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

Abstract and Introduction


Background and Aims: Individuals with non-alcoholic fatty liver disease (NAFLD) may be at greater risk of cancer. This study aimed to investigate the risk of hepatic and extrahepatic cancer compared to the general population in a population-based cohort of patients with NAFLD.

Methods: We used the Swedish National Patient Registry from 1987 to 2016 to identify patients with a NAFLD diagnosis and no prior cancer. All patients with NAFLD were compared to up to 10 controls matched for age, sex and living location. The primary outcome was the first occurrence of any cancer as ascertained from national registries. As secondary outcomes, we analysed the risk of pre-specified cancer subtypes. Cox regression models, adjusted for baseline diabetes, hypertension, hyperlipidaemia and chronic obstructive pulmonary disease were applied.

Results: We identified 8415 patients with NAFLD. Over a median follow-up of 6.0 years (IQR 2.5–11.2 years), an increased risk for any cancer was found in patients with NAFLD compared to controls (9.7 vs. 8.6 cases per 1000 person-years): hazard ratio (HR) = 1.22 (95% confidence interval, CI = 1.12–1.33). The risk for hepatocellular carcinoma (HCC) was particularly high (adjusted HR, aHR = 12.18, 95% CI = 7.15–20.79). The risk for some other cancer subtypes increased (colorectal [aHR 1.38], kidney [aHR 2.12], bladder [aHR 2.51] and uterine [aHR 1.78]), but was low in absolute terms.

Conclusion: In this population-based cohort, NAFLD was associated with an increased risk of developing cancer (especially HCC). The absolute risk for other forms of cancer was generally comparable to the control population.


In recent decades, the increasing prevalence of obesity and type 2 diabetes (T2D) has been accompanied by an increase in non-alcoholic fatty liver disease (NAFLD). The global prevalence of NAFLD is estimated to be about 24%.[1–3] Increasing attention has focused on the hepatic (e.g. cirrhosis and hepatocellular carcinoma (HCC)) and extrahepatic (e.g. T2D, cardiovascular disease and extrahepatic cancers) complications of NAFLD.[4,5] An increased risk of HCC in patients with NAFLD has been repeatedly reported.[6–10] It was also recently noted that cancers are a significant contributor to mortality in patients with biopsy-proven NAFLD.[11]

However, the absolute risk of HCC in patients with NAFLD without cirrhosis has been reported to be low.[10] Mantovani et al. recently published a meta-analyses of 10 cohorts of over 180 000 individuals, mostly originating from Asia, and reported NAFLD to be associated with an increased risk of several extrahepatic cancers compared to reference individuals free of NAFLD.[12] In a study of a Chinese cohort of males with NAFLD without cirrhosis, an increased risk of any cancer was found compared to controls without NAFLD.[13] Allen et al. reported an increased risk of cancer in patients diagnosed with NAFLD compared to controls without NAFLD. In this same study, no increased risk of cancer was seen in obese patients without a diagnosis of NAFLD.[8] Other studies have shown an increased risk of colorectal cancer in males with NAFLD, but not females with NAFLD.[7,8,14] However, in a meta-analysis from 2018, an increased risk of colorectal cancer was found in patients with NAFLD independent of sex.[15]

The risk of breast cancer has been shown to increase in NAFLD.[7,8,16] In contrast, some studies have found an increased risk of breast cancer only in non-obese[17] or post-menopausal[18] women with NAFLD. For other cancers, such as lung, oesophageal, prostate and bladder cancer, results have been conflicting and lack replication.[7,8,13,19–21]

The results from previous studies have been inconclusive, which could be as a result of different methods with varying sensitivity and specificity for diagnosing NAFLD (e.g. non-invasive scores based on blood samples and body mass index,[10,18,21] lack of adjusting for important confounders[6] and studying selected, non-population-based cohorts).[7,10,14,16,17,19] A need for further studies on the association between NAFLD and cancer has been suggested.[4]

We aimed to investigate the risk of cancer in a population-based cohort of patients diagnosed with NAFLD, with and without cirrhosis, compared to the general population.