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Canadian Journal of Cardiology

Hepatic and Renal Consequences of Single-Ventricle Physiology Palliated With the Fontan Operation

  • Author Footnotes
    ‡ These first authors contributed equally.
    Steven L. Rathgeber
    Footnotes
    ‡ These first authors contributed equally.
    Affiliations
    Division of Cardiology, British Columbia Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
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  • Author Footnotes
    ‡ These first authors contributed equally.
    Charmaine Lam
    Footnotes
    ‡ These first authors contributed equally.
    Affiliations
    Division of Cardiology, Yasmin and Amir Virani Provincial Adult Congenital Heart Program, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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  • Author Footnotes
    § These authors contributed equally.
    Kevin C. Harris
    Footnotes
    § These authors contributed equally.
    Affiliations
    Division of Cardiology, British Columbia Children’s Hospital, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
    Search for articles by this author
  • Author Footnotes
    § These authors contributed equally.
    Jasmine Grewal
    Correspondence
    Corresponding author: Dr Jasmine Grewal, Division of Cardiology, St. Paul’s Hospital, 478-1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada. Tel.: +1-604-806-8785.
    Footnotes
    § These authors contributed equally.
    Affiliations
    Division of Cardiology, Yasmin and Amir Virani Provincial Adult Congenital Heart Program, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
    Search for articles by this author
  • Author Footnotes
    ‡ These first authors contributed equally.
    § These authors contributed equally.

      Abstract

      Over time, long-term survival has dramatically increased for patients with complex congenital heart disease who undergo the Fontan operation. With this increased survival, it has become apparent that such a circulation has important consequences for other organ systems, particularly the liver and kidney. The adverse milieu created by chronic venous hypertension, low cardiac output, and an inflammatory state contribute to the pathologic changes observed in the liver and kidneys over the long term in Fontan patients. The clinical importance of these hepatic and renal comorbidities have only recently begun to be recognized in the context of increasing life expectancy in this population. The objectives of this review are to provide an overview of the pathophysiology of the Fontan circulation and how liver and kidney disease evolve in this setting; to summarize the current evidence base as it relates to the diagnostic approach to liver and kidney disease in Fontan patients; and to discuss the therapeutic approaches to Fontan- associated liver and kidney disease. Given that this is a very active area of research in congenital heart disease, we have identified knowledge gaps and priority research areas to improve the care of Fontan patients. These include establishing the optimal diagnostic tests to detect and track liver and kidney disease change over time, determining which treatable risk factors contribute to the development of liver and kidney disease, and evaluating therapies to prevent or slow progression of liver and kidney disease.

      Résumé

      Au fil du temps, la survie à long terme a considérablement augmenté chez les patients atteints de cardiopathies congénitales complexes qui subissent l’intervention de Fontan. Dans ce contexte de survie accrue, il est devenu évident que la circulation de Fontan a des conséquences notables sur d’autres organes, en particulier le foie et les reins. Le mélange néfaste que constituent l’hypertension veineuse chronique, le faible débit cardiaque et l’inflammation est propice à la survenue des changements pathologiques observés à long terme au niveau du foie et des reins des patients ayant subi l’intervention de Fontan. L’importance clinique de cette comorbidité hépatique et rénale n’est reconnue que depuis peu par suite de l’augmentation de l’espérance de vie des patients. Le présent article de synthèse vise à : i) brosser un portrait de la physiopathologie de la circulation de Fontan ainsi que de l’évolution des troubles hépatiques et rénaux dans ce contexte; ii) résumer les données probantes actuelles concernant l’approche diagnostique des troubles hépatiques et rénaux chez les patients ayant subi l’intervention de Fontan; et iii) aborder les approches thérapeutiques des troubles hépatiques et rénaux associés à la circulation de Fontan. Étant donné qu’il est question ici d’un domaine de recherche très actif en matière de cardiopathies congénitales, nous avons cerné des lacunes sur le plan des connaissances et mis en lumière des domaines de recherche prioritaires en vue d’améliorer les soins aux patients ayant subi l’intervention de Fontan. Dans cette optique, il faudrait notamment : i) convenir des tests diagnostiques à utiliser pour détecter et suivre de façon optimale les changements pathologiques touchant le foie et les reins au fil du temps; ii) recenser les facteurs de risque traitables qui contribuent à l’apparition de troubles hépatiques et rénaux; et iii) évaluer les traitements visant à prévenir ou à ralentir la progression de ces troubles.
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      References

        • Egbe A.C.
        • Connolly H.M.
        • Miranda W.R.
        • et al.
        Hemodynamics of Fontan failure: the role of pulmonary vascular disease.
        Circ Heart Fail. 2017; 10004515
        • Rychik J.
        • Atz A.M.
        • Celermajer D.S.
        • et al.
        Evaluation and management of the child and adult with Fontan circulation: a scientific statement from the American Heart Association.
        Circulation. 2019; : e234-e284
        • Agnoletti G.
        • Ferraro G.
        • Bordese R.
        • et al.
        Fontan circulation causes early, severe liver damage: should we offer patients a tailored strategy?.
        Int J Cardiol. 2016; 209: 60-65
        • Rathgeber S.L.
        • Harris K.C.
        Fontan-associated liver disease: evidence for early surveillance of liver health in pediatric Fontan patients.
        Can J Cardiol. 2019; 35: 217-220
        • Rychik J.
        • Veldtman G.
        • Rand E.
        • et al.
        The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium.
        Pediatr Cardiol. 2012; 33: 1001-1012
        • Eipel C.
        • Abshagen K.
        • Vollmar B.
        Regulation of hepatic blood flow: the hepatic arterial buffer response revisited.
        World J Gastroenterol. 2010; 16: 6046-6057
        • Rathgeber S.L.
        • Guttman O.R.
        • Lee A.F.
        • et al.
        Fontan-associated liver disease: spectrum of disease in children and adolescents.
        J Am Heart Assoc. 2020; 9e012529
        • Wu F.M.
        • Opotowsky A.R.
        • Raza R.
        • et al.
        Transient elastography may identify Fontan patients with unfavorable hemodynamics and advanced hepatic fibrosis.
        Congenit Heart Dis. 2014; 9: 438-447
        • Poterucha J.T.
        • Johnson J.N.
        • Qureshi M.Y.
        • et al.
        Magnetic resonance elastography: a novel technique for the detection of hepatic fibrosis and hepatocellular carcinoma after the Fontan operation.
        Mayo Clin Proc. 2015; 90: 882-894
        • Sugimoto M.
        • Oka H.
        • Kajihama A.
        • et al.
        Non-invasive assessment of liver fibrosis by magnetic resonance elastography in patients with congenital heart disease undergoing the Fontan procedure and intracardiac repair.
        J Cardiol. 2016; 68: 202-208
        • Lightsey J.M.
        • Rockey D.C.
        Current concepts in ischemic hepatitis.
        Curr Opin Gastroenterol. 2017; 33: 158-163
        • Schwartz M.C.
        • Glatz A.C.
        • Daniels K.
        • et al.
        Hepatic abnormalities are present before and early after the Fontan operation.
        Ann Thorac Surg. 2015; 100: 2298-2304
        • Maskaki N.
        • Ryo I.
        • Kei I.
        • et al.
        Incidence and expected probability of liver cirrhosis and HCC after Fontan operation.
        Circulation. 2021; 144: 2043-2045
        • Schwartz M.C.
        • Sullivan L.M.
        • Glatz A.C.
        • et al.
        Portal and sinusoidal fibrosis are common on liver biopsy after Fontan surgery.
        Pediatr Cardiol. 2013; 34: 135-142
        • Kendall T.J.
        • Stedman B.
        • Hacking N.
        • et al.
        Hepatic fibrosis and cirrhosis in the Fontan circulation: a detailed morphological study.
        J Clin Pathol. 2008; 61: 504-508
        • Surrey L.F.
        • Russo P.
        • Rychik J.
        • et al.
        Prevalence and characterization of fibrosis in surveillance liver biopsies of patients with Fontan circulation.
        Hum Pathol. 2016; 57: 106-115
        • Munsterman I.D.
        • Duijnhouwer A.L.
        • Kendall T.J.
        • et al.
        The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort.
        Eur Heart J. 2019; 40: 1057-1068
        • Emamaullee J.
        • Khan S.
        • Weaver C.
        • et al.
        Non-invasive biomarkers of Fontan-associated liver disease.
        JHEP Rep. 2021; 3: 100362
        • Evans W.N.
        • Acherman R.J.
        • Reardon L.C.
        • et al.
        An observation from liver biopsies two decades post-Fontan.
        Pediatr Cardiol. 2016; 37: 1119-1122
        • Evans W.
        • Acherman R.
        • Ciccolo M.
        • et al.
        A composite noninvasive index correlates with liver fibrosis scores in post-Fontan patients: preliminary findings.
        Congenit Heart Dis. 2018; 13: 38-45
        • Bae J.M.
        • Jeon T.Y.
        • Kim J.S.
        • et al.
        Fontan-associated liver disease: spectrum of US findings.
        Eur J Radiol. 2016; 85: 850-856
        • Wu F.
        • Kogon B.
        • Earing M.
        • et al.
        Liver health in adults with Fontan circulation: a multicenter cross-sectional study.
        J Thorac Cardiovasc Surg. 2017; 153: 656-664
        • Evans W.
        • Winn B.
        • Yumiaco N.
        • et al.
        Transvenous hepatic biopsy in stable Fontan patients undergoing cardiac catheterization.
        Pediatr Cardiol. 2014; 35: 1273-1278
        • Kieswetter C.
        • Sheron N.
        • Vettukatill J.
        • et al.
        Hepatic changes in failing Fontan circulation.
        Heart. 2007; 93: 579-584
        • Reinhardt Z.
        • Giovanni J.
        • Stickley J.
        • et al.
        Catheter interventions in the staged management of hypoplastic left heart syndrome.
        Cardiol Young. 2014; 24: 212-219
        • Feltes T.
        • Bacha E.
        • Beekman R.
        • et al.
        Indications for cardiac catheterization and intervention in pediatric cardiac disease.
        Circulation. 2011; 123: 2607-2652
        • D'Souza B.
        • Fuller S.
        • Gleason L.
        • et al.
        Single-center outcomes of combined heart and liver transplantation in the failing Fontan.
        Clin Transplant. 2017; 31e12892
        • Wu F.
        • Jonas M.
        • Opotowsky A.
        • et al.
        Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes.
        J Heart Lung Transplant. 2015; 34: 883-891
        • Simpson K.E.
        • Esmaeeli A.
        • Khanna G.
        • et al.
        Liver cirrhosis in Fontan patients does not affect 1-year post-heart transplant mortality or markers of liver function.
        J Heart Lung Transplant. 2014; 33: 170-177
        • Emamaullee J.
        • Zaidi A.
        • Schiano T.
        • et al.
        Fontan-associated liver disease: screening, management, and transplant considerations.
        Circulation. 2020; 142: 591-604
        • Wong T.
        • Gandhi M.
        • Daly R.
        • et al.
        Liver allograft provides immunoprotection for the cardiac allograft in combined heart-liver transplantation.
        Am J Transplant. 2016; 16: 3522-3531
        • Katz D.
        • Peck D.
        • Lubert A.
        • et al.
        Hepatic steatosis in patients with single ventricle and a Fontan circulation.
        J Am Heart Assoc. 2021; 10e019942
        • Dimopoulos K.
        • Diller G.-P.
        • Koltsida E.
        • et al.
        Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease.
        Circulation. 2008; 117: 2320-2328
        • Zafar F.
        • Lubert A.M.
        • Katz D.A.
        • et al.
        Long-term kidney function after the Fontan operation: JACC Review Topic of the Week.
        J Am Coll Cardiol. 2020; 76: 334-341
        • Cruz D.N.
        • Schmidt-Ott K.M.
        • Vescovo G.
        • et al.
        Pathophysiology of cardiorenal syndrome type 2 in stable chronic heart failure: workgroup statements from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI).
        ADQI Consens AKI Biomark Cardiorenal Syndr. 2013; 182: 117-136
        • Ohuchi H.
        Where is the “optimal” Fontan hemodynamics?.
        Korean Circ J. 2017; 47: 842-857
        • Broda C.R.
        • Sriraman H.
        • Wadhwa D.
        • et al.
        Renal dysfunction is associated with higher central venous pressures in patients with Fontan circulation.
        Congenit Heart Dis. 2018; 13: 602-607
        • Anne P.
        • Du W.
        • Mattoo T.K.
        • Zilberman M.V.
        Nephropathy in patients after Fontan palliation.
        Int J Cardiol. 2009; 132: 244-247
        • Madsen N.L.
        • Goldstein S.L.
        • Frøsley T.
        • Christiansen C.F.
        • Olsen M.
        Cardiac surgery in patients with congenital heart disease is associated with acute kidney injury and the risk of chronic kidney disease.
        Kidney Int. 2017; 92: 751-756
        • Niaz T.
        • Stephens E.H.
        • Gleich S.J.
        • et al.
        Acute kidney injury and renal replacement therapy after Fontan operation.
        Am J Cardiol. 2021; 161: 84-94
        • Perloff J.K.
        • Latta H.
        • Barsotti P.
        Pathogenesis of the glomerular abnormality in cyanotic congenital heart disease.
        Am J Cardiol. 2000; 86: 1198-1204
        • Khuong J.N.
        • Wilson T.G.
        • Grigg L.E.
        • et al.
        Fontan-associated nephropathy: predictors and outcomes.
        Int J Cardiol. 2020; 306: 73-77
        • Wilson T.G.
        • d’Udekem Y.
        • Winlaw D.S.
        • et al.
        Hepatic and renal end-organ damage in the Fontan circulation: A report from the Australian and New Zealand Fontan Registry.
        Int J Cardiol. 2018; 273: 100-107
        • Alsaied T.
        • Bokma J.P.
        • Engel M.E.
        • et al.
        Factors associated with long-term mortality after Fontan procedures: a systematic review.
        Heart. 2017; 103: 104-110
        • Lee D.
        • Levin A.
        • Kiess M.
        • et al.
        Chronic kidney damage in the adult Fontan population.
        Int J Cardiol. 2018; 257: 62-66
        • Opotowsky A.R.
        • Baraona F.R.
        • McCausland F.R.
        • et al.
        Estimated glomerular filtration rate and urine biomarkers in patients with single-ventricle Fontan circulation.
        Heart. 2017; 103: 434-442
        • Kirelik D.
        • Fisher M.
        • DiMaria M.
        • Soranno D.E.
        • Gist K.M.
        Comparison of creatinine and cystatin C for estimation of glomerular filtration rate in pediatric patients after Fontan operation.
        Congenit Heart Dis. 2019; 14: 760-764
        • Opotowsky A.R.
        • Carazo M.
        • Singh M.N.
        • et al.
        Creatinine versus cystatin C to estimate glomerular filtration rate in adults with congenital heart disease: results of the Boston Adult Congenital Heart Disease Biobank.
        Am Heart J. 2019; 214: 142-155
        • Delsart P.
        • Vambergue A.
        • Ninni S.
        • et al.
        Prognostic significance of the renal resistive index in the primary prevention of type II diabetes.
        J Clin Hypertens. 2020; 22: 223-230