Prognostic Value of Fibrosis-4 in Male Patients with Alcohol-Related Hepatocellular Carcinoma: Implications for Ultrasound-Based Therapeutic Strategies
Restricted accessReview articleFirst published online 2025
Prognostic Value of Fibrosis-4 in Male Patients with Alcohol-Related Hepatocellular Carcinoma: Implications for Ultrasound-Based Therapeutic Strategies
Hepatocellular carcinoma (HCC) is still the largest cause of cancer-related death globally, with alcohol-related HCC (AR-HCC) being a particularly difficult subtype with poor clinical results. Noninvasive biomarkers, such as the fibrosis-4 (FIB-4) index, may provide significant prognostic information that might aid in guiding new interventional techniques, such as ultrasound-based treatments.
Methods:
The authors did a retrospective cohort analysis on male AR-HCC patients diagnosed between January 2008 and December 2018. Clinical data and survival outcomes were obtained from electronic medical records, with HCC diagnosed as the baseline. The major endpoint was 12-month mortality. Multivariate logistic regression and limited cubic spline analysis were used to assess the relationship between FIB-4 and mortality risk.
Results:
Among 786 AR-HCC patients (mean age 57 years), 90.1% reported a history of alcohol usage for more than 10 years. The Barcelona Clinic Liver Cancer staging showed 42.8% in stage 0/A, 45.9% in stage B/C, and 11.3% in stage D. Deceased individuals had substantially higher FIB-4 levels (p < 0.05). Logistic regression demonstrated that higher FIB-4 was independently related with increased mortality, and spline analysis revealed a linear risk increase with a threshold of 5.61.
Conclusion:
Elevated FIB-4 (≥5.61) predicts worse mortality in AR-HCC, indicating its potential relevance in stratifying patients for ultrasound-based cancer therapy. The level of fibrosis may impact both therapeutic response and procedural risk. Routine incorporation of FIB-4 into clinical processes may aid precision decision-making in choosing AR-HCC patients most likely to benefit from ultrasound-guided or ultrasound-enhanced biotherapeutic.
PölönenP, Di GiacomoD, SeffernickAE, et al.The genomic basis of childhood T-lineage acute lymphoblastic leukaemia. Nature, 2024; 632(8027):1082–1091.
7.
Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet, 2020; 396(10258):1204–1222.
8.
HuangDQ, MathurinP, Cortez-PintoH, et al.Global epidemiology of alcohol-associated cirrhosis and HCC: Trends, projections and risk factors. Nat Rev Gastroenterol Hepatol, 2023; 20(1):37–49.
9.
SuhB, ParkS, ShinDW, et al.High liver fibrosis index FIB-4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers. Hepatology, 2015; 61(4):1261–1268.
10.
IoannouGN, BesteLA, GreenPK, et al.Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology, 2019; 157(5):1264–1278.e4.
11.
CholankerilG, KramerJR, ChuJ, et al.Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease. J Hepatol, 2023; 78(3):493–500.
12.
WuY, TangH, LiaoQ, et al.Curcumol inhibits the progression of hepatocellular carcinoma by regulating the expression of hsa_circ_0028861. Cancer Biother Radiopharm, 2024; 39(3):203–210; doi: 10.1089/cbr.2023.0061
13.
WangH, GuanW, ZhangX, et al.TGF-β promotes hepatocellular carcinoma metastasis through m6A modification of PCDHGA9. Cancer Biother Radiopharm, 2024; 39(9):644–653; doi: 10.1089/cbr.2023.0144
14.
LiuZ, WangX, XingL, et al.The application comparison of contrast-enhanced ultrasound and contrast-enhanced computed tomography in radiofrequency ablation treatment for hepatocellular carcinoma. Cancer Biother Radiopharm, 2019 Dec;34(10):621–625.
15.
WangM, YuanF, WeiY, et al.Hepatocellular carcinoma: In Vivo evaluation of water percentage as a prognostic biomarker using magnetic resonance imaging 3D-VIBE multiecho dixon. Cancer Biother Radiopharm, 2018 Sep;33(7):300–306.
16.
HectorsSJ, LewisS, BesaC, et al.Magnetic resonance imaging assessment of fibrosis, inflammation, and treatment response in patients with liver disease. Radiology, 2016; 281(2):443–458; doi: 10.1148/radiol.2016150463
17.
Ter HaarG, CoussiosC. High intensity focused ultrasound: Physical principles and devices. Int J Hyperthermia, 2007; 23(2):89–104; doi: 10.1080/02656730601186138
18.
European association for the study of the liver, european organisation for research and treatment of cancer. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol, 2012; 56(4):908–943.
19.
LlovetJM, BruC, BruixJ. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis, 1999; 19(3):329–338.
20.
SterlingRK, LissenE, ClumeckN, et al.; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology, 2006; 43(6):1317–1325.
21.
CasteraL. Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Non-invasive tests are enough. Liver Int, 2018; 38 (Suppl 1):67–70.
22.
ValiY, LeeJ, BoursierJ, et al.; Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium investigators. Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): A comparative diagnostic accuracy study. Lancet Gastroenterol Hepatol, 2023; 8(8):714–725.
23.
XiaoG, YangJ, YanL. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: A systemic review and meta-analysis. Hepatology, 2015; 61(1):292–302.
24.
HuttmanM, ParigiTL, ZoncapèM, et al.Liver fibrosis stage based on the four factors (FIB-4) score or Forns index in adults with chronic hepatitis C. Cochrane Database Syst Rev, 2024; 8(8):CD011929.
25.
XuX-L, JiangL-S, WuC-S, et al.The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool? J Formos Med Assoc, 2022; 121(2):454–466.
26.
TamakiN, KurosakiM, YasuiY, et al.Change in Fibrosis-4 Index as predictor of high risk of incident hepatocellular carcinoma after eradication of hepatitis C virus. Clin Infect Dis, 2021; 73(9):e3349–e3354.
27.
TorkadiPP, ApteIC, BhuteAK. Biochemical evaluation of patients of alcoholic liver disease and non-alcoholic liver disease. Indian J Clin Biochem, 2014; 29(1):79–83.
28.
HeC, PengW, LiC, et al.Postoperative aspartate aminotransferase to lymphocyte ratio index change is an independent predictor of survival in patients with small hepatocellular carcinoma. Medicine (Baltimore), 2017; 96(45):e8540.
29.
KaewdechA, SripongpunP, AssawasuwannakitS, et al.FAIL-T (AFP, AST, tumor size, ALT, and tumor number): A model to predict intermediate-stage HCC patients who are not good candidates for TACE. Front Med (Lausanne), 2023; 10:1077842.
30.
ZhangL-X, LuoP-Q, ChenL, et al.Model to predict overall survival in patients with hepatocellular carcinoma after curative hepatectomy. Front Oncol, 2020; 10:537526.
31.
DingY, LiuK, XuY, et al.Combination of inflammatory score/liver function and AFP improves the diagnostic accuracy of HBV-related hepatocellular carcinoma. Cancer Med, 2020; 9(9):3057–3069.
32.
HuangC, XiaoX, TongL, et al.Risks and clinical predictors of hepatocellular carcinoma in Chinese populations: A real-world study of 10,359 patients in six medical centers. J Hepatocell Carcinoma, 2024; 11:411–425.
33.
GuiuB, GarinE, AllimantC, et al.TARE in hepatocellular carcinoma: From the right to the left of BCLC. Cardiovasc Intervent Radiol, 2022; 45(11):1599–1607.
34.
QianX, LiuS, LongH, et al.Reappraisal of the diagnostic value of alpha-fetoprotein for surveillance of HBV-related hepatocellular carcinoma in the era of antiviral therapy. J Viral Hepat, 2021; 28(1):20–29.
35.
ZhuAX, FinnRS, KangY-K, et al.Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer, 2021; 124(8):1388–1397.
36.
HuangP, LiuC, LiB, et al.Preoperative mean corpuscular hemoglobin affecting long-term outcomes of hepatectomized patients with hepatocellular carcinoma. Mol Clin Oncol, 2016; 4(2):229–236.
37.
JiD, ChenY, BiJ, et al.Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B. J Hepatol, 2022; 77(6):1515–1524.
38.
TsaiM-Y, YenY-H, HuangP-Y, et al.The pre- and postoperative FIB-4 indexes are good predictors to the outcomes of HBV-related HCC patients after resection. Gastroenterol Res Pract, 2019; 2019:8945798.
LinhartK, BartschH, SeitzHK. The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol, 2014; 3:56–62.
41.
GinèsP, KragA, AbraldesJG, et al.Liver cirrhosis. Lancet, 2021; 398(10308):1359–1376.
42.
ChangB, TianH, HuangA, et al.Prevalence and prediction of hepatocellular carcinoma in alcohol-associated liver disease: A retrospective study of 136,571 patients with chronic liver diseases. eGastroenterology, 2024; 2(1):e100036.
43.
LinC-W, LinC-C, MoL-R, et al.Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis. J Hepatol, 2013; 58(4):730–735.
44.
LiuSY, TsaiIT, HsuYC. Alcohol-related liver disease: Basic mechanisms and clinical perspectives. Int J Mol Sci, 2021; 22(10):5117–5170.
45.
Sasaki-TanakaR, RayR, MoriyamaM, et al.Molecular changes in relation to alcohol consumption and hepatocellular carcinoma. Int J Mol Sci, 2022; 23(17):9615–9679.
