{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:33:53Z","timestamp":1790616833585,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Research on Hepatitis from the Japan Agency for Medical Research and Development","award":["JP23fk0210097h0003"],"award-info":[{"award-number":["JP23fk0210097h0003"]}]},{"name":"JSPS KAKENHI","award":["24K11116"],"award-info":[{"award-number":["24K11116"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>The creatinine-to-cystatin C ratio (CCR), a surrogate for skeletal muscle mass, may also be associated with liver fibrosis due to the strong link between sarcopenia and liver disease progression. We aimed to evaluate the utility of CCR as a noninvasive marker of liver fibrosis in metabolic-dysfunction-associated steatotic liver disease (MASLD). This retrospective study included 104 patients with biopsy-proven MASLD. CCR was calculated using serum creatinine and cystatin C levels. Liver fibrosis was staged histologically (F0\u2013F4), and skeletal muscle mass was assessed using the skeletal muscle index (SMI) on computed tomography. Associations between CCR and liver fibrosis, SMI, and nonalcoholic fatty liver disease activity score were analyzed. ROC analysis evaluated CCR performance alone and in combination with FIB-4 and enhanced liver fibrosis (ELF) scores. CCR values were significantly lower in patients with significant fibrosis (\u2265F2). The AUROC of CCR for detecting \u2265F2 fibrosis was 0.621 (95% CI: 0.509\u20130.733), with an optimal cutoff of 0.664. CCR alone yielded an AUC of 0.815 for predicting \u2265F2 fibrosis. Combining CCR with FIB-4 and ELF substantially improved diagnostic accuracy, increasing the AUROC from 0.621 (CCR alone) to 0.820 for the combined model. CCR correlated positively with SMI (r = 0.451, p &lt; 0.001). CCR is a simple, cost-effective biomarker reflecting muscle mass and liver fibrosis in MASLD. Combining CCR with established markers may enhance risk stratification and reduce the need for liver biopsy in selected cases.<\/jats:p>","DOI":"10.3390\/ijms26199560","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T15:38:55Z","timestamp":1759246735000},"page":"9560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Creatinine-to-Cystatin C Ratio Combined with FIB-4 and ELF for Noninvasive Fibrosis Assessment in MASLD"],"prefix":"10.3390","volume":"26","author":[{"given":"Masafumi","family":"Oyama","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-5318","authenticated-orcid":false,"given":"Tadashi","family":"Namisaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Shibamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-5609","authenticated-orcid":false,"given":"Satoshi","family":"Iwai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Takami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2402-574X","authenticated-orcid":false,"given":"Yukihisa","family":"Fujinaga","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Takaya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Evidence-Based Medicine, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6295-3283","authenticated-orcid":false,"given":"Norihisa","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3049-3443","authenticated-orcid":false,"given":"Shinya","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5794-1512","authenticated-orcid":false,"given":"Koh","family":"Kitagawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Kaji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-5633","authenticated-orcid":false,"given":"Akira","family":"Mitoro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4515-6047","authenticated-orcid":false,"given":"Kiyoshi","family":"Asada","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Masuda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9174-2477","authenticated-orcid":false,"given":"Junichi","family":"Hanatani","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Yoshiji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, 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Obes. Metab. Syndr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"479","DOI":"10.2147\/DMSO.S499517","article-title":"Association of sensitivity to thyroid hormones and non-alcoholic fatty liver disease and the severity of liver fibrosis in euthyroid adults: A retrospective study","volume":"18","author":"Zhou","year":"2025","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.tem.2024.02.007","article-title":"Current status and future trends of the global burden of MASLD","volume":"35","author":"Miao","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1097\/HEP.0000000000000323","article-title":"AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease","volume":"77","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/hep.29179","article-title":"Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient data-based meta-analysis","volume":"67","author":"Herrmann","year":"2018","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3748\/wjg.v20.i2.475","article-title":"Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"20","author":"Sumida","year":"2014","journal-title":"World. J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1002\/jcsm.13334","article-title":"Impact of sarcopenia on the survival of patients undergoing liver transplantation for decompensated liver cirrhosis","volume":"14","author":"Zhou","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sandireddy, R., Sakthivel, S., Gupta, P., Behari, J., Tripathi, M., and Singh, B.K. (2024). Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1433857"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41574-022-00641-2","article-title":"Exerkines in health, resilience and disease","volume":"18","author":"Chow","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_11","first-page":"101165","article-title":"Sarcopenia and metabolic dysfunction-associated steatotic liver disease: The role of exercise-related biomarkers","volume":"17","year":"2025","journal-title":"World J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zheng, W.H., Zhu, Y.B., Yao, Y., and Huang, H.B. (2022). Serum creatinine\/cystatin C ratio as a muscle mass evaluating tool and prognostic indicator for hospitalized patients: A meta-analysis. Front. Med., 9.","DOI":"10.3389\/fmed.2022.1058464"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ning, X., Xie, C., and Kong, Y. (2024). Serum creatinine- and cystatin C-based indices are associated with the risk of subsequent sarcopenia: Evidence from the China Health and Retirement Longitudinal Study. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1471068"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Shi, S., Jiang, Y., Chen, W., Chen, K., Liao, Y., and Huang, K. (2022). Diagnostic and prognostic value of the Creatinine\/Cystatin C ratio for low muscle mass evaluation among US adults. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.897774"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ding, P., Guo, H., Sun, C., Chen, S., Yang, P., Tian, Y., Lowe, S., and Zhao, Q. (2022). Serum creatinine\/cystatin C ratio is a systemic marker of sarcopenia in patients with gastrointestinal stromal tumours. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.963265"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100635","DOI":"10.1016\/j.jnha.2025.100635","article-title":"Creatinine and cystatin C-based indices for predicting sarcopenia, frailty and disability in older community-dwelling adults","volume":"29","author":"Bai","year":"2025","journal-title":"J. Nutr. Health Aging"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"He, Q., Jiang, J., Xie, L., Zhang, L., and Yang, M. (2018). A sarcopenia index based on serum creatinine and cystatin C cannot accurately detect either low muscle mass or sarcopenia in urban community-dwelling older people. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-29808-6"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116","DOI":"10.14283\/jfa.2024.13","article-title":"Serum creatinine\u2013cystatin C based screening of sarcopenia in community dwelling older adults: A cross-sectional analysis","volume":"13","author":"Matsuzawa","year":"2024","journal-title":"J. Frailty Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e70040","DOI":"10.1002\/jcsm.70040","article-title":"The predictive power of the cystatin C-creatinine score in assessing frailty","volume":"16","author":"Deng","year":"2025","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/cen.14990","article-title":"Lower creatinine to cystatin C ratio is associated with an increased risk of MASLD: A cross-sectional and prospective study of 368,634 UK biobank participants","volume":"100","author":"Wang","year":"2024","journal-title":"Clin. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1136\/gutjnl-2020-321299","article-title":"Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology","volume":"69","author":"Neuberger","year":"2020","journal-title":"Gut"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zambon Azevedo, V., Silaghi, C.A., Maurel, T., Silaghi, H., Ratziu, V., and Pais, R. (2021). Impact of sarcopenia on the severity of the liver damage in patients with non-alcoholic fatty liver disease. Front. Nutr., 8.","DOI":"10.3389\/fnut.2021.774030"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105346","DOI":"10.3748\/wjg.v31.i20.105346","article-title":"Metabolic dysfunction-associated steatotic liver disease: A story of muscle and mass","volume":"31","author":"Isakov","year":"2025","journal-title":"World J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1016\/j.clnu.2019.07.027","article-title":"Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study","volume":"39","author":"Tabara","year":"2020","journal-title":"Clin. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18162","DOI":"10.1073\/pnas.1317049110","article-title":"Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-kappaB-mediated mechanism","volume":"110","author":"Qiu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.34067\/KID.0003202022","article-title":"Advantages, limitations, and clinical considerations in using cystatin C to estimate GFR","volume":"3","author":"Chen","year":"2022","journal-title":"Kidney360"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1111\/hepr.13679","article-title":"Reduced handgrip strength predicts poorer survival in chronic liver diseases: A large multicenter study in Japan","volume":"51","author":"Nishikawa","year":"2021","journal-title":"Hepatol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/ageing\/afy169","article-title":"Sarcopenia: Revised European consensus on definition and diagnosis","volume":"48","author":"Bahat","year":"2019","journal-title":"Age Ageing"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"112721","DOI":"10.1016\/j.exger.2025.112721","article-title":"Prevalence of sarcopenia in asian older adults: A comparison of nine diagnostic criteria across different regions","volume":"202","author":"Chiu","year":"2025","journal-title":"Exp. Gerontol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Aleknavi\u010di\u016bt\u0117-Valien\u0117, G., and Banys, V. (2022). Clinical importance of laboratory biomarkers in liver fibrosis. Biochem. Med., 32.","DOI":"10.11613\/BM.2022.030501"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/s41401-022-00874-x","article-title":"Histological assessment based on liver biopsy: The value and challenges in NASH drug development","volume":"43","author":"Tong","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings","volume":"53","author":"Brunt","year":"2011","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_34","first-page":"282","article-title":"Spectrum of histological features in non-alcoholic fatty liver disease","volume":"20","author":"Vasdev","year":"2007","journal-title":"Natl. Med. J. India"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1007\/s00535-024-02154-3","article-title":"Alcohol-associated liver disease increases the risk of muscle loss and mortality in patients with cirrhosis","volume":"59","author":"Kunzler","year":"2024","journal-title":"J. Gastroenterol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T15:58:06Z","timestamp":1759247886000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":35,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199560"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199560","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]}}}