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Congenital heart disease
Late hepatic complications after Fontan operation; non-invasive markers of hepatic fibrosis and risk factors
  1. Jae Suk Baek1,
  2. Eun Jung Bae1,
  3. Jae Sung Ko1,
  4. Gi Beom Kim1,
  5. Bo Sang Kwon1,
  6. Sang Yun Lee1,
  7. Chung Il Noh1,
  8. Eun-Ah Park2,
  9. Whal Lee2
  1. 1Department of Pediatrics, Seoul National University Children's Hospital, Seoul, South Korea
  2. 2Department of Radiology, Seoul National University Hospital, Seoul, South Korea
  1. Correspondence to Eun Jung Bae, Department of Pediatrics, Seoul National University Children's Hospital, 101 Daehag-Ro, Jongno-gu, Seoul 110-744, South Korea; eunjbaek{at}snu.ac.kr

Abstract

Objective To identify the prevalence, clinical characteristics, risk factors of hepatic complications after a Fontan operation.

Methods This was a cross-sectional study of 139 Fontan patients who underwent cardiac CT scans out of a total of 204 patients who had undergone the Fontan procedure between 1986 and 2003. Mean age was 19.0±6.3 years and mean elapsed time since the initial Fontan operation was 11.5±4.7 years. Subjects' clinical features, echocardiograms, radiological features and biochemical test results were reviewed. Various non-invasive hepatic fibrosis blood markers were also evaluated.

Results Fifty-seven patients had hepatic complications, including radiological features of liver cirrhosis (25.9%), thrombocytopenia (7.2%), hyperbilirubinaemia (20.9%) and hepatic masses (2.9%). Hepatic complications were also significantly associated with ventricular dysfunction (p=0.020), absence of fenestration (p=0.004), thrombus in the Fontan tract (p=0.027), sinus node dysfunction (p=0.034) and tachyarrhythmia (p<0.001). In a multivariate analysis, the elapsed time since the initial Fontan operation was the only measure that was correlated with hepatic complications; the odds ratio of the post-Fontan duration of 16–20 years to that of 0–5 years was 9.00 (CI 2.24 to 36.17). The non-invasive hepatic fibrosis blood marker (Forns index) was also correlated with the elapsed time since the initial Fontan operation (r=0.718, p<0.001).

Conclusion Late hepatic dysfunction and cirrhotic change were often seen in Fontan patients. Moreover, hepatic complications were correlated with the duration of Fontan circulation. Therefore, after a Fontan operation, regular evaluation of the hepatic condition is required—for which some non-invasive hepatic fibrosis markers can be effectively used.

  • Liver cirrhosis
  • Fontan operation
  • congenital heart defect
  • paediatric cardiology

https://doi.org/10.1136/hrt.2010.201772

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    Introduction

    Since 1971, the Fontan operation and modifications of the method have been used for definitive palliation of patients with various forms of functionally univentricular hearts. However, the Fontan operation can result in various complications, including central venous hypertension, depressed dynamic cardiac output, impaired ventricular arterial coupling or late ventricular dysfunction,1 venous thrombosis and cardiac arrhythmia.

    In addition to the cardiac and haemodynamic disadvantages of Fontan circulation, a series of case reports have demonstrated that hepatic abnormalities may occur after the Fontan operation. These include coagulation disorders,2–4 cholestasis,2 liver fibrosis,1 5 and hepatomegaly with or without ascites.6 A few extreme cases exhibited hepatocellular carcinoma.5 7 However, the prevalence and progression of cirrhotic changes in the Fontan population, together with the risk factors of hepatic change, have not been clearly identified. Furthermore, non-invasive diagnostic tools for hepatic fibrosis are not well established.

    The aim of this study was to elucidate the characteristics and risk factors of hepatic change and identify helpful non-invasive hepatic fibrosis markers in the Fontan population.

    Methods

    Of 204 late follow-up patients who had undergone the Fontan operation in our institute between 1986 and 2003, 139 patients (68%) were enrolled in this cross-sectional study (86 men). These 139 patients underwent cardiac CT, extended over the upper abdomen, in order to image the liver. We reviewed their clinical, laboratory and radiological assessments. The interval between CT scan and laboratory assessment was 2.2±2.7 months.

    Echocardiography was also carried out in order to evaluate patients' ventricular functions and haemodynamic status. In addition, 12-lead ECG and 24 h Holter ECG recordings were conducted on the patients.

    We measured haemoglobin; white blood cell count; platelet count; alanine aminotransferase (ALT); aspartate aminotransferase (ALT); γ-glutamyl transpeptidase (GGT); total bilirubin; total protein; total albumin; prothrombin time; international normalised ratio (INR); and hepatitis A, B and C serology. Cholestasis was defined as a total bilirubin level >2 mg/dl. Thrombocytopenia was defined as a platelet count of <100 000 mm3. The enrolled patients had neither signs of hepatic dysfunction preoperatively nor evidence of autoimmune thrombocytopenia.

    CT images were obtained at the arterial phase and delayed phase using the SOMATOM Definition (Siemens Medical Solutions, Forchheim, Germany) and SOMATOM Sensation (Siemens Medical Solutions). CT scans were assessed by two consultant radiologists (EP and WL). We checked for the presence of stenosis or thrombosis of pulmonary arteries in the Fontan pathway; irregular or nodular liver surfaces; and liver parenchymal abnormalities, including regenerative and dysplastic nodules, ascites, mesenteric oedema, splenomegaly, collateral veins, hepatic congestion and inferior vena cava congestion. In this study, the definition of CT evidence of liver cirrhosis (CT-LC) was the presence of irregular or nodular liver surfaces.8 9

    We divided the patients into two groups: one without hepatic complications (group I; n = 82) and another with hepatic complications (group II; n =57); we compared these groups based on the parameters listed above. Hepatic complications included CT-LC, hepatic nodules, thrombocytopenia and hyperbilirubinaemia.2 5 6 Isolated splenomegaly was not included because of ill-defined diagnostic criteria in children. The isolated existence of collateral veins was also not included either owing to poor aetiological discrimination between liver cirrhosis or simple systemic venous hypertension after the Fontan operation. Furthermore, patients with isolated prolongation of prothrombin time were excluded since warfarin was used in 41% of patients (57/139).

    The time after an initial Fontan operation was divided into four periods with 5-year intervals: period I: 0–5 years, period II: 5–10 years, periods III: 10–15 years and period IV: 15–20 years.

    For the assessment of severity, we also evaluated various non-invasive hepatic fibrosis blood markers including the Forns index, AST/platelet ratio index (APRI), AST/ALT ratio (AAR), cirrhosis discriminant score (CDS) and Pohl score. Their definitions are summarised below:

    Forns index

    Forns index combines, platelet count, GGT, age and cholesterol in the following formula: 7.811–3.131.ln(platelet count) +0.781.ln(GGT) +3.467.ln(age)—0.014(cholesterol). As recommended by Forns et al, values <4.21 were considered normal.10

    APRI

    APRI is the ratio of the quantitative AST result to the platelet count. As recommended by Wai et al, it uses two different cut-off values for exclusion or prediction of significant fibrosis (<0.5/≥1.5).11

    AAR

    AAR is AST/ALT ratio, values <1 were considered normal.12–15

    CDS

    Three laboratory parameters were scored as follows: (1) platelets (×1000/mm3): >340=0, 280–339=1, 220–279=2, 160–219=3, 100–159=4, 40–99=5 and <40=6. (2) ALT/AST ratio: >1.7=0, 1.2–1.7=1, 0.6–1.19=2 and <0.6=3. (3) prothrombin time (PT): <1.1 INR=0, 1.1–1.4 INR =1 and >1.4 INR =2. The sum of the above represented the total modified CDS score with a possible numerical value of 0 to 11.16

    Pohl score

    The Pohl score, recommended by Pohl et al, is positive; AST/ALT ratio ≥1 in combination with a platelet count of <150 000 mm.3 17

    We compared various non-invasive hepatic fibrosis markers between patient groups with and without CT-LC (referred to as CT-LC group and non-CT-LC group, respectively). We investigated the correlation between significant markers and possible risk factors of hepatic complications.

    The study protocol was approved by the institutional ethics committee.

    Statistical analysis

    The data were analysed using SPSS version 12.0 software. Quantitative variables were expressed as the mean±SD, while qualitative variables were expressed as percentages. Statistical analysis was performed using the Student t test for quantitative variables, χ2 test and the logistic regression model for qualitative variables. The diagnostic value of each non-invasive marker was assessed by the area under the receiver operating curve (ROC). p Values <0.05 were considered significant.

    Results

    The enrolled patients' mean (SD) age was 19.0±6.3 years (range 5–41.5) and their mean (SD) age at the time of the initial Fontan procedure was 4.2±4.1 years (range 0.8–36.3). Atriopulmonary connection was performed in 35 patients, a lateral tunnel Fontan operation in 71 and an extracardiac Fontan operation in 33. The mean (SD) elapsed time since the initial Fontan operation was 11.5±4.7 years.

    Functional status and Fontan complications

    The New York Heart Association functional class was class II for 21 patients and class III for four patients; the other patients were in class I. Thirty patients had undergone re-operation owing to arrhythmia, thrombus in the Fontan tract, protein-losing enteropathy (PLE) and other causes after the initial Fontan surgery. Eight patients had active PLE at the time of the assessment and they were included in group II except for one patient. Episodes of tachyarrhythmia were documented by ECG as atrial flutter in 29 patients, atrial fibrillation in one patient and flutter and fibrillation in one patient. However, only one patient had persistent atrial flutter or fibrillation. Twenty-three patients had sinus node dysfunction. A permanent pacemaker was implanted in 16 patients.

    Mild cyanosis (pulse oxygen saturation value <90%)) was seen in 34 patients—20 patients in group I and 14 patients in group II. No difference was seen in the incidence of Fontan hepatopathy between cyanotic patients and non-cyanotic patients.

    Haematological and biochemical profiles

    Table 1 shows the laboratory characteristics. Hyperbilirubinaemia was found in 29 patients (20.9%). Thrombocytopenia was found in 10 patients (7.2%). Leucopenia was seen in 17 patients (12.2%). Viral hepatitis serology was negative in all but one patient. Hypoalbuminaemia was found only in patients with PLE. Raised INR of prothrombin time (1.3–2.0) was found in eight patients among the 82 who were not receiving warfarin.

    View this table:
    Table 1

    Baseline characteristics of patients and a comparison of haemodynamic parameters between groups

    Haemodynamic profiles

    Nineteen patients had moderate or severely depressed systemic ventricular function. Seventeen patients had significant atrioventricular regurgitation over a moderate degree, including seven who also showed ventricular dysfunction. Moderate or severe aortic regurgitation was found in two patients.

    Radiological characteristics

    CT results showed hepatic vein congestion in 109 patients (78%), inferior vena cava engorgement in 93 patients (67%), ascites in 22 patients (16%) and mesenteric oedema in 18 patients (13%). The irregularity of the liver surface of patients with CT-LC was detected in 36 (25.9%). Among them, four patients had hypervascular masses and three of them had multiple nodules of various sizes in the liver (up to 1.4 cm in one patient; figure 1). On the other hand, the remaining patient of the four had a single nodule of 9 mm. One patient had a liver biopsy, but the result was inconclusive, showing non-neoplastic liver parenchyma with focal sinusoidal dilatation. No correlation was found between imaging CT-LC and total bilirubin increase (r=0.001, p=0.994).

    Figure 1
    Figure 1

    Arterial-phase CT scan showing surface irregularity and multiple hypervascular liver nodules (arrows).

    Hepatic complications

    Hepatic complications were found in 57 patients (41%; group II). The complications included nodular liver surface (n=36, 35.8%), hepatic nodules (n=4, 2.9%), hyperbilirubinaemia (n=29, 20.9%) and thrombocytopenia (n=10, 7.2%).

    Univariate and multivariate analysis

    Table 1 shows the univariate analysis of various parameters between groups I and II. In this analysis, hepatic complications occurred more frequently in patients with longer follow-up durations (p<0.001). Moreover, hepatic complications were significantly associated with Fontan type (p<0.001), a decrease in ventricular function (p=0.02), absence of initial fenestration (p=0.004), thrombus in the Fontan tract (p=0.027), sinus node dysfunction (p=0.034) and arrhythmia (p<0.001). The morphology of the single ventricle, early postoperative hospital stay, sex, degree of valve regurgitation and stenosis of the Fontan tract were not significantly correlated with hepatic complications.

    In the multivariate analysis, the elapsed time since an initial Fontan operation was the only parameter correlated with hepatic complications. In other words, the risk of hepatic complications after a Fontan operation increases as the follow-up duration increases. The odds ratios of the post-Fontan duration of 6–10 years, 11–15 years and 16–20 years to 0–5 years were 0.56 (CI 0.10 to 3.10), 4.38 (CI 1.11 to 17.23) and 9.00 (CI 2.24 to 36.17), respectively.

    Non-invasive hepatic fibrosis markers

    Global results for non-invasive fibrosis markers are summarised in table 2. Non-invasive fibrosis markers except CDS showed significant abnormalities in the CT-LC group. Areas under the ROC were 0.786 for the Forns index (95% confidence interval (CI) 0.61 to 0.95), 0.702 for the Pohl score (95% CI 0.47 to 0.94), 0.631 for CDS (95% CI 0.325 to 0.937), 0.571 for AAR (95% CI 0.34 to 0.81) and 0.563 for APRI (95% CI 0.27 to 0.86). There was also a positive correlation between the duration of follow-up after the Fontan operation and non-invasive fibrosis markers: Forns index (r=0.718, p<0.001; figure 2), Pohl score (r=0.219, p=0.010).

    View this table:
    Table 2

    Non-invasive fibrosis markers

    Figure 2
    Figure 2

    Correlation between non-invasive hepatic fibrosis marker (Forns index) and elapsed time after Fontan operation.

    Discussion

    The hepatic complications after Fontan operations are varied and include abnormalities in biochemical liver function and coagulation profile, which may progress to liver cirrhosis and hepatocellular carcinoma. Camposilvan et al reported that hepatic abnormalities were found in up to 53% of Fontan patients; the hepatic abnormalities exhibited included hepatomegaly, splenomegaly, abnormal transaminases, elevated GGT, elevated bilirubin and coagulopathy.6 Our results corroborated the results of a previous study, which showed that the frequency of hepatic complications was significantly high. Moreover, the radiological evidence of liver cirrhosis seen in a quarter of our patients during the follow-up period of 11.5±4.7 years was novel. The number of patients enrolled in our study was larger than that for similar reported studies and this increases the validity of our findings.

    It is well known that longstanding hepatic congestion may result in cardiac cirrhosis—which is irreversible and is the end-stage of hepatic damage. Although there is little information about the incidence, risk factors, or prognosis of liver cirrhosis during exposure to long-term hepatic venous congestion, it is certain that cardiac cirrhosis can be serious. In the univentricular Fontan physiology, the neurohormonal activation caused by portal hypertension may be profound, which exacerbates volume retention and curbs functional ability.18 The progression to hepatocellular carcinoma in cardiac cirrhosis has also been reported in several case studies.5 7 19 20 Although there was no mortality due to liver cirrhosis reported in our patients, this complication may become one of the most likely causes of late death in addition to thromboembolism, heart failure and sudden death.21

    In the univariate analysis, hepatic complications of Fontan circulation were related to various factors—exposure time to Fontan circulation, Fontan type, a decrease in ventricular function, absence of initial fenestration, thrombus in Fontan tract, sinus node dysfunction and arrhythmia. However, the exposure time to Fontan circulation was the only related factor in the multivariate analysis. Atriopulmonary (AP) Fontan may influence the progression of hepatic fibrosis because it has a large amount of reflux deep into hepatic veins during atrial contraction. However, the era effect might confound the effect of AP Fontan on the liver. Unfortunately, AP Fontan is not performed anymore and therefore, it is a little difficult to conduct a further study to completely discriminate between the effect of the Fontan type and that of an exposure time to Fontan circulation on hepatic complications.

    Our results were similar to the findings of Kiesewetter et al, in which a significant positive correlation was observed between the duration after Fontan operations and hepatic complications.22 In other words, as the time after Fontan operation increases, the incidence of hepatic complications also tends to increase. The risk of hepatic complications particularly increased as the time exceeded 10 years. However, the risk during period II (6–10 years) was less than that of period I (0–5 years); this is not in line with overall tendencies. Hepatic dysfunction by acute hepatic congestion after Fontan palliation may have a period of adaptation and stabilisation and thus lead to the reduced risk during period II. However, 10 years after an operation, non-invasive evidence of hepatic fibrotic change increased.

    In general, the Fontan circuit is complete by 1–5 years of age depending on the centre preference, growth of vascular structures and cyanosis during exercise and at rest.23 Based on these results, one-third to two-thirds of Fontan patients may have hepatic complications by the time they become teenagers. However, details of the progression from early hepatic fibrosis to irreversible liver cirrhosis are currently unknown. Therefore, patients who underwent the Fontan procedure should be monitored specifically for hepatic complications. Based on the multivariate analysis result, we suggest that the most appropriate timing for monitoring is 11 years after Fontan completion.

    In addition, early intervention may be necessary for Fontan patients in order to avoid additional hepatic venous congestion. In order to reach a consensus on optimal timing of a second intervention, the main problem faced is the lack of data on the nature and progression of this specific complication. Thus, the question arises: how do we detect hepatic complications (especially liver cirrhosis) in an efficient manner in order to determine when to conduct a second intervention? The ideal diagnostic test for hepatic fibrosis should be simple, readily available, inexpensive and accurate. In order to find a test close to this ideal, we applied well-known, non-invasive hepatic fibrosis markers to our patients. Our results showed that a few markers were correlated with CT-LC. This suggests that these markers are reliable tools for predicting the liver histology of young adult and adolescent Fontan patients. Our results showed that, among the considered markers, the Forns index had the highest area under the ROC. Therefore, we suggest that the Forns index is the best predictor of the presence of Fontan hepatopathy.

    The effectiveness of some non-invasive markers has been reported, but only for adult patients with chronic hepatitis C; our study is the first to show similar effectiveness in adolescent and young adults. Furthermore, adult data has shown that some non-invasive fibrosis markers, such as AAR and CDS, are also helpful in assessing the degree of severity of hepatic fibrosis.11 12 16 Thus, based on the similarities observed between studies, we can formulate a hypothesis in which such markers might be used in adolescents and young adults in addition to grading hepatic fibrosis and determining when to conduct a second intervention.

    Finally, we discuss CT as a diagnostic tool for liver cirrhosis. The morphological features of liver cirrhosis determined by CT imaging have been well described in the literature and have been used in a clinical setting; these include irregular or nodular surfaces, blunt edge and lacelike types of fibrosis in the liver. However, only a few studies have compared the diagnostic accuracy of CT imaging with the histopathological diagnosis of liver cirrhosis9 24; in these studies, the accuracy, sensitivity and specificity of CT were reported to be 67–72%, 77–84% and 53–68%, respectively. Unfortunately, those studies were restricted to patients with chronic viral hepatitis-related liver cirrhosis which causes macronodular cirrhosis. In contrast, liver cirrhosis in Fontan patients is considered to be cardiac cirrhosis that develops after protracted right-sided congestive heart failure. The gross pattern is one of fine nodularity, resembling micronodular cirrhosis. 25 Because the morphological changes in micronodular cirrhosis are visible in CT scans in the advanced stage of cirrhosis, we believe that the rate of false-positive diagnosis of liver cirrhosis by CT may be low. Among the imaging tools used for the detection of liver cirrhosis, CT is more reproducible and has less observer variability than ultrasonography and is more convenient and economic than MRI.

    Study limitations

    Our study has the following limitations: it was a cross-sectional study and as a result, does not analyse the progression of hepatic fibrosis. LC was indirectly diagnosed using CT and not in a pathological manner. However, using CT for the prediction of cirrhosis is useful.9 Lastly, liver biopsy was difficult to carry out in all Fontan patients despite the fact that it is a safe procedure, in general, and is currently the best method to assess liver histology.

    Conclusion

    Hepatic complications were common in patients who underwent the Fontan procedure. Moreover, hepatic complications were related to the duration of the Fontan circulation. Thus, the hepatic condition of patients who undergo the Fontan procedure should be regularly evaluated. Non-invasive hepatic fibrosis markers and imaging modalities can be useful.

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    Footnotes

    • Competing interests None.

    • Ethics approval This study was conducted with the approval of the Seoul National University Hospital Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.