Commentary: Hepatocellular carcinoma: A threat for patients with Fontan circulation

Central MessageHepatocellular carcinoma has a low prevalence in Fontan patients, but it is a serious and potentially lethal complication. Further efforts are needed to systematize risk stratification and screening.See Article page 128. Hepatocellular carcinoma has a low prevalence in Fontan patients, but it is a serious and potentially lethal complication. Further efforts are needed to systematize risk stratification and screening. See Article page 128. Since the first Fontan operation was performed in 1968, several modifications have been introduced that led to improvement in short- and long-term survival. The current 30-year survival after Fontan completion is 85%.1Rychik 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)Crossref PubMed Scopus (158) Google Scholar,2d'Udekem Y. Iyengar A.J. Galati J.C. Forsdick V. Weintraub R.G. Wheaton G.R. et al.Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand.Circulation. 2014; 130: S32-S38Crossref PubMed Scopus (302) Google Scholar Hemodynamic changes associated with the Fontan circulation, including elevated central venous pressure and diminished cardiac output, as well as chronic hypoxic injury of the liver, are responsible for the development of Fontan-associated liver disease (FALD).1Rychik 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)Crossref PubMed Scopus (158) Google Scholar In Fontan circulation, the hepatic veins discharge directly into the Fontan circuit and the liver is therefore particularly susceptible to the effects of central venous hypertension. The elevated central venous pressure produces a centrilobular hepatic congestion and necrosis, and activation of inflammatory mediators that perpetuate the chronic inflammation and subsequent fibrosis of the liver.3Gordon-Walker T.T. Bove K. Veldtman G. Fontan-associated liver disease: a review.J Cardiol. 2019; 74: 223-232Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,4Kiesewetter C.H. Sheron N. Vettukattill J.J. Hacking N. Stedman B. Millward-Sadler H. et al.Hepatic changes in the failing Fontan circulation.Heart. 2007; 93: 579-584Crossref PubMed Scopus (239) Google Scholar The pathophysiological mechanisms promoting liver injury and fibrosis in FALD are summarized in Figure 1. Histological studies suggest that 43% of patients with Fontan circulation have evidence of advanced liver fibrosis 30 years after the Fontan completion.5Pundi K. Pundi K.N. Kamath P.S. Hacking N. Stedman B. Millward-Sadler H. et al.Liver disease in patients after the Fontan operation.Am J Cardiol. 2016; 117: 456-460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Liver fibrosis appears to be an inevitable complication in the Fontan circulation and the degree of fibrosis is increasing over time. In a retrospective study of Fontan patients receiving surveillance for FALD, 62% had evidence of chronic liver disease.6Nandwana S.B. Olaiya B. Cox K. Sahu A. Mittal P. Abdominal imaging surveillance in adult patients after Fontan procedure: risk of chronic liver disease and hepatocellular carcinoma.Curr Probl Diagn Radiol. 2018; 47: 19-22Crossref PubMed Scopus (32) Google Scholar Among patients with liver cirrhosis, longitudinal studies suggest an annual risk of hepatocellular carcinoma (HCC) of 1% to 8%.7Ioannou G.N. Splan M.F. Weiss N.S. McDonald G.B. Beretta L. Lee S.P. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.Clin Gastroenterol Hepatol. 2007; 5: 938-945Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar HCC is considered the most extreme manifestation of FALD. Most patients are asymptomatic and the diagnosis is usually incidental. The prognosis of HCC is very poor with survival rates estimated at 50% within 2 years of diagnosis.8Egbe A.C. Poterucha J.T. Warnes C.A. Connolly H.M. Baskar S. Ginde S. et al.Hepatocellular carcinoma after Fontan operation: multicenter case series.Circulation. 2018; 138: 746-748Crossref PubMed Scopus (28) Google Scholar,9Asrani S.K. Warnes C.A. Kamath P.S. Hepatocellular carcinoma after the Fontan procedure.N Engl J Med. 2013; 368: 1756-1757Crossref PubMed Scopus (118) Google Scholar Wilson and colleagues10Wilson T.G. Iyengar A.J. Hardikar W. Sood S. d'Udekem Y. Prevalence of hepatocellular carcinoma in the entire Fontan population of Australia and New Zealand.J Thorac Cardiovasc Surg Tech. 2020; 2: 128-130Google Scholar describe a low prevalence (5 of 1620 patients) of HCC from the Australian and New Zealand Fontan Registry, which is among the largest series of Fontan patients with excellent short- and long-term outcomes. All patients in the registry who develop HCC had evidence of cirrhosis, portal hypertension, and history of failing Fontan circulation. Although the reported prevalence of HCC in patients with Fontan circulation is low, there is currently no consensus on the optimal timing to initiate screening and imaging in post-Fontan populations. Patients with failing Fontan, portal hypertension, or evidence of liver cirrhosis are at higher risk of HCC. Surveillance for HCC includes serum tests (eg, total and direct bilirubin, aminotransaminases, alkaline phosphatase, gamma-glutamyl transferase, albumin, and international normalized ratio) and imaging. Post-Fontan patients with a confirmed diagnosis of cirrhosis should undergo more rigorous screening. Follow-up in these patients should include ultrasound and alpha-fetoprotein measurement. Immunization against hepatitis A, hepatitis B, pneumococcal pneumonia, and influenza is also recommended. The use of pharmacologic agents such as pulmonary vasodilators (eg, sildenafil and bonsentan) and antifibrotic therapies could be considered to prevent the progression of FALD, although the effect on hepatic vascular resistance and on the prevalence of HCC is unknown and remains to be studied.4Kiesewetter C.H. Sheron N. Vettukattill J.J. Hacking N. Stedman B. Millward-Sadler H. et al.Hepatic changes in the failing Fontan circulation.Heart. 2007; 93: 579-584Crossref PubMed Scopus (239) Google Scholar Further efforts are needed to systematize risk stratification and screening guidelines in patients with FALD. Prevalence of hepatocellular carcinoma in the entire Fontan population of Australia and New ZealandJTCVS TechniquesVol. 2PreviewHepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) are now well recognized as complications of Fontan palliation.1,2 The occurrence of HCC in particular has caused alarm among clinicians, patients, and families, with high mortality rates reported following diagnosis.3 Although many cases of HCC after Fontan are now described in the literature, the population-based prevalence of this complication is not known. Full-Text PDF Open Access

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