Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection†‡

Sterling, Richard K.; Lissen, Eduardo; Clumeck, Nathan; Sola, Ricard; Correa, Mendes Cassia; Montaner, Julio; S. Sulkowski, Mark; Torriani, Francesca J.; Dieterich, Doug T.; Thomas, David L.; Messinger, Diethelm; Nelson, Mark

doi:10.1002/hep.21178

Cited by 5,021Liver Disease Diagnosis and TreatmentLiver Disease and TransplantationHepatitis C virus research

Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection†‡

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Sterling, Richard K., Lissen, Eduardo, Clumeck, Nathan, Sola, Ricard, Correa, Mendes Cassia, Montaner, Julio, S. Sulkowski, Mark, Torriani, Francesca J. +4 more·2006·Hepatology

DOI 10.1002/hep.21178

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Abstract

Liver biopsy remains the gold standard in the assessment of severity of liver disease. Noninvasive tests have gained popularity to predict histology in view of the associated risks of biopsy. However, many models include tests not readily available, and there are limited data from patients with HIV/hepatitis C virus (HCV) coinfection. We aimed to develop a model using routine tests to predict liver fibrosis in patients with HIV/HCV coinfection. A retrospective analysis of liver histology was performed in 832 patients. Liver fibrosis was assessed via Ishak score; patients were categorized as 0-1, 2-3, or 4-6 and were randomly assigned to training (n = 555) or validation (n = 277) sets. Multivariate logistic regression analysis revealed that platelet count (PLT), age, AST, and INR were significantly associated with fibrosis. Additional analysis revealed PLT, age, AST, and ALT as an alternative model. Based on this, a simple index (FIB-4) was developed: age ([yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ALT [U/L])(1/2)). The AUROC of the index was 0.765 for differentiation between Ishak stage 0-3 and 4-6. At a cutoff of <1.45 in the validation set, the negative predictive value to exclude advanced fibrosis (stage 4-6) was 90% with a sensitivity of 70%. A cutoff of >3.25 had a positive predictive value of 65% and a specificity of 97%. Using these cutoffs, 87% of the 198 patients with FIB-4 values outside 1.45-3.25 would be correctly classified, and liver biopsy could be avoided in 71% of the validation group. In conclusion, noninvasive tests can accurately predict hepatic fibrosis and may reduce the need for liver biopsy in the majority of HIV/HCV-coinfected patients.

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The VACS Index is substantially more predictive of all causes of mortality than an index restricted to HIV-1 RNA, CD4 count, and age.
“It includes HIV-1 RNA, CD4 count, hepatitis C co-infection, FIB 4, eGFR, anemia, and age and is substantially more predictive of all causes of mortality than an index restricted to HIV-1 RNA, CD4 count, and age.”
From HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group (2012) · cites this paper as [56]
FIB 4 and APRI indicate risk of liver fibrosis among those with HIV and HCV infections.
“These composite markers of liver injury have been repeatedly shown to indicate risk of liver fibrosis among those with HIV and HCV infections (56).”
From HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group (2012) · cites this paper as [56]

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AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease
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BackgroundInfluential
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Method
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Background
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Method
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“Monitoring of fibrosis progression in the clinic might rely on a combination of noninvasive scores (NFS, FIB-4 and ADAPT) and LSM [263, 264] although this strategy requires further validation.”
BackgroundInfluential
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Method
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Wong, V. W., Adams, L. A., de Lédinghen, V., Wong, G. L., & Sookoian, S. C. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0014-9 · Cited by 617 · see citing works
Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers
Vilar‐Gómez, E., & Chalasani, N. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.11.013 · Cited by 608 · see citing works
Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study
Jsg-Nafld, Eguchi, Y., Hyogo, H., Ono, M., Mizuta, T., Ono, N., Fujimoto, K., Chayama, K., & Saibara, T. (2012) · Journal of Gastroenterology · doi:10.1007/s00535-012-0533-z · Cited by 551 · see citing works
“30 had a 90% negative predictive value to predict NASH with advanced liver fibrosis [14, 15].”
BackgroundMethod
HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group
High, K. P., Brennan-Ing, M., Clifford, D. B., Cohen, M. H., Currier, J., Deeks, S. G., Deren, S., Effros, R. B., Gebo, K., Goronzy, J. J., et al. (2012) · JAIDS Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/qai.0b013e31825a3668 · Cited by 522 · see citing works
“FIB 4 Index and Aminotransferase/Platelet Ratio Index These composite markers of liver injury have been repeatedly shown to indicate risk of liver fibrosis among those with HIV and HCV infections.(58) The FIB 4 Index is also clearly associated with risk of all-cause mortality and strongly predictive of incident hepato…”
BackgroundMethod
Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: A nationwide cohort study
Rentsch, C. T., Kidwai‐Khan, F., Tate, J. P., Park, L. S., King, J. T., Skanderson, M., Hauser, R. G., Schultze, A., Jarvis, C. I., Holodniy, M., et al. (2020) · PLoS Medicine · doi:10.1371/journal.pmed.1003379 · Cited by 513 · see citing works
Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis
Mózes, F. E., Lee, J. A., Selvaraj, E. A., Jayaswal, A. N. A., Trauner, M., Boursier, J., Fournier, C., Staufer, K., Stauber, R. E., Bugianesi, E., et al. (2022) · Gut · doi:10.1136/gutjnl-2021-324243 · Cited by 477 · see citing works
Comparison of MAFLD and NAFLD diagnostic criteria in real world
Lin, S., Huang, J., Wang, M.-F., Kumar, R., Liu, Y., Liu, S., Wu, Y., Wang, X., & Zhu, Y. (2020) · Liver International · doi:10.1111/liv.14548 · Cited by 518 · see citing works
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
Xiao, G., Yang, J., & Yan, L. (2014) · Hepatology · doi:10.1002/hep.27382 · Cited by 512 · see citing works
“Though we focus on monoHBV infection, there was observed heterogeneity in diagnostic accuracy of APRI and FIB-4.”
MethodInfluential
Deep learning Radiomics of shear wave elastography significantly improved diagnostic performance for assessing liver fibrosis in chronic hepatitis B: a prospective multicentre study
Wang, K., Lu, X., Zhou, H., Gao, Y., Zheng, J., Tong, M., Wu, C., Liu, C., Huang, L., Jiang, T., et al. (2018) · Gut · doi:10.1136/gutjnl-2018-316204 · Cited by 503 · see citing works
Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography
Wong, V. W., Chu, C. W., Wong, G. L., Chan, R., Chim, A. M., Ong, A., Yeung, D. K., Yiu, K. K., Chu, S. H.-T., Woo, J., et al. (2011) · Gut · doi:10.1136/gutjnl-2011-300342 · Cited by 491 · see citing works
Obesity as a multisystem disease: Trends in obesity rates and obesity‐related complications
Sarma, S., Sockalingam, S., & Dash, S. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14290 · Cited by 461 · see citing works
AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma
Bowlus, C. L., Arrivé, L., Bergquist, A. M., Deneau, M. R., Forman, L., Ilyas, S. I., Lunsford, K. E., Martínez, M., Sapisochín, G., Shroff, R. T., et al. (2022) · Hepatology · doi:10.1002/hep.32771 · Cited by 447 · see citing works
Noninvasive assessment of liver fibrosis
Martínez, S. M., Crespo, G., Navasa, M., & Forns, X. (2010) · Hepatology · doi:10.1002/hep.24013 · Cited by 420 · see citing works
Noninvasive In Vivo Liver Fibrosis Evaluation Using Supersonic Shear Imaging: A Clinical Study on 113 Hepatitis C Virus Patients
Bavu, É., Gennisson, J., Couade, M., Bercoff, J., Mallet, V. O., Fink, M., Badel, A., Vallet‐Pichard, A., Nalpas, B., Tanter, M., et al. (2011) · Ultrasound in Medicine & Biology · doi:10.1016/j.ultrasmedbio.2011.05.016 · Cited by 413 · see citing works
“…transaminase to platelet ratio (APRI), Fib 4 or Forn’s score and morphologic tests such as FibroScan (FS, Echosens, Paris, France) (Trinchet 1995; Halfon et al. 2005; Wai et al. 2003; Forns et al. 2002; Imbert-Bismut et al. 2001; Ono et al. 1999; Sterling et al. 2006; Vallet-Pichard et al. 2007).”
Background
Noninvasive Tests for Fibrosis and Liver Stiffness Predict 5-Year Outcomes of Patients With Chronic Hepatitis C
Vergniol, J., Foucher, J., Terrebonne, É., Bernard, P., Bail, B. L., Merrouche, W., Couzigou, P., & de Lédinghen, V. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.02.058 · Cited by 411 · see citing works
Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease--the role of transient elastography and plasma cytokeratin-18 fragments
Kwok, R., Tse, Y. ‐., Wong, G. L. ‐., Ha, Y., Lee, A. U., Ngu, M. C., Chan, H. L. ‐., & Wong, V. W. ‐. (2014) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12569 · Cited by 405 · see citing works
MAFLD identifies patients with significant hepatic fibrosis better than NAFLD
Yamamura, S., Eslam, M., Kawaguchi, T., Tsutsumi, T., Nakano, D., Yoshinaga, S., Takahashi, H., Anzai, K., George, J., & Torimura, T. (2020) · Liver International · doi:10.1111/liv.14675 · Cited by 401 · see citing works
“ALT (U/L) 19 (14-29) 4-122 22 (16-33) 4-188 .”
Influential
Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease
Boursier, J., Vergniol, J., Guillet, A., Hiriart, J.-B., Lannes, A., Le Bail, B., Michalak, S., Chermak, F., Bertrais, S., Foucher, J., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.04.023 · Cited by 400 · see citing works
“Eight blood fibrosis tests were calculated according to published or patented formulas: NFS (12), BARD (20), FibroMeter NAFLD (21), APRI (22), FIB4 (23), Fibrotest (24), Hepascore (25), and FibroMeter V2G (26).”
MethodInfluential
Diagnosis and Quantitation of Fibrosis
Manning, D. S., & Afdhal, N. H. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.001 · Cited by 398 · see citing works
The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials
Sanyal, A. J., Harrison, S. A., Ratziu, V., Abdelmalek, M. F., Diehl, A. M., Caldwell, S., Shiffman, M. L., Aguilar Schall, R., Jia, C., McColgan, B., et al. (2019) · Hepatology · doi:10.1002/hep.30664 · Cited by 390 · see citing works
“Serum fibrosis markers including the Enhanced Liver Fibrosis (ELF) test score (Siemens Healthcare, Erlangen, Germany), FibroSure (LabCorp, Burlington, NC)/FibroTest (Biopredictive, Paris, France), NAFLD fibrosis score, fibrosis-4 (FIB-4) index,(18) and aspartate aminotransferase-to-platelet ratio index (APRI)(19) were…”
Method
Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population
Sumida, Y., Yoneda, M., Hyogo, H., Itoh, Y., Ono, M., Fujii, H., Eguchi, Y., Suzuki, Y., Aoki, N., Kanemasa, K., et al. (2012) · BMC Gastroenterology · doi:10.1186/1471-230x-12-2 · Cited by 388 · see citing works
The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in patients with chronic HBV infection in West Africa
Lemoine, M., Shimakawa, Y., Nayagam, S., Khalil, M., Suso, P., Lloyd, J., Goldin, R. D., Njai, H. F., Ndow, G., Taal, M. A., et al. (2015) · Gut · doi:10.1136/gutjnl-2015-309260 · Cited by 369 · see citing works
Blood Tests to Diagnose Fibrosis or Cirrhosis in Patients With Chronic Hepatitis C Virus Infection
Chou, R., & Wasson, N. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-158-11-201306040-00005 · Cited by 369 · see citing works
Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging
Dyson, J. K., Anstee, Q. M., & McPherson, S. (2013) · Frontline Gastroenterology · doi:10.1136/flgastro-2013-100403 · Cited by 358 · see citing works
Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis
Corpechot, C., Carrat, F., Poujol-Robert, A., Gaouar, F., Wendum, D., Chazouillères, O., & Poupon, R. (2012) · Hepatology · doi:10.1002/hep.25599 · Cited by 351 · see citing works
“APRI and FIB-4 were calculated according to published formulas.(12,13) Serum HA concentration was measured by enzyme-linked immunosorbent assay (Corgenix, Broomfield, CO).”
Non-invasive diagnosis of liver fibrosis and cirrhosis
Lurie, Y. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i41.11567 · Cited by 353 · see citing works
Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel
Soriano, V., Puoti, M., Sulkowski, M., Cargnel, A., Benhamou, Y., Peters, M. G., Mauss, S., Bräu, N., Hatzakis, A. E., Pol, S., et al. (2007) · AIDS · doi:10.1097/qad.0b013e3281084e4d · Cited by 346 · see citing works
Association between non-alcoholic fatty liver disease and cancer incidence rate
Kim, G., Lee, H. C., Choe, J., Kim, M.-J., Lee, M. J., Chang, H.-S., Bae, I. Y., Kim, H., An, J., Shim, J. H., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.012 · Cited by 330 · see citing works
“45) serves as a strong predictor of the absence of liver fibrosis.(13)”
BackgroundMethod
Non-invasive assessment of liver fibrosis with impulse elastography: Comparison of Supersonic Shear Imaging with ARFI and FibroScan®
Cassinotto, C., Lapuyade, B., Mouries, A., Hiriart, J., Vergniol, J., Gaye, D., Castain, C., Bail, B. L., Chermak, F., Foucher, J., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.04.044 · Cited by 325 · see citing works
“These parameters were then used to calculate the aspartate-to-platelet ratio index (APRI) [15], the aspartate aminotransferase/alanine aminotransferase ratio index (AST/ALT) [16], the Forns index (Forns) [17], and the Fib-4 [18], according to the published formulas.”
Method
Viral hepatitis and HIV coinfection
Sulkowski, M. (2007) · Journal of Hepatology · doi:10.1016/j.jhep.2007.11.009 · Cited by 319 · see citing works
“Currently a number of tests are available which can reliably separate patients with minimal fibrosis from those with cirrhosis but fail to clearly distinguish intermediate stages of fibrotic disease progression [41–45].”
Background
A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes
Ajmera, V., Cepin, S., Tesfai, K., Hofflich, H., Cadman, K., Lopez, S., Madamba, E., Bettencourt, R., Richards, L., Behling, C., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2022.11.010 · Cited by 327 · see citing works
Prevalence and Severity of Nonalcoholic Fatty Liver Disease in Non-Obese Patients: A Population Study Using Proton-Magnetic Resonance Spectroscopy
Wei, J. L., Leung, J. C., Loong, T. C., Wong, G. L., Yeung, D. K., Chan, R., Chan, H. L., Chim, A. M., Woo, J., Chu, C. W., et al. (2015) · The American Journal of Gastroenterology · doi:10.1038/ajg.2015.235 · Cited by 317 · see citing works
Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population
Graupera, I., Thiele, M. S., Serra‐Burriel, M., Caballería, L., Roulot, D. M., Wong, G. L., Fabrellas, N., Guha, I. N., Arslanow, A., Expósito, C., et al. (2021) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2021.12.034 · Cited by 302 · see citing works
The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease
Fujii, H., Kawada, N., & Japan Study Group of NAFLD (JSG-NAFLD) (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113863 · Cited by 300 · see citing works
“Conversely, a FIB-4 with a high cutoff value of 2.67 had a sensitivity of 22% in patients with T2DM and 0% in those without [80].”
MethodInfluential
Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus-infected patients
Kim, B. K., Kim, D. Y., Park, J. Y., Ahn, S. H., Chon, C. Y., Kim, J. K., Paik, Y. H., Lee, K. S., Park, Y. N., & Han, K. (2010) · Liver International · doi:10.1111/j.1478-3231.2009.02192.x · Cited by 298 · see citing works
“Firstly, there have been few studies assessing its diagnostic value in patients with CHB, because most studies have been performed primarily in western populations with HCV mono- or HCV/HIV-co-infection (18, 19, 21, 22).”
BackgroundMethod
Non-Invasive markers for hepatic fibrosis
Baranova, A. V., Lal, P., Birerdinc, A., & Younossi, Z. M. (2011) · BMC Gastroenterology · doi:10.1186/1471-230x-11-91 · Cited by 297 · see citing works
Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients
Kim, W. R., Berg, T., Asselah, T., Flisiak, R., Fung, S. K., Gordon, S. C., Janssen, H. L. A., Lampertico, P., Lau, D., Bornstein, J. D., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.11.012 · Cited by 297 · see citing works
Oxidative Stress and Non-Alcoholic Fatty Liver Disease: Effects of Omega-3 Fatty Acid Supplementation
Yang, J., Fernández‐Galilea, M., Martínez‐Fernández, L., González‐Muniesa, P., Pérez-Chávez, A., Martínez, J. A., & Moreno-Aliaga, M. J. (2019) · Nutrients · doi:10.3390/nu11040872 · Cited by 294 · see citing works
“FIB-4 index FIB-4 Score = age ([yr] × AST [U/L])/((PLT [109/L]) × (ALT [U/L])1/2) [101].”
Background
Plasma proteome profiling discovers novel proteins associated with non‐alcoholic fatty liver disease
Niu, L., Geyer, P. E., Albrechtsen, N. J. W., Gluud, L. L., Santos, A., Doll, S., Treit, P. V., Holst, J. J., Knop, F. K., Vilsbøll, T., et al. (2019) · Molecular Systems Biology · doi:10.15252/msb.20188793 · Cited by 278 · see citing works
“…of these enzymes are often combined with patient data such as age and platelet count in NAFLD severity indices such as the fibrosis-4 (FIB-4) index (Sterling et al , 2006) and with biomarkers in the case of fatty liver index (Bedogni et al , 2006), NAFLD liver fat score (Kotronen et al , 2009),…”
Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage
Siddiqui, M. S., Yamada, G., Vuppalanchi, R., Van Natta, M., Loomba, R., Guy, C., Brandman, D., Tonascia, J., Chalasani, N., Neuschwander-Tetri, B., et al. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.12.031 · Cited by 272 · see citing works
Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease
Alexander, M., Loomis, A. K., Fairburn-Beech, J., van der Lei, J., Duarte‐Salles, T., Prieto‐Alhambra, D., Ansell, D., Pasqua, A., Lapi, F., Rijnbeek, P. R., et al. (2018) · BMC Medicine · doi:10.1186/s12916-018-1103-x · Cited by 273 · see citing works
Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis‐4 score and aspartate aminotransferase‐platelet ratio index
Bachofner, J., Valli, P. V., Kröger, A., Bergamin, I., Künzler‐Heule, P., Baserga, A., Braun, D. L., Seifert, B., Moncsek, A., Fehr, J. S., et al. (2016) · Liver International · doi:10.1111/liv.13256 · Cited by 272 · see citing works
Accuracy of the Enhanced Liver Fibrosis Test vs FibroTest, Elastography, and Indirect Markers in Detection of Advanced Fibrosis in Patients With Alcoholic Liver Disease
Thiele, M. S., Madsen, B. S., Hansen, J. F., Detlefsen, S., Antonsen, S., & Krag, A. A. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.01.005 · Cited by 272 · see citing works
ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis
Daniels, S. J., Leeming, D. J., Eslam, M., Hashem, A. M., Nielsen, M. J., Krag, A., Karsdal, M. A., Grove, J. I., Neil Guha, I., Kawaguchi, T., et al. (2019) · Hepatology · doi:10.1002/hep.30163 · Cited by 273 · see citing works
“(44) Similarly, platelet count is routinely measured and is strongly correlated with liver fibrosis and has been incorporated into multiple other noninvasive scoring systems.(10,12,14) A study by Mofrad et al.”
BackgroundMethod
KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease
Kang, S. H., Lee, H. W., Yoo, J., Cho, Y., Kim, S. U., Lee, T. H., Jang, B. K., Ahn, S. B., Ahn, S. B., Kim, H., et al. (2021) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2021.0178 · Cited by 269 · see citing works
“67, advanced liver fibrosis can be diagnosed (accuracy, 80%).(175) A recent study of subjects with biopsy-proven NAFLD showed that the diagnostic accuracy of the NFS and FIB-4 was significantly higher than that of other noninvasive panels for liver fibrosis and similar to that of MRE in diagnosing advanced liver fibro…”
Background
Liver fibrosis scores predict liver disease mortality in the United States population
Ünalp–Arida, A., & Ruhl, C. E. (2017) · Hepatology · doi:10.1002/hep.29113 · Cited by 261 · see citing works
“(40-42) A previous analysis of the NHANES III population with mortality follow-up through 2006 found higher overall and cardiovascular disease mortality in association with three of the same fibrosis scores among persons with suspected NAFLD.”
BackgroundMethodInfluential
Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999–2016
Zou, B., Yeo, Y. H., Nguyen, V. H., Cheung, R. C., Ingelsson, E., & Nguyen, M. H. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13069 · Cited by 250 · see citing works
Hepatic Decompensation in Antiretroviral-Treated Patients Co-Infected With HIV and Hepatitis C Virus Compared With Hepatitis C Virus–Monoinfected Patients
Re, V. L., Kallan, M. J., Tate, J. P., Localio, A. R., Lim, J. K., Goetz, M. B., Klein, M. B., Rimland, D., Rodriguez‐Barradas, M. C., Butt, A. A., et al. (2014) · Annals of Internal Medicine · doi:10.7326/m13-1829 · Cited by 249 · see citing works
“Baseline FIB-4, a noninvasive measure of advanced hepatic fibrosis, was determined by: (age [years] × AST [U/L])/((platelet count [109/L]) × (ALT [U/L])1/2) (26).”
Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice
Zhou, J., Cai, J., She, Z., & Li, H. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i11.1307 · Cited by 248 · see citing works
Nonalcoholic Fatty Liver Disease in HIV‐Infected Patients Referred to a Metabolic Clinic: Prevalence, Characteristics, and Predictors
Guaraldi, G., Squillace, N., Stentarelli, C., Orlando, G., D’Amico, R., Ligabue, G., Fiocchi, F., Zona, S., Loria, P., Esposito, R., et al. (2008) · Clinical Infectious Diseases · doi:10.1086/589294 · Cited by 241 · see citing works
“The FIB-4 index was calculated as the putative predictor of liver fibrosis in a subgroup of patients in our cohort [20].”
Method
Prevalence of Nonalcoholic Steatohepatitis-Associated Cirrhosis in the United States: An Analysis of National Health and Nutrition Examination Survey Data
Kabbany, M. N., Selvakumar, P. K. C., Watt, K. D. S., López, R., Akras, Z., Zein, N. N., Carey, W., & Alkhouri, N. (2017) · The American Journal of Gastroenterology · doi:10.1038/ajg.2017.5 · Cited by 241 · see citing works
Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver
Feldman, A., Eder, S. K., Felder, T. K., Kedenko, L., Paulweber, B., Stadlmayr, A., Huber-Schönauer, U., Niederseer, D., Stickel, F., Auer, S., et al. (2016) · The American Journal of Gastroenterology · doi:10.1038/ajg.2016.318 · Cited by 239 · see citing works
Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis
Lang, S., Duan, Y., Liu, J., Torralba, M., Kuelbs, C., Cots, M. V., Abraldeṣ, J. G., Bosques‐Padilla, F., Verna, E. C., Brown, R. S., et al. (2019) · Hepatology · doi:10.1002/hep.30832 · Cited by 239 · see citing works
“GGT (IU/L), n = 121 95 (15-1131) 257 (33-3632) <0.”
Influential
Comparison of FIB‐4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non‐alcoholic fatty liver disease: A meta‐analysis study
Sun, W., Cui, H., Li, N., Wei, Y., Lai, S., Yang, Y., Yin, X., & Chen, D. (2016) · Hepatology Research · doi:10.1111/hepr.12647 · Cited by 236 · see citing works
AGA clinical practice update on the role of noninvasive biomarkers in the evaluation and management of nonalcoholic fatty liver disease: expert review
Wattacheril, J. J., Abdelmalek, M. F., Lim, J. K., & Sanyal, A. J. (2023) · Gastroenterology · doi:10.1053/j.gastro.2023.06.013 · Cited by 236 · see citing works
Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: Noninvasive Assessment with MR Elastography
Kim, D., Kim, W. R., Talwalkar, J. A., Kim, H. J., & Ehman, R. L. (2013) · Radiology · doi:10.1148/radiol.13121193 · Cited by 229 · see citing works
A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011–2015 update
Tateishi, R., Uchino, K., Fujiwara, N., Takehara, T., Okanoue, T., Seike, M., Yoshiji, H., Yatsuhashi, H., Shimizu, M., Torimura, T., et al. (2018) · Journal of Gastroenterology · doi:10.1007/s00535-018-1532-5 · Cited by 232 · see citing works
The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease
Chu, H., Duan, Y., Lang, S., Jiang, L., Wang, Y., Llorente, C., Liu, J., Mogavero, S., Bosques‐Padilla, F., Abraldeṣ, J. G., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.09.029 · Cited by 230 · see citing works
Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study
Takahashi, K., Ono, N., Eguchi, Y., Eguchi, T., Kitajima, Y., Kawaguchi, Y., Nakashita, S., Ozaki, I., Mizuta, T., Toda, S., et al. (2009) · Liver International · doi:10.1111/j.1478-3231.2009.02130.x · Cited by 225 · see citing works
“To compare the diagnostic performance of ARFI elastography and commonly used biochemical index systems including APRI (9), Fib-4 index (29) and Forns’ index (30), the diagnostic performance was determined in terms of sensitivity, specificity and area under the ROC curves.”
Method
Twelve-Month Outcomes After Transplant of Hepatitis C–Infected Kidneys Into Uninfected Recipients
Reese, P. P., Abt, P. L., Blumberg, E. A., Deerlin, V. M. V., Bloom, R. D., Potluri, V. S., Levine, M. H., Porrett, P. M., Sawinski, D. L., Nazarian, S. M., et al. (2018) · Annals of Internal Medicine · doi:10.7326/m18-0749 · Cited by 225 · see citing works
AASLD Practice Guideline on imaging-based noninvasive liver disease assessment of hepatic fibrosis and steatosis
Sterling, R. K., Duarte‐Rojo, A., Patel, K., Asrani, S. K., Alsawas, M., Dranoff, J. A., Fiel, M. I., Murad, M. H., Leung, D. H., Levine, D., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000000843 · Cited by 232 · see citing works
Impact of non-invasive biomarkers on hepatology practice: past, present and future
Anstee, Q. M., Castera, L., & Loomba, R. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.03.026 · Cited by 224 · see citing works
Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH
Hendrikx, T., Porsch, F., Kiss, M. G., Rajcic, D., Papac-Miličević, N., Hoebinger, C., Goederle, L., Hladik, A., Shaw, L. E., Horstmann, H., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.06.004 · Cited by 220 · see citing works
Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study
Vali, Y., Lee, J., Boursier, J., Petta, S., Wonders, K., Tiniakos, D., Bedossa, P., Geier, A., Francque, S., Allison, M., et al. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(23)00017-1 · Cited by 224 · see citing works
“There were no significant differences in detecting advanced fibrosis between the two subgroups, with similar AUCs (appendix p 13).”
Predictive Accuracy of the Veterans Aging Cohort Study Index for Mortality With HIV Infection
Justice, A. C., Modur, S. P., Tate, J. P., Althoff, K. N., Jacobson, L. P., Gebo, K. A., Kitahata, M. M., Horberg, M. A., Brooks, J. T., Buchacz, K. A., et al. (2012) · JAIDS Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/qai.0b013e31827df36c · Cited by 220 · see citing works
“FIB-4, composed of AST, ALT, platelets, and age, has been validated as an indicator of liver fibrosis [FIB-4 = (years of age · AST)/(platelets in 100/ L · square root of ALT)].(31) eGFR, composed of serum creatinine age, gender, and race, was included as a validated indicator of impaired renal function [eGFR = 186.”
Method
Differential Clinical Characteristics and Mortality Outcomes in Persons With NAFLD and/or MAFLD
Nguyen, V. H., Le, M. H., Cheung, R. C., & Nguyen, M. H. (2021) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2021.05.029 · Cited by 217 · see citing works
Development and Validation of a Deep Learning System for Staging Liver Fibrosis by Using Contrast Agent–enhanced CT Images in the Liver
Choi, K. J., Jang, J. K., Lee, S. S., Sung, Y. S., Shim, W. H., Kim, H. S., Yun, J., Choi, J., Lee, Y., Kang, B.-K., et al. (2018) · Radiology · doi:10.1148/radiol.2018180763 · Cited by 219 · see citing works
Non-invasive diagnosis of advanced fibrosis and cirrhosis
Sharma, S. A. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i45.16820 · Cited by 214 · see citing works
The ALBI score: From liver function in patients with HCC to a general measure of liver function
Toyoda, H., & Johnson, P. J. (2022) · JHEP Reports · doi:10.1016/j.jhepr.2022.100557 · Cited by 221 · see citing works
Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non‐alcoholic fatty liver disease
Schwimmer, J. B., Newton, K. P., Awai, H. I., Choi, L., Garcia, M. A., Ellis, L., VanderWall, K. J., & Fontanesi, J. (2013) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12518 · Cited by 212 · see citing works
Statins Are Associated With a Decreased Risk of Decompensation and Death in Veterans With Hepatitis C–Related Compensated Cirrhosis
Mohanty, A., Tate, J. P., & García–Tsao, G. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.10.007 · Cited by 209 · see citing works
“The FIB-4 index was calculated at baseline as follows: (age in years aspartate aminotransferase level in U/L)/(platelet count 10(9)/L) (ALT level in U/L).(16) Prior studies have shown that it is useful in ruling in cirrhosis in patients with chronic liver disease,(17)”
Biomarkers of liver fibrosis: Clinical translation of molecular pathogenesis or based on liver-dependent malfunction tests
Gressner, O. A., Weiskirchen, R., & Gressner, A. M. (2007) · Clinica Chimica Acta · doi:10.1016/j.cca.2007.02.038 · Cited by 207 · see citing works
“ulin, age, gender HCV 63 89 [21] HCV 78 79 [39] HCV/HIV 70 74 [40]”
Feasibility of liver transient elastography with FibroScan® using a new probe for obese patients
de Lédinghen, V., Vergniol, J., Foucher, J., El-Hajbi, F., Merrouche, W., & Rigalleau, V. (2010) · Liver International · doi:10.1111/j.1478-3231.2010.02258.x · Cited by 205 · see citing works
“Liver International (2010) c 2010 John Wiley & Sons A/S 1045 Results presented in Table 3 show that, in the subset of patients who could be measured successfully with both probes, liver stiffness measurement obtained with the M probe correlated significantly with platelets count, PT, GGT, AST, ALT, fasting glucose, FI…”
MethodInfluential
Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C
Nagata, H., Nakagawa, M., Asahina, Y., Sato, A., Asano, Y., Tsunoda, T., Miyoshi, M., Kaneko, S., Otani, S., Kawai‐Kitahata, F., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.05.028 · Cited by 205 · see citing works
Does an Index Composed of Clinical Data Reflect Effects of Inflammation, Coagulation, and Monocyte Activation on Mortality Among Those Aging With HIV?
Justice, A. C., Freiberg, M. S., Tracy, R. P., Kuller, L. H., Tate, J., Goetz, M. B., Fiellin, D. A., Vanasse, G. J., Butt, A. A., Rodriguez‐Barradas, M. C., et al. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cir989 · Cited by 204 · see citing works
“Further, although there is growing evidence that FIB-4 is an excellent indicator of liver fibrosis among those with HIV and/or HCV infection [28, 29], its association with inflammation and all-cause mortality has not been previously reported.”
Background
Collagen biology and non‐invasive biomarkers of liver fibrosis
Karsdal, M. A., Daniels, S. J., Holm Nielsen, S., Bager, C., Rasmussen, D. G. K., Loomba, R., Surabattula, R., Villesen, I. F., Luo, Y., Shevell, D., et al. (2020) · Liver International · doi:10.1111/liv.14390 · Cited by 197 · see citing works
Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV
Limketkai, B. N., Mehta, S. H., Sutcliffe, C. G., Higgins, Y. M., Torbenson, M. S., Brinkley, S., Moore, R. D., Thomas, D. L., & Sulkowski, M. (2012) · JAMA · doi:10.1001/jama.2012.7844 · Cited by 202 · see citing works
Novel 3D Magnetic Resonance Elastography for the Noninvasive Diagnosis of Advanced Fibrosis in NAFLD: A Prospective Study
Loomba, R. S., Cui, J. Y., Wolfson, T. J., Haufe, W. M., Hooker, J. C., Szeverenyi, N. M., Ang, B., Bhatt, A., Wang, K., Aryafar, H., et al. (2016) · The American Journal of Gastroenterology · doi:10.1038/ajg.2016.65 · Cited by 202 · see citing works
Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events
Boursier, J., Hagström, H., Ekstedt, M., Moreau, C., Bonacci, M., Cure, S., Ampuero, J., Nasr, P., Tallab, L., Canivet, C. M., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2021.12.031 · Cited by 206 · see citing works
Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease
Hagström, H., Talbäck, M., Andreasson, A., Walldius, G., & Hammar, N. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.06.007 · Cited by 199 · see citing works
An internationally generalizable risk index for mortality after one year of antiretroviral therapy
Tate, J. P., Justice, A. C., Hughes, M. D., Bonnet, F., Reiss, P., Mocroft, A., Nattermann, J., Lampe, F. C., Bucher, H. C., Sterling, T. R., et al. (2012) · AIDS · doi:10.1097/qad.0b013e32835b8c7f · Cited by 199 · see citing works
“FIB-4, composed of AST, ALT, platelets and age, is a validated indicator of liver fibrosis [FIB41⁄4 (years of age AST)/(platelets in 100/l sqrt of ALT)] [21].”
Background
Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial
Thompson, R. J., Arnell, H., Artan, R., Baumann, U., Calvo, P. L., Czubkowski, P., Dalgıç, B., D’Antiga, L., Durmaz, Ö., Fischler, B., et al. (2022) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(22)00093-0 · Cited by 199 · see citing works
Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease
Younes, R., Caviglia, G. P., Govaere, O., Rosso, C., Armandi, A., Sanavia, T., Pennisi, G., Liguori, A., Francione, P., Gallego-Durán, R., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.05.008 · Cited by 196 · see citing works
Prevalence of NAFLD, MAFLD and associated advanced fibrosis in the contemporary United States population
Ciardullo, S., & Perseghin, G. (2021) · Liver International · doi:10.1111/liv.14828 · Cited by 191 · see citing works

Validation and Comparison of Simple Noninvasive Indexes for Predicting Liver Fibrosis in HIV-HCV-Coinfected Patients: ANRS CO3 Aquitaine Cohort
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FIB-4: A simple, inexpensive and accurate marker of fibrosis in HCV-infected patients
Vallet‐Pichard, A., Mallet, V. O., & Pol, S. (2006) · Hepatology · doi:10.1002/hep.21334 · Cited by 100 · see citing works
Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: The fibrovic study – ANRS HC02
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Identification of liver fibrosis in HIV/HCV‐coinfected patients using a simple predictive model based on routine laboratory data
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Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes
Macı́as, J., González, J. A. G., González-Serrano, M., Merino, D., Cano, P., Mira, J. A., Arizcorreta-Yarza, A., Ruíz-Morales, J., Lomas-Cabeza, J. M., García-García, J. Á., et al. (2005) · Gut · doi:10.1136/gut.2005.065904 · Cited by 123 · see citing works

Authors: Sterling, R. K., Lissen, E., Clumeck, N., Sola, R., Correa, M. C., Montaner, J., S. Sulkowski, M., Torriani, F. J., Dieterich, D. T., Thomas, D. L., Messinger, D., & Nelson, M.
Affiliations: Virginia Commonwealth University (US)
James J. Peters VA Medical Center (US)
Centre Hospitalier Universitaire de Saint-Pierre (BE)
Universitat Autònoma de Barcelona (ES)
University of British Columbia (CA)
University of California San Diego (US)
Icahn School of Medicine at Mount Sinai (US)
Johns Hopkins University (US)
Chelsea and Westminster Hospital (GB)
Corresponding author: Sterling, Richard K.
ORCID: Sterling, Richard K.
Montaner, Julio
Torriani, Francesca J.
Thomas, David L.
Nelson, Mark
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-06
Volume: 43
Issue: 6
Pages: 1317-1325
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1002/hep.21178
OpenAlex: W2064387090
Cited by: 5,021
References: 48
Citations by year: 2026: 497 · 2025: 523 · 2024: 523 · 2023: 490 · 2022: 492 · 2021: 494 · 2020: 390 · 2019: 333 · 2018: 239 · 2017: 210 · 2016: 204 · 2015: 158 · 2014: 92 · 2013: 83 · 2012: 67
FWCI: 29.41
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 3379 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Funders: National Institute on Drug Abuse (R01DA016078)
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK064578)
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
Health Sciences › Medicine › Hepatology › Hepatitis C virus research
Keywords: HIV/HCV coinfection, liver fibrosis, FIB-4, liver biopsy avoidance, platelet count, transaminases, international normalized ratio, Ishak score, fibrosis staging
MeSH terms: Age Factors, Biopsy, Needle, Blood Chemical Analysis, Diagnostic Tests, Routine, Female, Humans, Immunohistochemistry, Liver Cirrhosis, Liver Function Tests, Male, Predictive Value of Tests, Probability, Prognosis, Retrospective Studies, ROC Curve, Sensitivity and Specificity, Severity of Illness Index, Sex Factors, Reproducibility of Results, Cohort Studies, HIV Infections, Logistic Models, Disease Progression, Risk Assessment, Hepatitis C, Chronic

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Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection†‡

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