{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:51:47Z","timestamp":1789678307552,"version":"4.0.1"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"\nAims<\/jats:title>\nThe incidence of hepatocellular carcinoma (HCC) in patients with Fontan-associated liver disease (i.e., FALD-HCC) has increased over time. However, the risk factors for HCC development remain unclear. Here, we compared the levels of non-invasive markers to the survival rate of FALD-HCC patients.<\/jats:p>\n<\/jats:sec>\n\nMethods<\/jats:title>\nFrom 2003 to 2021, 154 patients (66 men, 42.9%) developed liver disease after undergoing Fontan procedures. HCC was diagnosed in 15 (9.7%) (8 men, 53.3%) at a median age of 34 years (range, 21\u201345 years). We compared FALD-HCC and non-HCC cases; we generated marker level cutoffs using receiver operating characteristic curves. We sought to identify risk factors for HCC and mortality.<\/jats:p>\n<\/jats:sec>\n\nResults<\/jats:title>\nThe incidence of HCC was 4.9% in FALD patients within 20 years after the Fontan procedure. Compared with non-HCC patients, FALD-HCC patients exhibited higher incidences of polysplenia and esophageal varices. At the time of HCC development, the hyaluronic acid (HA) level (p = 0.04) and the fibrosis-4 index (p = 0.02) were significantly higher in FALD-HCC patients than in non-HCC patients; the total bilirubin (T-BIL) level (p = 0.07) and the model for end-stage liver disease score [excluding the international normalized ratio (MELD-XI)] (p = 0.06) tended to be higher in FALD-HCC patients. Within approximately 20 years of the Fontan procedure, 10 patients died (survival rate, 96.9%). Kaplan\u2013Meier curve analysis indicated that patients with T-BIL levels \u2265 2.2 mg\/dL, HA levels \u2265 55.5 ng\/mL, and MELD-XI scores \u2265 18.7 were at high risk of HCC, a generally poor prognosis, and both polysplenia and esophageal varices. Multivariate Cox regression analyses indicated that the complication of polysplenia [Hazard ratio (HR): 10.915] and a higher MELD-XI score (HR: 1.148, both p < 0.01) were independent risk factors for FALD-HCC.<\/jats:p>\n<\/jats:sec>\n\nConclusions<\/jats:title>\nThe complication of polysplenia and a MELD-XI score may predict HCC development and mortality in FALD patients.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0270230","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T17:35:28Z","timestamp":1655487328000},"page":"e0270230","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":40,"title":["Risk factors for Fontan-associated hepatocellular carcinoma"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-4324","authenticated-orcid":true,"given":"Tomomi","family":"Kogiso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi","family":"Sagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Taniai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Shimada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Inai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2268-3266","authenticated-orcid":true,"given":"Tokuko","family":"Shinohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsutoshi","family":"Tokushige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"pone.0270230.ref001","author":"P 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Japan.","volume":"82","author":"M Kuwabara","year":"2018","journal-title":"Circ J"},{"key":"pone.0270230.ref008","article-title":"Characteristics of hepatocellular carcinoma arising from Fontan-associated liver disease","author":"T Sagawa","year":"2020","journal-title":"Hepatol Res"},{"issue":"4","key":"pone.0270230.ref009","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.jhep.2019.10.027","article-title":"Prevalence, features and predictive factors of liver nodules in Fontan surgery patients: The VALDIG Fonliver prospective cohort","volume":"72","author":"L T\u00e9llez","year":"2020","journal-title":"J Hepatol"},{"issue":"25","key":"pone.0270230.ref010","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1161\/CIRCULATIONAHA.121.056870","article-title":"Incidence and Expected Probability of Liver Cirrhosis and Hepatocellular Carcinoma After Fontan Operation","volume":"144","author":"M Nii","year":"2021","journal-title":"Circulation"},{"key":"pone.0270230.ref011","doi-asserted-by":"crossref","first-page":"162","DOI":"10.9794\/jspccs.29.162","article-title":"Liver diseases in the fontan circulation","volume":"29","author":"T. Fujisawa","year":"2013","journal-title":"Pediatr. Cardiol Cardiac Surg"},{"issue":"2","key":"pone.0270230.ref012","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.healun.2016.07.011","article-title":"Predictive value of biomarkers of hepatic fibrosis in adult Fontan patients","volume":"36","author":"FM Wu","year":"2017","journal-title":"J Heart Lung Transplant"},{"issue":"6","key":"pone.0270230.ref013","doi-asserted-by":"crossref","first-page":"100362","DOI":"10.1016\/j.jhepr.2021.100362","article-title":"Non-invasive biomarkers of Fontan-associated liver disease","volume":"3","author":"J Emamaullee","year":"2021","journal-title":"JHEP Rep"},{"issue":"7","key":"pone.0270230.ref014","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1007\/s00246-016-1428-1","article-title":"MELD-XI Scores Correlate with Post-Fontan Hepatic Biopsy Fibrosis Scores","volume":"37","author":"WN Evans","year":"2016","journal-title":"Pediatr 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Sterling","year":"2006","journal-title":"Hepatology"},{"issue":"10","key":"pone.0270230.ref018","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cgh.2009.05.033","article-title":"Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease","volume":"7","author":"AG Shah","year":"2009","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"6","key":"pone.0270230.ref019","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1097\/01.sla.0000254368.65878.da","article-title":"Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC\/UICC TNM systems in a cohort of 13,772 patients in Japan.","volume":"245","author":"M Minagawa","year":"2007","journal-title":"Ann Surg"},{"issue":"1","key":"pone.0270230.ref020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1443-1661.2009.00929.x","article-title":"General rules for recording endoscopic findings of esophagogastric varices (2nd edition).","volume":"22","author":"T Tajiri","year":"2010","journal-title":"Dig Endosc"},{"issue":"8","key":"pone.0270230.ref021","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.cgh.2007.02.039","article-title":"Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis","volume":"5","author":"GN Ioannou","year":"2007","journal-title":"Clin Gastroenterol Hepatol"},{"key":"pone.0270230.ref022","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ijcard.2020.08.057","article-title":"Hepatocellular carcinoma and the Fontan circulation: Clinical presentation and outcomes","volume":"322","author":"M Possner","year":"2021","journal-title":"Int J Cardiol"},{"issue":"10","key":"pone.0270230.ref023","doi-asserted-by":"crossref","first-page":"e0257441","DOI":"10.1371\/journal.pone.0257441","article-title":"Platelet count and abdominal dynamic CT are useful in predicting and screening for gastroesophageal varices after Fontan 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Abe","year":"2014","journal-title":"PLoS One."},{"issue":"10","key":"pone.0270230.ref030","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1111\/j.1478-3231.2007.01597.x","article-title":"Hepatocellular carcinoma with situs inversus totalis and polysplenia syndrome","volume":"27","author":"T Li","year":"2007","journal-title":"Liver Int"},{"issue":"1","key":"pone.0270230.ref031","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000118830","article-title":"Extended hemi-hepatectomy with portal vein reconstruction in a patient with situs ambiguous","volume":"2","author":"K Sugimachi","year":"2008","journal-title":"Case Rep Gastroenterol"},{"issue":"6","key":"pone.0270230.ref032","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s00595-014-0997-y","article-title":"Hepatic resection for hepatocellular carcinoma in a patient with situs ambiguous with polysplenia: report of a case","volume":"45","author":"M Matsuda","year":"2015","journal-title":"Surg 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