/SingaporeProspective996152 (15.3)100 (65.8)F0 = 78 (51.7); F1 = 10 (6.6); F2 = 45 (29.8); F3 = 9 (6); F4 = 9 (6)↓ tumor size in NAFLD-HCC (0.7 cm) vs non-NAFLD-HCC (4 cm) (P < 0.001)
Hassan and Gane[35]2019/New ZealandRetrospective1985159 (5.1) (Undefined cirrhosis stage in 57)25 (24.5) (based on well-defined stage patients)F0 = 2 (8); F1 = 3 (14); F2 = 1 (3); F3/4 = 19 (75.5)NA
Gawrieh et al[36]2019/United StatesRetrospective5144767 (14.9)159 (26.3)NANA
Hester et al[16]2020/United StatesRetrospective1247130191565NANA
Hong et al[37]2018/AustraliaProspective27239 (14.3)NANANA
Jamwal et al[38]2020/IndiaProspective5620 (35.7)20 (100)NANA
Pais et al[15]2017/FranceRetrospective32339 (12.1)30 (76.9)F0 = 16 (40); F1 = 9 (23); F2 = 0 (0); F3 = 5 (14); F4 = 9 (23)↑ tumor size in NAFLD-HCC (8.7 cm) vs non-NAFLD-HCC (6.2 cm) (P = 0.002)
Dyson et al[13]2013/United KingdomProspective632136 (21.5)31 (22.8)NANA
Phipps et al[39]2020/United StatesRetrospective5327790 (14.8)NANANA
Bengtsson et al[40]2019/SwedenRetrospective1562225 (14.4)83 (36.9)F0 = 1; F1 = 13; F2 = 16; F3 = 5 (Undefined fibrosis stage in 48 patients)NSD in tumor size between NAFLD-HCC vs non-NAFLD-HCC; ↑ tumor size in non-cirrhotic vs cirrhotic NAFLD-HCC (P = 0.001)
Tokushige et al[41]2013/JapanRetrospective14.530292 (2)111 (38)NAΝΑ
Reddy et al[42]2012/United StatesRetrospective30352 (NASH) (17.2)14 (26.9)NANSD in tumor size between NAFLD-HCC (3.2 cm) vs non-NAFLD-HCC (3 cm)
Phan et al[43]2019/United StatesRetrospective54528 (5.1)3 (10.7)NANA
Van Meer et al[44]2016/NetherlandsRetrospective1221181 (14.8)67 (28)NA↑ tumor size in NAFLD-HCC (6 cm) vs HCV-HCC (3 cm) (P < 0.001)
Yang et al[45]2017/United StatesRetrospective9310 (11)3 (27.3)NANA
Table 2 Characteristics of non-alcoholic fatty liver disease-associated hepatocellular carcinoma based on studies including cohorts of non-alcoholic fatty liver disease-associated hepatocellular carcinoma patients
Ref.
Year/Country
Total NAFLD-HCC patients
Prevalence of NAFLD-HCC without cirrhosis, n (%)
Fibrosis stage of non-cirrhotic NAFLD-HCC patients, n (%)
Tumor characteristics in cirrhotic vs non-cirrhotic NAFLD-HCC patients (differentiation)
Piscaglia et al[24]2015/Italy145 patients67 (46)F0 = 3 (18.75); F1-F2 = 2 (12.5); F3 = 11 (68.75) (Undefined fibrosis stage in 51 patients)NSD in tumor size
Leung et al[46]2015/Australia54 patients8 (15)F0 = 2 (33.3); F1-F2 = 4 (66.7) (Undefined fibrosis stage in 2 patients)↑ tumor diameter in non-cirrhotic (4.7 cm) vs cirrhotic (3.2 cm) (P = 0.041). NSD in median number of tumors in non-cirrhotic (2) vs cirrhotic (1). NSD in HCC differentiation
Kodama et al[47]2019/Japan104 patients58 (55.8)F0 = 6 (5.8); F1 = 11 (10.6); F2 = 18 (17.3); F3 = 23 (22.1)NSD in HCC differentiation
Mohamad et al[48]2015/United States of America83 patients36 (43.4)F0 = 18 (55.9); F1 = 6 (17.6); F2 = 3 (8.8); F3 = 6 (17.6)↑ incidence of single nodules in non-cirrhotic (80.6%) vs cirrhotic (52.2%) (P < 0.05). ↑ proportion of large nodule size (> 5 cm) in non-cirrhotic (77.8%) vs cirrhotic (10.6%) (P < 0.05). NSD in HCC differentiation
Tobari et al[49]2020/Japan119 patients48 (40.3)F0-F1 = 12 (32.4); F2 = 17 (46); F3 = 8 (21.6) (Undefined fibrosis stage in 11 patients)↑ tumor size in non-cirrhotic (46 mm) vs cirrhotic (28 mm) (P < 0.01). NSD in HCC differentiation. NSD in median number of tumors
Yasui et al[25]2011/Japan87 patients43 (49.4)F1 = 10 (23.2); F2 = 15 (34.9); F3 = 18 (41.9)NA
Thompson[50]2018/United States48 patients26 (54)F0 = 10 (38.5); F1 = 8 (30.8); F2 = 5 (19.2); F3 = 1 (3.8)↓ tumor size in non-cirrhotic (3.3 cm) vs cirrhotic (5.7 cm) (P < 0.01). NSD in HCC differentiation
Cotrim et al[51]2016/Brazil110 patients20 (48.5)F0 = 2 (12.5); F1-3 = 14 (87.5)NA
Iannaccone et al[52]2007/France22 patients16 (72.3)F0 = 7 (31.8); F1-3 = 9 (40.9)NA
Table 3 Treatment outcomes and prognosis in patients with non-alcoholic fatty liver disease-related hepatocellular carcinoma vs other etiologies-related hepatocellular carcinoma
Ref.
Year/country/type of study
Total HCC patients (underlying disease)
Features of hepatocellular carcinoma (NAFLD vs other etiologies)
Treatment
Overall survival (NAFLD vs other etiologies)
Recurrence-free survival (NAFLD vs other etiologies)
Younossi et al[30]2015/United States/Retrospective4979 with HCC; 701 NAFLD, 254 AH/BC, 817 ALD, 471 HBV, 2736 HCVNAFLD: ↑ possibility of unstaged HCC vs HCV/HBVLTNAFLD: ↓ OS vs HCV/HBV (NAFLD: 1-yr mortality risk is 61% vs 50% for the HCV/HBV group)NA
Golabi et al[94]2017/United States/Retrospective11187 total HCC patients; 1277 NAFLD, 1421 ALD, 586 HBV, 3591 HCV Among HCC patients treated with SR: 57% had HCV vs 17% had NAFLD LT, SR, TACENAFLD: ↓ OS vs HCV and/or HBV (HR: 0.82) but ↑ OS vs ALD (HR: 1.59)NA
Piscaglia et al[24]2016/Italy/Prospective756 total HCC patients; 145 NALFD, 611 HCVNAFLD: More advanced BCLC HCC stage and more commonly outside the Milan criteria vs HCV LT, SR, PEI, Thermal ablation, TACE, BSC or trialsNAFLD: ↓ 1-yr and 3-yr OS vs HCV (1-yr and 3-yr survival; 76.4% and 48.7% in the NAFLD-HCC group and 84.2% and 61.1% in the HCV-HCC respectively) NSD among treatment choicesNA
Hester et al[96]2019/United States/Retrospective1051 total HCC patients; 92 NASH, 153 ALD, 87 HBV, 719 HCVNASH and HBV HCC patients: Larger median tumor size vs HCV and ALD. NSD in BCLC staging among the groupsLT, SR or ablative techniques, TACE, yttrium 90, or TARE or radiation therapy, systemic therapyNAFLD: ↓ OS vs ALD (HR: 1.92) NSD between NAFLD-HCC and viral-related HCCNA
Giannini et al[97]2009/Italy/Prospective471 total HCC patients; 45 CC, 426 HCVCC: ↑ prevalence of multinodular and diffuse lesions, ↑ size of the largest lesion and advanced classification according to Milano criteria (69% vs 41%) vs HCVLT, SR, PEI, RFA, TACECC: ↓ OS vs HCVNA
Koh et al[34]2019/Singapore/Prospective996 total HCC patients; 152 with NAFLD, 844 non-NAFLDNAFLD: Smaller median tumor sizeTotal liver resectionNAFLD: ↑ 5-yr and 10-yr OS vs non-NAFLD groups (5-yr and 10-yr OS; 70.1% and 49.6% in the NAFLD-HCC group vs 60.9% and 41.0% in the non-NAFLD-HCC respectively)NSD in RFS (P = 0.0931)
Reddy et al[42]2012/United States/Retrospective303 HCC patients; 52 with NAFLD vs 162 HCV/ALDNASH: NSD in largest tumor size, tumor differentiation and presence of satellite lesions vs HCV/ALDResection, ablation, and LTNASH: ↑ 3-yr OS vs HCV/ALD (60.9% vs 36.2%)NSD
Benhammou et al[98]2020/United States/Retrospective454 total HCC patients; 125 NAFLD, 170 HBV, 159 HCV NAFLD and HCV more likely to be within Milan and UCSF criteria for LT vs HBVLT, SR, RFA, PEI, TACE/Y-90, chemotherapy, BSCNAFLD: ↑ OS vs HBV (HR: 0.35) and HCV (HR: 0.37)NAFLD: ↑ RFS vs HCV (HR: 0.64) and HBV (HR: 0.69)
Viganò et al[99]2015/United States/Retrospective1563 total HCC patients; 96 HCV, 96 MetS matched MetS: NSD in satellite nodules and microvascular invasion vs HCVSR, preoperative PVE, TACEMetS: ↑ OS vs HCV (65.6% vs 61.4%)MetS: Trend for ↑ RFS vs HCV (37.0% vs 27.5%, P = 0.077)
Bengtsson et al[40]2019/Sweden/Retrospective1562 total HCC patients; 225 NAFLD, 1337 non-NAFLDNAFLD: NSD in BCLC staging, number of tumors and largest tumor size vs non-NAFLDLT ± RFA or TACE, SR, RFA, TACE, systemic therapy or BSCNAFLD: NSD in OS vs non-NAFLD (HR: 1.04)NA
Than et al[100]2017/United States/Retrospective487 total HCC patients; 212 NAFLD, 275 HCVNAFLD: ↑ tumor size vs HCVTACE, RFA, SR, PEI, sorafenib, LTNAFLD: NSD vs HCV (44% vs 56% respectively)NA
Wakai et al[101]2011/Japan/Retrospective225 total HCC patients; 17 NAFLD, 61 HBV, 147 HCVNAFLD: ↑ tumor size vs HCV & HBVSRNAFLD: ↑ postoperative morbidity and 30-d mortality rates (59% and 12% in NAFLD vs 31% and 0.7% in HCV respectively & 28% and 3.3% in HBV respectively)NAFLD: ↑ RFS vs HBV & HCV
Jung et al[95]2021/South Korea/Retrospective426 total HCC patients; 32 NAFLD, 200 HBV, 194 HBV/NAFLD NAFLD: ↑ average tumor size vs HBV group (4.4 cm vs 3.4 cm)HepatectomyBefore PSM: NAFLD: ↓ 5-yr OS vs HBV (63% vs 80%). After PSM, NSD in 5-yr OS ratesNSD in RFS or disease-specific survival before and after PSM
Tokushige et al[102]2010/Japan/Prospective90 total HCC patients; 34 NASH, 56 HCV NASH: NSD in tumor size vs HCVSR, RFA, TACENASH: NSD in 5-yr survival rate (55.2% in NASH vs 50.6% in all HCV)NSD in 5-yr recurrence rate
Pais et al[15] 2017/France/Retrospective323 total HCC patients; 39 NAFLD, 284 non-NAFLDNAFLD: ↑ larger tumor size vs non-NAFLDNSD in other tumor characteristicsSR, TACE, PVE, PEI, LTNSD in 2.5 post-LT OS (Mortality: 36% in NAFLD, 48% in ALD, 45% in HCV and 36% in CHB)NSD
Hernandez-Alejandro et al[103]2012/Canada/Retrospective81 total HCC patients; 17 NASH, 64 HCVNASH: ↓ proportion had poorly differentiated HCC vs HCVLTNANASH: trend of ↑ 5-yr RFS (P = 0.11)