The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - A longitudinal cohort study

Abstract

Background & aims: Cancer is a major cause of death in patients with non-alcoholic fatty liver disease (NAFLD). Obesity is a risk factor for cancers; however, the role of NAFLD in this association is unknown. We investigated the effect of NAFLD versus obesity on incident cancers.

Methods: We identified all incident cases of NAFLD in a US population between 1997-2016. Individuals with NAFLD were matched by age and sex to referent individuals from the same population (1:3) on the index diagnosis date. We ascertained the incidence of cancer after index date until death, loss to follow-up or study end. NAFLD and cancer were defined using a code-based algorithm with high validity and tested by medical record review. The association between NAFLD or obesity and cancer risk was examined using Poisson regression.

Results: A total of 4,722 individuals with NAFLD (median age 54, 46% male) and 14,441 age- and sex-matched referent individuals were followed for a median of 8 (range 1-21) years, during which 2,224 incident cancers occurred. NAFLD was associated with 90% higher risk of malignancy: incidence rate ratio (IRR) = 1.9 (95% CI 1.3-2.7). The highest risk increase was noted in liver cancer, IRR = 2.8 (95% CI 1.6-5.1), followed by uterine IRR = 2.3 (95% CI 1.4-4.1), stomach IRR = 2.3 (95% CI 1.3-4.1), pancreas IRR = 2.0 (95% CI 1.2-3.3) and colon cancer IRR = 1.8 (95% CI 1.1-2.8). In reference to non-obese controls, NAFLD was associated with a higher risk of incident cancers (IRR = 2.0, 95% CI 1.5-2.9), while obesity alone was not (IRR = 1.0, 95% CI 0.8-1.4).

Conclusions: NAFLD was associated with increased cancer risk, particularity of gastrointestinal types. In the absence of NAFLD, the association between obesity and cancer risk is small, suggesting that NAFLD may be a mediator of the obesity-cancer association.

Lay summary: We studied the incidence of malignancies in a community cohort of adults with non-alcoholic fatty liver disease (NAFLD) in reference to age- and sex-matched adults without NAFLD. After 21 years of longitudinal follow-up, NAFLD was associated with a nearly 2-fold increase in the risk of developing cancers, predominantly of the liver, gastrointestinal tract and uterus. The association with increased cancer risk was stronger in NAFLD than obesity.

Keywords: Epidemiology; NAFLD; NASH; Natural history; Outcomes.

FIGURE 1.

Flowchart of identification of individuals with nonalcoholic fatty liver disease in the medical record-linkage system.

FIGURE 2.

Forrest plot of risk of incident cancer among nonalcoholic fatty liver disease (NAFLD) subjects compared to age- and sex-matched referent subjects without NAFLD (controls) from the same population. Plot shows the incidence rate ratios and 95% confidence intervals. Incidence rate ratios >1 indicate increased cancer risk in obese compared to non-obese.

FIGURE 3.

Incidence of cancer by age in NAFLD (red) and referent individuals (black). Smooth curve illustrating the results of Poisson regression, performed using SEER rates at each decade of age, as the reference category.

FIGURE 4.

Forrest plot of risk of incident cancers, adjusted by age and sex. A. Obese versus non-obese participants, irrespective of NAFLD status. B. NAFLD versus non-obese controls (red), obese controls versus non-obese controls (blue). Plot shows the incidence rate ratios and 95% confidence intervals.. Incidence rate ratios >1 indicate increased cancer risk.