Risk of Hepatic and Extrahepatic Cancer in NAFLD

A Population-based Cohort Study

Karl Björkström; Linnea Widman; Hannes Hagström


Liver International. 2022;42(4):350-362. 

In This Article


In this population-based cohort study of over 8000 patients with NAFLD and matched controls, we found an association between NAFLD and an increased risk of cancer. The increased risk of cancer was mainly attributed to HCC, but an increased risk for other cancers (colorectal cancer in men, bladder, kidney and uterine cancer) was also observed. The absolute increase in risk for non-HCC cancers was low compared to matched controls. While the proportion of patients with NAFLD who developed cancer during follow-up was similar in controls (6.3% vs. 6.6%), the incidence rate of cancer was higher in patients with NAFLD (9.7 per 1000 PYs vs. 8.6 in controls).

Most patients with NAFLD in our cohort (66.1%) were diagnosed with NAFLD during the last 7 years of the study period (2010–2016), which could be as a result of a true increase in NAFLD incidence. However, it could also be because of an increased awareness of NAFLD and improved disease awareness among healthcare professionals. We observed similar risk estimates for our outcomes after adjusting for relevant covariates (diabetes, hypertension, hyperlipidaemia and COPD), indicating that the observed associations between NAFLD and cancer are independent of these risk factors. The estimates obtained from a competing risk regression were also significant, suggesting that the observed increased risk for cancer is not solely as a result of higher mortality in patients with NAFLD compared to controls.

Kim et al. investigated the risk of cancer in 25 947 individuals (33.6% with NAFLD diagnosed by ultrasound).[7] In a univariate analysis, NAFLD was associated with an increased risk of cancer (HR 1.32). Allen et al., investigating a cohort of 4722 patients with NAFLD and 14 441 matched controls, found an increased risk of cancer (incidence rate ratio 1.9). Wang et al., in a cohort of 54 187 men (32% with NAFLD diagnosed by ultrasound), reported an increased risk of cancer in patients with NAFLD (HR 1.09 in univariate analysis).[13] Using population-based registries with a high validity for the outcomes studied, our results corroborate the above findings.

The association between NAFLD and the risk of colorectal cancer has been investigated in several studies. Most of these studies included Asian populations.[14,15,26–31] In a meta-analysis of 11 studies, Mantovani et al. reported an association between NAFLD and risk of colorectal cancer.[15] The included studies used different diagnostic modalities for NAFLD and heterogeneity between studies was rather large.[15] In the above-mentioned study by Kim et al., NAFLD was associated with an increased risk of colorectal cancer in men (HR 2.21) but not in women,[7] a finding in line with our results. In a more recent meta-analysis from 2021 by Mantovani et al., including results from eight studies including over 44 000 patients with NAFLD, an association between NAFLD and risk of colorectal cancer was also reported (HR 1.64). The included studies had significant heterogeneity (I[2] = 57.9%) and all but one study were on Asian cohorts.[12] Contrary to our study, the 2021 study by Mantovani et al. reported associations between NAFLD and risk of oesophageal (HR 1.93), stomach (HR 1.81), lung (HR 1.30) and breast cancer (HR 1.39).[12] The different ethnic constitution of our cohorts and the larger population size in the study by Mantovani et al. could explain these differences.

In a meta-analysis, Liu et al. investigated the association between NAFLD and the risk of cholangiocarcinoma, colon, breast, gastric, pancreatic, prostate and oesophageal cancer.[32] In logistic regression, NAFLD was associated with colorectal (odds ratio [OR] 1.72 [p < .01]), gastric (OR 1.74 [p = .01]) and prostate cancer (OR 1.36 [p < .01]).[32] The heterogeneity between the studies investigating colorectal, gastric and prostate cancers was significant (I 2 83.5% for colorectal, 73.6% for gastric and 81.9% for prostate cancer).

Kanwal et al. reported an increased risk of HCC (aHR 7.62 compared to patients without NAFLD) in 296 707 patients with NAFLD (diagnosed using consecutively increased alanine aminotransferase levels). These NAFLD patients had received healthcare from the Veterans Health Administration.[10] An IR of 0.08 cases of HCC per 1000 person-years in patients with NAFLD without cirrhosis was reported. In comparison, we found an IR of 0.7 cases of NAFLD per 1000 person-years in NAFLD patients without cirrhosis (Table S2). The difference in diagnostic methods and the inclusion of study participants from a population-based registry of patients receiving specialized care in our study could explain these differences.[10]

Simon et al. reported that, after adjusting for several important confounders, patients with biopsy-proven NAFLD had an increased risk of cancer compared to matched controls (aHR 1.27, 95% CI = 1.18–1.36).[33] This finding is supported by our study using a less selected cohort with study participants who were identified and included using ICD codes. Since the study by Simon et al. included all Swedish patients with biopsy proven from 1966 to 2016, our two cohorts likely included many of the same patients. As in our cohort, the strongest association was observed between NAFLD and the risk of HCC development (aHR 17.08, 95% CI = 11.56–25.25). In contrast to the findings of our study, Simon et al. did not report an association between NAFLD and risk of colorectal and uterus cancer, which could be explained by the different selection criteria of our cohorts.[33]

Our study has several strengths. First, we used data from high-quality population-based registries to ascertain both exposure and outcomes. This approach reduces selection bias and increases the generalization of the results to countries with a similar population to Sweden. Second, we compared the risk of cancer in patients with NAFLD to the risk in the general population. Third, owing to the high validity of malignancies in the SCR, we likely had a high capture rate for the assessed outcomes.

The study had some limitations. In general, these are related to the register-based design, which introduces the possibility of selection bias and limited possibility to identify confounders. First, because NAFLD is generally underdiagnosed and we used ICD codes from hospital discharges (and from specialized care outpatients visits since 2001), we likely underestimated the prevalence of NAFLD in the study population, leading to false low-risk estimates in our study. Second, the NPR does not include patients from primary care, which may introduce a selection bias towards more severe cases with NAFLD. However, the relatively low prevalence of cirrhosis in our cohort suggests that selection bias is not a concern. However, this low prevalence of cirrhosis could also be attributed to misclassification bias as a result of suboptimal coding. To assess this possibility, we investigated how many of the 40 NAFLD patients without cirrhosis at baseline but who received a diagnosis of HCC during follow-up had been diagnosed with cirrhosis after baseline but before their HCC diagnosis. Excluding these individuals (n = 10) from the Cox regression analysis of the risk of HCC, we observed similar results to those of the main analysis. It is possible that some patients diagnosed with NAFLD in our cohort consumed excess amounts of alcohol and had undiagnosed alcohol-related liver disease. Therefore, we excluded all individuals with a diagnosis of alcohol or drug abuse. Patients with a formal diagnosis of NAFLD might not be representative of patients with NAFLD in the general population. The risk of cancer might be higher in patients with a formal diagnosis, if these are in general sicker. Also, underestimation of the possible confounders of interest in both patients with NAFLD and their general population controls might occur in this study, possibly more so in controls since they are not followed actively in the used registers. Hence, the risk estimates for cancer obtained in this study might be falsely high. However, this do not in a meaningful manner affect our conclusions that risk of extrahepatic cancer in NAFLD is in general low. It is also possible that some patients diagnosed after baseline had already developed cancer before baseline. Thus, we introduced a lag time value in which we only considered outcomes occurring at least 1 year after baseline. The baseline covariates included in the regression models (i.e. diabetes, COPD, hypertension and hyperlipidaemia) were ascertained through the NPR. Because patients with NAFLD could be more likely to contact healthcare than individuals without NAFLD, patients with NAFLD could also be more likely to receive a diagnosis of one or more of the covariates. Finally, we relied on COPD as a proxy for smoking. Such a proxy, however, only captures the most severe cases. Thus, some residual confounding from smoking in the estimates is possible.

Future studies should include cohorts with a more precise definition of NAFLD, including a higher level of granularity of liver fibrosis stage, have a longer follow-up and more detailed data on important confounding comorbidities and lifestyle-related risk factors. In general, there is always risk of bias in register-based, observational studies, and therefore the results should be interpreted with some caution. Verifying the results from this study with other studies is important.

In summary, using a population-based cohort of patients with NAFLD compared to controls without NAFLD, we found NAFLD to be associated with a slightly increased risk of cancer (primarily HCC). In general, the risk of cancer was low and these results do not call for specific surveillance of cancer in patients with NAFLD.