Gender differences in the prevalence of nonalcoholic fatty liver disease in the Northeast of Thailand: A population-based cross-sectional study

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and a major public health problem worldwide¹. Its prevalence is increasing globally, and is currently estimated to be as high as 17–45% of the general population in Western countries², while among Asian populations it is reported to be between 15 and 20%³. A progressive form of NAFLD called nonalcoholic steatohepatitis (NASH) can further progress to liver cirrhosis and hepatocellular carcinoma (HCC)⁴. Recent studies have found that HCC may complicate non-cirrhotic NAFLD with or without fibrosis⁵. In addition, NASH patients run an increased risk of cardiovascular mortality as a result of the metabolic risk factors that are common to both NAFLD and cardiovascular disease⁶.

Major risk factors of NAFLD include a sedentary lifestyle and diet with poor nutrition^2,4,7. Other factors that influence the development of NAFLD include age, being a man between the ages of 40–65 years and Hispanic ethnicity^1,8–11. In addition, insulin resistance (IR), metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are considered to increase the risk of NAFLD². NAFLD is closely associated with T2DM, and therefore T2DM is used as a determinant for the presence and severity of NAFLD^12,13. Various studies have demonstrated that NAFLD is more prevalent in men, elderly populations, and post-menopausal women¹⁴.

Gender differences as a risk factor for NAFLD still need to be fully understood. There is controversy regarding gender and NAFLD; some studies claim that various gender-specific mechanisms, such as the effect of sex hormones and differences in lifestyles and physiology, have an influence on the prevalence of NAFLD¹⁵. In addition, a number of studies report NAFLD as being more frequently detected in men than women^{8,10,14,16,17}. However, there are also some studies, both from Western and Asian populations, that suggest that the disease is generally more common in women^9,11,18.

Understanding the association between gender differences and NAFLD will allow us to target specific groups to improve health promotion and disease prevention activity, as well as provide proper treatment strategies in order to reduce the rates of morbidity and mortality associated with NAFLD and its associated pathologies. Therefore, this study investigated the gender differences in the prevalence of NAFLD from the general population of Northeast Thailand.

Methods

This was a population-based cross-sectional study that retrieved the data from the baseline survey of an ongoing cohort research project called the Cholangiocarcinoma Screening and Care Program (CASCAP, www.cascap.in.th)¹⁹. All participants of CASCAP were enrolled between March 2013 and September 2015 were included into the study. In accordance with the CASCAP protocol, participants gave written informed consent and completed a baseline survey form. The standardized form included socio-demographic information including gender, behavioral factors, such as smoking status and alcohol consumption, and previous or current illnesses. After completion of the baseline survey, participants underwent hepatobiliary ultrasonography (US) performed by board-certified radiologists, who provided the participants with information on NAFLD. For the purpose of this study, subjects with alcohol consumption or those with incomplete information of US findings were excluded.

The primary outcome was the ultrasonographic diagnosis of NAFLD based on the presence of a diffuse increase of fine echoes in the liver parenchyma compared to the kidney or spleen parenchyma²⁰. This was performed after excluding other causes of liver disease, such as viral hepatitis B or C and/or a history of current or past alcohol consumption¹⁵. In addition, the protocol also classified the severity of NAFLD as follows: absent, mild, moderate or severe steatosis^20,21. Finally, the participatns were divided into those with and without NAFLD, according to the US results. Participants with absence of NAFLD were used as the comparison group for the study. The factor of interest in this study was gender.

Demographic characteristics and other information of the participants serving as covariates that could have an effect on the association between gender and NAFLD were accounted for in the statistical analysis. These included age, the presence of diabetes mellitus (DM) and other underlying diseases. Age was initially treated as a continuous variable based on the assumption of a linear relationship. For practical purposes, age was then categorized into six groups comprising: <45 years, 46–50 years, 51–55 years, 56–60 years, 61–65 years and more than 65 years. Other confounder factors included: the presence of DM and presence of other underlying diseases. These were dichotomous variables, and were also analyzed for the relationship with NAFLD.

Results

A total of 65,571 participants living in northeastern Thailand participated in CASCAP during the study period as shown in Figure 1. We excluded 30,661 participants who were known to consume alcohol, or to have viral hepatitis or alcoholism. Of the remaining participants, 201 were excluded because of incomplete data. Finally, a total of 34,709 participants were included for analysis.

Figure 1. Flow of participants in the Cholangiocarcinoma Screening and Care Program.

Baseline characteristics of the study populations are shown in Table 1. Of 34,709 participants enrolled in this study, 27,073 were women (78.0%), while 7,636 were men (22.0%). Both were predominantly middle-aged with a mean age of 55.5±38.3 years old. There were similar characteristics between men and women, except that women were older (57.8 versus 54.3 years old, and had a lower proportion of being a current smoker or previously having smoked than men (1.0% vs. 18.7%).

Of 34,709 participants who underwent US, 7,584 had NAFLD; hence, the overall prevalence was 21.9% (95% CI: 21.4 to 22.3). The prevalence of NAFLD was 22.9% in women (95% CI: 22.5 to 23.5) and 18.3% in men (95% CI: 17.4 to 19.2) (Table 2). Based on an absolute effect represented by the prevalence difference, the prevalence of NAFLD was significantly higher in women than men by 4.6% (95% CI: 3.6 to 5.6). Similarly, based on a relative effect represented by the OR, women were 1.3 times (1.3; 95% CI: 1.2 to 1.4) as likely to have NAFLD compared with men. After adjusting for effect of other covariates, the prevalence difference was 4.2% (95% CI: 3.2 to 5.2), but adjusted OR remained unchanged (1.3; 95% CI: 1.2 to 1.4).

The overall prevalence difference between gender was 4.6% (95%CI: 3.6 to 5.6), the prevalence difference in severity of ultrasonographic NAFLD with mild NAFLD was 3.8% (95%CI: 2.9 to 4.9) (Table 3). The majority of participants with NAFLD were also found to have periductal fibrosis (PDF), i.e., 1,143 with PDF out of 7,584 with NAFLD for women. After combining NAFLD with the PDF, the increased prevalence in women remained, but the gender difference was smaller (1.1%; 95% CI: 0.6 to 1.3).

Based on univariate analysis, prevalence differences stratified by age group demonstrated a noticeable pattern. That is, the difference in NAFLD prevalence tended to increase as the age increased. Moreover, while the overall prevalence difference was 4.6%, the stratified differences were 6.2% and 6.3% in the 56–60-year-old and 61–65-year-old age groups, respectively. The prevalence increased markedly in the age group up to 50 years, whereas both women and men at the age of 56–60 years have the highest prevalence of NAFLD (27.4% and 21.2%, respectively) (Figure 2). Results also showed that the prevalence of NAFLD increased from 16.8% to 21.5% in women younger than 45 versus women aged 45–50 years, and then peaked at 27.4% in women aged 55–60 years. However, the prevalence differences of NAFLD decreased slightly in the ≥65-year-old age group.

Figure 2. Prevalence differences of nonalcoholic fatty liver disease between women and men stratified by age group and underlying diseases.

Results of multivariable analysis, the prevalence difference of NAFLD between men and women stratified by age group exhibited similar patterns, but with larger differences than were found in the univariate analysis. That is, while the overall adjusted prevalence difference was 4.2%, the stratified adjusted differences were 9.4% and 8.8% in the 56–60-year-old and 61–65-year-old age groups, respectively. The largest prevalence difference was observed among participants with DM or underlying diseases (12.2%; 95% CI: 9.8 to 14.7) (Figure 3).

Figure 3. Adjusted prevalence differences of nonalcoholic fatty liver disease between women and men stratified by age group and underlying diseases.

Each was adjusted for all others.

Discussion

We investigated the inconsistencies in the literature regarding gender differences in NAFLD prevalence with a population-based study in Thailand. While many studies have indicated that NAFLD is more common in men than women^10,14,16,17, others have suggested the opposite^9,11,18. Our study supported the findings of a higher NAFLD prevalence in women, with a 4.2% (95% CI: 3.2 to 5.2) prevalence, compared with men (18.3%; 95%CI: 17.4 to 19.2), even after adjusting for the effects of other covariates. In addition, we found that these differences increased with age, where the largest difference was found in the age group 56–60 years old (prevalence difference = 9.4%; 95% CI: 7.9 to 10.9). Moreover, the largest gender difference in NAFLD prevalence was also found among DM participants (12.2%; 95% CI: 9.8 to 14.7).

This study utilized data from CASCAP, in which most female participants were over 50 years old (64.5%), with a mean age of 57.8 ±42.3 years. The largest group (35.9%) of the over-50-year group being between 51–60 years old, and most were likely post-menopausal. Although the prevalence of NAFLD tended to be higher in women for every age group, the largest difference was found among the 56–60-year-old age group. This suggests that sex hormones might play a role in NAFLD^18,22, for the younger age group. However, the current study revealed a smaller difference in NAFLD prevalence. This might be because NAFLD in men tends to occur earlier, especially in middle age (40–49 years) than in women (>50 years), which could lead to a male predominance in younger and middle-aged populations¹⁴.

The gender differences on NAFLD prevalence became more pronounced as the age of the participants increased^7,23,24. The highest NAFLD rate was found in 56–60-year-olds. This suggested a correlation between NAFLD and the various major risk factors commonly found in older people, such as MS, obesity, DM, and dyslipidemia. Moreover, older patients are more likely to have advanced fibrosis, cirrhosis, and HCC when compared with middle-aged patients⁹. Remarkably, the study found increased NAFLD prevalence in women in the transitional post-menopausal stage, especially among women aged 56–60 years. This statistic is consistent with a previous study that reported a 2 to 2.5 times higher prevalence in the 56–60-year-old age group compared with those aged less than 45 years²⁵. Our study also found that an increased prevalence of NAFLD in female participants persisted in the post-menopausal group, while the prevalence trend declined in those aged more than 65 years compared with premenopausal women.

Conclusion

NAFLD is more likely to affect women than men, in particular among the population 56–60 years of age, which is the post-menopausal transitional period. This suggests that post-menopausal women should be concerned about metabolic disorders that are exacerbated by changing hormonal status. Monitoring and prevention by dietary control, behavioral changes, and exercise may play an important role in preventing diseases, including NAFLD. We strongly recommend and encourage Thai health professionals promotion of the development of NAFLD targeted screening and prevention programs focusing on post-menopausal women and DM risk groups.

Data availability

Researchers can request the CASCAP data by applying to the CASCAP Database Committee using a Data Analysis Plan Proposal. This can be found at http://www.cascap.in.th/damus/analysis_plan.php. More information can be requested from the corresponding author (bandit@kku.ac.th) and information about research proposals can be found at https://cloud.cascap.in.th/article/research/index