Hepatic steatosis predicts metachronous liver metastasis in colorectal cancer patients: a nested case-control study and systematic review

Abstract

Nearly twenty-five percent of colorectal cancer (CRC) patients develop metachronous colorectal liver metastasis (CRLM) after curative surgery. Hepatosteatosis is the most prevalent liver condition worldwide, but its impact on the incidence of metachronous CRLM is understudied. In the present study, we aimed to investigate the predictive value of hepatic steatosis on the development of metachronous CRLM. First, a nested case-control study was conducted, enrolling stage I to III CRC patients in the National Colorectal Cancer Cohort (NCRCC) database. Metachronous CRLM patients and recurrence-free patients were matched via propensity-score matching. Fatty liver was identified based on treatment-naïve CT scans and the degree of hepatic fibrosis was scored. Multivariable analysis was conducted to investigate the association between fatty liver and metachronous CRLM. In our database, a total of 414 patients were included. Metachronous CRLM patients had considerably higher rates of hepatic steatosis (30.9% versus 15.9%, P<0.001) and highly fibrotic liver (11.6% versus 2.9%, P=0.001) compared to recurrence-free patients. Multivariable analysis showed that fatty liver (odds ratios [OR]=1.99, 95% confidence interval [CI] 1.19-3.30, P=0.008) and fibrotic liver (OR=4.27, 95% CI 1.54-11.81, P=0.005) were associated with high risk of metachronous CRLM. Further, a systematic literature review was performed to assess available evidence on the association between hepatosteatosis and development of metachronous CRLM. In the systematic review, 1815 patients were pooled from eligible studies, and hepatic steatosis remained a significant risk factor for metachronous CRLM (OR=1.90, 95% CI 1.35-2.66, P<0.001, I²=25.3%). In conclusion, our data suggest that patients with a steatotic liver and a high fibrosis score at CRC diagnosis have elevated risk of developing metachronous CRLM.

Keywords: Hepatic steatosis; L/S ratio; colorectal cancer; metachronous liver metastasis; tumor stage.

Figure 1

Flow chart of patient inclusion, case-matching and data gathering process. A: The National Colorectal Cancer Cohort (NCRCC) database was utilized. Stage I to III colorectal cancer patient with metachronous colorectal liver metastasis (CRLM) and patients with no disease recurrence during more than 3 years of survey were identified; B: The identified patients underwent screening process and eligible patients in both groups were matched according to baseline information, disease stage and tumor location via propensity-score-matching PSM.

Figure 2

Logistic regression was used to determine the risk factors for metachronous colorectal liver metastasis. Multivariate logistic regression analysis of factors presenting p-value <0.1 during univariate logistic regression, and was adjusted with baseline characteristics and tumor location. OR: odds ratio; CI: confidence interval; *: statistically significant.

Figure 3

A Positive correlation between hepatic steatosis and disease aggressiveness was observed. A: Patients were stratified by disease stages at colorectal cancer diagnosis. Fraction of patients presenting hepatic steatosis in each stage was calculated. Additionally, comparison was made between early stage (stage I and II) and advanced stage (stage III) patients; B: The violin plot of liver-spleen attenuation ratio in patients stratified by T stages. Dashed line represents the trend of median Liver-spleen ratio (L/S ratio) alteration with advancing T stages. Pearson correlation test suggested a significant negative correlation between T stage and L/S ratio. *: p value <0.05; **: p value <0.01.

Figure 4

Funnel plot of studies identified in systematic research and forest plot of odds ratio (OR) for liver steatosis on metachronous colorectal liver metastasis (CRLM) by meta-analysis. A: Funnel plot of studies identified in systematic research. In all identified studies, one study presented significant publication bias via Egger’s test. B: Studies with no publication bias was selected for following analysis. C: No significant heterogeneity was identified in our database (National Colorectal Cancer Cohort, NCRCC) and other studies (I²<50%, P=0.260), and a fixed effect model was adopted for analysis. In pooled data, hepatic steatosis at cancer diagnosis was risk factor for developing metachronous CRLM (OR=1.90, 95% confidence intervals [CI] 1.35-2.66, P<0.001).