Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link

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 States	Retrospective	460	61 (13.27)	NA	NA	NA
Schütte et al[27]	2014/Germany	Retrospective	664	43 (6.5)	6 (13.95)	NA	NA
Chun et al[28]	2014/United States	Retrospective	27	13 (48.1)	NA	NA	NA
Edenvik et al[29]	2015/Sweden	Retrospective	616	69 (11.2)	15 (21.7)	NA	NA
Younossi et al[30]	2015/United States	Retrospective	4979	701 (14.1)	NA	NA	NA
Weinmann et al[31]	2015/Germany	Retrospective	1119	45 (4)	10 (22.2)	NA	Trend towards ↑ tumor size in NASH-HCC (6 cm) vs non-NASH-HCC (4.8 cm) (P = 0.18)
Mittal et al[23]	2016/United States	Retrospective	1500	107 (8)	37 (34.6)	NA	ΝΑ
Wong et al[32]	2017/United States	Retrospective	17.664	5898 (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/Australia	Prospective	270	38 (14)	9 (23.7)	NA	ΝΑ
Koh et al[34]	2019/Singapore	Prospective	996	152 (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 Zealand	Retrospective	1985	159 (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 States	Retrospective	5144	767 (14.9)	159 (26.3)	NA	NA
Hester et al[16]	2020/United States	Retrospective	12471	3019	1565	NA	NA
Hong et al[37]	2018/Australia	Prospective	272	39 (14.3)	NA	NA	NA
Jamwal et al[38]	2020/India	Prospective	56	20 (35.7)	20 (100)	NA	NA
Pais et al[15]	2017/France	Retrospective	323	39 (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 Kingdom	Prospective	632	136 (21.5)	31 (22.8)	NA	NA
Phipps et al[39]	2020/United States	Retrospective	5327	790 (14.8)	NA	NA	NA
Bengtsson et al[40]	2019/Sweden	Retrospective	1562	225 (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/Japan	Retrospective	14.530	292 (2)	111 (38)	NA	ΝΑ
Reddy et al[42]	2012/United States	Retrospective	303	52 (NASH) (17.2)	14 (26.9)	NA	NSD in tumor size between NAFLD-HCC (3.2 cm) vs non-NAFLD-HCC (3 cm)
Phan et al[43]	2019/United States	Retrospective	545	28 (5.1)	3 (10.7)	NA	NA
Van Meer et al[44]	2016/Netherlands	Retrospective	1221	181 (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 States	Retrospective	93	10 (11)	3 (27.3)	NA	NA

NAFLD: Non-alcoholic fatty liver disease; HCC: Hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis; HCV: Hepatitis C virus; NSD: No significant difference; NA: Not applicable.

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/Italy	145 patients	67 (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/Australia	54 patients	8 (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/Japan	104 patients	58 (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 America	83 patients	36 (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/Japan	119 patients	48 (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/Japan	87 patients	43 (49.4)	F1 = 10 (23.2); F2 = 15 (34.9); F3 = 18 (41.9)	NA
Thompson[50]	2018/United States	48 patients	26 (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/Brazil	110 patients	20 (48.5)	F0 = 2 (12.5); F1-3 = 14 (87.5)	NA
Iannaccone et al[52]	2007/France	22 patients	16 (72.3)	F0 = 7 (31.8); F1-3 = 9 (40.9)	NA

NAFLD: Non-alcoholic fatty liver disease; HCC: Hepatocellular carcinoma; NSD: No significant difference; NA: Not applicable.

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/Retrospective	4979 with HCC; 701 NAFLD, 254 AH/BC, 817 ALD, 471 HBV, 2736 HCV	NAFLD: ↑ possibility of unstaged HCC vs HCV/HBV	LT	NAFLD: ↓ 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/Retrospective	11187 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, TACE	NAFLD: ↓ OS vs HCV and/or HBV (HR: 0.82) but ↑ OS vs ALD (HR: 1.59)	NA
Piscaglia et al[24]	2016/Italy/Prospective	756 total HCC patients; 145 NALFD, 611 HCV	NAFLD: More advanced BCLC HCC stage and more commonly outside the Milan criteria vs HCV	LT, SR, PEI, Thermal ablation, TACE, BSC or trials	NAFLD: ↓ 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 choices	NA
Hester et al[96]	2019/United States/Retrospective	1051 total HCC patients; 92 NASH, 153 ALD, 87 HBV, 719 HCV	NASH and HBV HCC patients: Larger median tumor size vs HCV and ALD. NSD in BCLC staging among the groups	LT, SR or ablative techniques, TACE, yttrium 90, or TARE or radiation therapy, systemic therapy	NAFLD: ↓ OS vs ALD (HR: 1.92) NSD between NAFLD-HCC and viral-related HCC	NA
Giannini et al[97]	2009/Italy/Prospective	471 total HCC patients; 45 CC, 426 HCV	CC: ↑ prevalence of multinodular and diffuse lesions, ↑ size of the largest lesion and advanced classification according to Milano criteria (69% vs 41%) vs HCV	LT, SR, PEI, RFA, TACE	CC: ↓ OS vs HCV	NA
Koh et al[34]	2019/Singapore/Prospective	996 total HCC patients; 152 with NAFLD, 844 non-NAFLD	NAFLD: Smaller median tumor size	Total liver resection	NAFLD: ↑ 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/Retrospective	303 HCC patients; 52 with NAFLD vs 162 HCV/ALD	NASH: NSD in largest tumor size, tumor differentiation and presence of satellite lesions vs HCV/ALD	Resection, ablation, and LT	NASH: ↑ 3-yr OS vs HCV/ALD (60.9% vs 36.2%)	NSD
Benhammou et al[98]	2020/United States/Retrospective	454 total HCC patients; 125 NAFLD, 170 HBV, 159 HCV	NAFLD and HCV more likely to be within Milan and UCSF criteria for LT vs HBV	LT, SR, RFA, PEI, TACE/Y-90, chemotherapy, BSC	NAFLD: ↑ 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/Retrospective	1563 total HCC patients; 96 HCV, 96 MetS matched	MetS: NSD in satellite nodules and microvascular invasion vs HCV	SR, preoperative PVE, TACE	MetS: ↑ 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/Retrospective	1562 total HCC patients; 225 NAFLD, 1337 non-NAFLD	NAFLD: NSD in BCLC staging, number of tumors and largest tumor size vs non-NAFLD	LT ± RFA or TACE, SR, RFA, TACE, systemic therapy or BSC	NAFLD: NSD in OS vs non-NAFLD (HR: 1.04)	NA
Than et al[100]	2017/United States/Retrospective	487 total HCC patients; 212 NAFLD, 275 HCV	NAFLD: ↑ tumor size vs HCV	TACE, RFA, SR, PEI, sorafenib, LT	NAFLD: NSD vs HCV (44% vs 56% respectively)	NA
Wakai et al[101]	2011/Japan/Retrospective	225 total HCC patients; 17 NAFLD, 61 HBV, 147 HCV	NAFLD: ↑ tumor size vs HCV & HBV	SR	NAFLD: ↑ 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/Retrospective	426 total HCC patients; 32 NAFLD, 200 HBV, 194 HBV/NAFLD	NAFLD: ↑ average tumor size vs HBV group (4.4 cm vs 3.4 cm)	Hepatectomy	Before PSM: NAFLD: ↓ 5-yr OS vs HBV (63% vs 80%). After PSM, NSD in 5-yr OS rates	NSD in RFS or disease-specific survival before and after PSM
Tokushige et al[102]	2010/Japan/Prospective	90 total HCC patients; 34 NASH, 56 HCV	NASH: NSD in tumor size vs HCV	SR, RFA, TACE	NASH: 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/Retrospective	323 total HCC patients; 39 NAFLD, 284 non-NAFLD	NAFLD: ↑ larger tumor size vs non-NAFLDNSD in other tumor characteristics	SR, TACE, PVE, PEI, LT	NSD 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/Retrospective	81 total HCC patients; 17 NASH, 64 HCV	NASH: ↓ proportion had poorly differentiated HCC vs HCV	LT	NA	NASH: trend of ↑ 5-yr RFS (P = 0.11)

HCC: Hepatocellular carcinoma; NAFLD: Non-alcoholic fatty liver disease; AH/BC: Autoimmune hepatitis/Biliary cirrhosis; ALD: Alcohol-related liver disease; HBV: Hepatitis B virus; HCV: Hepatitis C virus; LT: Liver transplantation; OS: Overall survival; NA: Not applicable; SR: Surgical resection; TACE: Transarterial chemoembolization; BCLC: Barcelona-Clinic Liver Cancer; PEI: Percutaneous ethanol injection; BSC: Best supportive care; NSD: No significant difference; RFS: Recurrence-free survival; NASH: Non-alcoholic steatohepatitis; TARE: Transarterial radioembolization; HR: Hazard ratio; CC: Cryptogenic cirrhosis; RFA: Radiofrequency ablation; MetS: Metabolic syndrome; PVE: Portal vein embolization; OR: Odds ratio; UCSF: University of California at San Francisco.