Heart, Lung and Circulation
Original Article|Articles in Press

Fontan Hepatopathy – Managing Unknowns

Published:January 13, 2023DOI:

      Background and Aims

      How to best monitor Fontan associated liver disease (FALD) remains unclear. We describe results from a prospective liver care pathway in adults (n=84) with a Fontan circulation.


      Routine assessment of the liver, by acoustic radiation force frequency and ultrasound was undertaken. Results, including liver biochemistry, systemic ventricular function (echocardiography), functional class, medication use and clinical endpoints (varices, hepatocellular carcinoma, heart transplantation and death) were collated.


      Most individuals returned a cirrhotic range acoustic radiation force impulse imaging (ARFI) result. ARFI values were greater in the proportion of individuals with hepatic nodularity (p=0.024). Univariate analysis demonstrated moderate correlation with platelet number (Spearmans rho= -0.376, p=0.049). Patients with clinical endpoints had lower platelets (p=0.012) but only a trend to hepatic nodularity (p=0.057). Clinical endpoints were more common in those with ventricular dysfunction (p=0.011).
      Multivariate analysis revealed that age at Fontan and being on angiotensin converting enzyme inhibitors (ACEI) predicted ARFI score (β=0.06 (95% CI 0.01–0.09), p=0.007 and β=0.53 (95% CI 0.17–0.89), p=0.005, respectively). However, these associations were not significant once adjusted for Fontan type, age at ARFI, systemic ventricle morphology, ventricle function, or Model for End-stage Liver Disease (MELD-XI) excluding international normalised ratio (INR) (p>0.05 for all).


      Ideal FALD monitoring remains unclear. ARFI has utility as a binary non-invasive indicator of cirrhosis, highlighting individuals who may need more frequent ongoing monitoring for hepatocellular carcinoma. However, no definite advantage to serial ARFI, once cirrhotic range ARFI results are present, has been identified.


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        • Bouma B.J.
        • Mulder B.J.
        Changing landscape of congenital heart disease.
        Circ Res. 2017; 120: 908-922
        • Wu F.M.
        • Ukomadu C.
        • Odze R.D.
        • Valente A.M.
        • Mayer Jr., J.E.
        • Earing M.G.
        Liver disease in the patient with Fontan circulation.
        Congenit Heart Dis. 2011; 6: 190-201
        • Gordon-Walker T.T.
        • Bove K.
        • Veldtman G.
        Fontan-associated liver disease: a review.
        J Cardiol. 2019; 74: 223-232
        • Keung C.Y.
        • Zentner D.
        • Gibson R.N.
        • Phan D.H.
        • Grigg L.E.
        • Sood S.
        • et al.
        Fontan-associated liver disease: pathophysiology, investigations, predictors of severity and management.
        Eur J Gastroenterol Hepatol. 2019;
        • Greenway S.C.
        • Crossland D.S.
        • Hudson M.
        • Martin S.R.
        • Myers R.P.
        • Prieur T.
        • et al.
        Fontan-associated liver disease: implications for heart transplantation.
        J Heart Lung Transplant. 2016; 35: 26-33
        • Zentner D.
        • Celermajer D.S.
        • Gentles T.
        • d'Udekem Y.
        • Ayer J.
        • Blue G.M.
        • et al.
        Management of people with a Fontan circulation: a Cardiac Society of Australia and New Zealand position statement.
        Heart Lung Circ. 2020; 29: 5-39
        • Rychik J.
        • Veldtman G.
        • Rand E.
        • Russo P.
        • Rome J.J.
        • Krok K.
        • et al.
        The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium.
        Pediatr Cardiol. 2012; 33: 1001-1012
        • Daniels C.J.
        • Bradley E.A.
        • Landzberg M.J.
        • Aboulhosn J.
        • Beekman 3rd, R.H.
        • Book W.
        • et al.
        Fontan-associated liver disease: proceedings from the American College of Cardiology Stakeholders Meeting, October 1 to 2, 2015, Washington DC.
        J Am Coll Cardiol. 2017; 70: 3173-3194
        • Stout K.K.
        • Daniels C.J.
        • Aboulhosn J.A.
        • Bozkurt B.
        • Broberg C.S.
        • Colman J.M.
        • et al.
        2018 AHA/ACC guideline for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J Am Coll Cardiol. 2019; 73: 1494-1563
        • Rychik J.
        • Atz A.M.
        • Celermajer D.S.
        • Deal B.J.
        • Gatzoulis M.A.
        • Gewillig M.H.
        • et al.
        Evaluation and management of the child and adult with Fontan Circulation: a scientific statement from the American Heart Association.
        Circulation. 2019; CIR0000000000000696
        • Vaikunth S.S.
        • Higgins J.P.
        • Concepcion W.
        • Haeffele C.
        • Wright G.E.
        • Chen S.
        • et al.
        Does liver biopsy accurately measure fibrosis in Fontan-associated liver disease? A comparison of liver biopsy pre-combined heart and liver transplant and liver explant post-transplant.
        Clin Transplant. 2020; 34e14120
        • Wallihan D.B.
        • Podberesky D.J.
        Hepatic pathology after Fontan palliation: spectrum of imaging findings.
        Pediatr Radiol. 2013; 43: 330-338
        • Mancini M.
        • Salomone Megna A.
        • Ragucci M.
        • De Luca M.
        • Marino Marsilia G.
        • Nardone G.
        • et al.
        Reproducibility of shear wave elastography (SWE) in patients with chronic liver disease.
        PLoS One. 2017; 12e0185391
        • Melero-Ferrer J.L.
        • Osa-Saez A.
        • Buendia-Fuentes F.
        • Ballesta-Cunat A.
        • Flors L.
        • Rodriguez-Serrano M.
        • et al.
        Fontan circulation in adult patients: acoustic radiation force impulse elastography as a useful tool for liver assessment.
        World J Pediatr Congenit Heart Surg. 2014; 5: 365-371
        • Buendia-Fuentes F.
        • Melero-Ferrer J.L.
        • Plaza-Lopez D.
        • Rueda-Soriano J.
        • Osa-Saez A.
        • Aguero J.
        • et al.
        Noninvasive liver assessment in adult patients with Fontan circulation using acoustic radiation force impulse elastography and hepatic magnetic resonance imaging.
        World J Pediatr Congenit Heart Surg. 2018; 9: 22-30
        • Kim S.O.
        • Lee S.Y.
        • Jang S.I.
        • Park S.J.
        • Kwon H.W.
        • Kim S.H.
        • et al.
        Hepatic stiffness using shear wave elastography and the related factors for a Fontan circulation.
        Pediatr Cardiol. 2018; 39: 57-65
        • Di Maria M.V.
        • Silverman L.
        • Younoszai A.K.
        • Meyers M.L.
        • Capocelli K.E.
        • Narkewicz M.R.
        Acoustic radiation force impulse of the liver after Fontan operation: correlation with cardiopulmonary exercise test.
        Congenit Heart Dis. 2018; 13: 444-449
        • Lubert A.M.
        • Opotowsky A.R.
        • Palermo J.J.
        • Alsaied T.
        • Szugye C.
        • Anwar N.
        • et al.
        Relation of liver volume to adverse cardiovascular events in adolescents and adults with Fontan circulation.
        Am J Cardiol. 2022; 165: 88-94
        • Leong H.K.
        • Gibson R.N.
        • Sood S.
        • Nadebaum D.
        • Gorelik A.
        • Nicoll A.
        Change in acoustic radiation force impulse is a better indicator of liver disease progression or regression.
        Gastroenterol Hepatol Endosc. 2018; 3: 1-6
      1. EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
        J Hepatol. 2015; 63: 237-264
        • Fidai A.
        • Dallaire F.
        • Alvarez N.
        • Balon Y.
        • Clegg R.
        • Connelly M.
        • et al.
        Non-invasive investigations for the diagnosis of Fontan-associated liver disease in pediatric and adult fontan patients.
        Front Cardiovasc Med. 2017; 4: 15
        • Keung C.Y.
        • Zentner D.
        • Gibson R.N.
        • Phan D.H.
        • Grigg L.E.
        • Sood S.
        • et al.
        Fontan-associated liver disease (FALD): pathophysiology, investigations, predictors of severity and management.
        Eur Journal Gastroenterol Hepatol. 2020; 32: 907-915
        • Kamath P.S.
        • Wiesner R.H.
        • Malinchoc M.
        • Kremers W.
        • Therneau T.M.
        • Kosberg C.L.
        • et al.
        A model to predict survival in patients with end-stage liver disease.
        Hepatology. 2001; 33: 464-470
        • Assenza G.E.
        • Graham D.A.
        • Landzberg M.J.
        • Valente A.M.
        • Singh M.N.
        • Bashir A.
        • et al.
        MELD-XI score and cardiac mortality or transplantation in patients after Fontan surgery.
        Heart. 2013; 99: 491-496
        • Nadebaum D.
        • Gibson R.N.
        • Howell J.
        • Halliday J.
        • Christie M.
        • Gorelik A.
        • et al.
        Inter-operator concordance in acoustic radiation force impulse imaging (ARFI): a practical role for multiple operators to improve diagnostic performance.
        Journal of Gastroenterology and Hepatology. 2014; 29: 65-101
        • Bota S.
        • Sporea I.
        • Sirli R.
        • Popescu A.
        • Danila M.
        • Sendroiu M.
        Factors that influence the correlation of acoustic radiation force impulse (ARFI), elastography with liver fibrosis.
        Med Ultrason. 2011; 13: 135-140
        • Wai C.T.
        • Greenson J.K.
        • Fontana R.J.
        • Kalbfleisch J.D.
        • Marrero J.A.
        • Conjeevaram H.S.
        • et al.
        A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.
        Hepatology. 2003; 38: 518-526
        • Deng H.
        • Qi X.
        • Guo X.
        Diagnostic accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex scores in predicting the presence of esophageal varices in liver cirrhosis: a systematic review and meta-analysis.
        Medicine (Baltimore). 2015; 94e1795
        • Su C.W.
        • Chan C.C.
        • Hung H.H.
        • Huo T.I.
        • Huang Y.H.
        • Li C.P.
        • et al.
        Predictive value of aspartate aminotransferase to alanine aminotransferase ratio for hepatic fibrosis and clinical adverse outcomes in patients with primary biliary cirrhosis.
        J Clin Gastroenterol. 2009; 43: 876-883
        • Lin Z.H.
        • Xin Y.N.
        • Dong Q.J.
        • Wang Q.
        • Jiang X.J.
        • Zhan S.H.
        • et al.
        Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis.
        Hepatology. 2011; 53: 726-736
        • Sterling R.K.
        • Lissen E.
        • Clumeck N.
        • Sola R.
        • Correa M.C.
        • Montaner J.
        • et al.
        Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
        Hepatology. 2006; 43: 1317-1325
        • Evans W.N.
        • Acherman R.J.
        • Ciccolo M.L.
        • Carrillo S.A.
        • Galindo A.
        • Rothman A.
        • et al.
        MELD-XI scores correlate with post-Fontan hepatic biopsy fibrosis scores.
        Pediatr Cardiol. 2016; 37: 1274-1277
        • Heuman D.M.
        • Mihas A.A.
        • Habib A.
        • Gilles H.S.
        • Stravitz R.T.
        • Sanyal A.J.
        • et al.
        MELD-XI: a rational approach to "sickest first" liver transplantation in cirrhotic patients requiring anticoagulant therapy.
        Liver Transpl. 2007; 13: 30-37
        • Friedrich-Rust M.
        • Koch C.
        • Rentzsch A.
        • Sarrazin C.
        • Schwarz P.
        • Herrmann E.
        • et al.
        Noninvasive assessment of liver fibrosis in patients with Fontan circulation using transient elastography and biochemical fibrosis markers.
        J Thorac Cardiovasc Surg. 2008; 135: 560-567
        • Ghaferi A.A.
        • Hutchins G.M.
        Progression of liver pathology in patients undergoing the Fontan procedure: chronic passive congestion, cardiac cirrhosis, hepatic adenoma, and hepatocellular carcinoma.
        J Thorac Cardiovasc Surg. 2005; 129: 1348-1352
        • Kutty S.S.
        • Zhang M.
        • Danford D.A.
        • Hasan R.
        • Duncan K.F.
        • Kugler J.D.
        • et al.
        Hepatic stiffness in the bidirectional cavopulmonary circulation: the Liver Adult-Pediatric-Congenital-Heart-Disease Dysfunction Study group.
        J Thorac Cardiovasc Surg. 2016; 151: 678-684
        • DiPaola F.W.
        • Schumacher K.R.
        • Goldberg C.S.
        • Friedland-Little J.
        • Parameswaran A.
        • Dillman J.R.
        Effect of Fontan operation on liver stiffness in children with single ventricle physiology.
        Eur Radiol. 2017; 27: 2434-2442
        • Yoo B.W.
        • Choi J.Y.
        • Eun L.Y.
        • Park H.K.
        • Park Y.H.
        • Kim S.U.
        Congestive hepatopathy after Fontan operation and related factors assessed by transient elastography.
        J Thorac Cardiovasc Surg. 2014; 148: 1498-1505
        • Agnoletti G.
        • Ferraro G.
        • Bordese R.
        • Marini D.
        • Gala S.
        • Bergamasco L.
        • et al.
        Fontan circulation causes early, severe liver damage. Should we offer patients a tailored strategy?.
        Int J Cardiol. 2016; 209: 60-65
        • Talwar S.
        • Gudala V.
        • Joshi R.
        • Shalimar D.M.
        • Madhusudhan K.S.
        • Kalaivani M.
        • et al.
        Noninvasive assessment of liver stiffness in patients undergoing the Fontan procedure.
        World J Pediatr Congenit Heart Surg. 2020; 11: 572-577
        • Alsaied T.
        • Possner M.
        • Lubert A.M.
        • Trout A.T.
        • Szugye C.
        • Palermo J.J.
        • et al.
        Relation of magnetic resonance elastography to Fontan failure and portal hypertension.
        Am J Cardiol. 2019; 124: 1454-1459
        • Munsterman I.D.
        • Duijnhouwer A.L.
        • Kendall T.J.
        • Bronkhorst C.M.
        • Ronot M.
        • van Wettere M.
        • et al.
        The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort.
        Eur Heart J. 2019; 40: 1057-1068
        • Lu P.
        • Liu H.
        • Yin H.
        • Yang L.
        Expression of angiotensinogen during hepatic fibrogenesis and its effect on hepatic stellate cells.
        Med Sci Monit. 2011; 17: BR248-BR256
        • Yoshiji H.
        • Noguchi R.
        • Kuriyama S.
        • Yoshii J.
        • Ikenaka Y.
        • Yanase K.
        • et al.
        Suppression of renin-angiotensin system attenuates hepatocarcinogenesis via angiogenesis inhibition in rats.
        Anticancer Res. 2005; 25: 3335-3340
        • Abu Dayyeh B.K.
        • Yang M.
        • Dienstag J.L.
        • Chung R.T.
        The effects of angiotensin blocking agents on the progression of liver fibrosis in the HALT-C Trial cohort.
        Dig Dis Sci. 2011; 56: 564-568
        • Ho C.M.
        • Lee C.H.
        • Lee M.C.
        • Zhang J.F.
        • Wang J.Y.
        • Hu R.H.
        • et al.
        Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study.
        BMC Cancer. 2018; 18: 401
        • Reese L.J.
        • Tider D.S.
        • Stivala A.C.
        • Fishbein D.A.
        Effects of angiotensin converting enzyme inhibitors on liver fibrosis in HIV and hepatitis C coinfection.
        AIDS Res Treat. 2012; 2012978790