Hepatocellular carcinoma after the Fontan procedure in a 16-year-old girl: A case report.

INTRODUCTION: The Fontan procedure (FP) has become the standard operation for patients with single ventricle physiology. However, a long period of elevated systemic venous pressure and low cardiac output after the procedure result in chronic inflammation and liver cirrhosis, which may eventually lead to the occurrence of hepatocellular carcinoma (HCC). CLINICAL
FINDINGS: We described the case of a 16-year-old female who developed HCC after the FP. At 21 months, the patient received a lateral tunnel FP, and 14 years later, she began complaining of abdominal distension, telangiectasia, and fatigue. Imaging studies revealed a large hepatic mass involving most of the right lobe and multiple masses in the left lobe. Evidence suggested severe liver cirrhosis, and the presence of ascites, hepatosplenomegaly, paraesophageal gastric varices reflecting the severity of the disease. In addition, tumor thrombosis was found in the right hepatic vein, middle hepatic vein, and inferior vena cava, as well as multiple metastatic nodules in both lungs. The patient received an incisional biopsy and the diagnosis of HCC was pathologically confirmed. After treatment with 1 cycle of systemic chemotherapy, she received ongoing supportive care for disease-related complications, and died 2 months after chemotherapy due to hematemesis.
CONCLUSION: With the advances in medicine, the incidence of Fontan physiology-related complications is likely to increase, and the incidence of HCC will also increase accordingly. As early diagnosis of HCC results in better patient outcomes, a surveillance guideline for HCC after the FP should be developed.

Introduction

The Fontan procedure (FP) is a palliative surgical procedure used in children with single ventricle physiology. It involves diverting the venous blood from the right atrium to the pulmonary arteries without passing through the morphologic right ventricle.[ Since first described in 1971, the Fontan procedure has become the standard operation for patients with single ventricle physiology.[ Despite saving numerous lives for the past 45 years, the Fontan circulation is often associated with long-term complications such as heart failure, pleural effusion, hypercoagulability, portal hypertension, and atrial fibrillation.[ Among these, long-term elevated systemic venous pressure and low cardiac output may lead to the development of liver cirrhosis, and such a progression may eventually result in the incidence of hepatocellular carcinoma (HCC) in some patients.[

In this study, we presented the case of a 16-year-old female patient who developed HCC at a young age after receiving the FP. Informed consent was written by the patient and her parents.

Case report

This female patient was born full-term at 2.6 kg with an unremarkable perinatal history. At 3 months of age, she was evaluated for a heart murmur, and after receiving a diagnosis of tricuspid atresia with double outlet right ventricle, she was admitted to our hospital for treatment and further evaluation. At 5 months, she received a pulmonary artery banding operation, at 21 months she underwent bilateral bidirectional cavopulmonary shunt, and at 21 months, finally underwent a lateral tunnel FP. At 6 years of age, the patient began complaining of dizziness, and evaluation findings were consistent with sinus bradycardia. While receiving follow-up care for this condition, she was also diagnosed with a moderate degree of aortic regurgitation. The patient received a pacemaker insertion and an aortic valve replacement at the age of 10 years to treat sinus bradycardia and aortic regurgitation, respectively. At 9 years of age, the patient was evaluated for gait ataxia and developmental delay. Magnetic resonance imaging of her brain revealed a small lacunar infarction and cerebellar atrophy.

At 15 years of age, the patient developed peripheral edema and an abdominal ultrasound was performed. The ultrasound revealed mild hepatic lobulations with no signs of ascites or liver cirrhosis. Laboratory evaluations showed normal liver enzyme levels, and alpha-fetoprotein (AFP) levels were not measured.

One year later, the patient was readmitted to our hospital because of abdominal distension, telangiectasia, and fatigue. The liver, on abdominal ultrasound imaging, showed a heterogeneous echotexture, warranting the need for further evaluation studies. A computed tomography (CT) of the abdomen showed a large mass involving most of the right hepatic lobe, as well as multiple masses in the left lobe (Fig. 1). This image also revealed signs of progressive liver cirrhosis, such as ascites, hepatosplenomegaly, paraesophageal varicies, along with evidence of tumor thrombosis in the inferior vena cava and right and left hepatic veins. On laboratory evaluations, blood test results were as follows: aspartate transaminase (AST) 82 IU/L(normal range; 1–40), alanines transaminase (ALT) 28 IU/L(normal range; 1–40), gamma-glutamyl transaminase (GGT) 123 IU/L(normal range; 8–35), total bilirubin 1.8 mg/dL(normal range; 0.2–1.2), and AFP and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels were measured at 211,580 ng/mL(normal range; 0.89–8.78) and 35,721 mAU/mL(normal range; 0–40), respectively. The patient was seronegative for hepatitis B and C and reported no history of alcohol consumption. Her body mass index was 15.11 kg/m2. She had a Child–Pugh score of 8. Echocardiography revealed that ejection fraction of left ventricle was 59%. A chest CT performed on the same day showed multiple metastatic nodules in both lungs (Fig. 2).

Figure 1

Abdominal CT images show a large mass in the right hepatic lobe (black arrow, 12.5 × 10.5 × 7.5 cm) and multiple masses in the left lobe (white arrow): (A) axial view, (B) coronal view. CT = computed tomography.

Figure 2

Chest CT reveals multiple metastatic nodules in right lung (arrow). CT = computed tomography.

Three days later, the patient began experiencing hematemesis and hematochezia and an endoscopic variceal ligation was performed. Due to the presence of large volume ascites, peritoneal seeding could not be excluded and a percutaneous liver biopsy was not done. An incisional biopsy was obtained from segments 4 and 5 of the liver, and a diagnosis of HCC was pathologically confirmed (Fig. 3). The patient received 1 cycle of cisplatin-based chemotherapy. She received 3 subsequent endoscopic variceal ligations. Currently, the patient is no longer taking warfarin for her underlying heart conditions, and as she is not a candidate for a liver transplantation, she receives supportive care for disease-related complications. After 2 months of chemotherapy, she died at home with hematemesis, possibly due to variceal bleeding.

Figure 3

Histologic appearance of the HCC: (A) histologic pattern: compact and trabecular, (B) Edmondson–Steiner nuclear grade II/IV, (C) presence of vascular invasion (arrow). HCC = Hepatocellular carcinoma.

Discussion

In the United States, ∼650,000 to 1.3 million people are born with congenital heart diseases, and this number continues to show 5% increases every year.[ Warnes et al[ reported that with successful surgery, 85% of these cases survive to adulthood. Since first described in 1971, the FP has been used to treat various congenital heart diseases with single ventricle physiology.[ Forty-five years after receiving this operation, some patients have experienced Fontan physiology-related complications. The postoperative circulatory changes result from the following 4 major changes: (1) single ventricle circulation, (2) nonpulsatile pulmonary perfusion, (3) systemic venous hypertension, and (4) intracardiac scarring.[

Chronic elevation of central venous pressure and tissue hypoxia are associated with hepatic complications. After the FP (with the exception of the atrioventricular Fontan), blood flow into the superior vena cava bypasses the right ventricle by going directly into the pulmonary artery (PA) or into the right atrium that is connected to the PA. Due to this configuration, the central venous pressure is not reflective of the intracardiac preload, but is instead representative of the chronically elevated PA pressure. Such mechanisms cause repetitive mechanical stretch and compression via passive congestion on hepatocytes.[ In addition, high systemic venous pressure results in low cardiac output, which, in turn, causes low hepatic perfusion and chronic tissue hypoxia. Passive congestion and tissue hypoxia cause repetitive hepatocyte injury and inflammation, leading to the progression of liver cirrhosis, ultimately resulting in the development of HCC.[

Cardiac cirrhosis-related HCC was first reported by Ho et al[ in 1990. There are 10 published PubMed case reports of HCC after the FP, and with the addition of our case, this number has increased to a total of 11 (Table 1).[ HCC incidence after the FP has not been frequently reported. The incidence of hepatic complications including HCC are correlated with the duration of elapsed time since the initial FP.[ According to Baek et al[, the odds of hepatic complications were 4.4 times higher in patients belonging to a group with a postoperative duration of 11 to 15 years compared to patients with a postoperative duration of 5 years or less. The odds were even higher (OR 9.0) for patients belonging to a group with a postoperative duration of 16 to 20 years. Patients belonging to a group with a median postoperative duration of 11.5 years showed signs of hepatomegaly (53%), splenomegaly (9%), abnormal transaminases (30%), elevated GGT (61%), elevated biliruibin (32%), and coagulopathy (58%).[

Table 1

Reported cases of HCC after the Fontan procedure.

A study conducted by Kiesewetter et al[ in 2007 focused on patients with a mean postoperative duration of 14.1 years (range: 6.9–26.4 years); they reported that 58.3% of patients belonging to this group had developed liver cirrhosis. Although subsequent studies failed to report postoperative duration, the authors reported that 15% of patients with a mean age of 26 ± 9 years showed signs of liver cirrhosis.[ For patients with liver cirrhosis, the risk of HCC increases annually by 1.5 to 5.0%.[ However, screening guidelines for subsequent HCC after the FP have yet to be made. Both our case and the case reported by Yamada et al[ described patients who developed HCC 14 years after receiving the FP. In addition, another case of a 13-year-old female patient who developed HCC after cardiac surgery has been reported; although this patient did not receive an FP, she did receive palliative surgery at 7 months of age for pulmonary atresia with an intact ventricular septum.[ Although AFP levels were not checked 1 year prior to the diagnosis, abdominal ultrasound images revealed no signs of liver cirrhosis and liver enzyme levels were within normal limits. The patient unfortunately showed rapid disease progression, and developed HCC within only 1 year. Thus, we propose that patients who have received the FP 10 years ago or earlier should receive AFP and abdominal ultrasound screening tests at 6 month intervals as part of an HCC surveillance program.

Conclusion

Patients who have previously received the FP experience long-term Fontan physiology-related complications in adulthood. In this study, we reported a case of a 16-year-old female who developed HCC 14 years after receiving the FP. With continued medical advancements, we expect the number of Fontan physiology-related complications to increase, and the incidence of HCC in these patients will also increase accordingly. Early diagnosis of HCC results in better patient outcomes, as many treatment modalities remain viable. Therefore, we conclude that a HCC surveillance guideline should be developed for patients who have undergone the FP.