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      Risk of Liver Cirrhosis and Hepatocellular Carcinoma after Fontan Operation: A Need for Surveillance


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          Liver cirrhosis and hepatocellular carcinoma (HCC) are serious late complications that can occur after the Fontan procedure. This study aimed to investigate the cumulative incidence of cirrhosis and HCC and to identify specific features distinguishing HCC from benign arterial-phase hyperenhancing (APHE) nodules that developed after the Fontan operation. We retrospectively enrolled 313 post-Fontan patients who had been followed for more than 5 years and had undergone ultrasound or computed tomography (CT) of the liver between January 2000 and August 2018. Cirrhosis was diagnosed radiologically. The estimated cumulative incidence rates of cirrhosis at 5, 10, 20, and 30 years after the Fontan operation were 1.3%, 9.2%, 56.6%, and 97.9%, respectively. Multiphasic CT revealed that 18 patients had APHE nodules that were ≥1 cm in size and showed washout in the portal venous phase (PVP)/delayed phase, which met current noninvasive HCC diagnosis criteria. Among them, only seven patients (38.9%, 7/18) were diagnosed with HCC. After cirrhosis developed, the annual incidence of HCC was 1.04%. The appearance of washout in the PVP ( p = 0.006), long time elapsed since the initial Fontan operation ( p = 0.04), large nodule size ( p = 0.03), and elevated serum α-fetoprotein (AFP) level ( p < 0.001) were significantly associated with HCC. In conclusion, cirrhosis is a frequent late complication after Fontan operation, especially after 10 years, and HCC is not a rare complication after cirrhosis development. Diagnosis of HCC should not be based solely on the current imaging criteria, and washout on PVP and clinical features might be helpful to differentiate HCC nodules from benign APHE nodules.

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          Most cited references28

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          Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association

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            The Fontan circulation.

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              Hepatic changes in the failing Fontan circulation.

              The failing Fontan circulation is associated with hepatic impairment. The nature of this liver injury is poorly defined. To establish the gross and histological liver changes of patients with Fontan circulation relative to clinical, biochemical and haemodynamic findings. Patients were retrospectively assessed for extracardiac Fontan conversion between September 2003 and June 2005, according to an established clinical protocol. Twelve patients, mean age 24.6 (range 15.8-43.4) years were identified. The mean duration since the initial Fontan procedure was 14.1 (range 6.9-26.4) years. Zonal enhancement of the liver (4/12) on CT was more common in patients with lower hepatic vein pressures (p = 0.007), and in those with absent cardiac cirrhosis on histological examination (p = 0.033). Gastro-oesophageal varices (4/12) were more common in patients with higher hepatic vein pressure (21 (6.3) vs 12.2 (2.2) mm Hg, p = 0.013) and associated with more advanced cirrhosis (p = 0.037). The extent of cirrhosis (7/12) was positively correlated with the hepatic vein pressure (r = 0.83, p = 0.003). A significant positive correlation was found between the Fontan duration and the degree of hepatic fibrosis (r = 0.75, p = 0.013), as well as presence of broad scars (r = 0.71, p = 0.021). Protein-losing enteropathy (5/12) occurred more frequently in patients with longer Fontan duration (11.7 (3.2) vs 17.9 (6.1) years, p = 0.038). Liver injury, which can be extensive in this patient group, is related to Fontan duration and hepatic vein pressures. CT scan assists non-invasive assessment. Cardiac cirrhosis with the risk of developing gastro-oesophageal varices and regenerative liver nodules, a precursor to hepatocellular carcinoma, is common in this patient group.

                Author and article information

                Cancers (Basel)
                Cancers (Basel)
                06 July 2020
                July 2020
                : 12
                : 7
                [1 ]Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea; yojusi@ 123456naver.com (J.S.Y.); yunbin@ 123456hanmail.net (Y.B.L.); pindra@ 123456empal.com (J.-H.L.); ydoctor2@ 123456hanmail.net (S.J.Y.); yoonjun@ 123456snu.ac.kr (Y.J.K.); yoonjh@ 123456snu.ac.kr (J.-H.Y.)
                [2 ]Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan 47392, Korea
                [3 ]Department of Radiology, Seoul National University College of Medicine, Seoul 03080, Korea; dhlee.rad@ 123456gmail.com (D.H.L.); choiyounghun@ 123456gmail.com (Y.H.C.)
                [4 ]Division of Pediatric Cardiology, Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul 03080, Korea; mksong52@ 123456hanmail.net (M.K.S.); ped9526@ 123456snu.ac.kr (G.B.K.)
                [5 ]Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea; medannabel@ 123456gmail.com
                Author notes
                [* ]Correspondence: creatio3@ 123456snu.ac.kr (E.J.C.); eunjbaek@ 123456snu.ac.kr (E.J.B.); Tel.: +82-2-2072-2242 (E.J.C.); +82-2-2072-3097 (E.J.B.); Fax: +82-2-762-9662 (E.J.C.); +82-2-743-3455 (E.J.B.)

                These two authors contributed equally to this work.


                These two authors are corresponding authors.

                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).


                fontan-associated liver disease,hepatocellular carcinoma,liver cirrhosis,surveillance


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