Literature search and study characteristics
A total of 3221 published studies were identified as potentially relevant from the databases searched. After removing animal studies, reviews, and nontopic studies, 1311 studies were retrieved for evaluation. After case reports, comments, non-English written articles, duplicates, and irrelevant resources were further removed, 131 studies remained for detailed evaluation. After excluding the studies which did not provide enough information of OR/HR/HRR, and those which without full text, 26 studies were included for systematic review and meta-analysis [21, 24-48] (Figure 1). Among these selected studies, some included two or more types of the following cancers: gastrointestinal (n = 15), cholangiocarcinoma (n = 7), breast (n = 4), gastric (n = 3), pancreatic (n = 3), prostate (n = 3), and esophageal (n = 2).
Association between NAFLD and gastrointestinal cancer
Fifteen of our selected studies evaluated relationships between NAFLD and risk of gastrointestinal cancers (e.g., colorectal cancer and colorectal adenoma) (Table 1). Among these studies, 7 were conducted in South Korea, 5 were conducted in China, 1 was conducted in Austria, 1 was conducted in Japan, and 1 was conducted in the USA. All of these studies were observational and included 6 cohort studies and 9 cross-sectional studies. According to NOS scores, 11 were high quality and 4 were fair quality (Table 2).
To investigate the association between NAFLD and the risk of colorectal cancer, pooled OR of colorectal cancer from ten studies was analyzed [21, 24-32]. A meta-analysis was conducted with the random-effect model (P < 0.01, I2 = 83.5%). The results indicated that patients with NAFLD have a significant risk of developing colorectal cancer (OR = 1.72, 95% CI: 1.40–2.11) (Figure 2A). Publication bias was also tested by using Begg’s test. The results suggested that an obvious publication bias exists among these studies (P < 0.01) (Figure 4A). Furthermore, the results of a subgroup analysis showed that the pooled OR of colorectal cancer in the cross-sectional studies [25, 26, 28, 30, 31] was 1.93 (95% CI: 1.48–2.53), and in the cohort studies [21, 24, 27, 29, 32] it was 1.52 (95% CI: 1.18–1.95) (Table 1, Figure 2A).
To investigate the association of NAFLD and the risk of colorectal adenoma, pooled OR of colorectal adenomas from nine studies was analyzed [28-31, 32-36, 47]. A meta-analysis was conducted with the random-effect effect model (P = 0.045, I2 = 49.4%). The results indicated a significant developmental risk of colorectal adenoma in patients with NAFLD (OR = 1.38, 95% CI: 1.22–1.56) (Figure 2B). When publication bias was tested, Begg’s test indicated no obvious publication bias (P = 0.754) (Figure 4B). Furthermore, the results of subgroup analysis showed that the pooled OR of colorectal adenoma in the cross-sectional studies [28, 30, 31, 34-36, 47] was 1.35 (95% CI: 1.17–1.55), and in the cohort studies [29, 33] it was 1.55 (95% CI: 1.18–2.03) (Table 1, Figure 2B). These results suggest that patients with NAFLD have a higher risk of developing colorectal cancer and colorectal adenoma than patients without NAFLD.
Association between NAFLD and cholangiocarcinoma
In this systematic review and meta-analysis, seven studies were included to evaluate relationships between NAFLD and the risk of cholangiocarcinomas [including intrahepatic and extrahepatic cholangiocarcinomas (ICC and ECC, respectively)] [37-43]. Three of these studies were conducted in the United States, 1 was conducted in Europe, 1 was conducted in China, 1 was conducted in Japan, and 1 was conducted in South Korea. All of these studies were cross-sectional studies. In addition, patients in four studies were from the community, while three studies were from hospital. According to NOS scores, 4 studies were high quality and 3 studies were fair quality (Table 3).
To investigate the association of NAFLD and the risk of ICC, pooled OR of ICC from six studies was analyzed [37-39, 41-43]. A meta-analysis was conducted with the random-effects model (P = 0.003, I2 = 72.60%). The results showed a significant risk of developing ICC in patients with NAFLD (OR = 2.46, 95% CI: 1.77–3.44) (Figure 3A). In addition, according to Begg’s test, no obvious publication bias was observed among these studies (P = 0.501) (Table 1, Figure 4C). To investigate the association of NAFLD and the risk of ECC, pooled OR of ECC from four studies was analyzed [37, 40, 41, 43]. A meta-analysis was conducted with the random-effect model (P = 0.024, I2 = 68.04%). The results showed that the risk of developing ECC was significantly higher in patients with NAFLD (OR = 2.24, 95% CI: 1.58–3.17) than in patients without NAFLD (Table 1, Figure 3B). These results suggest that NAFLD may increase the risk of developing ICC and ECC.
Association between NAFLD and breast cancer
In this systematic review and meta-analysis, four studies were included to evaluate the relationship between NAFLD and the risk of developing breast cancer [21, 24, 44, 45]. Among these studies, 2 were conducted in the United States, 1 was conducted in Korea, and 1 was conducted in Israel. Three of the studies were cohort studies, while the remaining study was a case-control study. NOS scores indicated that all four studies were high quality (Table 3). Based on the data in Table 1 and in Supplementary Figure 1, the pooled OR of breast cancer in patients with NAFLD was 1.69 (95% CI: 1.44–1.99), which suggests that patients with NAFLD are more susceptible to breast cancer.
Associations between NAFLD and other cancers
Three of the included studies evaluated the association between NAFLD and the risk of developing gastric cancer [21, 24, 27] (Supplementary Table 1). According to NOS scores, all three of these cohort studies were of high quality. The pooled OR of gastric cancer was 1.74 (95% CI: 1.03–2.95) (Table 1), which suggests that patients with NAFLD have a high risk of developing gastric cancer. Similarly, to investigate a possible association between NAFLD and the risk of developing pancreatic cancer, three studies were included [21, 24, 46] (Supplementary Table 1). All three cohort studies were of high quality according to their NOS scores. The pooled OR of pancreatic cancer was 2.12 (95% CI: 1.58–2.83) (Table 1), which suggests that patients with NAFLD have a high risk of developing pancreatic cancer. In addition, it was observed that patients with NAFLD have a high risk of developing prostate cancer (OR = 1.36, 95% CI: 1.03–1.79) (Tables 1 and Supplementary Table 1). Furthermore, two of the studies reported an association between NAFLD and a risk of developing esophageal cancer [21, 24], with the OR value of esophageal cancer being 1.77 (95% CI: 1.19–2.62) (Tables 1 and Supplementary Table 1).