Some 8415 patients with NAFLD and 70 934 controls were included (Figure 1). At baseline, study participants had a median age of 53 years and 56% were men. In patients with NAFLD, baseline comorbidities were more common than in controls (Table 1). A majority (66.1%) of patients with NAFLD were diagnosed between 2010 and 2016. Of patients with NAFLD, 183 (2.2%) had cirrhosis at baseline. Detailed baseline characteristics are presented in Table 1. The median follow-up was 6.0 years (IQR 2.5–11.2 years).
We identified 527 (6.3%) cancer cases in patients with NAFLD and 4716 (6.6%) in controls. The IR per 1000 person-years was 9.7 (95% CI = 8.9–10.6) in NAFLD compared to 8.6 (95% CI = 8.3–8.9) in controls, corresponding to an adjusted HR (aHR) of 1.22 (95% CI = 1.11–1.33). For HCC, we found 47 (0.5%) cases in patients with NAFLD and 34 (0.05%) in controls. The aHR for HCC in patients with NAFLD compared to controls was 12.2 (95% CI = 7.1–20.8). Results for all secondary outcomes are summarized in Table 2.
The analysis of cancer risk in patients with NAFLD without cirrhosis at baseline yielded similar results to the main analysis (Table S1). Because only nine cancer cases occurred in patients with NAFLD and cirrhosis at baseline, no analysis was performed separately for this group.
In the analysis, in which individuals whose first diagnosis of cancer was HCC were excluded, we found 483 (5.7%) cases of any non-HCC cancer in patients with NAFLD and 4688 (6.6%) in controls. The IR per 1000 person-years was 9.0 (95% CI = 8.2–9.8) in patients with NAFLD and 8.6 (8.3–8.8) in controls, with an aHR of 1.15 (95% CI = 1.05–1.26).
The sensitivity analysis of the risk of HCC in patients with NAFLD but without baseline cirrhosis (patients with NAFLD who developed cirrhosis during follow-up [n = 10] were excluded) yielded similar results to the main analysis (aHR = 8.33, 95% CI = 4.70–14.75).
In the sex-stratified analysis, we found 265 cases (5.8%) of any cancer in males with NAFLD compared to 2568 cases (6.5%) in controls. The IR per 1000 person-years was 8.5 (95% CI = 7.6.0–9.6) in men with NAFLD compared to 8.1 (95% CI = 7.8–8.5) in controls. The aHR was 1.18 (95% CI = 1.04–1.34). In women with NAFLD, we found 262 cases (6.8%) of cancer compared to 2148 cases (6.9%) in controls. The IR per 1000 person-years was 11.2 (95% CI = 10.0–12.7) in women with NAFLD compared to 9.3 (95% CI = 8.9–9.7) in controls. The aHR was 1.26 (95% CI = 1.11–1.43). An association between NAFLD and the risk of HCC, kidney and bladder cancer was found in males and females. In contrast, an association between NAFLD and risk of colorectal cancer was found in males (aHR = 1.54, 95% CI = 1.13–2.09) but not in females (aHR = 1.21, 95% CI = 0.84–1.73). No association was observed between NAFLD and the risk of other secondary outcomes in males or females. Table 3 presents data on sex-stratified cancer risk estimates.
In the competing risk regression, NAFLD was independently associated with an increased risk of any cancer (subdistribution HR [sHR] = 1.10, 95% CI = 1.02–1.20, p = .02). Figure 2 shows the cumulative incidence for any cancer in NAFLD and controls. Moreover, NAFLD was independently associated (sHR = 8.16, 95% CI 5.68–11.75, p < .01) with the risk of HCC and death from HCC, accounting for death from other causes as the competing risk. Table S2 shows unadjusted and adjusted sHRs. Figure 3 displays the cumulative incidence for HCC in patients with NAFLD and controls. In Table 4, cumulative incidence for all cancer and death by any cancer at 5, 10 and 15 years of follow-up is shown.
Cumulative incidence of all cancers in patients with NAFLD and reference individuals. Adjusted for baseline diabetes, hypertension, hyperlipidaemia and chronic obstructive pulmonary disease
Liver International. 2022;42(4):350-362. © 2022 Blackwell Publishing