Serum Total Bile Acid Levels Linked to Elevated HCC Risk in Cirrhosis

Hashem B. El-Serag, MD, MPH

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Elevated prediagnostic serum total bile acid (TBA) levels were linked to an increased risk of hepatocellular carcinoma (HCC) development among patients with multi-etiology cirrhosis, according to the results of a new analysis.

Further analysis revealed while higher TBA levels were associated with overall HCC risk, the extent of risk was not consistent among all individuals with cirrhosis, as those with established HCC risk factors, including hepatitis C virus (HCV), obesity, or diabetes, experienced a notably high risk.

“Our findings are suggestive of an etiological link between TBA and HCC and possible utility as a predictive biomarker for better risk stratification,” wrote the investigative team, led by Hashem B. El-Serag, MD, MPH, department of medicine, Baylor College of Medicine. “It is possible that elevated TBA is part of the metabolic abnormalities that underlie the severity of these etiological risk factors.”

Results of experimental studies have linked bile acids to the development and progression of HCC. Multiple studies with human subjects found elevated serum or plasma levels of total or specific bile acid levels among patients with HCC, or those at risk to develop HCC, compared with healthy controls.

However, few longitudinal studies explored the role of serum TBA as a risk factor for HCC in individuals with contemporary cirrhosis related to metabolic dysfunction–associated steatotic liver disease (MASLD) or cured HCV infection. In this analysis, El-Serag and colleagues assessed the connection between baseline serum TBA levels and the risk of new HCC among a multi-ethnic, multi-etiology prospective cohort of patients with compensated cirrhosis.

The study cohort was prospectively recruited at 7 liver clinics in the Texas HCC Consortium (THCC) cohort, with 940 unique patients with BA samples consecutively recruited between December 2016 and February 2020. The primary outcome was incident HCC, defined as tumors occurring ≥1 month after the index visit to minimize the risk of prevalent HCC.

Although some individuals matched multiple etiological categories, El-Serag and colleagues categorized them into mutually exclusive cohorts, including active/cured HCV, alcohol-associated liver disease, autoimmune disorders, MASLD, and others. Competing risk proportional hazard–adjusted models estimated the link between serum TBA level tertiles and the risk of HCC development, stratified by HCV, obesity, and diabetes status.

Upon analysis, across 3406 person-years of follow-up, 68 of the 940 patients in the study progressed to HCC. The underlying etiology for cirrhosis included MASLD (30%), active HCV (14%), curved HCV (29%), alcohol-associated liver disease (15%), or HBV (1%).

Among the overall patient population, the median TBA serum level was 14.58 µmol/L, with most (91.2%) having a TBA value <100 µmol/L. Analyses showed baseline serum TBA levels were associated with an increase in HCC risk—compared with the lowest TBA tertile, the highest tertile was linked to a nearly 4-fold significantly increased risk for HCC (adjusted hazard ratio [HR], 3.69; 95% CI, 1.85–7.37).

An analysis of TBA levels for HCC risk prediction revealed TBA modeled as tertiles had a notable additive effect on the total discrimination of the predictive model for 1- and 2-year HCC risk. Adding TBA to the baseline risk model raised the c-index for predicting 2-year HCC risk from 0.74 to 0.80 (P <.001).

Overall, El-Serag and colleagues identified a significant interaction between TBA level and HCV (P = .04). After stratifying by HCV status, the highest TBA tertile was associated with a nearly 6-fold higher risk for HCC versus the lowest tertile (adjusted HR, 5.92; 95% CI, 2.27–15.44).

Based on these findings, the investigative team suggested the contribution of TBA levels could provide an independent predictive effect on the dimensions of HCC pathophysiology not represented by other liver disease measures.

“This effect may have clinical implications, especially if our results are confirmed in other cohorts,” they wrote. “We expect that progress in HCC risk stratification will occur from adding biomarkers reflecting different biological domains (eg, genomics and radiomics) in progression to HCC.”

References

El-Serag, Hashem B.1,2,3; Thrift, Aaron P.4,5; Duong, Hao3; Ning, Jing6; Khaderi, Saira1; Singal, Amit G.7; Asrani, Sumeet K.8; Marrero, Jorge A.9; Powell, Hannah10; Rizwan, Kinza10; Najjar, Omar10; Amos, Christopher I.4; Luster, Michelle1; Al-Sarraj, Abeer1,2,3; Salem, Emad1,2; Scheurer, Michael E.5,11; Chhatwal, Jagpreet12; Kaochar, Salma4,5; Kanwal, Fasiha1,2,3. Serum levels of total bile acids are associated with an increased risk of HCC in patients with cirrhosis. Hepatology Communications 8(11):e0545, November 2024. | DOI: 10.1097/HC9.0000000000000545