Fatty liver disease (FLD) is the most prevalent form of liver disease worldwide.^(1,2) Overnutrition and excessive alcohol consumption are 2 major causes of FLD.⁽³⁾ Overnutrition can induce nonalcoholic fatty liver disease (NAFLD), a spectrum of conditions raging from simple steatosis [or nonalcoholic fatty liver (NAFL)] to nonalcoholic steatohepatitis and cirrhosis.^(1,4) NAFLD is considered the hepatic manifestation of the metabolic syndrome,^(5,6) and many studies have revealed strong relationships between NAFLD and hypertension (HT), type 2 diabetes mellitus (DM), and dyslipidemia (DL).⁽⁷⁾ In contrast, excessive alcohol consumption can lead to alcoholic liver disease (ALD), which includes simple steatosis [or alcoholic fatty liver (AFL)], alcoholic hepatitis, hepatic fibrosis, and cirrhosis.⁽²⁾ Less data are available on the relationship between ALD and HT, DM, and DL than that between NAFLD and such diseases. However, accumulating evidence indicates a positive relationship between excessive alcohol consumption and HT, DM, and DL.^(8–11) These findings indicate that ALD may also be closely linked to these diseases.

In the comprehensive management of FLD, it is important to understand the relationships between FLD and HT, DM, and DL in detail. To the best of our knowledge, no study has analyzed these relationships according to the FLD type. The goal of the present study was to compare AFL and NAFL, the most common FLD types, using data from a nationwide Japanese survey on FLD.

Answers to the questionnaire were obtained from 101 (11.3%) of the 894 institutions and data on FLD were obtained from 66 hospitals (7.4%). The numbers of patients with FLDs were as follows: AFL, 71; NAFL, 131; nonalcoholic steatohepatitis, 494. Of the 202 subjects with AFL or NAFL, 6 with AFL and 5 with NAFL were excluded because of a lack of anthropometric data or information on the presence/absence of HT, DM, and DL. Thus, this study was conducted using data for 191 subjects (65, AFL; 126, NAFL).

Table 1 shows the baseline characteristics of the subjects. The female-to-male ratio, BMI, and diastolic blood pressure were lower in subjects with AFL than in those with NAFL. Laboratory tests revealed that levels of serum AST, γ-GTP, and fasting blood glucose were higher in subjects with AFL than in those with NAFL, whereas levels of serum total cholesterol and LDL cholesterol were lower in subjects with AFL than in those with NAFL. There were no significant differences in prevalence of HT, DM, DL, HT + DM, HT + DL, DM + DL, HT + DM + DL, and any combination of ≥2 of the 3 diseases between subject groups.

Table 2 lists factors associated with HT, DM, or DL for the entire cohort. Regarding FLD types, AFL was an associated factor for HT whereas NAFL was one for DL. Age ≥55 years was identified as a significant factor for HT, DM, and all combinations of the diseases. BMI ≥25 kg/m² was significantly associated with HT and HT + DL. Serum γ-GTP ≥75 IU/L was another factor associated with DL.

Stratified analysis was performed with regard to the 3 associated factors (AFL, age ≥55 years, and BMI ≥25 kg/m²) for HT. First, the entire cohort was divided into 2 subgroups according to age (≥55 years, <55 years), and stratified analysis by FLD type and BMI was performed. Among subjects aged ≥55 years (n = 94), the prevalence of HT was the highest in subjects with AFL + BMI ≥25 kg/m² (Fig. 1A). After adjusting for other variables, AFL + BMI ≥25 kg/m² showed significantly higher odds ratio (OR) for HT compared with NAFL + BMI <25 kg/m² (Table 3). In interaction analysis between AFL and BMI ≥25 kg/m², AP (0.68, 95% CI, 0.19–1.17) was significant, whereas RERI and S were not. Among subjects aged <55 years (n = 97), the prevalence of HT was the highest in subjects with AFL + BMI <25 kg/m² (Fig. 1B). There were no significant differences between the relationship of each stratified group with HT (Table 3); moreover, neither RERI, AP, nor S was significant as per the interaction analysis.

We next divided the entire cohort into 2 subgroups according to BMI (≥25 kg/m², <25 kg/m²), and performed stratified analysis by FLD type and age. Among subjects with BMI ≥25 kg/m² (n = 93), the prevalence of HT was the highest in subjects with AFL + age ≥55 years (Fig. 2A). After adjusting for other variables, AFL + age ≥55 years and NAFL + age ≥55 years showed significantly higher ORs for HT compared with NAFL + age <55 years (Table 4). Regarding interaction analysis between AFL and age ≥55 years, AP (0.71, 95% CI, 0.24–1.18) was significant, whereas RERI and S were not. Among subjects with BMI <25 kg/m² (n = 98), the prevalence of HT was the highest in subjects with AFL + age ≥55 years (Fig. 2B). After adjustment for other variables, AFL + age ≥55 years and NAFL + age ≥55 years showed significantly higher ORs for HT compared with NAFL + age <55 years (Table 4). Neither RERI, AP, nor S was significant as per the interaction analysis.

The subjects were divided according to the FLD type and serum γ-GTP levels. The prevalence of DL was the highest in subjects with NAFL + γ-GTP ≥75 IU/L (Fig. 3). After adjusting for other variables, NAFL + γ-GTP ≥75 IU/L showed significantly higher ORs for DL than AFL + γ-GTP <75 IU/L (Table 5). A significant interaction between NAFL and γ-GTP ≥75 IU/L was not detected.

To the best of our knowledge, this is the first study to analyze the relationships between FLD and HT, DM, and DL according to the FLD type. Our results show that the FLD type influences the relationship between FLD and HT or DL. Thus, AFL was more strongly associated with HT than NAFL and NAFL was more strongly associated with DL than AFL. In contrast, the relationship between FLD and DM or the combinations of HT, DM, and DL were found not to be influenced by the FLD type.

Intensive studies have established excessive alcohol consumption as a risk factor for HT.⁽⁹⁾ Because hepatic steatosis occurs in almost all subjects who consume alcohol excessively,⁽²³⁾ the close relationship between AFL and HT was expected. However, a full understanding of the influence of the FLD type on the relationship between FLD and HT is still lacking. Studies have revealed various mechanisms by which excessive alcohol consumption induces HT, including increased sympathetic nervous system activity and stimulation of the renin–angiotensin–aldosterone system.⁽⁹⁾ These mechanisms also have been reported to be involved in the metabolic syndrome, which is usually accompanied by NAFLD.^(24,25) Insulin resistance, a key factor in the development of the metabolic syndrome,⁽²⁶⁾ is another mechanism in the pathogenesis of HT.⁽²⁷⁾ Recent studies have found that excessive alcohol consumption does not significantly increase insulin resistance.⁽²⁸⁾ Nevertheless, our study demonstrates that AFL is the FLD type more closely linked to HT. Potential differences in mechanisms of HT between the FLD types might influence planning therapeutic strategies for HT in subjects with such FLD types.

This study identified obesity and older age as other associated factors for HT. These factors are established risk factors for HT.^(29,30) In stratified analysis, the combination of AFL and obesity in older subjects and that of AFL and older age in both obese and nonobese subjects showed a significant increase in the ORs for HT. In interaction analysis, the results differed according to the indices for biological interaction. According to the interaction analysis for AFL and obesity in older subjects, AP was significant, whereas RERI and S were not. The relationship between AFL and older age in obese subjects followed this same pattern. However, a study on interaction analysis published in 2006 demonstrates that AP is the most robust measure in a logistic regression model.⁽³¹⁾ Hence our results could indicate that AFL, obesity, and older age interact to influence hypertension status.

Cross-sectional studies have suggested an interactive influence of excessive alcohol consumption and obesity on HT.^(32,33) Moreover, in overweight men, combined intervention involving restricted alcohol and food consumption leads to decreases in blood pressure more effectively than either intervention alone.⁽³⁴⁾ We were unable to find any published studies examining the interaction between excessive alcohol consumption and older age in relation to HT. On the basis of the theory of biological interaction,⁽³⁵⁾ the interactions found in our present study may indicate the presence of at least a pathway toward HT in which AFL, obesity, and older age, are all involved. However, future prospective studies will be necessary to confirm these interactions.

We show here that NAFL and increased serum γ-GTP levels are associated factors for DL, and their combination is most strongly associated with DL. We could not confirm the DL types with which these factors were associated because we did not collect the relevant information. Generally, baseline serum LDL cholesterol levels were higher in subjects with NAFL than in those with AFL, although the results were calculated using data from untreated as well as treated subjects. This finding is consistent with the results in large-scale studies investigating the influence of alcohol consumption on serum lipid levels in which serum LDL cholesterol levels were inversely correlated with alcohol consumption.^(36,37) Recent studies of subjects with DM have shown that serum γ-GTP levels are positively associated with DL.⁽³⁸⁾ Furthermore, elevation of serum γ-GTP levels has been identified as a predictor for cardiovascular diseases⁽³⁹⁾ as well as a marker of metabolic syndrome.⁽⁴⁰⁾ The complexes that form between γ-GTP forms and LDL lipoprotein facilitate the evolution of atherosclerotic plaques toward instability and rupture.⁽⁴¹⁾ Given these findings, the magnitude of risk for cardiovascular diseases in subjects with NAFL with elevated serum γ-GTP levels should be investigated.

There are some limitations to this study. First, because of its cross-sectional design, this study could not determine causality between HT, DM, and DL and associated factors. Second, the number of subjects was relatively small, constraining statistical power. Third, data on FLD were obtained from only a limited number of institutions in Japan, which might limit generalizability of the findings. Fourth, this study lacked data on smoking, a potential confounder in particular for HT.⁽⁴²⁾ Since a close link of excessive alcohol consumption to smoking has been reported,⁽⁴³⁾ it is possible that in our cohort, the proportion of smokers was higher in subjects with AFL than in those with NAFL. A large-scale study, however, has demonstrated that smoking has a smaller impact on elevation of blood pressure than excessive alcohol consumption in men, no such effect was seen in women.⁽⁴⁴⁾ Therefore, although our results should be interpreted with caution, we feel confident in concluding that they would not have changed significantly if smoking had been included as a variable.

The present study demonstrates that the relationships between FLD and HT, DM, and DL partly depend on the FLD type. We believe that these findings may be helpful in managing subjects with FLD. Future studies are needed to confirm our results and clarify mechanisms responsible for the development of HT in which AFL, obesity, and older age play a role.

This work was supported in part by a grant from the Health, Labour and Welfare Ministry of Japan and by grant SR2012-04 for research from Kanazawa Medical University, Japan. We are extremely grateful to the following institutions for providing detailed data on subjects with FLD: Sapporo Medical University Hospital, National Hospital Organization Hokkaido Cancer Center, Hokkaido P.W.F.A.C. Sapporo-Kosei General Hospital, Kushiro Rosai Hospital, Sapporo Social Insurance General Hospital, Hirosaki University School of Medicine and Hospital, Iwate Medical University Hospital, Tohoku University Hospital, Shiogama City Hospital, Yamagata University Hospital, Fukushima Medical University Hospital, Tsukuba University Hospital, Ashikaga Red Cross Hospital, Gunma University Hospital, Maebashi Red Cross Hospital, National Hospital Organization Takasaki General Medical Center, National Defense Medical College Hospital, Saitama Medical University Hospital, Dokkyo Medical University Koshigaya Hospital, Chiba University Hospital, Teikyo University Hospital, Tokyo Women’s Medical University Hospital, Toho University Omori Medical Center, Toshiba General Hospital, Toho University Ohashi Medical Center, Showa University Fujigaoka Hospital, St. Marianna University School of Medicine Hospital, Tokai University Hospital, Nippon Medical University Musashi Kosugi Hospital, Kanto Rosai Hospital, Hiratsuka City Hospital, Fujisawa Shounandai Hospital, University of Yamanashi Hospital, Shinshu University Hospital, Kanazawa University Hospital, National Hospital Organization Kanazawa Medical Center, Ishikawa-ken Saiseikai Kanazawa Hospital, University of Fukui Hospital, Iwata City Hospital, Aichi Medical University Hospital, Mie University Hospital, Shiga University of Medical Science Hospital, Fukuchiyama City Hospital, Kyoto Prefectural Yosanoumi Hospital, Osaka University Hospital, Osaka City University Hospital, Kansai Medical University Takii Hospital, Hyogo-Chuo National Hospital, Yamato Takada Municipal Hospital, Nara Prefectural Gojo Hospital, Okayama Saiseikai General Hospital, Hiroshima University Hospital, Tsuchiya General Hospital, Shakaihoken Shimonoseki Kosei Hospital, Ehime University Hospital, Matsuyama Shimin Hospital, Kochi Medical School Hospital, Kurume University Hospital, Asakura Medical Association Hospital, Saiseikai Futsukaichi Hospital, Nagasaki University Hospital, Nagasaki Municipal Hospital, Oita University Hospital, Okinawa Prefectural Chubu Hospital, and Nakagami Hospital. We also thank Minemi Shibayama and Kiri Nakashima for their excellent research assistance.

We have no financial disclosure or conflict of interest to report.