Recurrence of hepatocellular carcinoma in noncirrhotic patients with nonalcoholic fatty liver disease versus hepatitis B infection : European Journal of Gastroenterology & Hepatology

Secondary Logo

Journal Logo

Original article

Recurrence of hepatocellular carcinoma in noncirrhotic patients with nonalcoholic fatty liver disease versus hepatitis B infection

Lee, Jungnama,*; Chang, Jong-Inb,*; Jin, Young-Jooa; Lee, Jeong-Hoonc; Kim, Ju Yeonc; Sinn, Dong Hyund; Kim, Soon Sune; Lee, Hyun Woongf; Yoo, Sun Hongg; Yu, Jung Hwana; Lee, Jin-Wooa

Author Information
European Journal of Gastroenterology & Hepatology ():10.1097/MEG.0000000000002504, December 23, 2022. | DOI: 10.1097/MEG.0000000000002504

Abstract

Introduction

Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver cancers and was the 6th most common cancer and the 3rd most common cause of cancer-related death in 2020 [1]. Hepatitis B virus (HBV) infection is the primary cause of HCC development and accounts for ~50% of cases at the global level [2,3], and hepatitis C virus (HCV) infection is also a major contributor to HCC development. However, the introduction of effective antivirals for HBV or HCV has reduced their impacts [4]. On the other hand, the proportion of HCCs occurring in a background of nonalcoholic fatty liver disease (NAFLD) is increasing [5–8].

NAFLD is a biologically and clinically heterogeneous disease covering a wide range of histological conditions [9,10], and its incidence is on the rise due to the increasing prevalences of metabolic comorbidities, such as obesity, type 2 diabetes and hyperlipidemia [9,11,12]. Furthermore, NAFLD is a significant cause of liver disorders globally and is the most common liver disease in the USA [9,13]. However, the incidence of HCC in the NAFLD disease spectrum is poorly understood because tissue acquisitions from many patients with underlying liver disease are not possible in real clinical practice.

Currently, only a few comparative studies on the clinical patterns and outcomes between NAFLD-related HCC and HBV- or HCV-related HCC have been performed, and available results are heterogeneous and inconclusive [14–18]. Piscaglia et al. [14] reported that overall survival (OS) was significantly shorter in NAFLD-related HCC patients than in HCV-related HCC patients. However, the study was limited because NAFLD-related HCC was more frequently diagnosed at an advanced stage than HCV-related HCC, presumably due to differences in surveillance practices [14,19]. In addition, more than 70% of NAFLD included in these studies were clinically diagnosed without histologic confirmation [14]. In another study, Ahn et al. [18] reported no significant difference between the survival outcomes of NAFLD- and HBV-related HCC, and Yoon et al. [15] reported that concurrent NAFLD was not associated with survival outcomes in HBV-related HCC patients. Unfortunately, these two studies were also limited by their single-center designs [15,18]. Other retrospective studies have reported that NAFLD-related HCC patients who undergo curative resection have better survivals than HCC patients with other etiologies [16,17].

Regular follow-up for HCC surveillance is generally recommended for patients with liver cirrhosis or HBV infection without liver cirrhosis, and for noncirrhotic F3 patients, regardless of cause [20–24] However, no effective follow-up strategy has been devised after curative resection for HCC in NAFLD patients without cirrhosis, and no accurate data is available on recurrence of HCC or prognosis after curative resection for HCC in these patients.

Therefore, we conducted this multicenter study to evaluate the long-term cumulative recurrence rates of HCC and OSs after curative resection for HCC in noncirrhotic NAFLD patients. In addition, we compared these outcomes of noncirrhotic NAFLD patients with those of HBV patients with or without fatty liver.

Materials and methods

Study subjects

A flowsheet of the enrolled subjects is shown in Fig. 1. We retrospectively analyzed data extracted from the records of 791 consecutive patients that underwent surgical resection as an initial treatment for initially diagnosed primary HCC at six university hospitals between January 2005 and December 2015. HCC was histologically diagnosed in all subjects by the pathologic review of resected surgical specimens. No patient had been treated previously for HCC. The inclusion criteria were as follows: those who received R0 hepatic resection (In this study, R0 resection was defined as the absence of any tumor cell microscopically or grossly in the surgical resection margin or primary tumor bed [25].). NAFLD or HBV-associated HCC; Barcelona Clinic Liver Cancer (BCLC) 0 or A staged HCC; good Eastern Cooperative Oncology Group (performance status 0); no pathological cirrhosis; no vascular invasion or extrahepatic metastasis and first-line treatment by surgical resection. To minimize selection bias as much as possible, we excluded those with a coexisting other malignancy, BCLC stages B–D, HCC recurrence within 1 year after curative surgical resection, microscopically positive surgical resection margin or the age of <18 years. We also excluded those with etiologies other than NAFLD or HBV or those with extrahepatic, vascular or lymph node metastasis.

F1
Fig. 1.:
Study subjects of the 791 noncirrhotic patients without recurrence during 1 year following curative resection for HCC, 63 and 728 patients were enrolled in the NAFLD and HBV groups, respectively. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver.

Finally, 791 patients without recurrence within the 1 year following curative surgical resection for HCC were enrolled in this retrospective cohort study. Of these 791 patients, 63 (NAFLD group) and 728 (HBV group) were NAFLD and HBV patients without cirrhosis, respectively. In addition, the HBV group was subdivided into HBV with fatty liver (n = 237) and without fatty liver (n = 491). In this cohort, HBV patients were recruited as a comparative group. Clinical and follow-up data of all 791 study subjects were subjected to analysis. Institutional review board approval for this study was obtained at each participating hospital (Supplementary Table 1, Supplemental digital content 1, https://links.lww.com/EJGH/A819), and due to the retrospective nature of this study, the acquisition of informed consent from enrolled patients was waived.

Initial treatment and follow-up

Surgical resection was performed under general anesthesia, considering reserved the hepatic function and subsequent residual liver volume. Combined resection of adjacent liver segments (anatomic resection) with tumor-free margins of at least 10 mm was performed to remove all macroscopic HCC. The entire surgical procedure was conducted by expert surgeons at each institution with at least 5–10 years of professional experience in performing the procedures. Normal liver tissue adjacent to the tumor was assessed. Advanced fibrosis and cirrhosis were defined as METAVIR fibrosis scores of F3 and F4, respectively [26,27].

After initial treatment, patients were regularly followed by liver dynamic computed tomography (CT) or MRI at 1–3-month intervals for the first 6 months and then at 3–6-month intervals for 5 years, and are subsequently followed up every 6–12 months. These follow-up measures continued until the date of death, HCC recurrence, last follow-up or 31 December 2019.

Assessments of recurrence of hepatocellular carcinoma or patients’ survival

Surgical resection is a treatment administered with curative intent and thus, was considered curative when the resection margin was pathologically free of tumor or no enhancing and washout lesions were observed on liver dynamic CT scan or MR images obtained immediately after or 1 month after surgery. Although HCC recurrence is generally defined as tumor recurrence after curative treatment for HCC, it is not easy to completely differentiate between remnant tumor and tumor recurrence within 1 year after HCC treatment. Therefore, in the present study, subjects were considered tumor-free if there was no HCC recurrence within 1 year after surgical resection. We defined HCC recurrence as the development of HCC 1 year after surgical resection at a hepatic area different from that of the previous lesion. HCC was diagnosed as the development of a 1 cm or greater diameter with arterial enhancement and delayed washout lesions in dynamic CT scans or MR images. Recurrence rates of HCC were calculated from the date of surgical resection to the date of HCC recurrence 1 year after surgical resection or death from any cause or the last follow-up date. OS duration was calculated from the date of surgical resection to death from any cause, the last follow-up date. The patients lost to follow-up were censored at the time of the last follow-up.

Statistical analyses

The primary endpoint of this multicenter study was the difference between the recurrence rates of HCC in NAFLD- and HBV-associated patients without cirrhosis. The secondary endpoint was the differences between OSs in these two groups. Prognostic factors related to the recurrence of HCC or OS in the enrolled subjects were also evaluated.

The following variables were recruited: age, sex, BMI, comorbidity of hypertension or diabetes, cause of HCC, antiviral therapy (AVT) for HBV, albumin, total bilirubin, prothrombin time (PT), alpha-fetoprotein (AFP), Child-Turcotte- Pugh (CTP) class, tumor number and size, tumor gross type; BCLC stage, presence of microvascular invasion (MVI) in the surgical specimen and advanced fibrosis or cirrhosis. Potential relationships between these parameters and the primary and secondary endpoints were assessed. Tumor gross was classified into five types as followings; vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP] and infiltrative [INF] [28], and these were dichotomized into two groups [type 1 (VN/EN) vs. type 2 (MC/NP/INF)].

The clinical characteristics of the study subjects are expressed as the mean (±SD) for the continuous variables and the numbers (ratios) for the categorical variables. Differences between the groups were compared using the Student’s t-test for the continuous variables or the chi-square test for categorical variables. The significance of differences among the three groups was determined by the ANOVAtest with Tukey’s b multiple comparison test. The Cox proportional hazards model was used to assess the hazard ratios (HRs) and 95% confidence intervals (CI) for mortality. The two-tailed P-values of <0.05 were considered significant. The statistical analyses were conducted using SPSS v19.0 (SPSS Inc, Chicago, Illinois, USA).

Results

Baseline characteristics

The baseline clinical characteristics of the study patients are summarized in Table 1. Of the 791 patients, 63 and 728 were assigned to the NAFLD and HBV groups, respectively. The NAFLD group had a higher frequency of hypertension patients (P = 0.002), a lower frequency of advanced fibrosis (P < 0.001), an older age (P < 0.001), a higher BMI (P = 0.003) and albumin level (P < 0.001), a lower serum bilirubin level (P = 0.014), and a larger median tumor size (P < 0.001) than the HBV group. On the other hand, sex, presence of diabetes, PT, CTP class, AFP level and tumor gross types (VN/EN vs. MC/NP/INF) were similar in the NAFLD and HBV groups. The median follow-up durations of the NAFLD and HBV groups were 69.9 months (range, 3.5–166.8 months) and 85.2 months (range, 1.0–577.9 months), respectively (P = 0.011) (Table 1).

Table 1. - Baseline clinical characteristics of all study subjects
Variables NAFLD group (n = 63) HBV group (n = 728) P a
Age (years)b 65 ± 10.1 55 ± 9.7 <0.001
Sex, male, n (%) 51 (81.0) 568 (78.0) 0.750
BMI (kg/m2)b 25.4 ± 3.0 24.2 ± 2.9 0.003
Diabetes, presence, n (%) 25 (39.7) 243 (33.4) 0.332
Hypertension, presence, n (%) 27 (42.9) 186 (25.6) 0.005
AVT for HBV, n (%)
 Before/after HCC treatment NA 251/255 (34.5/35.1) NA
Albumin (g/dl)b 4.3 ± 0.4 4.2 ± 0.4 0.022
Bilirubin (mg/dl) 0.8 ± 0.3 0.9 ± 0.5 0.014
PT, INRb 1.1 ± 0.2 1.1 ± 0.1 0.978
CTP class A/B, n (%) 63/0 (100/0) 724/3 (99.6/0.4) 1.000
Advanced fibrosis, n (%) 1 (1.6) 299 (41.1) <0.001
AFP (ng/dL)b 1099 ± 4042 2960 ± 25 068 0.081
Tumor number, n (%)
 1/2–3 63/0 (100/0) 698/30 (95.9/4.1) 0.161c
Tumor sizeb 4.9 ± 2.8 3.5 ± 1.9 <0.001
Tumor. gross classification, n (%)d
 (VN, EN)/ (MC,NP,INF) 32/30(51.6/48.4) 287/440 (39.5/60.5) 0.062
BCLC stage
 0/A 7/56 (11.1/88.9) 137/591 (18.8/81.2) 0.172
MVI, presence, n (%) 13 (20.6) 192 (26.4) 0.370
FU duration (month)e 69.9 (3.5–166.8) 85.2 (1.0–577.9) 0.011
AFP, Alpha-fetoprotein; AVT, antiviral therapy; BCLC, Barcelona Clinic Liver Cancer; CTP, Child-Turcotte-Pugh; EN, expand nodule; FU, follow-up; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; INF, infiltrative; INR, international ratio; MC, multinodular confluent; MVI, microvascular invasion; NAFLD, nonalcoholic fatty liver disease; NP, nodular with perinodular extension; PT, prothrombin time; VN, vaguely nodular.
aP values were calculated using the t-test for continuous variables and the Chi-square test for categorical variables.
bMean (±SD).
cFisher’s exact test.
dData for tumor gross classification were available for 789 patients, and 2 patients showed unclassified tumor type.
eMedian (range).

&&Recurrence rates of hepatocellular carcinoma and overall survival rates in the nonalcoholic fatty liver disease versus hepatitis B virus groups

Recurrence of HCC was observed in 6 (9.5%) and 210 (28.8%) patients in the NAFLD and HBV groups, respectively, during the corresponding median follow-ups of 69.9 and 85.2 months. The cumulative recurrence rates of HCC at 2, 4, 6, 8 and 10 years in the NAFLD group (3.6, 9.4, 12.4, 12.4 and 12.4%, respectively) were significantly lower than in the HBV group (1.7, 16.9, 27.2, 37.1 and 44.4%, respectively) (P = 0.008) (Fig. 2a). During the corresponding median follow-ups of 69.9 and 85.2 months, 7 (11.1%) and 210 (4.1%) patients in the NAFLD and HBV groups died, respectively. The cumulative OS rates at 2, 4, 6, 8 and 10 years in the NAFLD group (98.2, 96.0, 84.0, 84.0 and 84.0%, respectively) were significantly lower than in the HBV group (99.3, 98.4, 97.3, 95.7 and 93.6%, respectively) (P = 0.003) (Fig. 2b).

F2
Fig. 2.:
Cumulative recurrence rates of HCC and OS rates of patients with NAFLD or HBV The cumulative recurrence rates of HCC in the NAFLD group were significantly lower than those in the HBV group (P = 0.008) (a). The cumulative OSs in the NAFLD group were significantly shorter than those in the HBV group (P = 0.003) (b). HBV, hepatitis B virus; HCC, hepatocellular carcinoma, NAFLD, nonalcoholic fatty liver; OS, overall survival.

Comparison of clinical characteristics of patients with nonalcoholic fatty liver disease versus hepatitis B virus with/without fatty liver

To identify the difference between the recurrence of HCC and OS rates after curative resection for HCC among patients with NAFLD, HBV with fatty liver and HBV without fatty liver, we compared the clinical characteristics of these three groups (Table 2). Individuals in the NAFLD were older age (P < 0.001) and had larger tumors (P < 0.001) than those in the HBV with or without fatty liver. The proportion of males was highest in the HBV with a fatty liver group (P = 0.022), and the mean BMI was lowest in the HBV without a fatty liver group (P < 0.001). Hypertension was most common in the NAFLD group (P < 0.001). Type 1 HCC (VN/EN) was most common in the NAFLD group, and type 2 HCC (MC/NP/INF) was most common in the HBV without a fatty liver group (P < 0.001). Advanced fibrosis was most frequently present in the HBV with a fatty liver group (P < 0.001), but MVI was most common in the HBV without a fatty liver group (P = 0.007). AVT for HBV infection was more commonly performed in the HBV with the fatty liver group than in the HBV without the fatty liver group (P = 0.010) (Table 2).

Table 2. - Clinical characteristics of all study subjects
Variables NAFLD group HBV/FL (+) group HBV/FL (−) group P valuea
(n = 63) (n = 237) (n = 491)
Age (years)b 65 ± 10.1c 57 ± 9.5d 55 ± 10.0d <0.001
Sex, male, n (%) 51 (81.0) 199 (84.0) 369 (75.2) 0.022
BMI (kg/m2)b 25.4 ± 3.0c 24.9 ± 2.8c 23.8 ± 2.8d <0.001
Diabetes, presence, n (%) 25 (39.7) 74 (31.2) 169 (34.4) 0.415
Hypertension, presence, n (%) 27 (42.9) 35 (14.8) 151 (30.8) <0.001
AVT for HBV, n (%) 0.559
 Before/after HCC treatment NA 96/85 (40.5/35.9) 155/170 (31.6/34.6) 0.010
Albumin (g/dl)b 4.3 ± 0.4 4.1 ± 0.4 4.2 ± 0.4 0.069
Bilirubin (mg/dl) 0.8 ± 0.3 0.9 ± 0.4 0.9 ± 0.5 0.156
Prothrombin time, INRb 1.1 ± 0.2 1.1 ± 0.1 1.1 ± 0.1 0.050
CTP class A/B, n (%) 63/0 (100/0) 236/1 (99.6/0.4) 488/2 (99.6/0.4) 0.877
Advanced fibrosis, n (%) 1 (1.6) 124 (52.3) 175 (35.6) <0.001
AFP (ng/dl)b 1,099 ± 4,042 2070 ± 19,345 3392 ± 27,423 0.663
Tumor number, n (%)
 1/2–3 63/0 (100/0) 226/11 (95.4/4.6) 472/19 (96.1/3.9) 0.222e
Tumor sizeb 4.9 ± 2.8c 3.2 ± 1.7d 3.6 ± 2.1d <0.001
Tumor, gross class, n (%)f
(VN,EN)/ (MC,NP,INF) 32/30 (51.6/48.4) 119/118 (50.2/49.8) 168/322 (34.3/65.7) <0.001
BCLC stage
 0/A 7/56 (11.1/88.9) 50/187 (21.1/78.9) 87/404 (17.7/82.3) 0.170
MVI, presence, n (%) 13 (20.6) 46 (19.4) 146 (29.7) 0.007
FU duration (month) g 69.0 (0.1–162.6)c 78.4 (6.9–174.2)c 93.9 (1.0–577.9)d <0.001
AFP, Alpha-fetoprotein; AVT, antiviral therapy; BCLC, Barcelona Clinic Liver Cancer; CTP, Child-Turcotte-Pugh; EN, expand nodule; FU, follow-up; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; INF, infiltrative; INR, international ratio; MC, multinodular confluent; MVI, microvascular invasion; NAFLD, nonalcoholic fatty liver disease; NP, nodular with perinodular extension; PT, prothrombin time; VN, vaguely nodular.
aP values were calculated using the ANOVA test with Tukey’s b multiple comparison test to determine the significance of differences among three groups, the chi-square test.
bMean (±SD).
eThe Fisher-exact test.
fData for tumor gross classification were available for 789 patients, and 2 patients showed unclassified tumor type.
gMedian (range).

Comparisons of recurrence of hepatocellular carcinoma and overall survival in the nonalcoholic fatty liver disease and hepatitis B virus with/without fatty liver groups

Recurrence of HCC was observed in 6 (9.5%), 71 (30.0%) and 139 (28.3%) patients in the NAFLD, HBV with fatty liver and HBV without fatty liver groups, respectively, during median follow-ups of 69.0, 78.4 and 93.9 months, respectively. The cumulative recurrence rates of HCC at 2, 4, 6, 8 and 10 years in the NAFLD group (3.6, 9.4, 12.4, 12.4 and 12.4%, respectively) were lower than in the HBV with a fatty liver group (1.7, 16.9, 27.2, 37.1 and 44.4%, respectively) (P = 0.005) and in the HBV without a fatty liver group (2.7, 15.8, 22.4, 28.9 and 35.5%, respectively) (P = 0.014), (Fig. 3a). During the median follow-ups of 69.0, 78.4 and 93.9 months, 7 (11.1%), 6 (2.5%) and 24 (4.9%) patients in the NAFLD, HBV with fatty liver, and HBV without fatty liver groups, respectively, died. The cumulative OS rates (98.2, 96.0, 84.0, 84.0 and 84.0 %, respectively) at 2, 4, 6, 8 and 10 years in the NAFLD group were lower than in the HBV with a fatty liver group (100, 100, 99.0, 96.8, and 93.1%, respectively) (P = 0.002) and in the HBV without a fatty liver group (99.0, 97.9, 96.4, 95.1, and 93.4%, respectively) (P = 0.035) (Fig. 3b). Subgroup analysis was performed after excluding patients with advanced fibrosis (Supplementary Table 2, Supplemental digital content 2, https://links.lww.com/EJGH/A820), but the results obtained were similar to those obtained when patients with advanced fibrosis were included (Fig. 4a,b).

F3
Fig. 3.:
Cumulative recurrence rates of HCC and OS rates of patients with NAFLD or HBV with/without fatty liver The cumulative recurrence rates of HCC in the NAFLD group were lower than those in the HBV with FL (P = 0.005) and those in the HBV without FL groups (P = 0.014) (a). The cumulative OSs in the NAFLD group were shorter than those in the HBV with FL (P = 0.002) and those of the HBV without FL groups (P = 0.035) (b). FL, fatty liver; Gr, group; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver; OS, overall survival.
F4
Fig. 4.:
Cumulative recurrence rates of HCC and OS rates of patients with NAFLD or HBV with/without fatty liver after excluding patients with advanced fibrosis. The cumulative recurrence rates of HCC in the NAFLD group were lower than those in the HBV with FL (P = 0.036) and those of the HBV without FL groups (P = 0.055) (a). The cumulative OSs in the NAFLD group were shorter than those in the HBV with FL (P = 0.035) and those of the HBV without FL groups (P = 0.014) (b). FL, fatty liver; Gr, group; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver; OS, overall survival.

Significant predictors of recurrence of hepatocellular carcinoma and overall survival after curative resection for hepatocellular carcinoma

In all study subjects, older age (HR, 1.03; 95% CI, 1.01–1.04; P < 0.001), higher BMI (HR, 1.05; 95% CI, 1.00–1.10; P = 0.044), presence of advanced fibrosis (HR, 1.47; 95% CI, 1.12–1.93; P = 0.006) and HBV infection with fatty liver (HR, 3.18; 95% CI, 1.35–7.46; P = 0.008) or without fatty liver (HR, 3.10; 95% CI, 1.34–7.15; P = 0.008) were significant prognostic factors for recurrence of HCC after curative resection for HCC (Table 3). In addition, the presence of MVI (HR, 2.63; 95% CI, 1.33–5.21; P = 0.006), HBV infection with fatty liver (HR, 0.29; 95% CI, 0.09–0.88; P = 0.029) or HBV infection without fatty liver (HR, 0.37; 95% CI, 0.15–0.90; P = 0.029) were significantly associated with OS after curative resection for HCC (Table 4).

Table 3. - Multivariable analysis for prognostic factors of recurrence of hepatocellular carcinoma of all study patients
Variables Univariate analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value
Age (years) 1.02 (1.01–1.04) 0.001 1.03 (1.01–1.04) <0.001
Sex (male) 1.29 (0.92–1.82) 0.134
BMI (kg/m2) 1.05 (1.01–1.11) 0.029 1.05 (1.00–1.10) 0.044
Diabetes, presence 1.27 (0.96–1.67) 0.091
Hypertension, presence 0.92 (0.67–1.25) 0.581
CTP class B vs. A 1.43 (0.20–10.19) 0.723
Advanced fibrosis, presence 1.63 (1.24–2.12) <0.001 1.47 (1.12–1.93) 0.006
AFP (ng/dl) 1.00 (1.00–1.01) 0.345
Tumor size (cm) 0.99 (0.93–1.06) 0.900
Tumor number
 Multiple vs. single 2.16 (0.52–9.03) 0.291
Tumor gross type (type 1 vs. 2) 1.06 (0.81–1.39) 0.673
BCLC stage, A vs. 0 1.09 (0.78–1.54) 0.610
MVI, presence 1.00 (0.74–1.36) 0.983
Underlying cause
 NAFLD, reference
 HBV with FL 3.20 (1.39–7.38) 0.006 3.18 (1.35–7.46) 0.008
 HBV without FL 2.69 (1.19–6.09) 0.018 3.10 (1.34–7.15) 0.008
Type 1: vaguely nodular and expanding nodular types.
Type 2: multinodular confluent, nodular with perinodular extension, and infiltrative types.
Event: hepatocellular carcinoma (HCC) recurrence after 1 year after surgery for HCC (n = 216; 27.3%).
AFP, Alpha-fetoprotein; BCLC, Barcelona clinic liver cancer; CI, confidence interval; CTP, Child-Turcotte-Pugh; FL, fatty liver; HBV, hepatitis B virus; HR, hazard ratio; MVI, microvascular invasion; NAFLD, nonalcoholic fatty liver disease.

Table 4. - Multivariable analysis for prognostic factors of overall survival of all study patients
Variables Univariate analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value
Age (years) 1.03 (1.00–1.06) 0.031 1.03 (0.99–1.07) 0.052
Sex (male) 0.77 (0.37–1.59) 0.479
BMI (kg/m2) 0.92 (0.82–1.04) 0.167
Diabetes, presence 0.97 (0.49–1.92) 0.921
Hypertension, presence 2.10 (1.09–4.03) 0.025 1.78 (0.91–3.45) 0.091
CTP class B vs. A 0.05 (0.00–8.44) 0.820
Advanced fibrosis, presence 0.68 (0.33–1.37) 0.274
AFP (ng/dl) 1.00 (1.00–1.01) 0.829
Tumor size (cm) 1.14 (0.99–1.29) 0.066
Tumor number
 Multiple vs. single 2.16 (0.52–9.03) 0.291
Tumor gross type (type 1 vs. 2) 0.90 (0.46–1.78) 0.771
BCLC stage, A vs. 0 1.54 (0.60–3.96) 0.367
MVI, presence 2.23 (1.17–4.28) 0.016 2.63 (1.33–5.21) 0.006
Underlying cause
 NAFLD, reference
 HBV with FL 0.21 (0.07–0.64) 0.006 0.29 (0.09–0.88) 0.029
 HBV without FL 0.34 (0.15–0.79) 0.012 0.37 (0.15–0.90) 0.029
Type 1: vaguely nodular and expanding nodular types.
Type 2: multinodular confluent, nodular with perinodular extension, and infiltrative types.
Event: death (n = 37, 4.7%).
AFP, Alpha-fetoprotein; BCLC, Barcelona clinic liver cancer; CI, confidence interval; CTP, Child-Turcotte-Pugh; FL, fatty liver; HBV, hepatitis B virus; HR, hazard ratio; MVI, microvascular invasion; NAFLD, nonalcoholic fatty liver disease.

Discussion

In this study, we compared recurrences of HCC and survival outcomes between noncirrhotic patients with NAFLD comparing those with HBV infection. We found that recurrence rates of HCC in NAFLD patients were significantly lower than those in HBV patients, regardless of whether HBV patients were accompanied by fatty liver. On the other hand, cumulative OS rates were lower in NAFLD patients than in HBV patients. However, multivariate analysis showed HBV infection per se compared to NAFLD was a more potent risk factor for the recurrence of HCC. Furthermore, the present study, which was conducted on histologically confirmed noncirrhotic NAFLD patients, identified factors associated with the recurrence of HCC during the long-term follow-up period.

In general, liver cirrhosis is an important risk factor for HCC development regardless of the underlying causes of liver disease [29]. We intended to evaluate the risk of recurrence of HCC in NAFLD patients using HBV patients as controls, and thus, excluded liver cirrhosis patients. In clinical practice, it is not easy to track HCC development in noncirrhotic NAFLD patients for an extended period or to histologically diagnose NAFLD. Considering these practical limitations, we believe the results of the present study have meaningful clinical implications. First, this study provides a valuable reference for future prospective research related to the recurrence of HCC in noncirrhotic NAFLD patients and for the establishment of predictive models related to the occurrence of NAFLD-HCC. Second, appropriate tailored surveillance guidelines for patients with NAFLD at high risk of HCC are needed but have yet to be established, and thus, our results may be important data for conducting future surveillance studies.

As was expected, in the present study, HCC occurrence continued to increase over time in the HBV group with or without fatty liver [30]. Moreover, the risk of HCC development in the HBV group could not be eliminated despite the use of AVT for HBV [31]. These results suggest that concomitant fatty liver in noncirrhotic HBV patients does not significantly affect the risk of HCC development and that HBV per se is a decisive risk factor for HCC development. Moreover, advanced fibrosis was more common in the HBV group than in the NAFLD group, which suggests that it may also be responsible for the high risk of HCC development observed in the HBV group. Furthermore, in the present study, noncirrhotic NAFLD patients were found to have a lower HCC development risk than noncirrhotic HBV patients but had a high risk of HCC occurrence over time despite the exclusion of patients with advanced fibrosis. These observations suggest that NAFLD is a risk factor for the recurrence of HCC despite the absence of advanced fibrosis or liver cirrhosis.

On the other hand, the frequency of accompanying advanced fibrosis was low in the NAFLD group in the present study. Although the number of NAFLD patients recruited was relatively small in the present study, only 1 (1.6%) patient in the NAFLD group had advanced fibrosis. Paradis et al. [32] reported that HCC in patients with metabolic syndrome is often not accompanied by fibrosis. These findings suggest the possibility of an alternative mechanism of HCC development in NAFLD, especially in early resectable NAFLD-HCC, unlike that in HBV- or HCV-related HCC. Given that the proportion of HCC patients with NAFLD is increasing, further large-scale research studies are warranted in these patients.

In the present study, patients in the NAFLD group were older, more obese and more frequently had accompanying comorbidities, such as hypertension, than patients in the HBV group, which concurs with a recently reported meta-analysis [33]. In addition, in the previous study, it was reported that NAFLD patients often die from causes associated with metabolic comorbidity and that cardiovascular disease is the most common cause of death [33]. Similarly, in the present study, hypertension tended to be associated with poorer OS. However, our findings and those of this meta-analysis differ in some respects [33], that is the meta-analysis was conducted on patients with NAFLD-associated HCC [33], whereas the present study was performed on noncirrhotic NAFLD patients that did not experience recurrence during the 1 year following curative surgery for HCC. With regard to tumor type (VN/EN vs. MC/NP/INF), it was not associated with tumor recurrence and patient survival in the present study, unlike the previous study [28]. This may be due to differences in baseline characteristics between the studies.

The previous study showed OS was similar for patients with NAFLD-HCC and those with another cause related to HCC [33]. However, another study showed that patients with NAFLD-HCC had longer survivals than those with HCV-HCC but reported no survival difference between noncirrhotic patients with NAFLD-HCC and those with HCV-HCC [14]. However, the previous study had a relatively short median follow-up of 13 months [14]. On the other hand, the present study compared noncirrhotic patients with NAFLD and those with HBV and excluded liver cirrhosis patients to eliminate its effects and to enable evaluation of the effect of the fatty liver itself on the HCC development and patient survival. Furthermore, we found cumulative OS rates were lower in NAFLD patients than in HBV patients with or without fatty liver. Although direct causes of death between the study groups were not evaluated in the present study, we offer the following explanations. First, the older age or higher frequency of hypertension in the NAFLD group than in the HBV group may have contributed to poorer survival in the NAFLD group because multivariate analysis showed that hypertension was associated with OS. Second, higher BMI is known as a reversible risk factor for cardiovascular disease, but weight reduction in elderly patients with NAFLD is not easy. Third, it is thought that AVT for HBV may have a positive effect on patient survival by preventing progression to liver cirrhosis [34,35].

Several limitations of the current study require consideration. First, the present study was conducted in a retrospective observational manner based on retrieved medical records. However, our study has the advantage of a multi-center design with a relatively long median follow-up duration of about 70 months in the NAFLD group. Second, due to the limitations of the retrospective nature of this study, data on the cause of death could not be obtained from all deceased patients and could not be evaluated. This study would have benefited from more exact clinical information on causes of mortality such as liver disease or metabolic disease-related mortality. Third, occult HBV infection could not be excluded because the anti-HBc antibody test is not routinely performed in the clinical setting [18], and thus, occult HBV infection may have been overlooked in the NAFLD group. Based on the 2015 Korean Association for the Study of the Liver clinical practice guidelines for the management of chronic hepatitis B infection, antiviral therapy was not applied for all HBV-associated HCC patients until 2015 due to a lack of evidence for the use of antiviral drugs after surgery in them. Because of this, in the present study, antiviral drugs could not be used in all patients in the HBV group, and sufficient data on replication suppression and change in anti-HBe positivity or anti-HBs positivity could not be analyzed on the same HBV treatment criteria. In the future, analysis with perfect variable values without missing data on the same basis may be clinically meaningful. Finally, pathologic information on non-alcoholic steatohepatitis in normal liver tissue could not be available for analysis. However, we were able to obtain information on degrees of fibrosis and liver cirrhosis. In addition, the present study was conducted on Koreans, who are not as obese as their Western counterparts, and thus, could reflect the characteristics of nonobese Koreans or East Asians. Considering the pivotal effect of liver fibrosis on prognosis in NAFLD patients, we believe our results are clinically implicative for determining the risk of recurrence of HCC in NAFLD patients despite the absence of advanced fibrosis or liver cirrhosis [36].

In conclusion, noncirrhotic NAFLD patients were found to have lower recurrence rates of HCC but poorer survival outcomes than noncirrhotic HBV patients with or without fatty liver. Despite a noncirrhotic liver background, the risk of recurrence of HCC persists in NAFLD patients. Considering the advanced ages of NAFLD patients, tailored surveillance strategies need to be developed for NAFLD patients without cirrhosis, and strict control of metabolic risk factors may be required. We believe this study provides a meaningful reference for future studies on noncirrhotic NAFLD patients.

Acknowledgements

This study was supported by the Scientific Research Fund of the Korean Liver Cancer Study Group.

J.L., J.I.C., Y.J.J. and J.H.L. were responsible for the concept and design of the study, the acquisition, analysis and interpretation of the data and the drafting of the manuscript. J.Y.K., D.H.S., S.S.K., H.W.L., S.H.Y., J.H.Y. and J.W.L. helped with data acquisition.

Conflicts of interest

There are no conflicts of interest.

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71:209–249.
2. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. Global Burden of Disease Liver Cancer Collaboration. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol 2017; 3:1683–1691.
3. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7:6.
4. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017; 153:996–1005.e1.
5. Allen AM, Hicks SB, Mara KC, Larson JJ, Therneau TM. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity–a longitudinal cohort study. J Hepatol 2019; 71:1229–1236.
6. Kim G-A, Lee HC, Choe J, Kim M-J, Lee MJ, Chang H-S, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol 2018; 68:140–146.
7. Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018; 155:1828–1837.e2.
8. Shen H, Lipka S, Kumar A, Mustacchia P. Association between nonalcoholic fatty liver disease and colorectal adenoma: a systemic review and meta-analysis. J Gastrointest Oncol 2014; 5:440–446.
9. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64:73–84.
10. Salomao M, Yu WM, Brown RS, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am J Surg Pathol 2010; 34:1630–1636.
11. Plaz Torres MC, Bodini G, Furnari M, Marabotto E, Zentilin P, Strazzabosco M, et al. Surveillance for hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: universal or selective? Cancers 2020; 12:1422.
12. Ng CH, Chan KE, Chin YH, Zeng RW, Tsai PC, Lim WH, et al. The effect of diabetes and prediabetes on the prevalence, complications and mortality in non-alcoholic fatty liver disease. Clin Mol Hepatol 2022; 28:565–574.
13. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40:1387–1395.
14. Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 2016; 63:827–838.
15. Yoon JS, Lee HY, Chung SW, Kim SW, Chang Y, Lee YB, et al. Prognostic impact of concurrent nonalcoholic fatty liver disease in patients with chronic hepatitis B-related hepatocellular carcinoma. J Gastroenterol Hepatol 2020; 35:1960–1968.
16. Reddy SK, Steel JL, Chen HW, DeMateo DJ, Cardinal J, Behari J, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 2012; 55:1809–1819.
17. Viganò L, Conci S, Cescon M, Fava C, Capelli P, D'Errico A, et al. Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC. J Hepatol 2015; 63:93–101.
18. Ahn SY, Kim SB, Song IH. Clinical patterns and outcome of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol 2020; 2020:4873875.
19. Kang SH, Lee HW, Yoo J-J, Cho Y, Kim SU, Lee TH, et al. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021; 27:363–401.
20. Korean Liver Cancer Association. 2018 Korean Liver Cancer Association–National Cancer Center Korea practice guidelines for the management of hepatocellular carcinoma. Korean J Radiol 2019; 20:1042.
21. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology (Baltimore, Md) 2011; 53:1020–1022.
22. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943.
23. Liu D, Chan AC, Fong DY, Lo C-M, Khong P-L. Evidence-based surveillance imaging schedule after liver transplantation for hepatocellular carcinoma recurrence. Transplantation 2017; 101:107–111.
24. Korean Association for the Study of the Liver. KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276.
25. Hermanek P, Wittekind C. Residual tumor (R) classification and prognosis. Semin Surg Oncol 1994; 10:12–20.
26. Asselah T, Marcellin P, Bedossa P. Improving performance of liver biopsy in fibrosis assessment. J Hepatol 2014; 61:193–195.
27. French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20:15–20.
28. Lee Y, Park H, Lee H, Cho JY, Yoon Y-S, Choi Y-R, et al. The clinicopathological and prognostic significance of the gross classification of hepatocellular carcinoma. J Pathol Transl Med 2018; 52:85–92.
29. Harris PS, Hansen RM, Gray ME, Massoud OI, McGuire BM, Shoreibah MG. Hepatocellular carcinoma surveillance: an evidence-based approach. World J Gastroenterol 2019; 25:15501550155011559.
30. Chan AW, Wong GL, Chan HY, Tong JHM, Yu Y-H, Choi PCL, et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B. J Gastroenterol Hepatol 2017; 32:667–676.
31. Lee I-C, Chau G-Y, Yeh Y-C, Chao Y, Huo TI, Su CW, et al. Risk of recurrence in chronic hepatitis B patients developing hepatocellular carcinoma with antiviral secondary prevention failure. PLoS One 2017; 12:e0188552e0188552.
32. Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49:851–859.
33. Tan DJH, Ng CH, Lin SY, Pan XH, Tay P, Lim WH, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol 2022; 23:521–530.
34. Liaw Y-F, Sung JJ, Chow WC, Farrell G, Lee C-Z, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351:1521–1531.
35. Sohn W, Paik Y-H, Kim JM, Kwon CH, Joh JW, Cho JY, et al. HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma. Ann Surg Oncol 2014; 21:2429–2435.
36. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015; 149:389–97.e10.
Keywords:

hepatitis B virus; hepatocellular carcinoma; nonalcoholic fatty liver; overall survival; recurrence

Supplemental Digital Content

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.