Fatty liver disease, an emerging etiology of hepatocellular carcinoma in Argentina

Table 1 Patients’ baseline characteristics

Variable	P values
Age, yr (± SD)	62 ± 10
Male gender, n (%)	537 (75.9)
Non-cirrhotic liver, n (%)	89 (12.6)
Child Pugh A/B/C, n (%)	352 (49.7)/238 (33.6)/118 (16.7)
Comorbidities, n (%)	299 (42.2)
Diabetes mellitus, n (%)	196 (27.7)
Ascites, n (%)	253 (35.7)
Mild	144 (20.3)
Moderate-severe	109 (15.4)
Encephalopathy, n (%)	147 (20.8)
Grade I-II	137 (19.3)
Grade III-IV	10 (1.4)
Esophageal varices, n (%)	394 (56.7)
ECOG 0-2/3-4, n (%)	637 (89.9)/71 (10.1)
Median HCC number, (IQR)	1.0 (1.0-2.0)
Largest HCC diameter, mm (IQR)	53 ± 37
Within Milan, n (%)	334 (46.9)
Bilobar involvement, n (%)	159 (22.1)
Diffuse HCC pattern, n (%)	28 (3.9)
Median AFP, ng/mL (IQR)	23.0 (5.0-337.0)
≤ 100 ng/mL, n (%)	476 (66.3)
101-1000 ng/mL, n (%)	128 (17.7)
> 1000 ng/mL, n (%)	115 (16.0)
Tumor vascular invasion, n (%)	74 (10.4)
Extrahepatic disease, n (%)	48 (6.8)

ECOG: Eastern Cooperative Oncology Group; HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein.

Table 2 Underlying etiologies of liver disease per year (frequencies)

	HCV	HBV	Alcohol	NASH	CC	Cholestasis	AI	Other1	Total
2009	24 (34.3)	7 (10.0)	18 (25.7)	3 (4.3)	9 (12.9)	0	0	9 (12.9)	70
2010	51 (48.6)	5 (4.8)	16 (15.2)	5 (4.8)	12 (11.4)	3 (2.9)	1 (0.9)	12 (11.5)	105
2011	34 (35.6)	5 (5.3)	26 (27.4)	10 (10.5)	9 (9.5)	1 (1.0)	1 (1.0)	7 (6.4)	95
2012	43 (38.0)	5 (4.4)	21 (18.6)	14 (12.4)	10 (8.8)	3 (2.6)	0	5 (8.0)	113
2013	43 (33.1)	9 (6.9)	24 (18.5)	14 (10.8)	17 (13.1)	2 (1.5)	1 (0.8)	13 (10.0)	130
2014	43 (36.7)	4 (3.4)	22 (18.8)	15 (12.8)	9 (7.7)	3 (2.6)	0	16 (13.7)	117
2015	24 (30.8)	3 (3.8)	20 (25.6)	20 (25.6)	2 (2.6)	1 (1.3)	0	4 (5.2)	78
Total (%)	262 (37.0)	38 (5.4)	147 (20.8)	81 (11.4)	68 (9.6)	13 (1.8)	3 (0.4)	60 (9.9)	708

¹Other causes of cirrhosis, Hemochromatosis. NASH: Non-alcoholic steatohepatitis; AI: Autoimmune; CC: Cryptogenic cirrhosis; HBV: Hepatitis B virus; HCV: Hepatitis C virus.

Table 3 Comparative analysis between non alcoholic fatty liver disease and other than non alcoholic fatty liver disease

Variable	NAFLD n = 81 (11.4%)	Non-NAFLD n = 627 (88.6%)	P value
Age, yr (± SD)	63 ± 8	62 ± 4	0.39
Gender, male, n (%)	68 (83.9)	469 (74.9)	0.06
Non-cirrhotic liver, n (%)	7 (8.6)	62 (9.9)	0.72
Child Pugh A/B/C, n (%)	41 (50.6)/32 (39.5)/8 (9.9)	311 (49.6)/206 (32.8)/110 (17.5)	0.15
Comorbidities, n (%)	60 (74.1)	239 (38.1)	< 0.0001
Diabetes mellitus, n (%)	50 (61.7)	146 (23.3)	< 0.0001
Median AFP level, ng/mL	6.6 (4-380)	26 (5.3-332)	0.017
AFP > 1000 ng/mL, n (%)	9 (12.0)	97 (16.1)	0.34
Ascites, n (%)
Mild	17 (21.0)	127 (20.3)	0.7
Moderate-severe	10 (12.3)	99 (15.8)	0.7
Encephalopathy, n (%)
Grade I-II	18 (22.2)	119 (19.0)	0.2
Grade III-IV	3 (3.7)	7 (1.1)	0.2
Esophageal varices, n (%)	50 (63.3)	344 (55.8)	0.5
ECOG 0-2, n (%)	73 (90.1)	564 (89.9)	0.96
Median HCC number, (IQR)	1 (1-2)	1 (1-2)	0.38
Largest HCC diameter, mm (IQR)	55 ± 37	52 ± 37	0.51
Within Milan, n (%)	38 (46.9)	295 (47.0)	0.98
Bilobar involvement, n (%)	16 (19.7)	142 (22.7)	0.82
Diffuse HCC pattern, n (%)	3 (3.7)	20 (3.2)	0.82

AFP: Alpha-fetoprotein; MELD: Model for end stage liver disease; AFLD: Alcoholic fatty liver disease; Non-NAFLD: Other than NAFLD (includes all other etiologies).

Table 4 Baseline pre-treatment variables associated with 5-year mortality, univariate cox regression

Variable	5-yr mortality rate, (%)	Hazard ratio (95%CI)	P value
Age (yr)		1.02 (1.01; 1.04)	< 0.0001
Gender: male (n = 537)	42.7	1.08 (0.83; 1.42)	0.58
Female (n = 170)	42.3
Comorbidity
Yes (n = 299)	45.1	1.08 (0.86; 1.37)	0.49
No (n = 409)	40.6
Diabetes mellitus
Yes (n = 196)	38.8	0.83 (0.63; 1.08)	0.17
No (n = 512)	44
NAFLD
Yes (n = 81)	35.9	1.16 (0.81; 1.69)	0.41
No (n = 627)	56.9
ECOG 0-2
Yes (n = 637)	37.9	0.19 (0.14; 0.26)	0.0001
No (n = 71)	84.5
BCLC 0-A
Yes (n = 335)	26	0.29 (0.23; 0.38)	0.0001
No (n = 373)	57.4
Cirrhosis
Yes (n = 639)	42.9
No (n = 69)	39.1	0.86 (0.58; 1.28)	0.45
Child Pugh
A (n = 352)	34.5	-
B (n = 238)	41.6	1.38 (1.06; 1.83)	0.019
C (n = 118)	68.6	3.23 (2.41; 4.34)	0.0001
Clinically significant portal hypertension
Yes (n = 484)	40.2	1.22 (0.94; 1.57)	0.13
No (n = 224)	43.7
AFP > 1000 ng/mL
Yes (n = 106)	64.1	3.09 (2.31; 4.15)	0.0001
No (n = 569)	39.5
Tumor vascular invasion
Yes (n = 74)	77	4.74 (3.48; 6.44)	0.0001
No (n = 634)	38.5
Extrahepatic tumor disease
Yes (n = 48)	70.8	3.29 (2.25; 4.81)	0.0001
No (n = 660)	40.5

Normal Values: Alpha-fetoprotein 0.6-4.4 ng/mL. AFP: Alpha-fetoprotein; BCLC: Barcelona clinic liver cancer; ECOG: Eastern cooperative oncology group; HCC: Hepatocellular carcinoma; LT: Liver transplantation; WL: Waiting list; NAFLD: Non-alcoholic fatty liver disease.

Table 5 Multivariate cox regression analysis of risk factors associated with 5-year mortality

Variable	HR	95%CI	P value
Age	1.03	1.01; 1.04	< 0.0001
BCLC 0-A	0.50	0.37; 0.68	< 0.0001
Child Pugh B1	1.54	1.61; 2.05	0.003
Child Pugh C1	2.59	1.84; 3.66	< 0.0001
AFP > 1000 ng/mL	2.09	1.52; 2.87	< 0.0001
Tumor vascular invasion	2.84	1.75; 3.53	< 0.0001

¹Compared to Child Pugh A, Harrell’s concordance statistic was 0.76.