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. 2025 Jan 22;20(1):e0316175. doi: 10.1371/journal.pone.0316175

Impact of high body mass index on hepatocellular carcinoma risk in chronic liver disease: A population-based prospective cohort study

Moonho Kim 1,‡, Baek Gyu Jun 2,‡, Hwang Sik Shin 3, Jee-Jeon Yi 4, Sang Gyune Kim 5,*, Sang-Wook Yi 6,*
Editor: Sona Frankova7
PMCID: PMC11753674  PMID: 39841714

Abstract

Background and aims

We investigated associations between body mass index (BMI) and hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) C (HCV) virus infection, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and liver cirrhosis (LC).

Methods

We followed 350,608 Korean patients with liver disease who underwent routine health examinations from 2003–2006 until December 2018 via national hospital discharge records. Multivariable adjusted hazard ratios (HRs) per 5-kg/m2 BMI increase (BMI ≥25 kg/m2) for HCC risk were calculated using Cox models. HCC developed in 17,752 patients.

Results

The HRs (95% CI) were 1.17 (1.06–1.28), 1.08 (0.87–1.34), 1.34 (1.14–1.58), 1.51 (1.17–1.94), and 1.11 (1.00–1.23) for HBV, HCV, ALD, NAFLD, and LC, respectively. The HRs for HBV were 1.45 (1.23–1.70) and 1.06 (0.95–1.19) in women and men, respectively; the corresponding HRs for LC were 1.27 (1.07–1.50) and 1.02 (0.90–1.16), respectively. In patients <65 years old with HBV, HCV, and NAFLD, the HRs were 1.17 (1.07–1.29), 1.33 (1.03–1.73), and 1.20 (0.87–1.64), respectively; the corresponding HRs were 1.05 (0.70–1.59), 0.74 (0.50–1.10), and 2.40 (1.62–3.54), respectively, in patients ≥65 years old. A BMI of 27.5–29.9 kg/m2 showed significantly higher HCC risks in patients with HBV, ALD, NAFLD, and LC.

Conclusions

Higher BMIs were associated with increased HCC risks in patients with HBV, ALD, NAFLD, and LC. Overweight status increased HCC risk. Women with HBV and LC had stronger BMI-HCC associations than men. The effect of high BMI was stronger in older patients with NAFLD and younger patients with viral hepatitis.

Introduction

Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and liver cirrhosis (LC) are well-known risk factors for hepatocellular carcinoma (HCC). The association between obesity and HCC in patients with these high-risk liver diseases (HLDs) is not well understood, and the role of a high body mass index (BMI) in HCC development and progression has not been clearly elucidated. Some studies have shown a positive association between BMI and HCC risk [1–5], whereas others have not [6, 7]. In patients with less severe liver diseases, such as non-alcoholic fatty liver disease (NAFLD) without LC, few studies have examined these associations; hence, the associations remain unclear. For example, in patients with NAFLD, obesity is not associated with a higher HCC risk [8].

We aimed to investigate the BMI-HCC association in patients with various liver diseases (HBV infection, HCV infection, LC, NAFLD, and alcoholic liver disease [ALD]). In addition, as previous studies have suggested potentially different BMI-HCC associations between men and women and between younger and older adults, we further investigated sex- and age-specific associations [6, 9–12].

Patients and methods

Study population and follow-up

This population-based prospective cohort study enrolled 355,670 Koreans with liver diseases (HBV infection, HCV infection, LC, ALD, and NAFLD) aged 18–99 years who were examined between 2003 and 2006 and had no known cancer or missing information on variables and examination date. Baseline data were collected at the time of the health examination (index date). We excluded 5,062 patients with multiple liver diseases. We followed the remaining 350,608 included patients (Fig 1) until December 31, 2018, via record linkage to hospital discharge records from the National Health Insurance Service (NHIS), in which certified health information managers reviewed medical records and assigned standardized diagnosis codes. All patients discharged from the hospital due to HCC (International Classification of Diseases 10th Revision code C220) for the first time were considered incident cases. The authors were granted access to anonymized data from the NHIS (From June 1, 2022, to June 30, 2023). This study was approved by the Institutional Review Board of Gangneung Asan Hospital, Gangneung, Republic of Korea (GNAH 2022-04-005). Informed consent was waived owing to the use of anonymized data that were constructed and provided by the NHIS according to a strict confidentiality protocol. All research was conducted in accordance with both the Declarations of Helsinki and Istanbul.

Fig 1. Flow diagram of the study cohort.

Fig 1

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Completeness of HCC incidence data by the NHIS

Ninety-seven percent of Koreans are NHIS-insured [13]. Additionally, patients with HLDs underwent liver cancer surveillance twice a year. Patients with high alpha-fetoprotein levels or a suspicious mass on ultrasonography were referred for HCC diagnosis using dynamic computed tomography or magnetic resonance imaging. All the procedures were covered by the NHIS. The completeness of cancer incidence data from the NHIS is comparable to that of the Korea National Cancer Incidence Database (> 95% for liver cancer) [14, 15].

Data collection

Data were collected during baseline examinations using measurements and questionnaires. Alanine transaminase and aspartate transaminase levels were measured using the nicotinamide adenine dinucleotide-ultraviolet or Reitman-Frankel method. Fasting serum glucose and total cholesterol levels were assessed using enzymatic methods [16]. Blood pressure was measured using a standard mercury sphygmomanometer. BMI was calculated as the measured weight (kg) divided by the square of measured height (m2). Smoking status, alcohol use, and history of cancer and cardiovascular disease were assessed using a questionnaire. Patients with a self-reported cancer history or patients admitted to a hospital for cancer before the baseline examination were considered to have preexisting cancer. Patient examinations and data collection followed a standard protocol documented by the government. The data collection methods for smoking and alcohol consumption were similar to those used in our previous study [7].

Prevalent diseases at baseline

We considered patients to have a baseline prevalent disease if they visited a hospital for the disease at least once within 12 months before or 2 months after the baseline examination. The diseases were selected using International Classification of Diseases 10th Revision codes: HBV infection (B16, B180, and B181), HCV infection (B171 and B182), diabetes (E10-E14), ALD (K70), LC (K74), and NAFLD (K758 and K760).

Statistical analysis

BMI was categorized into seven groups: <18.5, 18.5–20.9, 21–22.9, 23–24.9, 25–27.4, 27.5–29.9, and ≥30 kg/m2. BMI was also analyzed as a continuous variable (per 5 kg/m2 increase), assuming a linear association in the full, lower (<25 kg/m2), and upper (≥25 kg/m2) ranges. The effects of BMI on HCC were evaluated using stratified analysis across liver disease status. In the subgroup analysis, the BMI-HCC associations in patients with LC were examined according to LC etiology (HBV, HCV, ALD, or NAFLD).

The HRs for HCC incidence were obtained using Cox proportional hazards models stratified by age (years) at baseline (18–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and 85–99 years, using the STRATA statement). The multivariable analysis was adjusted for age at baseline (continuous variable), sex, smoking status (never, former, or current smoker [<10, 10–19, or ≥20 cigarettes/day]), alcohol use (none, <10, 10–19, 20–39, and ≥40 g of ethanol/day; or missing information), physical activity (exercise with light sweating, none, 1–2 times/week, and 3–7 times/week), and income status (quartiles; 1 [low income], 2, 3, 4 [high income]). BMI effect mediators such as glycemic status (normoglycemia [<100 mg/dL], impaired fasting glucose levels [100–125 mg/dL], diabetes [≥126 mg/dL or prevalent diabetes]), total cholesterol levels (continuous variable) [17], and alanine transaminase levels (natural log-transformed levels) were further adjusted for in sensitivity analyses. Sex- and age-stratified analyses were performed.

Effect size differences between the sexes and age groups were evaluated using the Cochrane Q statistics test as an interaction test. All P-values were two-sided, and the analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Baseline characteristics

HBV, HCV, and LC were present in 120,994, 14,882, and 31,260 patients, respectively (Table 1). During a mean follow-up period of 13.7 years, HCC was diagnosed in 8,492 patients. The proportions of patients with HBV infection, HCV infection, and LC having a BMI ≥25 kg/m2 were 32.5%, 35.4%, and 34%, respectively. Patients with HBV infection were younger and had higher total cholesterol levels. Patients with LC were predominantly men and smokers, with higher glucose levels, more alcohol use, and less physical activity. HBV was the most common etiology of LC, followed by ALD (S1 Table).

Table 1. Baseline demographic and clinical characteristics.

Characteristic HBV
n = 120,994		 HCV
n = 14,882		 ALD
n = 106,112		 NAFLD
n = 88,353		 LC
n = 31,260
HCC 9,043 1,654 2,659 650 6,506
Sex
    Men 76,067 (62.9) 8,274 (55.6) 95,767 (90.3) 53,870 (61.0) 22,316 (71.4)
    Women 44,927 (37.1) 6,608 (44.4) 10,345 (9.7) 34,483 (39.0) 8,944 (28.6)
BMI, kg/m2
    <18.5 3,824 (3.2) 383 (2.6) 2,817 (2.7) 1,303 (1.5) 933 (3.0)
    18.5–20.9 18,815 (15.6) 1,889 (12.7) 12,981 (12.2) 7,001 (7.9) 4,384 (14.0)
    21–22.9 27,659 (22.9) 3,190 (21.4) 20,412 (19.2) 14,422 (16.3) 7,133 (22.8)
    23–24.9 31,441 (26.0) 4,150 (27.9) 27,028 (25.5) 22,751 (25.8) 8,184 (26.2)
    25–27.4 26,392 (21.8) 3,466 (23.3) 27,419 (25.8) 25,432 (28.8) 6,987 (22.4)
    27.5–29.9 9,389 (7.8) 1,302 (8.7) 11,257 (10.6) 11,995 (13.6) 2,668 (8.5)
    ≥30 3,474 (2.9) 502 (3.4) 4,198 (4.0) 5,449 (6.2) 971 (3.1)
Glycemic status
    Normoglycemia 87,980 (72.7) 9,505 (63.9) 61,990 (58.4) 56,414 (63.9) 18,449 (59.0)
    IFG 23,302 (19.3) 3,278 (22.0) 28,530 (26.9) 21,181 (24.0) 6,855 (21.9)
    Diabetes 9,712 (8.0) 2,099 (14.1) 15,592 (14.7) 10,758 (12.2) 5,956 (19.1)
Smoking, pack/day
    Never 76,565 (63.3) 10,087 (67.8) 302 (0.3) 157 (0.2) 19,013 (60.8)
    Former 12,537 (10.4) 1,447 (9.7) 42,255 (39.8) 55,046 (62.3) 3,430 (11.0)
    <0.5 7,777 (6.4) 872 (5.9) 15,196 (14.3) 9,758 (11.0) 2,765 (8.8)
    0.5–0.9 15,999 (13.2) 1,494 (10.0) 9,684 (9.1) 4,885 (5.5) 3,857 (12.3)
    1–1.9 5,267 (4.4) 592 (4.0) 24,181 (22.8) 11,196 (12.7) 1,394 (4.5)
    ≥2 2,634 (2.2) 373 (2.5) 12,818 (12.1) 5,436 (6.2) 737 (2.4)
    Unknown 215 (0.2) 17 (0.1) 1,676 (1.6) 1,875 (2.1) 64 (0.2)
Alcohol, ethanol (g)/day
    None 68,917 (57.0) 9,676 (65.0) 1,833 (1.7) 1,739 (2.0) 20,007 (64.0)
    <10 27,974 (23.1) 2,581 (17.3) 28,734 (27.1) 46,244 (52.3) 4,763 (15.2)
    10–19 13,670 (11.3) 1,330 (8.9) 21,144 (19.9) 18,797 (21.3) 2,561 (8.2)
    20–39 3,908 (3.2) 399 (2.7) 22,447 (21.2) 12,014 (13.6) 1,078 (3.4)
    ≥40 3,972 (3.3) 492 (3.3) 11,479 (10.8) 4,378 (5.0) 2,039 (6.5)
    Unknown 2,553 (2.1) 404 (2.7) 20,475 (19.3) 5,181 (5.9) 812 (2.6)
Physical activity, times/week
    None 62,244 (51.4) 7,994 (53.7) 59,009 (55.6) 46,538 (52.7) 18,044 (57.7)
    1–2 34,625 (28.6) 3,532 (23.7) 27,337 (25.8) 23,294 (26.4) 7,137 (22.8)
    ≥3 24,125 (19.9) 3,356 (22.6) 19,766 (18.6) 18,521 (21.0) 6,079 (19.4)
Income status, quartile
    Q1 (low) 24,235 (20.0) 2,788 (18.7) 20,164 (19.0) 16,790 (19.0) 6,076 (19.4)
    Q2 24,333 (20.1) 2,689 (18.1) 22,816 (21.5) 16,654 (18.8) 5,914 (18.9)
    Q3 31,972 (26.4) 3,866 (26.0) 30,046 (28.3) 23,338 (26.4) 7,890 (25.2)
    Q4 40,454 (33.4) 5,539 (37.2) 33,086 (31.2) 31,571 (35.7) 11,380 (36.4)
Age groups, years
    <65 11,4728 (94.8) 12,008 (80.7) 93,860 (88.5) 79,551 (90.0) 25,686 (82.2)
    ≥65 6,266 (5.2) 2,874 (19.3) 12,252 (11.5) 8,802 (10.0) 5,574 (17.8)
Total cholesterol, mg/dL
    <200 79,873 (66.0) 10,385 (69.8) 59,626 (56.2) 43,981 (49.8) 23,348 (74.7)
    200–239 31,497 (26.0) 3,401 (22.9) 32,149 (30.3) 30,222 (34.2) 5,975 (19.1)
    ≥240 9,624 (8.0) 1,096 (7.4) 14,337 (13.5) 14,150 (16.0) 1,937 (6.2)
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Data are expressed as numbers and percentages.

Abbreviations: ALD, alcoholic liver disease; LC, liver cirrhosis; HCC, hepatocellular carcinoma; BMI, body mass index; IFG, impaired fasting glucose

Categorical analyses

HRs for HCC were compared based on a BMI range of 23–24.9 kg/m2. In patients with HBV infection, the HRs of HCC were increased in the BMI ranges of 27.5–29.9 (HR 1.09, 95% CI 1.01–1.18) and ≥30 kg/m2 (HR 1.20, 95% CI 1.06–1.36) (Fig 2; S2 Table). In patients with HCV, the HRs were 0.99 (95% CI 0.86–1.13), 1.09 (95% CI 0.91–1.31), and 1.00 (95% CI 0.73–1.36) for BMI ranges of 25–27.4, 27.5–29.9, and ≥30 kg/m2, respectively. In patients with ALD, the HRs of HCC were significantly increased in the BMI ranges of 27.5–29.9 (HR 1.22, 95% CI 1.06–1.42) and ≥30 kg/m2 (HR 1.38, 95% CI 1.10–1.74). Similarly, in patients with NAFLD, the HRs of HCC were increased in the BMI ranges of 27.5–29.9 (HR 1.36, 95% CI 1.06–1.74) and ≥30 kg/m2 (HR 1.42, 95% CI 1.00–2.01). In patients with LC, the HRs of HCC were 1.00 (95% CI 0.93–1.07), 1.11 (95% CI 1.02–1.22), and 1.07 (95% CI 0.93–1.24) in BMI ranges of 25–27.4, 27.5–29.9, and ≥30 kg/m2, respectively. In the subgroup analysis of LC etiology, patients with HBV-LC co-occurrence showed increased HCC risks in the BMI range of 27.5–29.9 kg/m2 (HR 1.35, 95% CI 1.15–1.59).

Fig 2. Hepatocellular carcinoma risk according to liver disease, for each 5-kg/m2 BMI increase in patients with BMI ≥25 kg/m2.

Fig 2

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HBV, hepatitis B virus; HCV, hepatitis C virus; ALD, alcoholic liver disease; NAFLD, nonalcoholic fatty liver disease; LC, liver cirrhosis; BMI, body mass index.

Linear analyses

In linear analyses according to BMI, for each 5 kg/m2 increase from a BMI ≥25 kg/m2, the multivariable-adjusted HRs were 1.17 (P = 0.001), 1.08 (P = 0.486), 1.11 (P = 0.047), 1.34 (P<0.001), and 1.51 (P = 0.001) for HBV infection, HCV infection, LC, ALD, and NAFLD, respectively (Fig 2). Overall, positive BMI-HCC associations were shown in patients with chronic liver disease (CLD). In the subgroup analysis for patients with LC (BMI ≥25 kg/m2), the HRs for HCC per 5 kg/m2 increase in BMI were 1.19 (0.98–1.45, P = 0.075), 1.38 (0.75–2.51, P = 0.297), 1.36 (0.92–2.02, P = 0.125), and 1.59 (0.53–4.76, P = 0.410) in patients with HBV infection, HCV infection, ALD, and NAFLD, respectively (S3 Table).

Age- and sex-stratified analyses

In the sex-stratified analyses (BMI ≥25 kg/m2), women with HBV infection (1.45 vs. 1.06, P for interaction = 0.002) and LC (1.27 vs. 1.02, P for interaction = 0.050) showed stronger positive BMI-HCC associations than in men (Fig 3). However, for patients with NAFLD, the association was stronger in men than in women (1.84 vs. 1.03, P for interaction = 0.039). The association showed no sex difference in patients with ALD (1.35 vs. 1.30, P for interaction = 0.913). In the age-stratified analyses (patients divided into groups aged <65 years and ≥65 years; BMI ≥25 kg/m2), younger patients with HBV infection (1.17 vs. 1.05, P for interaction = 0.606) and HCV infection (1.33 vs. 0.77, P for interaction = 0.015) had a higher HCC risk than older patients (Fig 3). In the subgroup analysis of patients with LC, women with HBV infection (1.73 vs. 0.95, P for interaction = 0.003) and older patients with NAFLD (11.08 vs. 0.76, P for interaction = 0.036) had significantly higher risks of HCC associated with a higher BMI than men with HBV and younger patients with NAFLD, respectively (S4 Table).

Fig 3. Cox regression analysis of hepatocellular carcinoma risk according to liver disease, for each 5-kg/m2 BMI increase in patients with BMI ≥25 kg/m2.

Fig 3

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HBV, hepatitis B virus; HCV, hepatitis C virus; ALD, alcoholic liver disease; NAFLD, nonalcoholic fatty liver disease; LC, liver cirrhosis; BMI, body mass index.

Discussion

This prospective cohort study of more than 350,000 patients with CLDs showed that obesity increased HCC risk. In overweight (BMI ≥25 and <30 kg/m2) and obese (BMI ≥30 kg/m2) patients with HBV infection, LC, ALD, or NALFD, BMI increase was associated with higher HCC risks. In patients with a BMI ≥25 kg/m2, HCC risks associated with higher BMIs were more prominent in women than in men with HBV infection, HCV infection, or LC. Age-specific BMI-HCC associations differed by CLDs; the associations were stronger in younger adults than in older adults with HBV and HCV infections but stronger in older adults than in younger adults with NAFLD.

In our study, obesity increased the HCC risk in patients with HBV infection. Some previous studies have shown inconsistent associations between obesity and HCC risk in Western and Taiwanese patients with HBV infection [3, 18, 19], although the association was consistent in other studies [4, 20–22]. Recently, a large-scale Korean study reported an association between a high BMI and HCC risk [23]. Our study confirmed that obesity increased HCC incidence in Koreans with HBV infection. Previous studies may not have found a significant BMI-HCC association, mainly because of the relatively small study sample sizes and the modest nature of true associations. Notably, our study showed that overweight status (especially a BMI of 27.5–29.9 kg/m2) was associated with higher HCC risks.

In our study, patients with HCV infection showed a modest obesity-HCC association. Some previous studies showed increased obesity-associated HCC risks [4], although others did not [24–26]. In the current study, higher BMIs were significantly associated with HCC risk in patients with HBV infection but not in patients with HCV infection. Associations related to HCV than HBV were weaker in HBV-endemic areas [7], whereas the opposite findings have been reported in other areas. These findings might be partially explained by the fact that antiHCV medication efficacy was lower than anti-HBV medication efficacy in the early 2000s. The formal heterogeneity test showed no difference in the BMI-HCC association between HBV and HCV infections (P for heterogeneity = 0.509) in the current study. The modest association in patients with HCV infection was not significant because of the relatively small number of patients with HCV infection compared with the number of patients with HBV infection in the present study.

In previous studies, obesity was associated with HCC development, mostly in patients in Western countries with ALD-LC and HCV-LC co-occurrences [1, 5, 24, 27, 28]. The HCC risk associated with obesity was more pronounced in patients with ALD-LC co-occurrence than in patients with viral hepatitis-LC co-occurrence [5, 24]. In the current study, the BMI-HCC association was stronger in patients with ALD-LC and HCV-LC co-occurrences than in patients with HBV-LC co-occurrence. However, the association was not significant owing to the smaller number of participants with HCV infection.

In our study, NAFLD patients with overweight and obesity showed an increased HCC risk; moreover, a 5-kg/m2 BMI increment increased HCC risk by 51%. NAFLD is a known risk factor for HCC, and a BMI increase is associated with a higher NAFLD prevalence; nevertheless, few studies have reported an obesity-related increase in HCC risk in patients with NAFLD [24, 27, 29, 30]. The absence of a BMI-HCC association may be explained, at least partially, by crude BMI classification into two groups ([≥30 vs. <30 kg/m2] [8, 29] and [≥25 vs. <25 kg/m2] [30]), a retrospective study design [8, 24, 27], including patients with cirrhosis only [24, 27], and adjustment for the effect modifiers of BMI [24, 27]. We may have identified this association because of the prospective study design, the inclusion of patients with and without cirrhosis, the detailed BMI classification into seven groups, and the lack of adjustment for effect modifiers of BMI.

Regarding ALD, previous studies were conducted mostly in patients with cirrhosis, and few studies examined the BMI-HCC association in patients without LC [5, 27]. In the current study, patients with ALD without LC showed higher HCC risks associated with overweight and obesity, probably because of the synergistic interaction between alcohol intake and BMI [31]. The associations were similar in both sexes, albeit statistically insignificant in women due to the small number of women with ALD.

Furthermore, our study showed a higher relative risk of HCC associated with BMI in women than men with viral hepatitis-LC co-occurrence. Few studies have examined sex-specific BMI-HCC associations in patients with viral hepatitis-LC co-occurrence [6, 10, 23, 32–35]. In the current study, the BMI-HCC associations were similar between men and women with ALD; nevertheless, potentially stronger associations were observed in men than in women with NAFLD. Our study suggests different associations according to sex for each CLD. Unfortunately, except for the presumption of sex-specific differences in the hepatocarcinogenic mechanisms of high BMIs and each liver disease, proposing a mechanism that can adequately explain the sex differences in the obesity-related HCC risk observed in our study is difficult. Further studies are needed to clarify the potentially different associations according to sex for each CLD.

In the age-specific analysis, relative HCC risks associated with a higher BMI were higher in younger (<65 years) than in older adults with HBV and HCV infections, whereas the risks were higher in older than in younger adults with NAFLD. Younger patients with viral hepatitis may experience a stronger synergistic effect between viral infection and obesity due to lower comorbidity rates [13, 36]. Regarding NAFLD, our finding of stronger associations in older adults may reflect the fact that high BMI affects HCC development in the long run. For HCC prevention, comorbid obesity may not be ignored in younger patients with viral hepatitis; however, more attention may be needed in NAFLD patients with obesity, especially in patients aged ≥65 years.

The role of obesity in hepatocarcinogenesis in patients with HLD is not well understood. Patients with HBV/HCV infections and LC have a 10–100-fold higher HCC risk than patients without HLDs, whereas obesity is associated with a 2–3-fold higher HCC risk in the general population. If HLDs and obesity are independent risk factors for HCC, the effect of obesity on HCC would be negligible. The current study showed that a higher BMI increased HCC risk in patients with CLDs, including HLDs. Our results indicate a strong synergistic interaction between the hepatocarcinogenic mechanisms of CLDs (including HLDs) and obesity [37]. Detailed mechanisms underlying these synergistic interactions are yet to be elucidated.

This study had some strengths. We examined the relationship between HCC risk and obesity in patients with major liver diseases, such as HBV infection, HCV infection, LC, and NAFLD. Previous studies examined the relationship between obesity and HCC risk in patients with a single liver disease. However, we analyzed HCC risk in patients with each type of HLD in a nationwide cohort. Furthermore, this was a large-scale study that analyzed the relationship between HCC risk and obesity by age and sex. We also tested our hypothesis by adjusting for the main confounding variables but not for the effect mediators of obesity [38]. We used a prospective cohort design to minimize recall and selection biases related to retrospective studies.

Our study had several limitations. First, obesity was defined in terms of BMI only; other factors, such as visceral obesity (evaluated using the waist-to-hip ratio), could not be investigated owing to the nature of the raw data. Second, important data such as fibrosis score, antiviral therapies, and detailed viral factors for HBV and HCV were not available. For example, antiviral therapies are known to reduce the risk of HBV- and HCV-related HCC. Third, the proportion of Koreans with a BMI >30 kg/m2 (especially >35 kg/m2) was small. Therefore, the relationship between obesity and HCC incidence may have been underestimated. Fourth, we could not analyze the impact of the change in BMI on HCC risk. Only a few studies examined the association between BMI (or weight change) and HCC in persons with liver diseases [39]. The results were inconsistent. Our analysis based on a single measurement of BMI may underestimate the true association of dynamic change in BMI. Finally, the study population included only Koreans, which may limit its interpretation and applicability. For example, most cases of LC in Korea are caused by HBV infection. The potential differences in associations across LC etiologies suggest that the BMI-HCC association in patients with LC may depend on the population-specific distribution of the LC etiology.

In conclusion, in patients with CLD, obesity and overweight (specifically a BMI of 27.5–29.9 kg/m2) were associated with an increased HCC risk. In overweight and obese patients with CLDs, a BMI increase was associated with a higher HCC risk. The risk of HCC associated with a higher BMI was more pronounced in women than in men with viral hepatitis and LC. In patients with NAFLD, the impact of a high BMI on HCC was greater in older patients (≥65 years).

Supporting information

S1 Table. Patients’ baseline demographic and clinical characteristics.

(DOCX)

pone.0316175.s001.docx (23.8KB, docx)
S2 Table. Association between BMI and hepatocellular carcinoma (HCC) risk by liver disease.

(DOCX)

pone.0316175.s002.docx (20.1KB, docx)
S3 Table. Association between BMI and HCC risk by liver disease etiology, for each 5-kg/m2 BMI increase (BMI ≥25 kg/m2).

(DOCX)

pone.0316175.s003.docx (18.2KB, docx)
S4 Table. Cox regression of HCC risk by liver cirrhosis etiology, per 5-kg/m2 BMI (≥25 kg/m2) increase.

(DOCX)

pone.0316175.s004.docx (20.1KB, docx)

Acknowledgments

This research was supported by data from the National Health Insurance Service of Korea (NHIS-2024-1-264).

Data Availability

The data that support the findings of this study are available from the National Health Insurance Service (NHIS) [http://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do], but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.

Funding Statement

This study was supported by The Research Supporting Program of The Korean Association for the Study of the Liver and The Korean Liver Foundation (KASLKLF2021-08) and the Medical Research Promotion Program through Gangneung Asan Hospital funded by the Asan Foundation (2022II0016).

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Decision Letter 0

Miquel Vall-llosera Camps

4 Sep 2024

PONE-D-24-15224Impact of high body mass index on hepatocellular carcinoma risk in chronic liver disease: A population-based prospective cohort studyPLOS ONE

Dear Dr. Yi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I would like to sincerely apologise for the delay you have incurred with your submission. It has been exceptionally difficult to secure reviewers to evaluate your study. We have now received two completed reviews; the comments are available below. The reviewers have raised significant scientific concerns about the study that need to be addressed in a revision.

Please revise the manuscript to address all the reviewer's comments in a point-by-point response in order to ensure it is meeting the journal's publication criteria. Please note that the revised manuscript will need to undergo further review, we thus cannot at this point anticipate the outcome of the evaluation process.

Please submit your revised manuscript by Oct 18 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Miquel Vall-llosera Camps

Senior Staff Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a large-scale, population-based study primarily exploring the impact of BMI on hepatocellular carcinoma (HCC) risk in patients with chronic liver diseases. While several studies have already shown that obesity and BMI can increase the risk of HCC, this study investigates various chronic liver diseases such as HBV, HCV, ALD, NAFLD (non-alcoholic fatty liver disease), and LC, as well as the effects of age and gender, providing new evidence. However, several points need further discussion.

Major comments:

1. What are the diagnostic criteria for alcoholic liver disease and non-alcoholic fatty liver disease? Are they based on case diagnosis codes?

2. Regarding Figure 3, is there statistical significance when the confidence interval crosses 1? For example, for patients under 65 years old, the odds ratio for NAFLD is 1.2 with a confidence interval of 0.87 to 1.64. Please confirm with a statistician.

3. In the discussion section for the BMI-HCC association stratified by age and gender, it is very complex and may not be easily understood by readers. Please make substantial revisions to this discussion section.

Minor comments:

1. On page 13, item 186, it should be Figure 2. Is this a typos?

2. On page 14, item 192, the title of Figure 3 is incorrect. Please revise it.

3. Please specify whether the definition of obesity based on BMI uses Western standards or Asian standards (BMI >23 or >25)

4. On page 18, item 287: the abbreviation full name of HLD ?

Reviewer #2: In this study, Yi et al. investigated the association between BMI and HCC risk in patients with chronic liver disease. They found that higher BMIs were associated with increased HCC risks in patients with different etiologic chronic liver disease. Although the results showed clinically important, several points need be critically addressed.

Specific comments

1. Current evidence showed that several viral factors before antiviral therapies are associated with the risk of HBV and HCV related HCC. In addition, antiviral therapies decrease the risk of HBV and HCV related HCC. The major limitations of this study include the lack of baseline HBV and HCV related viral factors and the data of antiviral therapy.

2. The authors should describe the time point of baseline data collection.

3. Body weight may change during the follow-up period. Only baseline BMI was used for analysis, the impact of changes of BMI on HCC risk cannot be estimated.

4. As above mention, the authors should consider using BMI as a time-dependent covariate to analyze the impact of the dynamic change of BMI on HCC risk.

5. Regarding to the exclusion criteria, only 5062 patients with two or more chronic liver disease were excluded. Currently, the prevalence of NAFLD is so high, but the proportion of HBV or HCV combined with fatty liver is relatively low in this study. Please explain why?

6. The diagnosis of patients was by the ICD-10 codes. How to confirm the coding is correct? For example, whether different doctors have the same diagnostic criteria for ALD.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: review-comment-PONE-1130714.docx

pone.0316175.s005.docx (15.9KB, docx)
PLoS One. 2025 Jan 22;20(1):e0316175. doi: 10.1371/journal.pone.0316175.r002

Author response to Decision Letter 0

19 Sep 2024

We would like to express our sincere appreciation for carefully reviewing our paper and providing valuable feedback. Please find our point-by-point responses to your specific comments. Thank you.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0316175.s006.docx (33.4KB, docx)

Decision Letter 1

Ashwani Singal

8 Oct 2024

PONE-D-24-15224R1Impact of high body mass index on hepatocellular carcinoma risk in chronic liver disease: A population-based prospective cohort studyPLOS ONE

Dear Dr. Yi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 22 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ashwani Singal

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In the paper assessing the impact of BMI on the risk of hepatocellular carcinoma across various chronic liver diseases including HBV, HCV, ALD, NAFLD and LC, the authors have answered all the questions I previously raised comprehensively. After reviewing the clarifications, I have no additional questions this time. The detailed explanations provided valuable insight, and I appreciate the thoroughness of your work. The concerns about dual publication, research or publication ethics were not found.

Reviewer #2: This revised manuscript is improved and all previous comments were responded on point-to-point basis. However, the authors cannot analyze the impact of the dynamic change of BMI on HCC risk. The authors should provide more evidence to support that a single BMI measurement can determine the correlation with HCC.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2025 Jan 22;20(1):e0316175. doi: 10.1371/journal.pone.0316175.r004

Author response to Decision Letter 1

22 Oct 2024

Thank you for your thoughtful feedback. Please find our point-by-point responses to your specific comments.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0316175.s007.docx (25.3KB, docx)

Decision Letter 2

Sona Frankova

9 Dec 2024

Impact of high body mass index on hepatocellular carcinoma risk in chronic liver disease: A population-based prospective cohort study

PONE-D-24-15224R2

Dear Dr. Yi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Sona Frankova, M.D., PhD.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The revisions effectively address the raised concerns, and the updated manuscript demonstrates clarity and improved scientific rigor. The explanations provided for methodology and data interpretation are convincing, and the adjustments to the discussion strengthen the overall narrative. I appreciate your careful attention to detail and your dedication to enhancing the manuscript’s quality.

Reviewer #2: This revised manuscript is improved and the previous comment was fully

responded. I have no more comments.

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Reviewer #1: No

Reviewer #2: No

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Acceptance letter

Sona Frankova

10 Jan 2025

PONE-D-24-15224R2

PLOS ONE

Dear Dr. Yi,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

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If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Sona Frankova

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Patients’ baseline demographic and clinical characteristics.

    (DOCX)

    pone.0316175.s001.docx (23.8KB, docx)
    S2 Table. Association between BMI and hepatocellular carcinoma (HCC) risk by liver disease.

    (DOCX)

    pone.0316175.s002.docx (20.1KB, docx)
    S3 Table. Association between BMI and HCC risk by liver disease etiology, for each 5-kg/m2 BMI increase (BMI ≥25 kg/m2).

    (DOCX)

    pone.0316175.s003.docx (18.2KB, docx)
    S4 Table. Cox regression of HCC risk by liver cirrhosis etiology, per 5-kg/m2 BMI (≥25 kg/m2) increase.

    (DOCX)

    pone.0316175.s004.docx (20.1KB, docx)
    Attachment

    Submitted filename: review-comment-PONE-1130714.docx

    pone.0316175.s005.docx (15.9KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0316175.s006.docx (33.4KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0316175.s007.docx (25.3KB, docx)

    Data Availability Statement

    The data that support the findings of this study are available from the National Health Insurance Service (NHIS) [http://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do], but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.

    Articles from PLOS ONE are provided here courtesy of PLOS

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