Methods

In this institutional review board–approved single-center retrospective study, we reviewed the records of all patients (n = 1,138) who had their initial Fontan operation or Fontan revision at the Mayo Clinic from October 1973 to June 2012. Information regarding demographic, anatomic, preoperative, operative, and postoperative variables was abstracted into a secure electronic patient database. This database included information regarding preoperative and postoperative echocardiograms, cardiac catheterizations, electrocardiograms, Holter/event monitors, liver imaging, and surgical data. In addition, a medical questionnaire was mailed to all patients not known to be dead at the time of the study (n = 723). Nonresponders received second and third questionnaires. If the subsequent questionnaires were not returned or completed, an attempt was made to contact the patients by telephone. The overall survey response rate was 42% (305 of 723).

Data were available in the form of blood tests (aspartate aminotransferase, alanine aminotransferase, or bilirubin), liver ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), or liver biopsy. Cirrhosis was diagnosed based on either (1) histopathologic diagnosis on biopsy or autopsy or (2) correlation of imaging findings (radiologic interpretation of liver cirrhosis on CT, MRI, MRE, or liver ultrasound) with clinical evaluation by a hepatologist with experience caring for Fontan patients (P.S.K). Patients were excluded from this analysis if they had evidence of viral hepatitis, alcoholic liver disease, or had a diagnosis of cirrhosis before their initial Fontan operation.

Statistical analysis was performed using the date of the Fontan operation as time = 0. All deaths were considered in the survival analysis, irrespective if they occurred intraoperatively, during immediate postoperative hospitalization, or after hospital discharge. Kaplan-Meier curves were derived to calculate 10-, 20-, and 30-year freedom from cirrhosis. Cox regression models were used to find univariate and multivariate predictors of being diagnosed with cirrhosis. The multivariate model considered univariately significant variables (p <0.05) with model selection using the stepwise method. All statistical tests were 2 sided with the alpha level set at 0.05 for statistical significance. SAS 9.3 was used for the analysis (SAS Institute, Cary, North Carolina).

The cutoffs for discrete variables used in univariate and multivariate analyses were defined as follows: preoperative pulmonary artery pressures (>15 mm Hg), pulmonary arteriolar resistance (>3 U × m ² ), ventricular end-diastolic pressure (>12 mm Hg), post-bypass Fontan pressures (>20 mm Hg), and chest tube duration (>21 days). Bypass times and post-bypass left atrial pressures were analyzed as continuous variables. The complete set of variables evaluated for their association with survival and functional status of survivors are listed in Supplementary Table 1 .

Results

Overall, 1,138 patients had their initial Fontan or Fontan revision operation at our institution, with a mean duration of follow-up of 14.3 ± 9.5 years (median 14.1 years). Clinical follow-up of liver function and associated imaging were available for 195 patients with an average duration of follow-up of 20.6 ± 8.1 years (median 22 years). Demographics of this cohort are described in Table 1 . In comparison with all Fontan patients, there was a higher proportion of patients with extracardiac conduits, initial lesion of pulmonary atresia with intact ventricular septum, history of arrhythmia, or history of PLE in patients with liver imaging available (p <0.05). There were no other significant differences between the liver follow-up and the overall Fontan cohort. In long-term follow-up, there were no significant differences in cardiac function in the form of ejection fraction or systemic ventricle end-diastolic pressure, or in functional class between the groups.

For the 195 patients with available liver data, the mean age at Fontan operation was 9.6 ± 9.2 years with a range of 7 months to 53 years; 40 of 195 patients (21%) had a fenestration performed at the time of the operation, with most of the fenestrations being performed after 1995. At most recent follow-up, 150 of 195 patients (77%) were alive and 45 (23%) were known to be dead. Liver biochemical tests were available for all 195 patients; there were no significant differences in aspartate aminotransferase, alanine aminotransferase, total bilirubin, or direct bilirubin levels between patients who did or did not develop cirrhosis; 24 of 195 patients (12%) had a liver biopsy (3 of 24 postmortem), of which 23 (96%) were abnormal; 152 of 195 patients (78%) had a liver ultrasound, of which 86 (57%) were noted to be abnormal; 25 of 195 patients (30%) had a liver MRI (72% abnormal), 33 of 195 (17%) had a CT of the liver (91% abnormal), and 33 of 195 (17%) had an MRE of the liver (79% abnormal) with 81 of 195 (42%) having at least one form of cross-sectional liver imaging. For the 195 patients with available liver data, the overall 10-, 20-, and 30-year freedom from cirrhosis was 99%, 94%, and 57% respectively ( Figure 1 ).

Kaplan-Meier curve of freedom from developing cirrhosis in 195 patients with liver data after Fontan. There is an incremental incidence of cirrhosis with freedom from cirrhosis of 99% (98.3-100) in 171 patients at 10 years and 94% (90-98) in 115 patients at 20 years.

A total of 40 patients were diagnosed with cirrhosis by pathology or correlation of imaging findings with clinical evaluation by a gastroenterologist. An established clinical diagnosis of cirrhosis by a gastroenterologist was made in 37 of 40 patients on long-term follow-up; the remaining 3 patients had biopsy-proved cirrhosis. Of these 37 patients, the most common clinical characteristics were varices (43%), ascites (35%), and thrombocytopenia (30%); only 1 patient each had hepatorenal syndrome and hepatic encephalopathy. Of the patients with cirrhosis, 10 of 40 had evidence of cirrhosis by pathology, 13 of 40 had evidence of cirrhosis on CT imaging, 8 of 40 on MRI, and 6 of 40 on MRE. Only 6 of 40 patients did not have CT, MRI, or MRE, but all these patients had an abnormal liver ultrasound along with a clinical diagnosis of cirrhosis by the hepatologist. Overall, 31 of 40 patients (78%) with cirrhosis had available ultrasound data and 28 of 31 (90%) were abnormal. MRE-derived mean liver stiffness data were available for 7 of 40 patients with an average of 6.0 ± 1.3 kPa (>5 kPa interpreted as stage 4 fibrosis or cirrhosis based on institutional grading system derived for adult patients with other etiologies for liver disease).

For the 40 patients with cirrhosis, the mean duration from the Fontan operation to diagnosis of cirrhosis was 23.4 ± 6.3 years. There were 22 (55%) who had an atriopulmonary connection, 9 (22%) had a lateral tunnel, 5 (13%) had an extracardiac conduit, and 4 (10%) had other Fontan connections. A total of 6 patients had a fenestration during their initial operation. Only 1 patient had a cardiac transplantation before diagnosis of cirrhosis, 11 months after transplantation. There were 5 patients diagnosed with hepatocellular carcinoma at a mean duration of 20 ± 2.9 years after the Fontan operation (2 died in long-term follow-up), and none had a history of viral hepatitis. The earliest diagnosis of hepatocellular carcinoma occurred in a 20-year old, 17 years after Fontan operation.

Table 2 includes factors associated with the development of cirrhosis after Fontan operation by Cox regression analysis. Of note, initial anatomy of hypoplastic left heart syndrome (2 of 16 patients developed cirrhosis) was the only predictor of cirrhosis on multivariate analysis (p = 0.0133); sinus rhythm before the Fontan operation was the only protective factor on multivariate analysis (p = 0.009). After a diagnosis of cirrhosis, survival was 57% at 1 year and 35% at 5 years with a total of 16 patients who died in long-term follow-up. The cause of death was known for 9 patients (5 had multiorgan failure, 2 died of liver failure, and 2 patients died of heart failure.)

Table 2

Cox regression model for predictors of cirrhosis after the Fontan operation

Variable	Univariate Hazard Ratio (HR)	p-value	Multivariate Hazard Ratio (HR)	p-value
Anatomic Factors
Hypoplastic Left Heart Syndrome	5.95	0.025	7.33	0.0133
Pulmonary Artery Stenosis	2.91	0.049	NS	NS
Asplenia	2.56	0.081	NS	NS
Previous Surgical Procedures
Bidirectional Glenn	4.2	0.021	NS	NS
Pre-operative Factors
Pre-operative Diuretic Use	2.36	0.013	NS	NS
Pre-operative ACE-Inhibitor Use	4.11	0.007	NS	NS
ECG Sinus Rhythm	0.33	0.014	0.31	0.009
Operative Factors
Fontan – Atriopulmonary Connection	0.33	0.002	NS	NS
Fontan – Extracardiac Conduit	4.63	0.008	NS	NS
Fenestration at Initial Operation	3.9	0.016	NS	NS
AV Valve Replacement at Initial Operation	4.81	0.01	NS	NS
Intra-operative Sinus Rhythm	0.35	0.014	NS	NS

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