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. The evolution of anatomical hepatic derangements in these patients remains ill-defined thereby making it difficult to know whom to screen and how often. 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.
Methods
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 populations were calculated including aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, APRI (AST to platelet ratio) and FIB-4 score (age × AST/platelet count × ALT).
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 system 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. Hepatic imaging was assigned a score out of 4 with representing no identified hepatic abnormalities, minor changes believed to represent congestion or early fibrosis, consistent with cirrhosis and 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.
Results
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).
| Clinical Variable | N=60 |
|---|---|
| Male/female | 31/29 |
| Age at last follow-up (years) | 28 (18-43) |
| Age at Fontan (months) | 66 (14-324) |
| Type of Fontan | |
| Extra cardiac conduit | 20 (33%) |
| Lateral Tunnel | 20 (33%) |
| Atriopulmonary connection | 14 (23%) |
| Bjork modification of atriopulmonary connection | 6 (10%) |
| Atrial arrhythmias | 29 (48%) |
| Pacemaker | 24 (40%) |
| Asplenia | 12 (20%) |
| Protein Losing Enteropathy | 13 (22%) |
| Peak Oxygen consumption (ml/kg/min ± SD) | 60.8 ± 12.8 |
| Maximal severity of Liver Disease On Imaging | Number of patients |
|---|---|
| No hepatic abnormalities | 4 (7%) |
| Congestion only | 20 (38%) |
| Cirrhosis without nodules | 19 (36%) |
| Cirrhosis with nodules | 10 (19%) |
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.
| Variable | Hepatic Cirrhosis | p | |
|---|---|---|---|
| No (n=18) | Yes (n=35) | ||
| Gamma glutamyl transferase (U/L) | 103.9 ± 57.8 | 129 ± 83.4 | 0.28 |
| Aspartate aminotransferase (U/L) | 37.7 ± 13.6 | 43.1 ± 15.0 | 0.07 |
| Alanine aminotransferase (U/L) | 33.3 ± 17.6 | 35.4 ± 14.8 | 0.33 |
| Bilirubin (μmol/L) | 23.2 ± 11.9 | 22.2 ± 15.3 | 0.64 |
| Alkaline Phosphatase (U/L) | 89.8 ± 34.4 | 109.7 ± 59.1 | 0.23 |
| Platelets (x10 3 /μL) | 168.2 ± 46.7 | 184.6 ± 83.9 | 0.80 |
| α-2 macroglobulin (g/L) | 2.61 ± 1.0 | 3.44 ± 2.0 | 0.05 |
| Hepatitis C Antibody positivity | 1 (5) | 0 | NS |
| Aspartate aminotransferase to alanine aminotransferase ratio | 1.26 ± 0.44 | 1.41 ± 0.69 | 0.47 |
| Aspartate aminotransferase to platelet ratio | 0.48 ± 0.28 | 0.55 ± 0.36 | 0.52 |
| Age (years) x aspartate aminotransferase/ platelet count x alanine aminotransferase | 38.29 ± 27.63 | 40.62 ± 25.14 | 0.53 |
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