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Impact of Liver Disease After the Fontan Operation

2014; Elsevier BV; Volume: 115; Issue: 2 Linguagem: Inglês

10.1016/j.amjcard.2014.10.032

1879-1913

Ian Lindsay, Joyce T. Johnson, Melanie D. Everitt, James Hoffman, Anji T. Yetman,

Liver Disease and Transplantation

Liver disease is being reported with increased frequency in survivors of the Fontan operation. The clinical impact of structural hepatic abnormalities in these patients remains largely unknown. We sought to assess if, and how, cardiologists are screening for hepatic disease in these patients to evaluate for clinical or laboratory correlates of structural hepatic disease and determine the prevalence and clinical impact of such disease. Retrospective data analysis from tertiary institutions was performed. Hepatic imaging studies and serology performed over the last decade were reviewed and clinical and laboratory correlates of structural hepatic alterations on liver imaging or biopsy were sought. Outcomes were determined. In this cohort study, 53 of 60 adult survivors (88%) underwent hepatic imaging with computed tomography, magnetic resonance imaging, or ultrasound with a median number of 2 (0 to 10) studies over the past decade. The frequency of hepatic imaging varied widely with 70% of patients undergoing serial studies. Cirrhosis with or without abnormal hepatic nodules was seen in 29 of 53 patients (55%) at 18.4 ± 5.6 years after the Fontan procedure. Adverse hepatic-related outcome occurred in 22% of the entire patient cohort and was unrelated to time from Fontan operation. In conclusion, there exists significant variability in the type and timing of testing for hepatic complications after the Fontan procedure. Structural hepatic alterations are common and can be associated with significant morbidity and mortality. Routine imaging, and serologic evaluation, is recommended in all Fontan survivors. Liver disease is being reported with increased frequency in survivors of the Fontan operation. The clinical impact of structural hepatic abnormalities in these patients remains largely unknown. We sought to assess if, and how, cardiologists are screening for hepatic disease in these patients to evaluate for clinical or laboratory correlates of structural hepatic disease and determine the prevalence and clinical impact of such disease. Retrospective data analysis from tertiary institutions was performed. Hepatic imaging studies and serology performed over the last decade were reviewed and clinical and laboratory correlates of structural hepatic alterations on liver imaging or biopsy were sought. Outcomes were determined. In this cohort study, 53 of 60 adult survivors (88%) underwent hepatic imaging with computed tomography, magnetic resonance imaging, or ultrasound with a median number of 2 (0 to 10) studies over the past decade. The frequency of hepatic imaging varied widely with 70% of patients undergoing serial studies. Cirrhosis with or without abnormal hepatic nodules was seen in 29 of 53 patients (55%) at 18.4 ± 5.6 years after the Fontan procedure. Adverse hepatic-related outcome occurred in 22% of the entire patient cohort and was unrelated to time from Fontan operation. In conclusion, there exists significant variability in the type and timing of testing for hepatic complications after the Fontan procedure. Structural hepatic alterations are common and can be associated with significant morbidity and mortality. Routine imaging, and serologic evaluation, is recommended in all Fontan survivors. Hepatic cirrhosis after Fontan palliation for single ventricle cardiac anatomy has been well described in small patient cohorts.1Schwartz M.C. Sullivan L.M. Glatz A.C. Rand E. Russo P. Goldberg D.J. Rome J.J. Cohen M.S. Portal and sinusoidal fibrosis are common on liver biopsy after Fontan surgery.Pediatr Cardiol. 2013; 34: 135-142Crossref PubMed Scopus (82) Google Scholar, 2Kiesewetter C.H. Sheron N. Vettukattill J.J. Hacking N. Stedman B. Millward-Sadler H. Haw M. Cope R. Salmon A.P. Sivaprakasam M.C. Kendall T. Keeton B.R. Iredale J.P. Veldtman G.R. Hepatic changes in the failing Fontan circulation.Heart. 2007; 93: 579-584Crossref PubMed Scopus (260) Google Scholar, 3Ginde S. Hohenwalter M.D. Foley D. Sowinski J. Bartz P.J. Venkatapuram S. Weinberg C. Tweddell J.S. Earing M.G. Noninvasive assessment of liver fibrosis in adult patients following the Fontan procedure.Congenit Heart Dis. 2012; 7: 235-242Crossref PubMed Scopus (51) Google Scholar, 4Ghaferi 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: 1347-1352Google Scholar, 5Asrani S.K. Warnes C.A. Kamath P.S. Hepatocellular carcinoma after the Fontan procedure.N Engl J Med. 2013; 368: 1756-1757Crossref PubMed Scopus (128) Google Scholar The evolution of anatomical hepatic derangements in these patients remains ill-defined thereby making it difficult to know whom to screen and how often.4Ghaferi 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: 1347-1352Google Scholar, 5Asrani S.K. Warnes C.A. Kamath P.S. Hepatocellular carcinoma after the Fontan procedure.N Engl J Med. 2013; 368: 1756-1757Crossref PubMed Scopus (128) Google Scholar, 6Rychik J. Veldtman G. Rand E. Russo P. Rome J.J. Krok K. Goldberg D.J. Cahill A.M. Wells R.G. The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium.Pediatr Cardiol. 2012; 33: 1001-1012Crossref PubMed Scopus (201) Google Scholar We sought to characterize the frequency and modalities of hepatic screening used for evaluation of these patients and identify the type, severity, prevalence, and clinical impact of anatomic and physiologic hepatic derangements present. We also sought to assess for laboratory or clinical correlates of cirrhosis or other significant hepatic pathology in an adult cohort of patients surviving the Fontan procedure. An institutional review board approved review of data on all patients evaluated during the past 10 years who had undergone the Fontan procedure in childhood and survived to ≥18 years was performed. Serologic and clinical correlates of "significant" hepatic pathology were assessed for. Significant hepatic pathology was defined as the presence of advanced fibrosis, cirrhosis, hepatocellular carcinoma, hepatic adenomatosis, or dysplastic hepatic nodules on imaging and biopsy. This definition was chosen as it was believed that these particular findings, in contrast to isolated portal hypertension and/or early fibrotic changes, carried significant potential to alter long-term outcome. The presence or absence of protein losing enteropathy (defined by an elevated stool α-1 antitrypsin and associated hypoalbuminemia) was recorded. Cardiac catheterization data were recorded if performed within 1 year of imaging and/or biopsy evaluation for cirrhosis. Data from routine outpatient laboratory evaluation performed in adolescence and adulthood were reviewed. Testing was performed at the discretion of the primary cardiologist. The frequency and absolute number of times routine outpatient testing was performed were recorded. Values from routine out-patient testing performed at or near the time of hepatic imaging were recorded for the purposes of data analysis. International normalized ratio values were not recorded as most patients were on warfarin therapy. Several scores found to be predictive of hepatic fibrosis in other patient populations7Yang H.R. Kim H.R. Kim M.J. Ko J.S. Seo J.K. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease.World J Gastroenterol. 2012; 18: 1525-1530Crossref PubMed Scopus (65) Google Scholar, 8Karlas T. Neuschulz M. Oltmanns A. Güttler A. Petroff D. Wirtz H. Mainz J.G. Mössner J. Berg T. Tröltzsch M. Keim V. Wiegand J. Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.PLoS One. 2012; 7: e421-e439Crossref Scopus (38) Google Scholar, 9Sirli R. Sporea I. Bota S. Popescu A. Cornianu M. A comparative study of non-invasive methods for fibrosis assessment in chronic HCV infection.Hepat Mon. 2010; 10: 88-94PubMed Google Scholar were calculated including aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio,7Yang H.R. Kim H.R. Kim M.J. Ko J.S. Seo J.K. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease.World J Gastroenterol. 2012; 18: 1525-1530Crossref PubMed Scopus (65) Google Scholar APRI (AST to platelet ratio)8Karlas T. Neuschulz M. Oltmanns A. Güttler A. Petroff D. Wirtz H. Mainz J.G. Mössner J. Berg T. Tröltzsch M. Keim V. Wiegand J. Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.PLoS One. 2012; 7: e421-e439Crossref Scopus (38) Google Scholar and FIB-4 score (age × AST/platelet count × ALT).9Sirli R. Sporea I. Bota S. Popescu A. Cornianu M. A comparative study of non-invasive methods for fibrosis assessment in chronic HCV infection.Hepat Mon. 2010; 10: 88-94PubMed Google Scholar Evaluation for liver pathology was performed at the discretion of the primary cardiologist. Imaging of the liver was performed through ultrasound with Doppler, dual phase computed tomography with contrast, or magnetic resonance imaging. Liver biopsy was performed at the discretion of the hepatologist involved in the patient's care and was triggered by imaging findings consistent with cirrhosis and progressive serologic abnormalities, suspicious hepatic mass, or consideration of cardiac transplantation. Cirrhosis was defined on biopsy using the Metavir grading system3Ginde S. Hohenwalter M.D. Foley D. Sowinski J. Bartz P.J. Venkatapuram S. Weinberg C. Tweddell J.S. Earing M.G. Noninvasive assessment of liver fibrosis in adult patients following the Fontan procedure.Congenit Heart Dis. 2012; 7: 235-242Crossref PubMed Scopus (51) Google Scholar or in those patients without biopsy, as computed tomography or magnetic resonance imaging findings of parenchymal heterogeneity with irregular undulating liver margins, and caudate hypertrophy with or without enhancing nodules.3Ginde S. Hohenwalter M.D. Foley D. Sowinski J. Bartz P.J. Venkatapuram S. Weinberg C. Tweddell J.S. Earing M.G. Noninvasive assessment of liver fibrosis in adult patients following the Fontan procedure.Congenit Heart Dis. 2012; 7: 235-242Crossref PubMed Scopus (51) Google Scholar Hepatic imaging was assigned a score out of 4 with1Schwartz M.C. Sullivan L.M. Glatz A.C. Rand E. Russo P. Goldberg D.J. Rome J.J. Cohen M.S. Portal and sinusoidal fibrosis are common on liver biopsy after Fontan surgery.Pediatr Cardiol. 2013; 34: 135-142Crossref PubMed Scopus (82) Google Scholar representing no identified hepatic abnormalities,2Kiesewetter C.H. Sheron N. Vettukattill J.J. Hacking N. Stedman B. Millward-Sadler H. Haw M. Cope R. Salmon A.P. Sivaprakasam M.C. Kendall T. Keeton B.R. Iredale J.P. Veldtman G.R. Hepatic changes in the failing Fontan circulation.Heart. 2007; 93: 579-584Crossref PubMed Scopus (260) Google Scholar minor changes believed to represent congestion or early fibrosis,3Ginde S. Hohenwalter M.D. Foley D. Sowinski J. Bartz P.J. Venkatapuram S. Weinberg C. Tweddell J.S. Earing M.G. Noninvasive assessment of liver fibrosis in adult patients following the Fontan procedure.Congenit Heart Dis. 2012; 7: 235-242Crossref PubMed Scopus (51) Google Scholar consistent with cirrhosis and4Ghaferi 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: 1347-1352Google Scholar cirrhotic changes with enhancing nodules. Patients with a score of 3 or 4 were deemed to have cirrhosis whereas those with a lesser score were said to not have cirrhosis unless there was evidence to the contrary on liver biopsy. Frequency of an adverse hepatic outcome was calculated and defined as clinically symptomatic synthetic hepatic dysfunction including gastrointestinal pathology with bleeding requiring treatment, hepatic encephalopathy defined as altered level of consciousness in association with an elevated ammonia level, hepatocellular carcinoma or adenomatosis, hepatorenal syndrome in the face of normal systolic function, or progressive change in dysplastic hepatic nodules required listing for liver transplant in association with listing for cardiac transplant. Statistical analysis was conducted using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). Continuous data were expressed as means with SDs or medians with ranges as appropriate and categorical data were tabulated. A 2-sided p value of <0.05 was considered statistically significant. Demographic, clinical, and serologic variables for those patients with versus without significant liver pathology and those patients with versus without adverse clinical outcome were compared using a chi-square test for dichotomous or categorical variables and t test or Wilcoxon rank sum for continuous variables depending on their normality. Correlates of cirrhosis, and the presence of adverse clinical outcome were sought using a logistic regression model and odds ratios calculated. Using a logistic regression model, the area under the curve was determined to calculate the sensitivity and specificity of each laboratory test. Sixty adult patients who had undergone the Fontan procedure during childhood, and who were evaluated as adults in either a pediatric cardiology clinic or adult congenital cardiology clinic within the last 10 years, were identified. Clinical characteristics of the patient cohort are outlined in Table 1. At the time of last follow-up, 45 (75%) were alive without listing for heart transplantation, 1 alive awaiting heart transplantation, 3 (5%) alive and awaiting combined heart and liver transplantation, 6 (10%) alive after heart transplantation, and 5 (8%) deceased. Age at death was 24 ± 5 years. Of the 53 (88%) patients who underwent hepatic imaging for evaluation of cirrhosis (Table 2), initial hepatic imaging was performed at 24 ± 7 years occurring 18 ± 5 years after the Fontan procedure. Serial imaging was performed in 37 patients (70%). Patients underwent a median of 2 (0 to 10) studies during adolescence and adulthood. Patients with a normal initial study were less likely to undergo repeat imaging (33% vs 75%, p = 0.003). Of the 8 patients who had a normal first study and underwent repeat study, 4 (50%) had new abnormalities on repeat imaging 2.8 (1 to 10) years later. Of the 29 patients undergoing serial imaging who had abnormal findings on first study, 25 (86%) had new abnormalities on repeat scan 2 (1 to 7) years later. Comparing those patients who underwent hepatic imaging (n = 53) versus those that did not (n = 7), evaluation with hepatic imaging was not related to current age (25 ± 5 vs 26 ± 6, p = 0.6), age at Fontan procedure (7 ± 6 vs 6 ± 4 years, p = 0.8), interval from Fontan procedure (20 ± 6 vs 21 ± 5 years, p = 0.8), type of Fontan procedure (modern day vs atriopulmonary connection 69% vs 66%, p = 0.4), clinical symptoms, or presence of an abnormal liver function test (70% vs 57%, p = 0.4) but was related to whether the patient was seen in a pediatric cardiology versus adult congenital cardiology clinic (48% vs 100%, p = 0.001). Liver biopsy was performed in 19 of the 35 (54%) patients noted to have cirrhosis on imaging and demonstrated Metavir F1 stage (no fibrosis) in 0, F1 to F2 stage (portal fibrosis and/or bridging fibrosis with few septae) in 4 (21%), F3 stage (bridging fibrosis with many septae) in 4 (21%), and F4 stage (cirrhosis) in 11 (58%). Esophagogastroduodenoscopy was performed in 23 patients, with findings of varices in 10 (43%), erosive gastric or duodenal ulcers in 5 (26%), and hepatic gastropathy or duodenopathy without ulcers in 9 (39%). Outpatient laboratory evaluation as defined herein was performed a median of 5 (1 to 20) times per patient over the past 10 years. Routine testing in everyone included a comprehensive metabolic panel with assessment of AST, ALT, alkaline phosphatase, protein, and albumin. In addition, 29 (48%) patients underwent additional routine testing with gamma-glutamyl transferase (GGT), α-fetoprotein, complete blood count, and alpha2 macroglobulin as dictated by provider preference. All patients requiring surgery before 1992 or with findings of cirrhosis on imaging or biopsy underwent testing for Hepatitis C. One asymptomatic patient was hepatitis C antibody positive and did not merit treatment. Thrombocytopenia was present in 18 patients (30%). Patients without a functional spleen (n = 12) had a greater platelet count than those with a spleen (250 ± 77 vs 152 ± 51, p = 0.0006).Table 1Demographic data for the entire patient cohortClinical VariableN=60Male/female31/29Age at last follow-up (years)28 (18-43)Age at Fontan (months)66 (14-324)Type of Fontan Extra cardiac conduit20 (33%) Lateral Tunnel20 (33%) Atriopulmonary connection14 (23%) Bjork modification of atriopulmonary connection6 (10%)Atrial arrhythmias29 (48%)Pacemaker24 (40%)Asplenia12 (20%)Protein Losing Enteropathy13 (22%)Peak Oxygen consumption (ml/kg/min ± SD)60.8 ± 12.8 Open table in a new tab Table 2Liver imaging per patient (N=53)Maximal severity of Liver Disease On ImagingNumber of patientsNo hepatic abnormalities4 (7%)Congestion only20 (38%)Cirrhosis without nodules19 (36%)Cirrhosis with nodules10 (19%) Open table in a new tab Few clinical or laboratory correlates of cirrhosis or other significant anatomic hepatic derangements were identified in this patient cohort (Tables 3 and 4). In patients without protein losing enteropathy, and thus with a normal protein level, an elevated α-2 macroglobulin level was present in 13 of 14 patients (93%) with cirrhosis versus 1 of 11 patients (9%) without cirrhosis (p <0.0001). Using receiver operating characteristic analysis to calculate area under the curve, no other laboratory marker or calculation was found to be a good predictor of cirrhosis with the 95% confidence interval for area under the curve crossing 0.5 in all instances. GGT and alkaline phosphatase correlated with both Fontan and wedge pressure (r = 0.4; p = 0.012, r = 0.5; p = 0.007 for GGT and r = 0.5, p = 0.001; r = 0.5, p = 0.008), respectively. No laboratory parameter was shown to correlate with years from Fontan procedure.Table 3Laboratory correlates of hepatic pathologyVariableHepatic CirrhosispNo(n=18)Yes(n=35)Gamma glutamyl transferase (U/L)103.9 ± 57.8129 ± 83.40.28Aspartate aminotransferase (U/L)37.7 ± 13.643.1 ± 15.00.07Alanine aminotransferase (U/L)33.3 ± 17.635.4 ± 14.80.33Bilirubin (μmol/L)23.2 ± 11.922.2 ± 15.30.64Alkaline Phosphatase (U/L)89.8 ± 34.4109.7 ± 59.10.23Platelets (x103/μL)168.2 ± 46.7184.6 ± 83.90.80α-2 macroglobulin (g/L)2.61 ± 1.03.44 ± 2.00.05Hepatitis C Antibody positivity1 (5)0NSAspartate aminotransferase to alanine aminotransferase ratio1.26 ± 0.441.41 ± 0.690.47Aspartate aminotransferase to platelet ratio0.48 ± 0.280.55 ± 0.360.52Age (years) x aspartate aminotransferase/ platelet count x alanine aminotransferase38.29 ± 27.6340.62 ± 25.140.53 Open table in a new tab Table 4Clinical correlates of hepatic cirrhosisVariableHepatic CirrhosispNo(n= 18)Yes(n=35)Age at Fontan (months)89.0 ± 65.075.0 ± 48.20.51Years after Fontan20.3 ± 5.421.3 ± 5.10.71Systemic left ventricular10 (58%)17 (48%)0.45Recurrent atrial arrhythmias43.357.70.28Chronic amiodarone use (%)2 (11%)4 (11%)0.90Pacemaker7 (39%)13 (37%)0.80Years paced n= 215.2 ± 7.55.8 ± 7.70.83Resting Sa0290.4 ± 3.689.1 ± 4.30.17Peak exercise Sa02 n= 4886.6 ± 4.383.1 ± 6.20.04Peak % predicted V02 n= 4862.7 ± 12.559.0 ± 13.20.33Fontan pressure n= 3116.7 ± 3.915.9 ± 3.30.71Wedge pressure n= 3112.4 ± 3.710.2 ± 3.90.21NYHA Class III/IV (%)4 (22%)18 (51%)0.03Ascites4 (22%)19 (54%)0.005Pleural Effusion2 (11%)7 (20%)0.45Protein Losing Enteropathy2 (11%)11 (31%)0.12Original Fontan Type0.82 Classic APC5 (28%)12 (34%) LT6 (33%)12 (34%) EC7 (39%)11 (32%)Fontan Revision1 (5%)7 (20%)0.14 Open table in a new tab Interval between initial Fontan procedure to diagnosis of cirrhosis was 18 ± 5 years. Time to diagnosis of cirrhosis was explored for surgery type (contemporary Fontan procedure [lateral tunnel or extracardiac conduit] vs atriopulmonary connection), gender, and year of Fontan. Patients with a contemporary Fontan surgery had a shorter interval to diagnosis of cirrhosis than those with an atriopulmonary connection Fontan (17 ± 5 vs 25 ± 3 years, p = 0.01). Of the 29 patients with significant hepatic derangements on imaging, adverse hepatic outcome occurred in 13, representing 45% of those with abnormal routine liver imaging and 22% of the entire patient cohort of 60 patients. Type and frequency of adverse hepatic outcomes included liver failure with death in 4 (with 1 of these patients having hepatic adenomatosis), recurrent gastrointestinal bleeding in 4, hepatic encephalopathy in 3, and evolving dysplastic nodules in 2 patients listed for cardiac transplantation, requiring re-listing for heart and liver transplants. Adverse liver outcome was not related to age at Fontan (77 ± 49 vs 82 ± 60 months; p = 0.9) or time from Fontan (20 ± 6 vs 21 ± 4 years; p = 0.65). Patients with an adverse liver outcome had a higher AST on routine laboratory testing (48 ± 20 vs 37 ± 10 U/L; p = 0.04) but no other serologic marker or calculated laboratory score differed between those with or without adverse liver outcome. We describe an adult cohort of Fontan survivors who underwent hepatic evaluation and in whom significant hepatic pathology was found in the majority, and in whom, longitudinal testing demonstrated progression of hepatic disease. Although routine hepatic imaging to rule out significant liver pathology in these patients is becoming increasingly frequent, it is still not universal. Even when performed, the type and frequency of testing varies markedly as described herein. Clinicians may be relying on routine liver serology to guide further testing. As noted by others, we found that routine serologic liver tests did not correlate with the presence of cirrhosis. There are several potential reasons for this. GGT and total bilirubin tend to be elevated in most adult patients who underwent Fontan11Elder R.W. McCabe N.M. Hebson C. Veledar E. Romero R. Ford R.M. Mahle W.T. Kogon B.E. Sahu A. Jokhadar M. McConnell M.E. Book W.M. Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study.Int J Cardiol. 2013; 168: 3764-3769Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar and do not necessarily reflect cirrhotic changes but rather, hepatic congestion. Conversely, hepatic transaminases often remain normal despite the presence of significant hepatic derangements.10Kaulitz R. Haber P. Sturm E. Schafer J. Hofbeck M. Serial evaluation of hepatic function profile after Fontan operation.Herz. 2014; 39: 998-1004Crossref Scopus (27) Google Scholar, 11Elder R.W. McCabe N.M. Hebson C. Veledar E. Romero R. Ford R.M. Mahle W.T. Kogon B.E. Sahu A. Jokhadar M. McConnell M.E. Book W.M. Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study.Int J Cardiol. 2013; 168: 3764-3769Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Others have documented the serologic panel FibroSURE (Laboratory Corporation of America, Raritan, New Jersey) to be a good noninvasive marker for liver fibrosis in these patients.3Ginde S. Hohenwalter M.D. Foley D. Sowinski J. Bartz P.J. Venkatapuram S. Weinberg C. Tweddell J.S. Earing M.G. Noninvasive assessment of liver fibrosis in adult patients following the Fontan procedure.Congenit Heart Dis. 2012; 7: 235-242Crossref PubMed Scopus (51) Google Scholar The panel includes 6 biomarkers namely haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, and alpha-2 macroglobulin. In this series, this last biomarker was found to be highly correlated with the presence of cirrhosis, particularly in those patients without protein losing enteropathy who were able to mount an elevated globulin response in the face of hepatic pathology. More recently, investigators have proposed using the VAST score (varices, ascites, splenomegaly, thrombocytopenia) to assess which Fontan patients are at risk for adverse events secondary to portal hypertension.11Elder R.W. McCabe N.M. Hebson C. Veledar E. Romero R. Ford R.M. Mahle W.T. Kogon B.E. Sahu A. Jokhadar M. McConnell M.E. Book W.M. Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study.Int J Cardiol. 2013; 168: 3764-3769Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Similar to previous publications11Elder R.W. McCabe N.M. Hebson C. Veledar E. Romero R. Ford R.M. Mahle W.T. Kogon B.E. Sahu A. Jokhadar M. McConnell M.E. Book W.M. Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study.Int J Cardiol. 2013; 168: 3764-3769Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar we did note a higher incidence of varices and ascites in those patients with cirrhosis and adverse hepatic outcome, but did not find thrombocytopenia to correlate with adverse outcome. This may be due in whole or in part to a not insignificant number of patients with structural or functional asplenia. These patients had significantly higher platelet counts that would prevent using the score universally in this population. Because the frequency of hepatic imaging varied considerably in this study, the optimal frequency of screening remains unknown. We did demonstrate progressive hepatic anatomical derangements in the vast majority of patients undergoing serial screening with changes occurring over a period of as little as a year. Given that most patients had structural hepatic derangements at the initiation of screening, it appears that we are currently initiating imaging too late and that periodic imaging should be started in childhood or early adolescence and repeated at regular intervals. Timely diagnosis of structural hepatic derangements may allow for curative therapy for hepatocellular carcinoma, or modification to planned operative cardiosurgical interventions to mitigate risk. This was a retrospective study and thus data collection was limited to that obtained during the process of routine outpatient care. The vast majority of patients had hepatic imaging and no patient in this cohort was lost to follow-up thereby limiting, albeit not eliminating, potential selection bias. Not all patients underwent liver biopsy, and thus the diagnosis of significant hepatic pathology was based on imaging studies that may not reflect the degree of hepatic pathology in these patients.6Rychik J. Veldtman G. Rand E. Russo P. Rome J.J. Krok K. Goldberg D.J. Cahill A.M. Wells R.G. The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium.Pediatr Cardiol. 2012; 33: 1001-1012Crossref PubMed Scopus (201) Google Scholar Serial imaging, although universal in those patients seen in an adult congenital cardiology clinic, was not obtained in all adults seen in a pediatric cardiology clinic thus hampering assessment of the average rate of disease progression. Data collection was confined to those patients who had currently reached adulthood and thus the incidence of hepatic derangements in childhood and adolescence cannot be commented on. The authors have no conflicts of interest to disclose.