In adults, chronic congestive heart failure and systemic venous engorgement produce a spectrum of histologic and functional abnormalities in the liver, ranging from dilation of sinusoids with centrilobular necrosis to replacement of centrilobular hepatocytes with fibrous tissue and cirrhosis (29). Cardiac cirrhosis refers to the irreversible, end-stage phase of hepatic damage as a result of long-standing hepatic venous congestion from cardiac failure. In an autopsy study of 605 adults who died with chronic cardiac decompensation, 10% were noted to have histologic changes in the liver consistent with cardiac cirrhosis (30).
There is little information available regarding the long-term consequences of chronic hepatic congestion in children. Matsuda et al. (31) and Jenkins et al. (32) described a high incidence of acute liver dysfunction after the Fontan procedure, caused predominantly by low cardiac output, which did not correlate with the presence of abnormal standard liver blood tests obtained approximately 1 year after surgery. Moreover, serum aminotransferase levels were rarely elevated during long-term follow-up evaluation after the Fontan procedure (13,14). However, factors V (14) and VII (13) were low in 24% to 43% of patients during long-term follow-up evaluation after the Fontan procedure. Stanton et al. (33) described a patient who died suddenly 21 months after surgery, presumably from an arrhythmic event, who was found to have histologic evidence of cirrhosis. Lemmer et al. (11) reported a 13-year-old patient who developed cirrhosis 5 years after performance of a modified Fontan procedure for tricuspid atresia. Despite the concern for the potential deleterious consequences of the high central venous pressure on the liver, no study has examined the effect on quantitative tests of hepatic function in this clinical setting. It is important to define the scope of this problem for the following reasons. The indications for the Fontan procedure as corrective surgery have expanded beyond tricuspid atresia to include an increasing number of complex congenital cardiac defects. In addition, the operation is now being performed at an earlier age. Thus, there may be an increasing number of children who are at risk for the development of liver disease from chronically elevated systemic venous pressure. Orthotopic cardiac transplantation is now an option for patients who have undergone the Fontan procedure who experience late complications, or, in some cases, as an alternative treatment. Because cardiac transplantation risk is greatly increased if cirrhosis is established, cirrhosis is considered a relative contraindication to orthotopic cardiac transplantation at some centers. Liver biopsy in the setting of high right-sided cardiac pressures may carry an increased risk of bleeding from the higher pressures in the hepatic vein and the frequently associated coagulopathy. In addition, transjugular liver biopsy is usually precluded by the post-Fontan anatomy. Thus, it would be optimal to determine objective, noninvasive criteria that precede the development of cirrhosis so that intervention with cardiac transplantation could be offered to prevent further hepatic injury.
Although the Fontan procedure has been performed for more than 30 years in children with complex congenital heart diseases, the long-term effects of elevated right-sided cardiac pressure on the developing liver have not been delineated. In this pilot study, we observed that abnormalities of standard biochemical indices of hepatic injury are uncommon in children after the Fontan procedure, confirming previous reports (13,14). One of the major findings of this study was the frequency of abnormal coagulation in children who were studied at least 5 years after the Fontan procedure. Our patients frequently had prolonged PT and a reduction in factor V levels. Previous studies have suggested that intrahepatic microscopic thromboses contribute to the pathology of hepatic injury and fibrosis during hepatic congestion (19). However, the prolonged PT and low factor V levels were unlikely to be caused by consumption because factor VII and VIII levels were normal in almost all subjects, as noted previously by Kaulitz et al. (14). Thus, factor V synthesis appears to be dysregulated during hepatic congestion and may serve as an early biochemical marker of hepatic dysfunction after the Fontan procedure. The mechanism underlying this dysregulation requires further investigation.
An important clinical issue in children who have undergone the Fontan procedure is the development of significant hepatic fibrosis or cirrhosis and its impact on timing for a possible cardiac transplantation. Because cardiac cirrhosis would further reduce hepatic blood flow in a congested liver, we investigated indirect markers of hepatic blood flow. Galactose elimination half-life and GEC decreased as the interval since the Fontan procedure lengthened. These data suggest that GEC may be a useful marker for the gradual impairment of hepatic function that occurs with cardiac cirrhosis because galactose elimination depends on hepatocyte mass and hepatic blood flow.
Liver biopsy is the most accurate current means of quantifying hepatic fibrosis. In this study, liver biopsies were only performed for clinical indications (primarily evaluation for orthotopic cardiac transplantation). Ideally, we would have preferred to have liver histology for all patients; however, the potential increased risk of bleeding and lack of access for transjugular liver biopsy precluded biopsy for research purposes alone on ethical grounds.
Doppler ultrasound evaluation of portal and splenic venous blood flow did not demonstrate reduced flow, suggesting that the effect of hepatic injury after the Fontan procedure is likely a decrease of hepatocyte mass. Although there was a trend to a larger left portal vein diameter in subjects with clinical liver disease, left portal vein diameter did not appear to be as useful a discriminant function as PT or GEC. The temporally related increase of PT in conjunction with the decrease in GEC suggest that hepatocyte loss of function may be the earliest hepatic abnormality that develops within 5 years of the Fontan procedure.
In conclusion, routine biochemical indices of hepatic injury may underestimate the extent of congestive hepatopathy and hepatic fibrosis after the Fontan procedure. In contrast, our data suggest that PT and GEC may be useful markers of hepatic dysfunction and fibrosis in these patients. Sequential determination of PT may be a useful part of the routine monitoring after the Fontan procedure. Further, prospective investigation of serial galactose clearance testing will be necessary to determine if this test is a useful predictor of progressive hepatic dysfunction and fibrosis after the Fontan procedure (34).
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