Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis

Abstract

Background Cholangiocarcinoma is a cancer with poor prognosis. The detection of risk factors is fundamental to identify subjects at higher risk of cholangiocarcinoma. Nonalcoholic fatty liver disease (NAFLD) represents a leading cause of chronic liver disease worldwide. Recent data suggested that NAFLD increases the risk of cholangiocarcinoma development. However, it is necessary to better explain the strength of association between NAFLD and cholangiocarcinoma. Methods A systematic research of current case-control, cohort, clinical trial and meta-analysis on the main electronic databases was made. A recent systematic review was recognized. We performed cumulative meta-analyses with sensitivity analysis excluding studies with large sample size and with great clinical heterogeneity, then we checked for further studies. At the final step, three trial sequential analyses were done as well. Results NAFLD determines an increased risk of total cholangiocarcinoma and intrahepatic cholangiocarcinoma (iCCA) development: odds ratio (OR) (95% confidence interval [CI]): 1.88 (1.25–2.83), OR (95% CI): 2.19 (1.48–3.25), respectively. On the contrary, NAFLD does not show a significant effect on extrahepatic cholangiocarcinoma (eCCA) (OR (95% CI): 1.48 (0.93–2.36). The trial sequential analyses regarding total cholangiocarcinoma and iCCA showed that z-curve was outside computed alpha boundaries, proving that the positive association was conclusive. The trial sequential analysis about eCCA showed that z-curve was inside computed futile boundaries, proving that negative results were conclusive. Conclusion The performance of new sensitive analyses and the respective trial sequential analyses, after withdraw of confounding factors, suggested the existence of definitive association only between NAFLD and iCCA development and not with eCCA.

Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing?

“…In a recent meta-analysis involving six studies and after trial sequential analyses, Corrao et al [ 224 ] concluded that NAFLD was significantly associated with intrahepatic cholangiocarcinoma, but not with extrahepatic cholangiocarcinoma. Petrick et al [ 225 ] found that NAFLD was correlated with nearly three-times the risk of developing intrahepatic cholangiocarcinoma (OR, 3.52; 95% CI, 2.87–4.32; p < 0.0001) and extrahepatic cholangiocarcinoma (OR, 2.93; 95% CI, 2.42–3.55; p < 0.0001).…”

Metabolic-associated Fatty Liver Disease (MAFLD): A Multi-systemic Disease Beyond the Liver

“…102 A meta-analysis also found that NAFLD is significantly associated with extrahepatic cholangiocarcinoma but not with intrahepatic cholangiocarcinoma after excluding confounding factors. 103 Another meta-analysis found that NAFLD increased the risk of colorectal adenoma and carcinoma. 104,105 Among patients with NAFLD, the overall risk was higher for right colon tumors than for left colon tumors.…”

Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics

“…In addition, in U.K., patients with NAFLD-associated HCC were older than those with other HCC etiologies (71.3 years vs 67.1 years), being liver tumors less often detected by clinical surveillance, although their survival was comparable [ 17 ]. It has been proposed a potential relationship between NAFLD and iCCA, which suggests a common pathogenesis with HCC [ 18 , 19 ], however, no clear association between aging and MAFLD has already been established in this cancer.…”