Background
Toxoplasma gondii (T. gondii) infection is a major global public health problem. Approximately 30% of the world’s population show serological evidence of infection [
1]. Although most infections are subclinical and benign, some may cause severe consequences, including lymphadenopathy, hepatitis, ophthalmitis, schizophrenia and other important organ dysfunction [
2,
3]. When the liver is involved,
T. gondii infection can present with hepatomegaly, liver inflammation, liver granuloma formation and cirrhosis [
4,
5]. Several studies demonstrated a higher seroprevalence of
T. gondii antibody in patients with liver cancer, cirrhosis, acute and chronic hepatitis [
4‐
8].
Non-alcoholic fatty liver disease (NAFLD) is a disease with an excessive accumulation of fat in the liver, with different complications including inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. It is the most common chronic liver disease with a global prevalence of 30% [
9]. A recent study demonstrated that mice infected with
T. gondii had significant inflammation and steatosis in the liver [
10]. Epidemiological data from eastern China showed that the prevalence rate of
T. gondii was higher in people with liver steatosis (22.75%) compared to controls (13.86%) [
7]. Up to now, this has been the only clinical research looking into the relationship between
T. gondii infection and NAFLD. However, the data was from eastern China and the sample size was relatively small and poorly representative. It is important to explore this relationship further in a different population with a larger sample size. Determining this association between
T. gondii and NAFLD may contribute towards the further understanding and control of both diseases. This study analyzes the relationship between
T. gondii infection and incidence of NAFLD on a population-based dataset from the United States.
Discussion
The infection rate of
T. gondii still remains greater than 10% in the United States even though there has been a slightly decline in seroprevalence of
T. gondii from 13.2% in 2009–2010 [
18] to 11.14% in 2011–2014 [
19]. On the other hand, the prevalence of NAFLD is as high as 30% in the same population [
20,
21]. Our study showed a higher incidence of NAFLD in the
T. gondii seropositive group than in the seronegative group (27.10% vs 23.40%,
p < 0.001). However, multivariate regression indicated that infection might not be an independent risk for NAFLD.
Evidence from basic and clinical studies indicated the
T. gondii infection might be responsible for liver steatosis [
7,
8]. A significant change in pathology has been found in mice infected with
T. gondii, including inflammatory cell infiltration, hepatocyte necrosis and hepatosteatosis [
10]. Further transcriptomic analysis of
T. gondii infected mice showed downregulation of peroxisome proliferator-activated receptors signaling pathway in the liver [
10], which has long been proven to play key roles in regulating host bile biosynthesis, fatty acid metabolism, lipid metabolism and energy metabolism [
22]. Besides the direct influence in the liver,
T. gondii infection may play a role in diabetes mellitus, which is a well-known risk factor of NAFLD [
23‐
25].
T. gondii infected mice had a significant reduction of pancreatic islet cells, as well as an apparent decrease in insulin expression [
23]. The results from this study also demonstrated higher BMI, cholesterol, triglyceride, uric acid and FBG levels in
T. gondii seropositive group, also suggesting an effect of
T. gondii infection on metabolism. All these mechanisms might contribute to the higher NAFLD levels seen in the
T. gondii antibody seropositive population.
However, in multivariate analysis,
T. gondii infection was not an independent factor for NAFLD. Unmeasured confounders may explain the association between NAFLD and
T. gondii. Although basic and clinical studies had shown an increased risk of NAFLD in
T. gondii infected patients, the results of this study found that, rather than
T. gondii infection, only age, gender, BMI, uric acid, fasting blood-glucose and serum lipid levels were independent risk factors for the presence of NAFLD. This might be because
T. gondii infection alone is a confounder which is associated with other NAFLD-related variables, such as obesity, diabetes or hyperlipidemia [
25‐
27]. The prevalence of
T. gondii rises with age [
18,
19]. As shown in Fig.
1c, the incidence of NAFLD also increases with age, regardless of the presence of
T. gondii antibody. It is possible that the positive correlation between NAFLD and
T. gondii is indirect, and that age plays a key role in it. These questions require further exploration through basic research.
However, the direction of the causal relationship between NAFLD and T. gondii infection might be opposite. Based on this cross-sectional study, we could not rule out the possibility that NAFLD might increase the risk of
T. gondii infection. Patients with chronic liver diseases, including NAFLD, are susceptible to various pathogens infection [
8]. Those patients have a depressed immune response in both cell-mediated and humoral immunity [
20]. As a result, they might have a remarkably declined ability to protect the hosts against T. gondii infection. Several researches have shown a higher seroprevalence of
T. gondii in patients with chronic liver diseases than those without in China and Egypt [
7,
8]. In this study, the NAFLD patients also have an increasing
T. gondii seropositive rate(29.6% vs. 25.7%,
p < 0.001, data not shown). Those studies, including the present one, suggest the possibility that NAFLD is a risk factor for
T. gondii infection cannot be excluded. However, a small-sized study from Mexico including 75 adults with liver disease (approximately 50% were alcoholic liver diseases) and 150 controls failed to demonstrate a relationship between seroprevalence of anti-
T. gondii antibodies and liver disease [
28]. Therefore, the complex relationship between
T. gondii and NAFLD requires further research.
The limitation of this study was that data were collected from 1988 to 1994 when the prevalence of T. gondii was different from recent years. However, as far as we know, it was the largest population-based investigation containing datasets of both NAFLD and anti- T. gondii antibodies. Nevertheless, our results clarify the relationship between T. gondii infection and NAFLD to some extent and offer interesting and useful evidence to further the understanding of both diseases.
Acknowledgments
We thank Yulan Lin, MD, Ph.D., senior statistician, from School of Public Health, Fujian Medical University, China, for thoroughly reviewing our study methods and statistical analysis.