# Association between the dietary inflammatory index and the risk of hepatocellular carcinoma in a cirrhotic population

Maud Rizk, Cécile Roux-Levy, Brigitte Bernard-Chabert, Jean-Pierre

Bronowicki, Carine Richou, François Habersetzer, Jean-Louis Jouve, James R

Hebert, Nitin Shivappa, Marie-Christine Boutron-Ruault, et al.

► To cite this version:

Maud Rizk, Cécile Roux-Levy, Brigitte Bernard-Chabert, Jean-Pierre Bronowicki, Carine Richou, et al. Association between the dietary inflammatory index and the risk of hepatocellular carcinoma in a cirrhotic population. Clinical Nutrition, 2025, 44, pp.65-75. 10.1016/j.clnu.2024.11.021. hal-05390897

HAL Id: hal-05390897

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Original article

# Association between the dietary inflammatory index and the risk of hepatocellular carcinoma in a cirrhotic population☆

<figure><img src="image_2.png" /></figure>

Maud Rizk<sup>a, j</sup>, Cécile Roux-Levy<sup>a</sup>, Brigitte Bernard-Chabert<sup>c</sup>, Jean-Pierre Bronowicki<sup>d</sup>, Carine Richou<sup>e</sup>, François Habersetzer<sup>f</sup>, Jean-Louis Jouve<sup>b</sup>, James R. Hebert<sup>g</sup>, Nitin Shivappa<sup>g</sup>, Marie-Christine Boutron-Ruault<sup>h</sup>, Mona Diab Assaf<sup>i</sup>, Patrick Hillon<sup>a, b</sup>, Vanessa Cottet<sup>a, b, k, *</sup>, other members of the CirCE Study group<sup>1</sup>

ARTICLE INFO

Article history:
Received 22 April 2024
Accepted 10 November 2024

Keywords:
Case-control study
Hepatocellular carcinoma
Cirrhosis
DII scores
Pro-inflammatory diet

SUMMARY

**Background & aims:** Hepatocellular carcinoma (HCC) is recognized as an inflammation-related cancer. However, the relation between inflammation deriving from the diet and HCC risk among cirrhotic patients has not yet been investigated. This study aimed to examine the association between the dietary inflammatory index (DII®) and HCC risk among cirrhotic patients.

**Methods:** Clinical and dietary data were collected from the French case-control study CiRCE (Cirrhosis and Risk of hepatocellular Carcinoma in the East), which included 401 cirrhotic patients without HCC (controls) and 181 cirrhotic patients with HCC (cases) recruited between 2008 and 2012 in six French university hospitals. DII scores (36 food items and nutrients) were assessed using a validated self-administered diet history questionnaire. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated with logistic regression models (adjusted for age, gender, time from cirrhosis diagnosis, etiology of cirrhosis, Child-Pugh score, and diabetes).

**Results:** The DII scores ranged between -4.77 and +7.59 with a mean value of 1.03 ± 2.87 among cases and 0.83 ± 2.87 among controls, indicating that both groups were following a pro-inflammatory diet. After multi-variable adjustment, there was a positive association between HCC risk and the DII score when considered as a continuous variable (OR<sub>continuous</sub> = 1.14 [1.02–1.27], p-value = 0.021) or categorized in tertiles (OR<sub>T3vsT1</sub> = 2.33 [1.16–4.67], p-trend = 0.021). Similar results were found when alcohol was omitted from the DII calculation but considered as a co-variate: OR<sub>continuous</sub> = 1.15 [1.03–1.28], p-value = 0.013, and OR<sub>T3vsT1</sub> = 2.35 [1.18–4.68], p-trend = 0.015. A positive correlation was observed between the DII scores and two inflammatory biomarkers (CRP, IL-6) among controls.

**Abbreviations:** HCC, Hepatocellular Carcinoma; DII, Dietary Inflammatory Index; CiRCE, Cirrhosis and Risk of Hepatocellular Carcinoma in the East; OR, Odds ratios; CI, Confidence Intervals; HBV, Hepatitis B virus; HCV, Hepatitis C virus; IL-1β, Interleukin-1β; TNF-α, Tumor Necrosis Factor-alfa; CRP, C-Reactive Protein; PUFA, Polyunsaturated Fatty Acids; BMI, Body Mass Index; PLC, Primary Liver Cancer; MASLD, Metabolic dysfunction-Associated Steatotic Liver Disease.

* Data described in the manuscript, code book, and analytic code will not be made available because all data of this multicentric study are the property of the academic sponsor of the study.

* Corresponding author. INSERM UMR 1231, UFR des Sciences de Santé, Université de Bourgogne, F-21000 Dijon, France.

E-mail address: vanessa.cottet@u-bourgogne.fr (V. Cottet).

¹ Thiefin G, Di Martino V, Doffoel M, Barraud H, Minello A, Latournerie M, Sgro C, Valnet-Rabier Mb, Trenque T, Trechot P, Tebacher-Alt M, Binquet C, Jooste V, Petit JM, Masson D, Delmas D, Duvillard L, Guéant JL, Manfait M, Oudet P, Sockalingum G, Vuitton D, Faivre J (President, †).

<footnote><sup>a</sup> INSERM UMR 1231 & University of Burgundy, Dijon, France</footnote>

<footnote><sup>b</sup> University Hospital, Dijon, France</footnote>

<footnote><sup>c</sup> University Hospital, Reims, France</footnote>

<footnote><sup>d</sup> University Hospital & INSERM 954, Nancy, France</footnote>

<footnote><sup>e</sup> University Hospital, Besançon, France</footnote>

<footnote><sup>f</sup> University Hospital, Strasbourg, France</footnote>

<footnote><sup>g</sup> Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA</footnote>

<footnote><sup>h</sup> INSERM, CESP Centre for Research in Epidemiology and Population Health, U1018, Lifestyle, Genes and Health: Integrative Trans-generational Epidemiology, Villejuif, F-94805, France</footnote>

<footnote><sup>i</sup> Lebanese University, Beirut, Lebanon</footnote>

<footnote><sup>j</sup> Balamand University, Beirut, Lebanon</footnote>

<footnote><sup>k</sup> INSERM CIC1432 & University of Burgundy, Dijon, France</footnote>
**Conclusion:** The present study reported an association between a pro-inflammatory DII score and the risk of HCC in cirrhotic patients. Correlations between the scores and biological parameters support a potential role for inflammation in HCC among cirrhotic. Result should be confirmed in larger prospective studies, and could lead to nutritional prevention in cirrhotic patients.

**Clinical Trial Registry:** This study was registered in www.clinicaltrials.gov as NCT01798173.

© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

# 1. Introduction

Hepatocellular carcinoma (HCC) is considered as an inflammation-related cancer. It occurs in the setting of chronic liver inflammation that share cirrhosis as an endpoint in 80–90 % of patients with HCC [1]. Worldwide, HCC is the 6th most frequently diagnosed cancer in men and women. The estimated number of new cases of liver cancer in 2022 was 600 676 in men and 265 460 in women, while the estimated number of deaths was 521 826 and 236 899 respectively according to GLOBOCAN 2022 [2]. HCC incidence has increased over the past decades as a result of infections with hepatitis B (HBV) or C (HCV) viruses, consumption of food contaminated with aflatoxin, obesity, the metabolic syndrome, and alcoholic liver disease [3].

Progression from the status of fibrosis to cirrhosis, and finally to HCC involves a complex, chronic, non-resolving inflammation, and persistent hepatic injuries [4,5]. Epidemiological evidence confirms that chronic inflammation plays a double role in cancer proliferation. It affects the initiation, progression, and proliferation of cancer cells, and it decreases the efficacy of the immune system. The tumor micro-environment is composed of several types of immune cells (mainly macrophages), cytokines (e.g. interleukin-1β (IL-1β), Tumor Necrosis Factor-alfa (TNF-α)), and reactive mediators. Once the inflammatory cascade is activated, inflammatory signals are continuously emitted and, in the presence of reactive oxygen species, the injured tissue is altered, in turn favoring the transformation of premalignant cells into cancer cells [4,5].

The diet has an influence on the development of diseases through its link with immune responses. Several studies highlight the health benefits of various bioactive compounds from different food sources, primarily due to their antioxidant content. These compounds influence the activation and suppression of endogenous antioxidant enzymes, affect the cell cycle, prevent lipid oxidation in cells, scavenge free radicals, and play a role in cellular communication [6]. The Dietary Inflammatory Index (DII®) score was designed to evaluate the inflammatory potential of an individual's overall diet. It is based on a review of the literature examining the association between various dietary components and six known inflammatory markers: C-reactive protein (CRP), IL-4, IL-1β, IL-6, IL-10, and TNF-α [7].

Several studies have reported positive associations between the DII score and cardiovascular diseases, the metabolic syndrome, or cancers such as lymphoma, and prostate, breast, ovarian, gastric, pancreatic, and colorectal cancers [8–15]. The DII score and its association with HCC have been examined in three articles [16–18] and a meta-analysis [19]. These articles compared HCC risk in patients with and without liver disease and found that a pro-inflammatory diet (higher DII score) was associated with the risk of HCC especially among men, in patients not infected by hepatitis B or C (17), patients with lower education levels, smokers, and non-drinkers of alcohol [16]. The prospective American study analyzed the incidence and the mortality rate of primary liver cancer (PLC). Participants with higher DII scores tended to be younger, male, non-Hispanic white, and had higher BMI. They consumed more

dietary energy, had lower education levels, were more likely to be current smokers, less likely to be current alcohol drinkers, and were more likely to have a history of diabetes and a family history of liver cancer [18]. The meta-analysis reveals a strong correlation between dietary inflammation and liver cancer in general population, highlighting the significant impact of dietary inflammation compared to specific nutrients or dietary components. The differences between the articles were mainly related to the population parameters, alcohol exposure and outcome [19]. However, the possible relationship between exposure to an inflammatory diet and HCC risk in cirrhotic patients has not yet been investigated. Patients with cirrhosis certainly have specific dietary consumption profiles and have a high risk of developing cancer. Accordingly, the present study aimed to examine the inflammatory potential of the diet in a high-risk population by investigating the association between the DII score and the HCC risk in cirrhotic patients.

# 2. Materials and methods

## 2.1. Study sample

The French multicenter case-control study CiRCE, "Cirrhosis and Risk of Hepatocellular Carcinoma in the East", was conducted between June 2008 and December 2012 in six university hospitals in north-eastern France (Besançon, Dijon, Metz, Nancy, Reims, and Strasbourg). The characteristics of this population have been previously reported [20,21]. Patients were at least 35 years old and had cirrhosis, either histologically proven or, in the absence of a liver biopsy, established from clinical, morphological, and biological data. Cases were cirrhotic patients with HCC that was newly diagnosed in one of the participating hospitals through histology, echography, scanner, magnetic resonance imaging (MRI), or alpha-fetoprotein (AFP) according to criteria defined by the European Association for the Study of the Liver, European Organization for Research and Treatment of Cancer (EASL-EORTC) [22]. Controls were cirrhotic patients without HCC at inclusion. The absence of HCC was assessed through high-quality imaging examinations (abdominal ultrasound, computerized tomography or MRI), and AFP below 100 ng/mL within the two months preceding inclusion. Patients were excluded if they had progressive extrahepatic cancer, primary liver cancer other than HCC, HCC without cirrhosis, acute alcoholic hepatitis, human immunodeficiency virus infection, or other severe diseases resulting in an estimated life expectancy of less than one year. For the present study, only participants who completed the dietary questionnaire were included (n = 592); the description of this population has previously been published [21]. Patients with extreme values (1st and 99th percentiles) for the ratio between their energy intake and energy requirement (EIER) were excluded (n = 10). EIER and basal metabolic rate were calculated based on height, weight, physical activity, and occupational physical activity. Thus, the final analyses included 401 cirrhotic patients without HCC (controls) and 181 cirrhotic patients with HCC (cases). All patients read and signed an informed consent form before inclusion. The study protocol was approved by the local ethics committee (Comité de Protection des
Personnes Est I) and by the French legal authorities (Commission Nationale de l'Informatique et des Libertés).

## 2.2. Biological analyses

An overnight-fasting blood sample was taken from both HCC cases and controls (Results for CRP and the other biomarkers were available for 554 and 560 patients respectively) and aliquots were separated immediately by centrifugation and stored at -80 °C until centralized analysis in the coordinating centre (CRB-Dijon). Plasma CRP was measured using conventional laboratory techniques. Plasma levels of five other cytokines were assayed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Quantikine; R&D Systems Inc., Minneapolis, MN, USA) according to the manufacturer's instructions. All samples were assayed in duplicate. The intra- and inter-assay coefficients of variation were below 5 % for all measurements. All samples were analysed by trained staff blinded to the case-control status. Control and case samples were mixed in batches of <50 samples.

## 2.3. Data collection

At inclusion, every patient underwent a clinical examination, blood tests, and anthropometric measurements by physicians and qualified investigators. They completed a standardized questionnaire concerning clinical and sociodemographic data, family history of cancer and of diabetes, smoking status, and physical activity. They had to fill-in a self-administered validated diet history questionnaire [23,24]. It evaluated quantitative and qualitative food consumption according to the patients' eating habits for the year before inclusion, and allowed for seasonal variations. It recorded all meals and snacks throughout the day and was accompanied by a booklet of photographs to help patients assess portion sizes for 208 food items. Food portions and the frequency of consumption (11 possibilities, from never to 7 times per week) were converted into daily intake in grams, total energy intake, alcohol, and the breakdown for 23 nutrients (protein, carbohydrate, fat, vitamins, minerals, etc) using the French CIQUAL composition table (version 2008 and 2017) [25]; an online database for the polyphenol contents in foods was also used to provide details about polyphenol intake [26]. Trans-fatty acids were assessed from different sources including the USDA Standard Release database and manufacturer data [27,28].

## 2.4. Dietary inflammatory index

The Dietary Inflammatory Index was the first score to evaluate the inflammatory potential of an individual's diet. The development and validation of the DII have been described elsewhere [7]. Briefly, it is based on a wide-ranging literature review of 1943 articles published between 1950 and 2010, and it takes into consideration the effect of 45 dietary components on six well-known inflammatory biomarkers (IL-1β, IL-4, IL-6, IL-10, TNF-α and CRP) that increase in case of non-specific immune response. The 45 dietary components were scored according to whether they increased (+1) or decreased (-1) inflammation, or had no effect (0) on it. The final DII score for each participant was calculated by summing up all the calculated scores for each food component. A high DII score indicates a pro-inflammatory diet and conversely a low DII score denotes an anti-inflammatory diet. Only intake from foods, and not from supplements, was used in the DII calculations [7]. In the present study, 36 components of the 45 were available to calculate the DII score: carbohydrates, proteins, total fat, saturated fatty acids, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), ω-3 fatty acids, ω-6 fatty acids, alcohol, dietary fiber, cholesterol, vitamins A, B-6, B-12, C, D, and E, thiamin, riboflavin, niacin, iron,

magnesium, zinc, selenium, folic acid, β-carotene, onion, green/black tea, caffeine, trans-fatty acids, isoflavones, flavan-3-ol, flavones, flavonols, flavanones, and anthocyanidins. Food components not included were: energy, eugenol, garlic, ginger, saffron, turmeric, pepper, thyme/oregano and rosemary.

## 2.5. Statistical analysis

Occupational physical activity and leisure time physical activity were categorized as: inactive (<1 h/week), moderately active (1 h–3h30/week), and active (>3h30/week). Body mass index (BMI) was calculated as body weight in kilograms divided by the square of height in meters, and respondents were considered as: underweight/ normal weight, overweight, or obese (respectively: ≤25 kg/m², >25 and < 30 kg/m², ≥30 kg/m²). Time from diagnosis of cirrhosis was dichotomized according to the median: <2 or ≥2 years. The underlying cause of cirrhosis was divided into 3 categories which were determined according to medical records: alcohol abuse (alone), viral infection (associated or not with alcohol abuse), and other causes (autoimmune hepatitis, hemochromatosis, Wilson's disease, rare viral liver infections, parasitic infection, toxic chemicals, and some medications). Smoking status was categorized as: never, current, or former (former smoker was considered as having quit smoking for a period >6 months before inclusion). For alcohol status, consumption was considered as abusive for more than 2 glasses/day for women and 3 glasses/day for men. Two groups were established for educational level: ≤12 years of schooling or over 12 years and high-school diploma. BMI missing data (2 patients) were handled by imputation with linear regression method. While missing data from the inflammatory markers (CRP (29 patients), IL-4, IL-1β, IL-6, IL-10, and TNF-α (23 patients)) were handled with multiple imputation by fully conditional specification using predictive mean matching method.

The DII was analyzed both as a continuous variable and by tertiles of exposure computed among controls. Continuous variables were expressed as medians with interquartile ranges or as means with standard deviations, and qualitative variables as percentages. Associations between DII and individual characteristics of cases and controls, demographic, and clinical data were examined using the Chi-square test for qualitative variables (Fisher's exact test if conditions were not met) and the Anova test (or Kruskal–Wallis test in case of non-normal variables) or Student's test (Wilcoxon test, in case of non-normal variables) for continuous variables. A nonparametric test for trend (Cuzick's test) was used to assess the association with the biomarkers across DII score tertiles.

All covariates associated with DII or HCC risks (P-value ≤0.20) as well as potential confounding factors identified in the literature were retained for backward selection. To explore the relationships between DII and HCC risk, an unconditional logistic regression model was used to estimate odds ratios (OR) and 95 % confidence intervals (95%CI). The linear trend was estimated using the median values within each tertile of the DII score, thereby taking the unequal distances between tertiles into account.

Interactions between the DII and age, gender, and cirrhosis etiology were evaluated in specific analyses by including interaction terms in the final model.

All p-values were based on two-tailed statistical tests and a p-value of <0.05 was considered statistically significant. Analyses were performed with SAS® software, version 9.4 (SAS Institute Inc., Cary, NC).

## 3. Results

The present analyses included 582 cirrhotic patients, of whom 181 had HCC at inclusion and 401 no HCC. HCC patients were older than controls, with median ages of 64.4 years and 59.0 years,
respectively. HCC cases were more often male, diabetic, classified A on the Child-Pugh score, less active, and infected with HBV. The median time since cirrhosis diagnosis was 1 year [0–5] for HCC cases and 2 years [1–6] for controls (p < 0.001) (Table 1). The DII value for the whole population ranged from −4.77 to +7.59 with a mean value of 0.90 ± 2.87. The mean DII value was 1.03 ± 2.87 among cases, and 0.83 ± 2.87 among controls, indicating that both groups were following a pro-inflammatory diet, though cases had slightly higher DII scores.

Characteristics of the participants were presented across tertiles for the DII score (Annex 1). Patients in the third tertile were older than the other tertiles. Differences were minor and non-significant, or borderline for cirrhosis etiology, HCV and Child-Pugh.

Annex 2 presents the consumption of food groups and nutrients in medians with their IQR, and p-value from Kruskal–Wallis test when the conditions were not met for the Anova test. However, due to a large number of non-consumers, we also presented means and SD for some food groups with a particular distribution. Compared to participants in the first DII tertile, patients in the third tertile had

lower intakes of energy, fruit, vegetables, fish and seafood, dietary fiber, lipids, MUFAs, omega-3 and omega-6, PUFAs, vitamins A, C, E, and B1, folic acid, copper, manganese, potassium, and flavonoids. Inversely, a higher DII score was associated with higher intakes of cereals (mainly refined grains), alcohol, coffee, proteins, sodium, phosphorus, and zinc.

When analyzing different patterns of alcohol consumption according to DII tertiles, patients in the third tertile were mainly former or current drinkers. Among current drinkers, heavy drinkers mostly belonged to the third tertile.

Table 2 shows the ORs and 95 % CI for the association between HCC status and the DII score. When the DII was considered as a continuous variable, there was a positive association between increasing DII and HCC risk in the multivariate logistic regression model (adjusted OR = 1.14 [1.02–1.27], p-value = 0.021 per one-unit increment of the DII score, corresponding to approximately 8 % of its maximum range). When the DII score was categorized in tertiles, HCC risk was associated with the DII score (OR<sub>t3vst1</sub> = 2.33 [1.16–4.67], p-trend = 0.021).

<table><caption>**Table 1**

Baseline socio-demographic, clinical and medical characteristics of the 582 cirrhotic patients from the CiRCE study.</caption><thead><tr><th>Variables, n (%)</th><th>Cirrhotic Controls n = 401<sup>a</sup></th><th>HCC Cases n = 181<sup>a</sup></th><th>p-value<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Age, years<sup>c</sup></strong></td><td>59.0 [51.8–64.4]</td><td>64.4 [58.2–70.1]</td><td>&lt;0.001</td></tr><tr><td><strong>Gender</strong></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Male</td><td>267 (66.6)</td><td>156 (86.2)</td><td></td></tr><tr><td><strong>Education level</strong></td><td></td><td></td><td>0.092</td></tr><tr><td>&le;12 years of schooling</td><td>337 (84.3)</td><td>162 (89.5)</td><td></td></tr><tr><td>&gt;12 years or high school diploma</td><td>63 (15.7)</td><td>19 (10.5)</td><td></td></tr><tr><td><strong>Occupational physical activity</strong></td><td></td><td></td><td>0.005</td></tr><tr><td>Inactive</td><td>285 (71.4)</td><td>143 (80.3)</td><td></td></tr><tr><td>Moderately active</td><td>76 (19.1)</td><td>15 (8.4)</td><td></td></tr><tr><td>Active</td><td>38 (9.5)</td><td>20 (11.3)</td><td></td></tr><tr><td><strong>Leisure-time physical activity</strong></td><td></td><td></td><td>0.472</td></tr><tr><td>Inactive</td><td>192 (47.9)</td><td>80 (44.2)</td><td></td></tr><tr><td>Moderately active</td><td>94 (23.4)</td><td>40 (22.1)</td><td></td></tr><tr><td>Active</td><td>115 (28.7)</td><td>61 (33.7)</td><td></td></tr><tr><td><strong>BMI</strong></td><td></td><td></td><td>0.187</td></tr><tr><td>Underweight/normal weight (&le;25 kg/m<sup>2</sup>)</td><td>138 (34.4)</td><td>59 (32.6)</td><td></td></tr><tr><td>Overweight (&gt;25 and &lt; 30 kg/m<sup>2</sup>)</td><td>161 (40.2)</td><td>63 (34.8)</td><td></td></tr><tr><td>Obese (&ge;30 kg/m<sup>2</sup>)</td><td>102 (25.4)</td><td>59 (32.6)</td><td></td></tr><tr><td><strong>Smoking status</strong></td><td></td><td></td><td>0.057</td></tr><tr><td>Never</td><td>112 (27.9)</td><td>36 (19.9)</td><td></td></tr><tr><td>Current</td><td>129 (32.2)</td><td>56 (30.9)</td><td></td></tr><tr><td>Former</td><td>160 (39.9)</td><td>89 (49.2)</td><td></td></tr><tr><td><strong>Alcohol status</strong></td><td></td><td></td><td>0.112</td></tr><tr><td>Never</td><td>28 (7.0)</td><td>6 (3.3)</td><td></td></tr><tr><td>Non-abusive</td><td>127 (31.7)</td><td>51 (28.2)</td><td></td></tr><tr><td>Abusive</td><td>246 (61.3)</td><td>124 (68.5)</td><td></td></tr><tr><td><strong>DII score</strong></td><td></td><td></td><td>0.410</td></tr><tr><td>4.77 to –0.80</td><td>133 (72.7)</td><td>50 (27.3)</td><td></td></tr><tr><td>0.80–2.19</td><td>134 (67.0)</td><td>66 (33.0)</td><td></td></tr><tr><td>2.19–7.59</td><td>134 (67.3)</td><td>65 (32.7)</td><td></td></tr><tr><td><strong>Time since cirrhosis diagnosis</strong></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>&lt;2 years</td><td>160 (39.9)</td><td>107 (59.4)</td><td></td></tr><tr><td>&ge;2 years</td><td>241 (60.1)</td><td>73 (40.6)</td><td></td></tr><tr><td><strong>Cirrhosis etiology</strong></td><td></td><td></td><td>0.193</td></tr><tr><td>Virus infection associated with alcohol abuse</td><td>122 (30.4)</td><td>55 (30.4)</td><td></td></tr><tr><td>Alcohol abuse</td><td>215 (53.6)</td><td>107 (59.1)</td><td></td></tr><tr><td>Other<sup>d</sup></td><td>64 (16.0)</td><td>19 (10.5)</td><td></td></tr><tr><td><strong>Chronic C Hepatitis</strong></td><td>109 (27.2)</td><td>42 (23.2)</td><td>0.311</td></tr><tr><td><strong>Chronic B Hepatitis</strong></td><td>16 (4.0)</td><td>15 (8.3)</td><td>0.033</td></tr><tr><td><strong>Diabetic status</strong></td><td>128 (32.5)</td><td>88 (49.2)</td><td>&lt;0.001</td></tr><tr><td><strong>Child-Pugh Score</strong></td><td></td><td></td><td>0.006</td></tr><tr><td>A</td><td>210 (54.1)</td><td>122 (68.1)</td><td></td></tr><tr><td>B</td><td>126 (32.5)</td><td>42 (23.5)</td><td></td></tr><tr><td>C</td><td>52 (13.4)</td><td>15 (8.4)</td><td></td></tr></tbody></table>

<footnote><sup>a</sup> Total number may differ due to missing data: Education level (1 missing); Occupational physical activity (5 missing); cirrhosis diagnosis (1 missing); Hepatitis B virus (1 missing); Diabetic status (9 missing); Child-Pugh score (15 missing).</footnote>

<footnote><sup>b</sup> P-values were derived from the Chi-square test.</footnote>

<footnote><sup>c</sup> Values are median [IQR], p-value was obtained using the Wilcoxon test.</footnote>

<footnote><sup>d</sup> Other: autoimmune hepatitis, hemochromatosis, Wilson's disease, rare viral liver infections, parasitic infection, toxic chemicals, and some medications.</footnote>
<table><caption>**Table 2**
Association between the DII score and HCC risk, OR (95 % CIs) (n = 582 patients).</caption><thead><tr><th rowspan="2"></th><th rowspan="2">continuous DII score</th><th rowspan="2">p-value</th><th colspan="2">DII score in tertiles</th><th rowspan="2">p-trend</th></tr><tr><th>Tertile 2 (-0.80/2.19)</th><th>Tertile 3 (2.19/7.59)</th></tr></thead><tbody><tr><td>N= Cases/controls</td><td>181/401</td><td></td><td>66/134</td><td>65/134</td><td></td></tr><tr><td>Crude model</td><td>1.04 [0.98–1.11]</td><td>0.191</td><td>1.41 [0.90–2.21]</td><td>1.43 [0.91–2.24]</td><td>0.139</td></tr><tr><td>Adjusted model<sup>a</sup></td><td>1.14 [1.02–1.27]</td><td>0.021</td><td>1.75 [0.96–3.20]</td><td>2.33 [1.16–4.67]</td><td>0.021</td></tr></tbody></table>

<sup>a</sup> Odds ratios were estimated using unconditional logistic regression models, stratified by center. Regressions were adjusted for age, gender, total energy from nonalcoholic sources, cirrhosis diagnosis, Child-Pugh score, diabetes and etiology of cirrhosis.

No interaction term was statistically significant.

The association between DII score and plasmatic inflammatory biomarkers is difficult to interpret among cases with HCC during this phase. Table 3 presents the medians of cytokines across DII tertiles and DII score as continuous variable among controls. The values were often undetected for some inflammatory biomarkers, so the median was calculated only among patients with detected values. The percentage of undetected values was not significantly different across tertiles. The value of CRP and IL-6 significantly increased across the DII score tertiles (p-trend = 0.017 and 0.006 respectively). Among controls, there was a positive correlation observed between DII score and two plasmatic inflammatory biomarkers. The Spearman correlation coefficient was 0.12 (p-value = 0.021) with CRP, and 0.14 (p-value = 0.004) with IL-6.

### 3.1. A modified DII score

In our population, alcohol was the main cause of cirrhosis in 55.3 % of patients, and 63.6 % were heavy drinkers. Considering alcohol as an anti-inflammatory component in the DII score did not seem reasonable. Thus, the DII score not including alcohol was recalculated for the 582 cirrhotic patients. The new modified DII score, calculated without the alcohol component, ranged from -5.05 to +7.75 with a mean value of 0.82 ± 2.86 for the whole population. The mean of the modified DII score was 1.00 ± 2.85 among cases, and 0.74 ± 2.86 among controls, still indicating a pro-inflammatory diet in both groups.

Annex 3 presents the consumption of food groups and nutrients in medians with IQR, and the p-values from Kruskal–Wallis tests when the conditions were not met for Anova tests. However, due to a large number of non-consumers, we also presented means and SD for some food groups with unusual distributions. When compared to participants with a lower DII score, the results of the patients with a higher DII were similar to the initial results. However, there

was a difference in sugar intake since the patients in the third tertile consumed less than patients in the first tertile.

Table 4 shows the ORs and 95 % CI for the association between HCC status and modified DII score. Alcohol consumption was added as an adjustment variable in the multivariate logistic regression models. When considering DII as a continuous variable, a positive association was observed with HCC risk in the multivariate logistic regression model (adjusted OR = 1.15 [1.03–1.28], p-value = 0.013 for a one-unit increment of the DII score, corresponding to approximately 8 % of its maximum range). Additionally, when categorized in tertiles, HCC cirrhotic cases had a higher DII score than cirrhotic controls (OR<sub>t3vst1</sub> = 2.35 [1.18–4.68], p-trend = 0.015).

The modified DII score without alcohol was also correlated with CRP and IL-6: the Spearman correlation coefficient was 0.13 (p-value = 0.007) with CRP, and 0.16 (p-value = 0.001) with IL-6. For the modified DII score, the difference between tertiles was also significant, among controls, with CRP and IL-6 (p-trend = 0.017 and 0.003, respectively) (Table 5).

## 4. Discussion

This case-control study is the first to our knowledge to examine the relationships between the inflammatory potential of the diet, evaluated by the DII score, and HCC risk among cirrhotic patients. Our results showed that the DII score was associated with the risk of HCC. In our population, the DII score in controls was associated with plasmatic biomarkers of inflammation, including CRP and IL-6. As hypothesized, in specific populations with a liver disease such as cirrhosis, a pro-inflammatory diet does appear to increase HCC risk. A systematic review was conducted to evaluate the effects of anti-inflammatory dietary patterns on the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). The interventions included several types of diet: the Mediterranean diet in four studies, the Fatty Liver in Obesity diet in two studies, and the

<table><caption>**Table 3**
The medians of plasmatic inflammatory biomarkers across DII score among controls.</caption><thead><tr><th rowspan="3">Inflammatory markers</th><th colspan="3">DII score</th><th rowspan="3">p-value*</th><th rowspan="3">p-trend**</th><th rowspan="3">DII score<br>Continuous</th><th rowspan="3">p-value#</th></tr><tr><th>Tertile 1</th><th>Tertile 2</th><th>Tertile 3</th></tr><tr><th>n = 133</th><th>n = 134</th><th>n = 134</th></tr></thead><tbody><tr><td>CRP</td><td>6.15 [3.79–11.55]</td><td>6.63 [3.88–12.85]</td><td>7.76 [4.22–17.56]</td><td>0.052</td><td>0.017</td><td>0.12</td><td>0.021</td></tr><tr><td>IL-6</td><td>3.01 [1.48–7.06]</td><td>3.44 [1.72–7.73]</td><td>5.68 [1.86–12.38]</td><td>0.016</td><td>0.006</td><td>0.14</td><td>0.004</td></tr><tr><td>IL-1-β</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.902</td><td>0.934</td><td>0.01</td><td>0.850</td></tr><tr><td>Detected values of IL-1-β (n-%)<sup>a</sup></td><td>16 (12.0)</td><td>18 (13.4)</td><td>17 (12.7)</td><td>0.265</td><td>0.824</td><td></td><td></td></tr><tr><td>median [IQR]</td><td>1.40 [0.98–3.41]</td><td>3.04 [1.40–3.53]</td><td>1.40 [1.18–3.41]</td><td></td><td></td><td></td><td></td></tr><tr><td>IL-4</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–1.40]</td><td>0.00 [0.00–7.00]</td><td>0.234</td><td>0.229</td><td>0.06</td><td>0.259</td></tr><tr><td>Detected values of IL-4 (n-%)<sup>a</sup></td><td>25 (18.8)</td><td>34 (25.4)</td><td>36 (26.9)</td><td>0.853</td><td>0.578</td><td></td><td></td></tr><tr><td>median [IQR]</td><td>22.07 [8.84–29.46]</td><td>22.07 [13.04–29.46]</td><td>22.07 [14.31–29.80]</td><td></td><td></td><td></td><td></td></tr><tr><td>TNF-α</td><td>0.00 [0.00–1.53]</td><td>0.26 [0.00–1.80]</td><td>0.03 [0.00–2.42]</td><td>0.350</td><td>0.334</td><td>0.07</td><td>0.135</td></tr><tr><td>Detected values of TNF-α(n-%)<sup>a</sup></td><td>62 (46.6)</td><td>73 (54.5)</td><td>70 (52.2)</td><td>0.829</td><td>0.629</td><td></td><td></td></tr><tr><td>median [IQR]</td><td>1.60 [0.86–3.16]</td><td>1.60 [1.06–3.57]</td><td>2.32 [0.34–3.76]</td><td></td><td></td><td></td><td></td></tr><tr><td>IL-10</td><td>0.61 [0.00–1.78]</td><td>0.80 [0.00–1.86]</td><td>0.67 [0.00–1.72]</td><td>0.912</td><td>0.812</td><td>-0.02</td><td>0.737</td></tr></tbody></table>

<sup>a</sup> Values were presented as medians [IQR]. P-values were derived from *Kruskal-Wallis test, **Cuzick's test. The values were often undetected for some inflammatory biomarkers, so the median was calculated only among patients with detected values.
<table><caption>**Table 4**
Association between the modified DII score and HCC risk, OR (95 % CIs) (n = 582 patients).</caption><thead><tr><th rowspan="2"></th><th rowspan="2">DII score in continuous</th><th rowspan="2">p-value</th><th colspan="2">DII score in tertiles</th><th rowspan="2">p-trend</th></tr><tr><th>Tertile 2 (-0.83/2.00)</th><th>Tertile 3 (2.00/7.75)</th></tr></thead><tbody><tr><td>N= Cases/controls</td><td>181/401</td><td></td><td>61/134</td><td>67/135</td><td></td></tr><tr><td>Crude model</td><td>1.05 [0.99–1.12]</td><td>0.118</td><td>1.27 [0.81–2.00]</td><td>1.43 [0.91–2.23]</td><td>0.127</td></tr><tr><td>Adjusted model<sup>a</sup></td><td>1.15 [1.03–1.28]</td><td>0.013</td><td>1.54 [0.85–2.80]</td><td>2.35 [1.18–4.68]</td><td>0.015</td></tr></tbody></table>

a Odds ratios were estimated using unconditional logistic regression models, stratified by center. Regressions were adjusted for age, gender, total energy from nonalcoholic sources, cirrhosis diagnosis, Child-Pugh score, diabetes, etiology of cirrhosis and alcohol consumption.

Dietary Approaches to Stop Hypertension diet in one study. Comparison diets comprised a low-fat diet, a low-fat high-carbohydrate diet, the American Heart Association (AHA) diet, and macronutrient equivalents to anti-inflammatory diets. Four studies measured both inflammatory and anti-inflammatory markers and the results indicated that adherence to an anti-inflammatory diet (Mediterranean and DASH diet) led to improvements in MASLD severity indices, reductions in inflammatory markers, and better outcomes in liver enzymes, lipid profiles, anthropometric measures, and glycemic control in adults with MASLD [29]. In accordance with our hypothesis, an Iranian case-control study with 999 subjects [30], and the NHANES study with 3633 US participants showed that the consumption of a pro-inflammatory diet is associated with MASLD risk [31]. Moreover, a recent prospective cohort study of 171 544 UK Biobank participants, followed for approximately 10.2 years, found that individuals who consumed a more pro-inflammatory diet had a higher risk of developing severe MASLD [32].

The present findings, obtained using a score that reflects some specific properties of diet, confirmed previous results obtained in the same case-control study [21]. Some components of the DII score or foods associated with the score as referred in Annex 2 have been previously associated with the risk of HCC in our population. Carbonated beverages and total cereals (with potentially high levels of sugar or refined carbohydrates), processed meat, and sodium were found to be highly consumed by HCC cases, whereas the intake of dietary fiber, and some vitamins (E and B9) and minerals (manganese and potassium) were lower than in cirrhotic controls without HCC.

Other studies have also used the DII score to explore the consumption of nutrients and foods with anti-inflammatory values in

patients with HCC, but in comparison with individuals without liver disease [19,33–37]. Likewise, these studies found that a higher consumption of dairy products, soft drinks and juices, foods rich in saturated fat or sugar were associated with an increased risk of HCC [38–41]. On the other hand, regular consumption of vegetables, dietary fiber, fish, and coffee (3–4 cups/day) seemed to be associated with reduced risk of HCC [37,42–44]. Vitamin D, calcium, and the phenols contained in red wine, green tea, or olive oil may also have a protective role [33–36,38]. Some of these nutrients and food groups are listed as anti-inflammatory foods in the DII score [7].

Chronic inflammation is an important factor in the development of HCC. The body's inability to regenerate normal cells and to maintain normal hepatic function during inflammation leads to cirrhosis. The immune response that is triggered in an attempt to fight against this aggression results in the secretion of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 as well as the anti-inflammatory IL-10 by hepatic macrophages [45]. A higher DII score (pro-inflammatory diet) has been associated with a number of inflammatory biomarkers, including CRP, TNF-α, and IL-6 [46–49]. Our study actually revealed a positive association between the DII score and CRP or IL-6 concentrations. Previous studies have compared the effect of different types of diet on the inflammatory response by measuring the variation of plasma inflammatory biomarkers or by analyzing oxidative stress. The Western-type diet, defined by the consumption of red meat, high-fat dairy products, refined grains, and simple carbohydrates was associated with a pro-inflammatory status and higher levels of CRP and IL-6 [47,50]. The Mediterranean diet, rich in fruit and vegetables, fish, whole grains, and olive oil, and with moderate wine

<table><caption>**Table 5**
The medians of plasmatic inflammatory biomarkers across the modified DII score among controls.</caption><thead><tr><th rowspan="3">Inflammatory markers</th><th colspan="3">DII score</th><th rowspan="3">p-value*</th><th rowspan="3">p-trend**</th><th rowspan="3">DII score Continuous</th><th rowspan="3">p-value#</th></tr><tr><th>Tertile 1</th><th>Tertile 2</th><th>Tertile 3</th></tr><tr><th>n = 132</th><th>n = 134</th><th>n = 135</th></tr></thead><tbody><tr><td>CRP</td><td>6.03 [3.79–11.48]</td><td>6.63 [3.88–13.26]</td><td>7.90 [4.20–17.56]</td><td>0.056</td><td>0.017</td><td>0.13</td><td>0.007</td></tr><tr><td>IL-6</td><td>2.88 [1.41–6.03]</td><td>3.73 [1.72–8.91]</td><td>4.85 [1.88–11.78]</td><td>0.012</td><td>0.003</td><td>0.16</td><td>0.001</td></tr><tr><td>IL-1-β</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.745</td><td>0.963</td><td>0.01</td><td>0.868</td></tr><tr><td>Detected values of IL-1-β(n-%)<sup>a</sup></td><td>16 (12.1)</td><td>19 (14.2)</td><td>16 (11.9)</td><td>0.194</td><td>0.901</td><td></td><td></td></tr><tr><td>median [IQR]</td><td>1.40 [0.98–3.27]</td><td>2.95 [1.40–3.66]</td><td>1.40 [0.88–3.41]</td><td></td><td></td><td></td><td></td></tr><tr><td>IL-4</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–7.00]</td><td>0.469</td><td>0.400</td><td>0.06</td><td>0.243</td></tr><tr><td>Detected value of IL-4 (n-%)<sup>a</sup></td><td>28 (21.2)</td><td>30 (22.4)</td><td>37 (27.4)</td><td>0.850</td><td>0.755</td><td></td><td></td></tr><tr><td>median [IQR]</td><td>22.07 [10.94–41.74]</td><td>22.07 [13.04–27.42]</td><td>22.07 [13.04–25.90]</td><td></td><td></td><td></td><td></td></tr><tr><td>TNF-α</td><td>0.00 [0.00–1.53]</td><td>0.26 [0.00–1.80]</td><td>0.04 [0.00–2.48]</td><td>0.283</td><td>0.274</td><td>0.08</td><td>0.119</td></tr><tr><td>Detected value of TNF-α (n-%)<sup>a</sup></td><td>61 (46.2)</td><td>73 (54.5)</td><td>71 (52.6)</td><td>0.748</td><td>0.581</td><td></td><td></td></tr><tr><td>median [IQR]</td><td>1.60 [0.90–3.16]</td><td>1.60 [1.06–3.57]</td><td>2.42 [0.34–3.76]</td><td></td><td></td><td></td><td></td></tr><tr><td>IL-10</td><td>0.71 [0.00–1.86]</td><td>0.66 [0.00–1.86]</td><td>0.71 [0.00–1.69]</td><td>0.773</td><td>0.547</td><td>-0.03</td><td>0.576</td></tr></tbody></table>

a Values were presented as medians [IQR]. P-values were derived from *Kruskal Wallis tests, **Cuzick's tests. The values were often undetected for some inflammatory biomarkers, so the median was calculated only among patients with detected values.
consumption, is associated with a lower level of inflammation and a reduction in oxidative stress as well as a beneficial effect on the metabolic syndrome, cardiovascular diseases, cancer risk, and MASLD [35,51–53].

The inflammatory potential of the diet, as indicated by a high DII score, has been associated with higher risk of all-cause mortality, cardiovascular disease, and metabolic syndrome [54–57]. In numerous studies, the DII score was positively associated with various types of cancer, including breast, prostate, lymphoma, lung, and digestive, in many regions and populations [8–10,12,14,51]. In addition, several meta-analyses have summarized the current published literature discussing the association between DII and cancer risk and other non-communicable diseases [54,55,58]. Overall, individuals who consumed pro-inflammatory diets (higher DII score) had a 17 % higher risk of developing cancer on average (depending on the study and cancer type) compared with those who consumed an anti-inflammatory diet [54].

However, only three studies (one in Italy, one in China and one in United States) have investigated the association between DII and HCC. These studies compared HCC cases with hospitalized patients or healthy participants without any dietary modification or any medical condition related to major risk factors for HCC (controls). The first two studies found a positive association between higher DII and HCC risk, with an OR<sub>T3vsT1</sub> = 2.43 (95 % CI = 1.27–4.68; p-trend = 0.03) in the Italian study and OR<sub>T3vsT1</sub> = 3.22 (95 % CI = 1.30–7.98, p-trend = 0.009) in the Chinese study. Their results were very similar to our findings. The Italian study found that a higher DII was associated with HCC risk in male participants with no history of hepatitis B or C. In the Chinese study, a strong association between a pro-inflammatory diet and HCC was found only in male smokers with lower levels of education, and non-drinkers of alcohol [16,17]. However, our study did not show any interaction or statistically significant associations in stratified analyses. While the American study showed that individuals with higher DII scores from food were found to have an increased risk of developing PLC (HR<sub>Tertile 3 vs. 1</sub> 2.57; 95 % CI = 1.44–4.60, p-trend = 0.007) and death from this disease (SHR<sub>Tertile 3 vs. 1</sub> 2.38; 95 % CI = 1.27–4.46, p-trend = 0.028), similar results were obtained for DII score from food and supplements [18].

Our study presents some limitations. First, it has the usual limitations of a case–control design with classical associated risks of biases. Second, the limited number of participants who responded to the diet history questionnaire reflects the difficulty of asking patients to answer such an extensive nutritional questionnaire. Third, only 36 of 45 food parameters were available for the DII calculation. However, this is also often the case in the published literature. Moreover, some of the missing food parameters (eugenol, saffron, ginger and turmeric) are seldom consumed in our population and would barely have affected the final results. On the other hand, missing information on consumptions of rosemary, thyme, garlic, and pepper could have had some impact on the overall DII estimate.

The strengths of this study are, first, the use of a validated and reproducible diet history questionnaire which considers seasonal variations. Second, the use of a standardized protocol in six French university hospitals allowed for a comprehensive assessment of major metabolic, nutritional, and environmental risk factors for HCC among cirrhotic patients. Third, the detailed sociodemographic and clinical questionnaire filled in by qualified physicians and investigators concerning the major risk factors for HCC, made it possible to make detailed adjustments. Another one of our study's strengths lies in the measurement of inflammatory markers and DII score in the same population and confirmed the pertinence of the DII score.

## 5. Conclusion

In conclusion, the present study on the risk of HCC and the DII score in a French cirrhotic population showed that the inflammatory potential of one's diet may be associated with the risk of liver carcinogenesis. However, these results and the possibility to evaluate interventions must be confirmed in larger prospective studies. According to the World Cancer Research Fund International, increasing the consumption of vegetables and fruits that are rich in fiber and nutrients, replacing red meat by white meat, and increasing the consumption of coffee and unsaturated fatty acids (mainly n-3 and n-6 fatty acids) are good approaches for reducing the consumption of pro-inflammatory food. Taking such steps may subsequently decrease HCC risk. It would be worthwhile to carry out further investigations among cirrhotic patients to confirm the interest of an anti-inflammatory diet and to define recommendations for this specific population.

## Author contribution

The authors' responsibilities were as follows: VC and PH designed the research. MR and CR-L performed statistical analyses. VC supervised statistical analyses. MR and VC interpreted data and wrote the manuscript. JH and NS provided information about the DII score and revised the manuscript. CR-L and MDA provided critical revision of the manuscript. BB-C, J-PB, CR, MD, JLJ, MCBR, PH and the CIRCE Study Group conducted research or provided essential materials and critical revision of the manuscript. All authors read and approved the final manuscript.

## Disclosure

Dr. James R. Hébert owns controlling interest in Connecting Health Innovations LLC (CHI), a company planning to license the right to his invention of the dietary inflammatory index (DII) from the University of South Carolina in order to develop computer and smartphone applications for patient counselling and dietary intervention in clinical settings. Dr. Nitin Shivappa is an employee of CHI.

## Funding statement

This work was supported by a French Government grant managed by the French National Research Agency under the program "Investissements d'Avenir" [reference ANR-11-LABX-0021], and also by grants from the "Conseil Régional de Bourgogne", the "Fonds Européen de Développement Régional" (FEDER), the French National Cancer Institute, the "Ligue Nationale contre le Cancer", the "Cancéropôle Grand-Est" and the "Fondation de France".

## Declaration of competing interest

The authors declare no conflict of interest.

## Acknowledgment

We thank the staff of the Biological Resource Center Ferdinand Cabanne, Dijon University Hospital, France – (BB-0033-00044) for their assistance in handling and storing biological samples and the E3N team (INSERM UMR1018) for their help with the diet history questionnaire. We also thank Cyril Boisson for his assistance with statistics. We thank Suzanne Rankin from the Dijon University hospital for proof reading the manuscript.
# Appendix 1

## Annex 1

Baseline population characteristics by energy-adjusted DII tertiles, the CiRCE study.

<table><thead><tr><th rowspan="2">Characteristics, n (%)</th><th>DII tertile 1 (−4.77/-0.80)</th><th>DII score</th><th>DII tertile 3 (2.19/7.59)</th><th rowspan="2">p-value<sup>b</sup></th></tr><tr><th>n = 183<sup>a</sup></th><th>DII tertile 2 (−0.80/2.19)</th><th>n = 199<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Gender</strong></td><td></td><td></td><td></td><td>0.636</td></tr><tr><td>Male</td><td>134 (73.2)</td><td>149 (74.5)</td><td>140 (70.4)</td><td></td></tr><tr><td><strong>Age, years<sup>c</sup></strong></td><td>58.9 [51.5–65.9]</td><td>60.4 [54.2–67.6]</td><td>62.2 [55.6–66.7]</td><td>0.021</td></tr><tr><td><strong>Education level</strong></td><td></td><td></td><td></td><td>0.388</td></tr><tr><td>≤12 years of schooling</td><td>153 (83.6)</td><td>176 (88.4)</td><td>170 (85.4)</td><td></td></tr><tr><td>>12 years or high school diploma</td><td>30 (16.4)</td><td>23 (11.6)</td><td>29 (14.6)</td><td></td></tr><tr><td><strong>Occupational Physical activity</strong></td><td></td><td></td><td></td><td>0.091</td></tr><tr><td>Inactive</td><td>126 (69.2)</td><td>145 (73.2)</td><td>157 (79.7)</td><td></td></tr><tr><td>Moderate active</td><td>37 (20.3)</td><td>28 (14.2)</td><td>26 (13.2)</td><td></td></tr><tr><td>Active</td><td>19 (10.5)</td><td>25 (12.6)</td><td>14 (7.1)</td><td></td></tr><tr><td><strong>Leisure-Time Physical activity</strong></td><td></td><td></td><td></td><td>0.763</td></tr><tr><td>Inactive</td><td>80 (43.7)</td><td>93 (46.5)</td><td>99 (49.8)</td><td></td></tr><tr><td>Moderate active</td><td>47 (25.7)</td><td>44 (22.0)</td><td>43 (21.6)</td><td></td></tr><tr><td>Active</td><td>56 (30.6)</td><td>63 (31.5)</td><td>57 (28.6)</td><td></td></tr><tr><td><strong>BMI</strong></td><td></td><td></td><td></td><td>0.434</td></tr><tr><td>Underweight/normal weight (≤25 kg/m²)</td><td>53 (29.0)</td><td>68 (34.0)</td><td>76 (38.2)</td><td></td></tr><tr><td>Overweight (>25 and < 30 kg/m²)</td><td>77 (42.1)</td><td>75 (37.5)</td><td>72 (36.2)</td><td></td></tr><tr><td>Obese (≥30 kg/m²)</td><td>53 (28.9)</td><td>57 (28.5)</td><td>51 (25.6)</td><td></td></tr><tr><td><strong>Medical History</strong></td><td></td><td></td><td></td><td>0.728</td></tr><tr><td><strong>Time since cirrhosis diagnosis</strong></td><td></td><td></td><td></td><td>0.057</td></tr><tr><td><strong>Cirrhosis etiology</strong></td><td></td><td></td><td></td><td>0.057</td></tr><tr><td>Virus Infection (with or without alcohol abuse)</td><td>65 (35.5)</td><td>58 (29.0)</td><td>54 (27.1)</td><td></td></tr><tr><td>Alcohol</td><td>96 (52.5)</td><td>104 (52.0)</td><td>122 (61.3)</td><td></td></tr><tr><td>Other<sup>d</sup></td><td>22 (12.0)</td><td>38 (19.0)</td><td>23 (11.6)</td><td></td></tr><tr><td><strong>Diabetes</strong></td><td>63 (34.8)</td><td>74 (37.0)</td><td>79 (41.2)</td><td>0.437</td></tr><tr><td><strong>Chronic B hepatitis</strong></td><td>7 (3.8)</td><td>12 (6.0)</td><td>12 (6.0)</td><td>0.547</td></tr><tr><td><strong>Chronic C hepatitis</strong></td><td>59 (32.2)</td><td>48 (24.0)</td><td>44 (22.1)</td><td>0.058</td></tr><tr><td><strong>Smoking status</strong></td><td></td><td></td><td></td><td>0.708</td></tr><tr><td>Never</td><td>48 (26.2)</td><td>53 (26.5)</td><td>47 (23.6)</td><td></td></tr><tr><td>Current</td><td>55 (30.1)</td><td>59 (29.5)</td><td>71 (35.7)</td><td></td></tr><tr><td>Former</td><td>80 (43.7)</td><td>88 (44.0)</td><td>81 (40.7)</td><td></td></tr><tr><td><strong>Alcohol status</strong></td><td></td><td></td><td></td><td>0.260</td></tr><tr><td>Never</td><td>10 (5.5)</td><td>14 (7.0)</td><td>10 (5.0)</td><td></td></tr><tr><td>Non-abusive</td><td>58 (31.7)</td><td>69 (34.5)</td><td>51 (25.6)</td><td></td></tr><tr><td>Abusive</td><td>115 (62.8)</td><td>117 (58.5)</td><td>138 (69.3)</td><td></td></tr><tr><td><strong>Child-Pugh Score</strong></td><td></td><td></td><td></td><td>0.060</td></tr><tr><td>A</td><td>96 (53.9)</td><td>128 (65.3)</td><td>108 (56.0)</td><td></td></tr><tr><td>B</td><td>64 (36.0)</td><td>44 (22.5)</td><td>60 (31.1)</td><td></td></tr><tr><td>C</td><td>18 (10.1)</td><td>24 (12.2)</td><td>25 (12.9)</td><td></td></tr></tbody></table>

## Annex 2

Consumption of food groups and micronutrients by DII tertiles calculated for 1000 kcal of daily energy intake from nonalcoholic sources

<table><thead><tr><th rowspan="2"></th><th colspan="3">DII score</th><th rowspan="2">p-value<sup>b</sup></th></tr><tr><th>Tertile 1 n = 183</th><th>Tertile 2 n = 200</th><th>Tertile 3 n = 199</th></tr></thead><tbody><tr><td>Food groups<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Energy (kcal/day)</td><td>3851.49 [3067.35–5182.57]</td><td>2685.70 [2160.27–3188.75]</td><td>1830.67 [1398.17–2386.03]</td><td>&lt;0.001</td></tr><tr><td>Alcohol (g/day)</td><td>9.95 [0.00–130.37]</td><td>2.15 [0.00–153.72]</td><td>0.00 [0.00–241.11]</td><td>0.696</td></tr><tr><td>(mean ± SD)</td><td>116.34 ± 208.56</td><td>139.60 ± 320.32</td><td>205.75 ± 419.77</td><td>0.023</td></tr><tr><td>Added sugar (g/day)</td><td>6.14 [1.51–12.40]</td><td>4.90 [0.04–13.42]</td><td>3.19 [0.00–13.88]</td><td>0.057</td></tr><tr><td>Desserts (g/day)</td><td>44.26 [18.26–79.47]</td><td>34.62 [13.19–70.45]</td><td>33.32 [8.77–77.45]</td><td>0.144</td></tr><tr><td>Carbonated beverages (ml/day)</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.147</td></tr><tr><td>(mean ± SD)</td><td>19.66 ± 64.68</td><td>14.86 ± 72.02</td><td>18.84 ± 74.97</td><td>0.774</td></tr><tr><td>Coffee (ml/day)</td><td>70.80 [17.01–139.07]</td><td>106.22 [18.63–207.02]</td><td>115.30 [12.53–237.73]</td><td>0.004</td></tr><tr><td>All cereals (g/day)</td><td>47.20 [30.76–65.84]</td><td>61.09 [38.38–86.68]</td><td>75.95 [41.68–102.38]</td><td>&lt;0.001</td></tr><tr><td>Dairy products (g/day)</td><td>90.14 [50.39–131.61]</td><td>94.41 [47.81–155.59]</td><td>85.58 [48.11–166.86]</td><td>0.505</td></tr><tr><td>Total meat (g/day)</td><td>24.11 [11.79–41.21]</td><td>24.26 [11.18–44.49]</td><td>22.15 [5.82–46.98]</td><td>0.425</td></tr></tbody></table>

<footnote><sup>a</sup> Total number may differ due to missing data: Education level (1 missing); Occupational physical activity (5 missing); cirrhosis diagnosis (1 missing); Hepatitis B virus (1 missing); Diabetic status (9 missing); Child-Pugh score (15 missing).</footnote>

<footnote><sup>b</sup> P-values were derived from the Chi-square test.</footnote>

<footnote><sup>c</sup> Values are median [IQR], p-value was obtained using the Kruskal–Wallis test.</footnote>

<footnote><sup>d</sup> Other: autoimmune hepatitis, hemochromatosis, Wilson's disease, rare viral liver infections, parasitic infection, toxic chemicals, and some medications.</footnote>
**Annex 2 (continued)**

<table><thead><tr><th rowspan="2"></th><th colspan="3">DII score</th><th rowspan="2">p-value<sup>b</sup></th></tr><tr><th>Tertile 1 n = 183</th><th>Tertile 2 n = 200</th><th>Tertile 3 n = 199</th></tr></thead><tbody><tr><td>Processed meat (g/day)</td><td>15.91 [8.61–23.89]</td><td>13.59 [7.35–22.93]</td><td>16.78 [5.61–29.93]</td><td>0.381</td></tr><tr><td>Red meat (g/day)</td><td>13.07 [5.24–21.99]</td><td>13.47 [4.07–28.05]</td><td>8.06 [0.00–28.05]</td><td>0.067</td></tr><tr><td>Fish and seafood (g/day)</td><td>10.37 [5.19–17.68]</td><td>7.90 [3.94–13.46]</td><td>6.63 [2.65–15.89]</td><td>0.002</td></tr><tr><td>Eggs (g/day)</td><td>8.73 [4.48–14.39]</td><td>9.84 [4.72–16.99]</td><td>9.27 [3.10–22.12]</td><td>0.457</td></tr><tr><td>Fruits (g/day)</td><td>104.52 [57.46–179.63]</td><td>87.26 [35.42–174.67]</td><td>62.42 [10.39–140.99]</td><td>&lt;0.001</td></tr><tr><td>Vegetables (g/day)</td><td>94.33 [58.48–153.77]</td><td>99.08 [59.12–157.52]</td><td>75.87 [33.64–161.83]</td><td>0.029</td></tr><tr><td>Protein (g/day)</td><td>36.07 [32.58–40.29]</td><td>38.44 [33.83–43.37]</td><td>38.31 [32.71–44.33]</td><td>0.005</td></tr><tr><td>Carbohydrate (g/day)</td><td>112.52 [97.09–126.74]</td><td>114.47 [101.30–128.66]</td><td>116.27 [98.20–139.15]</td><td>0.071</td></tr><tr><td>Fat (g/day)</td><td>45.18 [38.74–51.39]</td><td>42.91 [36.48–48.57]</td><td>40.90 [33.35–48.61]</td><td>&lt;0.001</td></tr><tr><td>Saturated fat (g/day)</td><td>17.64 [14.76–21.07]</td><td>17.19 [13.62–20.97]</td><td>17.06 [13.51–22.77]</td><td>0.361</td></tr><tr><td>Monounsaturated fat (g/day)</td><td>15.04 [13.18–17.75]</td><td>14.58 [12.39–16.71]</td><td>13.48 [10.59–16.01]</td><td>&lt;0.001</td></tr><tr><td>Trans-fat (g/day)</td><td>0.70 [0.44–1.07]</td><td>0.64 [0.27–1.24]</td><td>0.58 [0.17–1.20]</td><td>0.185</td></tr><tr><td>Polyunsaturated fat (g/day)</td><td>7.46 [5.76–9.65]</td><td>6.88 [5.01–9.14]</td><td>5.24 [4.03–7.14]</td><td>&lt;0.001</td></tr><tr><td>N-3 PUFA (g/day)</td><td>0.62 [0.47–0.87]</td><td>0.53 [0.37–0.70]</td><td>0.43 [0.31–0.55]</td><td>&lt;0.001</td></tr><tr><td>N-6 PUFA (g/day)</td><td>6.11 [4.61–7.95]</td><td>5.33 [3.79–7.47]</td><td>4.42 [2.94–6.63]</td><td>&lt;0.001</td></tr><tr><td>Fiber (g/day)</td><td>10.03 [7.93–11.76]</td><td>9.35 [7.59–11.35]</td><td>7.86 [6.33–9.82]</td><td>&lt;0.001</td></tr><tr><td>Cholesterol (mg/day)</td><td>160.63 [129.55–201.71]</td><td>169.08 [131.83–205.16]</td><td>176.85 [132.76–228.35]</td><td>0.149</td></tr><tr><td>Micronutrients<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Vitamin B1 (mg/day)</td><td>0.58 [0.51–0.67]</td><td>0.58 [0.50–0.67]</td><td>0.54 [0.46–0.65]</td><td>0.007</td></tr><tr><td>Vitamin B2 (mg/day)</td><td>0.86 [0.75–1.08]</td><td>0.93 [0.76–1.11]</td><td>0.91 [0.77–1.10]</td><td>0.379</td></tr><tr><td>Vitamin B3 (mg/day)</td><td>7.71 [6.44–9.74]</td><td>8.14 [6.24–10.40]</td><td>7.24 [5.92–9.85]</td><td>0.057</td></tr><tr><td>Vitamin B5 (mg/day)</td><td>2.53 [2.21–2.98]</td><td>2.66 [2.33–3.03]</td><td>2.62 [2.21–3.19]</td><td>0.288</td></tr><tr><td>Vitamin B6 (mg/day)</td><td>0.77 [0.69–0.92]</td><td>0.77 [0.66–0.88]</td><td>0.74 [0.60–0.89]</td><td>0.059</td></tr><tr><td>Vitamin B9 (µg/day)</td><td>169.03 [145.04–204.32]</td><td>165.27 [136.18–192.89]</td><td>144.55 [117.56–177.46]</td><td>&lt;0.001</td></tr><tr><td>Vitamin B12 (µg/day)</td><td>2.79 [1.90–4.49]</td><td>2.69 [1.79–3.99]</td><td>2.56 [1.68–4.01]</td><td>0.239</td></tr><tr><td>Vitamin D (µg/day)</td><td>1.27 [1.01–1.63]</td><td>1.19 [0.95–1.53]</td><td>1.20 [0.84–1.63]</td><td>0.198</td></tr><tr><td>Vitamin C (mg/day)</td><td>67.81 [49.42–97.35]</td><td>58.79 [36.04–88.71]</td><td>40.39 [24.73–57.38]</td><td>&lt;0.001</td></tr><tr><td>Vitamin A (µg/day)</td><td>438.83 [273.06–693.85]</td><td>398.11 [226.64–639.44]</td><td>348.77 [234.10–624.47]</td><td>0.042</td></tr><tr><td>Vitamin E (mg/day)</td><td>6.83 [5.30–9.61]</td><td>6.10 [4.46–8.08]</td><td>4.59 [3.30–6.28]</td><td>&lt;0.001</td></tr><tr><td>Calcium (mg/day)</td><td>408.02 [330.05–491.60]</td><td>422.02 [350.87–512.97]</td><td>418.66 [308.72–533.85]</td><td>0.411</td></tr><tr><td>Copper (mg/day)</td><td>0.78 [0.66–0.97]</td><td>0.75 [0.64–0.96]</td><td>0.68 [0.60–0.93]</td><td>0.003</td></tr><tr><td>Iron (mg/day)</td><td>6.23 [5.30–7.78]</td><td>6.44 [5.17–7.58]</td><td>6.04 [4.92–8.14]</td><td>0.727</td></tr><tr><td>Selenium (µg/day)</td><td>24.14 [21.14–29.04]</td><td>25.07 [21.68–29.76]</td><td>25.79 [21.34–32.29]</td><td>0.066</td></tr><tr><td>Magnesium (mg/day)</td><td>134.21 [120.38–157.45]</td><td>138.62 [121.98–161.97]</td><td>133.80 [113.56–157.45]</td><td>0.095</td></tr><tr><td>Manganese (mg/day)</td><td>2.49 [1.95–3.24]</td><td>2.15 [1.64–2.82]</td><td>2.07 [1.52–2.71]</td><td>&lt;0.001</td></tr><tr><td>Sodium (mg/day)</td><td>1112.66 [954.14–1283.16]</td><td>1203.55 [1050.31–1411.39]</td><td>1253.46 [1068.92–1528.18]</td><td>&lt;0.001</td></tr><tr><td>Phosphorus (mg/day)</td><td>567.98 [510.29–635.28]</td><td>590.23 [527.93–669.02]</td><td>596.27 [508.54–691.90]</td><td>0.046</td></tr><tr><td>Potassium (mg/day)</td><td>1568.40 [1348.26–1875.31]</td><td>1577.54 [1337.25–1883.49]</td><td>1407.53 [1162.92–1781.30]</td><td>&lt;0.001</td></tr><tr><td>Iodine (mg/day)</td><td>56.14 [47.72–68.43]</td><td>59.24 [48.83–71.23]</td><td>58.16 [47.68–74.19]</td><td>0.364</td></tr><tr><td>Zinc (mg/day)</td><td>4.37 [3.75–4.84]</td><td>4.48 [3.96–5.18]</td><td>4.50 [3.88–5.49]</td><td>0.023</td></tr><tr><td>Total flavonoids (mg/day)</td><td>118.30 [68.07–215.51]</td><td>103.84 [40.87–221.42]</td><td>62.72 [12.95–217.67]</td><td>&lt;0.001</td></tr><tr><td>Flavanol (mg/day)</td><td>77.15 [39.82–139.30]</td><td>66.45 [23.18–159.45]</td><td>39.99 [5.44–137.06]</td><td>&lt;0.001</td></tr><tr><td>Flavone (mg/day)</td><td>0.00 [0.00–0.07]</td><td>0.00 [0.00–0.02]</td><td>0.00 [0.00–0.00]</td><td>0.003</td></tr><tr><td>(mean ± SD)</td><td>0.94 ± 5.93</td><td>0.35 ± 2.68</td><td>0.32 ± 3.09</td><td>0.252</td></tr><tr><td>Flavanol (mg/day)</td><td>15.22 [7.50–34.93]</td><td>8.71 [4.33–19.96]</td><td>5.28 [1.33–12.10]</td><td>&lt;0.001</td></tr><tr><td>Flavanone (mg/day)</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.786</td></tr><tr><td>(mean ± SD)</td><td>0.12 ± 1.14</td><td>0.42 ± 5.48</td><td>0.40 ± 2.59</td><td>0.669</td></tr><tr><td>Isoflavone (mg/day)</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>&lt;0.001</td></tr><tr><td>(mean ± SD)</td><td>0.40 ± 1.27</td><td>0.84 ± 4.41</td><td>0.12 ± 1.10</td><td>0.032</td></tr><tr><td>Anthocyanide (mg/day)</td><td>6.25 [2.14–14.98]</td><td>5.31 [1.01–14.93]</td><td>1.58 [0.00–8.88]</td><td>&lt;0.001</td></tr></tbody></table>

**Annex 3**

Consumption of food groups and micronutrients by modified DII tertiles calculated for 1000 kcal of daily energy intake from nonalcoholic sources

<table><thead><tr><th rowspan="2"></th><th colspan="3">Modified DII score<sup>a</sup></th><th rowspan="2">p-value<sup>b</sup></th></tr><tr><th>Tertile 1 n = 185</th><th>Tertile 2 n = 195</th><th>Tertile 3 n = 202</th></tr></thead><tbody><tr><td>Food groups<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Energy (kcal/day)</td><td>3794.01 [3058.05–5162.54]</td><td>2723.25 [2160.99–3217.27]</td><td>1835.92 [1403.98–2385.32]</td><td>&lt;0.001</td></tr><tr><td>Alcohol (g/day)</td><td>4.47 [0.00–112.23]</td><td>0.52 [0.00–153.63]</td><td>11.28 [0.00–297.98]</td><td>0.294</td></tr><tr><td>Added sugar (g/day)</td><td>5.83 [1.12–12.21]</td><td>4.98 [0.07–13.91]</td><td>3.31 [0.00–13.45]</td><td>0.047</td></tr><tr><td>Desserts (g/day)</td><td>43.61 [17.86–78.40]</td><td>34.86 [14.82–71.37]</td><td>33.96 [8.78–81.32]</td><td>0.317</td></tr><tr><td>Carbonated beverages (ml/day)</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.146</td></tr><tr><td>(mean ± SD)</td><td>19.93 ± 64.65</td><td>18.89 ± 89.78</td><td>14.60 ± 53.41</td><td>0.732</td></tr><tr><td>Coffee (ml/day)</td><td>68.46 [18.06–130.84]</td><td>112.89 [22.42–213.89]</td><td>108.57 [5.56–229.39]</td><td>0.001</td></tr><tr><td>All cereals (g/day)</td><td>48.00 [31.10–68.29]</td><td>60.54 [37.64–85.48]</td><td>74.79 [41.68–102.38]</td><td>&lt;0.001</td></tr><tr><td>Dairy products (g/day)</td><td>90.14 [49.82–134.41]</td><td>96.48 [51.37–154.35]</td><td>86.47 [47.11–166.86]</td><td>0.496</td></tr><tr><td>Total meat (g/day)</td><td>23.21 [11.16–41.09]</td><td>24.87 [11.29–46.55]</td><td>22.23 [6.79–44.53]</td><td>0.316</td></tr><tr><td>Processed meat (g/day)</td><td>15.82 [8.13–23.51]</td><td>13.52 [7.59–22.69]</td><td>17.73 [5.93–30.73]</td><td>0.255</td></tr></tbody></table>

(continued on next page)

<footnote><sup>a</sup> Values are presented as median [IQR] (or mean ± SD for some food groups with a particular distribution).</footnote>

<footnote><sup>b</sup> P-values were derived from Kruskal–Wallis test (or Anova test).</footnote>
<table><caption>**Annex 3 (continued)**</caption><thead><tr><th rowspan="2"></th><th colspan="3">Modified DII score<sup>a</sup></th><th rowspan="2">p-value<sup>b</sup></th></tr><tr><th>Tertile 1 n = 185</th><th>Tertile 2 n = 195</th><th>Tertile 3 n = 202</th></tr></thead><tbody><tr><td>Red meat (g/day)</td><td>12.73 [5.07–21.99]</td><td>13.71 [3.47–28.58]</td><td>9.05 [0.00–27.28]</td><td>0.057</td></tr><tr><td>Fish and seafood (g/day)</td><td>10.40 [5.38–18.30]</td><td>7.87 [3.93–13.32]</td><td>6.92 [2.63–15.54]</td><td>&lt;0.001</td></tr><tr><td>Eggs (g/day)</td><td>8.57 [4.43–14.34]</td><td>9.71 [4.72–16.91]</td><td>9.33 [3.28–24.06]</td><td>0.378</td></tr><tr><td>Fruits (g/day)</td><td>112.49 [60.45–182.71]</td><td>80.82 [37.03–167.11]</td><td>60.81 [10.39–140.99]</td><td>&lt;0.001</td></tr><tr><td>Vegetables (g/day)</td><td>94.41 [59.65–154.12]</td><td>99.54 [58.96–157.83]</td><td>75.66 [34.89–154.08]</td><td>0.015</td></tr><tr><td>Protein (g/day)</td><td>36.07 [32.18–40.29]</td><td>38.16 [33.76–42.79]</td><td>38.81 [32.82–44.33]</td><td>0.008</td></tr><tr><td>Carbohydrate (g/day)</td><td>112.89 [98.45–127.06]</td><td>114.01 [99.14–128.64]</td><td>116.14 [100.41–138.29]</td><td>0.107</td></tr><tr><td>Fat (g/day)</td><td>44.49 [38.33–50.78]</td><td>43.17 [36.52–49.65]</td><td>41.05 [33.35–48.49]</td><td>0.002</td></tr><tr><td>Saturated fat (g/day)</td><td>17.38 [14.59–20.90]</td><td>17.36 [13.87–21.11]</td><td>17.12 [13.34–22.64]</td><td>0.848</td></tr><tr><td>Monounsaturated fat (g/day)</td><td>14.92 [13.11–17.75]</td><td>14.75 [12.36–17.05]</td><td>13.59 [10.59–15.70]</td><td>&lt;0.001</td></tr><tr><td>Trans-fat (g/day)</td><td>0.68 [0.42–1.07]</td><td>0.68 [0.29–1.24]</td><td>0.57 [0.16–1.13]</td><td>0.103</td></tr><tr><td>Polyunsaturated fat (g/day)</td><td>7.36 [5.70–9.64]</td><td>6.95 [5.01–9.33]</td><td>5.25 [3.99–7.20]</td><td>&lt;0.001</td></tr><tr><td>N-3 PUFA (g/day)</td><td>0.62 [0.47–0.87]</td><td>0.53 [0.37–0.67]</td><td>0.42 [0.32–0.55]</td><td>&lt;0.001</td></tr><tr><td>N-6 PUFA (g/day)</td><td>6.09 [4.58–7.80]</td><td>5.34 [3.74–7.48]</td><td>4.40 [3.05–6.68]</td><td>&lt;0.001</td></tr><tr><td>Fiber (g/day)</td><td>10.13 [8.11–11.93]</td><td>9.17 [7.45–11.15]</td><td>7.91 [6.54–9.83]</td><td>&lt;0.001</td></tr><tr><td>Cholesterol (mg/day)</td><td>160.56 [125.67–201.19]</td><td>168.32 [131.85–205.83]</td><td>177.07 [133.76–229.00]</td><td>0.064</td></tr><tr><td>Micronutrients<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Vitamin B1 (mg/day)</td><td>0.58 [0.51–0.67]</td><td>0.57 [0.50–0.67]</td><td>0.55 [0.47–0.65]</td><td>0.039</td></tr><tr><td>Vitamin B2 (mg/day)</td><td>0.86 [0.75–1.08]</td><td>0.92 [0.76–1.11]</td><td>0.92 [0.77–1.11]</td><td>0.177</td></tr><tr><td>Vitamin B3 (mg/day)</td><td>7.74 [6.49–9.76]</td><td>8.18 [6.22–10.21]</td><td>7.22 [5.93–9.90]</td><td>0.122</td></tr><tr><td>Vitamin B5 (mg/day)</td><td>2.53 [2.21–2.98]</td><td>2.62 [2.30–3.01]</td><td>2.67 [2.26–3.20]</td><td>0.197</td></tr><tr><td>Vitamin B6 (mg/day)</td><td>0.77 [0.69–0.92]</td><td>0.76 [0.65–0.88]</td><td>0.75 [0.61–0.89]</td><td>0.123</td></tr><tr><td>Vitamin B9 (µg/day)</td><td>173.36 [145.11–207.49]</td><td>160.80 [135.03–190.56]</td><td>144.92 [119.27–178.63]</td><td>&lt;0.001</td></tr><tr><td>Vitamin B12 (µg/day)</td><td>2.79 [1.90–4.56]</td><td>2.67 [1.82–3.94]</td><td>2.63 [1.68–4.01]</td><td>0.212</td></tr><tr><td>Vitamin D (µg/day)</td><td>1.28 [1.01–1.64]</td><td>1.18 [0.95–1.54]</td><td>1.20 [0.84–1.62]</td><td>0.131</td></tr><tr><td>Vitamin C (mg/day)</td><td>68.87 [49.11–98.06]</td><td>57.88 [36.35–86.17]</td><td>40.46 [24.46–59.42]</td><td>&lt;0.001</td></tr><tr><td>Vitamin A (µg/day)</td><td>438.83 [273.77–693.85]</td><td>386.45 [227.96–628.96]</td><td>349.49 [227.13–624.68]</td><td>0.043</td></tr><tr><td>Vitamin E (mg/day)</td><td>6.83 [5.39–9.50]</td><td>6.08 [4.40–8.09]</td><td>4.58 [3.33–6.28]</td><td>&lt;0.001</td></tr><tr><td>Calcium (mg/day)</td><td>408.21 [330.05–487.66]</td><td>420.91 [351.60–512.72]</td><td>419.59 [315.48–533.85]</td><td>0.464</td></tr><tr><td>Copper (mg/day)</td><td>0.78 [0.66–0.94]</td><td>0.75 [0.63–0.96]</td><td>0.68 [0.60–0.93]</td><td>0.008</td></tr><tr><td>Iron (mg/day)</td><td>6.18 [5.28–7.62]</td><td>6.48 [5.16–7.70]</td><td>6.10 [5.02–8.32]</td><td>0.880</td></tr><tr><td>Selenium (mg/day)</td><td>24.31 [21.18–29.28]</td><td>24.93 [21.55–29.39]</td><td>26.02 [21.34–32.29]</td><td>0.080</td></tr><tr><td>Magnesium (mg/day)</td><td>134.21 [120.38–156.74]</td><td>138.29 [121.45–160.77]</td><td>134.42 [113.96–157.73]</td><td>0.287</td></tr><tr><td>Manganese (mg/day)</td><td>2.49 [1.94–3.18]</td><td>2.15 [1.65–2.81]</td><td>2.08 [1.53–2.71]</td><td>&lt;0.001</td></tr><tr><td>Sodium (mg/day)</td><td>1122.82 [959.00–1283.16]</td><td>1180.57 [1033.92–1416.90]</td><td>1259.39 [1087.81–1506.79]</td><td>&lt;0.001</td></tr><tr><td>Phosphorus (mg/day)</td><td>567.98 [506.81–637.36]</td><td>589.84 [528.01–666.90]</td><td>598.34 [512.08–701.74]</td><td>0.037</td></tr><tr><td>Potassium (mg/day)</td><td>1567.44 [1349.45–1875.31]</td><td>1564.23 [1309.20–1876.24]</td><td>1430.34 [1189.55–1796.50]</td><td>0.003</td></tr><tr><td>Iodine (mg/day)</td><td>56.00 [47.72–67.90]</td><td>59.20 [48.30–69.92]</td><td>59.14 [49.01–74.47]</td><td>0.145</td></tr><tr><td>Zinc (mg/day)</td><td>4.33 [3.72–4.85]</td><td>4.48 [4.03–5.19]</td><td>4.51 [3.89–5.48]</td><td>0.009</td></tr><tr><td>Total flavonoids (mg/day)</td><td>118.20 [68.07–210.02]</td><td>101.55 [40.37–222.54]</td><td>69.61 [15.30–224.51]</td><td>0.002</td></tr><tr><td>Flavanol (mg/day)</td><td>76.98 [39.81–137.92]</td><td>68.15 [21.93–157.84]</td><td>41.10 [7.55–144.24]</td><td>0.002</td></tr><tr><td>Flavone (mg/day)</td><td>0.00 [0.00–0.07]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.003</td></tr><tr><td>(mean ± SD)</td><td>0.94 ± 5.90</td><td>0.35 ± 2.71</td><td>0.32 ± 3.07</td><td>0.257</td></tr><tr><td>Flavonol (mg/day)</td><td>15.22 [7.66–31.57]</td><td>8.37 [3.98–20.36]</td><td>5.51 [1.74–11.66]</td><td>&lt;0.001</td></tr><tr><td>Flavanone (mg/day)</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.612</td></tr><tr><td>(mean ± SD)</td><td>0.12 ± 1.13</td><td>0.04 ± 0.25</td><td>0.78 ± 6.00</td><td>0.079</td></tr><tr><td>Isoflavone (mg/day)</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>0.00 [0.00–0.00]</td><td>&lt;0.001</td></tr><tr><td>(mean ± SD)</td><td>0.41 ± 1.28</td><td>0.85 ± 4.46</td><td>0.12 ± 1.09</td><td>0.028</td></tr><tr><td>Anthocyanide (mg/day)</td><td>6.49 [2.26–14.33]</td><td>4.28 [0.61–14.61]</td><td>2.03 [0.00–12.57]</td><td>&lt;0.001</td></tr></tbody></table>

a Values are presented as medians [IQR] (or mean ± SD for some food groups with a particular distribution).

b P-values were derived from the Kruskal–Wallis test (or Anova tests).

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