Incidence, Predictors, and Mortality in Patients With Liver Cancer After Fontan Operation

Incidence, Predictors, and Mortality in Patients With Liver Cancer After Fontan Operation.

Ohuchi H, Hayama Y, Nakajima K, Kurosaki K, Shiraishi I, Nakai M.

J Am Heart Assoc. 2021 Feb 16;10(4):e016617. doi: 10.1161/JAHA.120.016617. Epub 2021 Feb 4.

PMID: 33538186 Free PMC article.


Take Home Points:

  • Incidence of Liver Cancer (LC) increases markedly following Fontan surgery, particularly >30 years later.
  • Routine liver ultrasound, liver fibrosis indices and AFP and annual change in liver function tests should all be assessed as part of routine surveillance.
  • Mortality is high if LC is diagnosed after the development of symptoms.
  • Hepatocellular carcinoma is the most common but not the only type of LC that develops in patients with a Fontan circulation.

Commentary by Dr. Helen Parry (Leeds, UK), section editor of ACHD Journal Watch:



Fontan-associated liver disease (FALD) is an important non-cardiac complication in patients who have had Fontan surgery. This may take the form of hepatic fibrosis, cirrhosis and liver cancer.



To assess the following variables in patients with a Fontan circulation:

  1. Incidence of liver cancer (LC)
  2. Predictors of LC
  3. Current management of LC
  4. Prognosis after diagnosis of LC


This was a single-centre study in Osaka, Japan. Patients with a Fontan circulation were followed up between 2005 and 2019. Patients were assessed 6 months after surgery and on a 5-yearly basis thereafter. Assessment included:

  1. Liver ultrasound
  2. Assessment of liver fibrosis through calculation of the aspartate transaminase (AST) to platelets ratio (APRI), calculation of the Fib-4 score and the Forns index.
  3. Alpha-fetoprotein (AFP)
  4. Albumin, creatinine, bilirubin, alanine transaminase (ALT), gamma GT and INR

All patients were concomitantly screened for viral hepatitides. Patients were then classed as low, intermediate or high risk as per table 1:


Risk of advanced liver fibrosis


Fib-4 score

Forns index


















Diagnosis of LC was made pathologically on all confirmed cases. Chi- squared and Fisher’s exact test were used to assess the degree of liver abnormalities demonstrated on ultrasound versus the incidence of LC. Cox proportional hazard regression modelling was used to predict the association between the above clinical factors and new onset LC.


Three-hundred and thirty nine patients were identified and followed up as above. All patients were free of LC at 10 years post-Fontan surgery, 98.4% at 20 years and 94.3% at 30 years. The incidence is shown below.


Number of years since Fontan operation

Incidence (%)

Amongst n=











Assessment of fibrosis according to APRI, Fib-4 score and Forns index was performed on 267 patients (79%). Fourteen patients underwent evaluation for the presence of LC following concerning results in the above investigations: 3 of these presented with symptoms, 6 had a significant sized space occupying lesion on ultrasound and 5 had raised AFP. Ten of these patients had LC based on histopathology: 8 hepatocellular carcinoma, 1 intrahepatic cholangiocarcinoma and one combined hepatocellular cholangiocarcinoma. The youngest of these patients was 14 years old, all other patients were over 18 years of age. Four of these patients died during the follow up period including all 3 patients who had symptoms at the time of presentation.

The table below shows the treatment.


Type of treatment


Transarterial chemoembolization (TACE)


Radiofrequency ablation (RFA)


TACE and RFA combined


Surgical resection


Hospice referral



Patient age, number of years following Fontan surgery, increase in BMI, higher NYHA classification, abnormal live function tests, greater degree of annual change in assessment if fibrosis, APRI, Fib-4 score, AFP levels and the degree of abnormality demonstrated on ultrasound were all independent predictors of LC (p<0.05).

Positive aspects of the study:

  1. Highlights the importance of FALD and the importance of regular monitoring.
  2. The initial sample size of patients with a Fontan circulation was relatively large.
  3. The study was not limited to adult patients, paediatric patients were included (the youngest patient who developed LC was 14 years old)

Negative aspects of the study:

  1. The number of patients who developed LC (n=10) was very small
  2. The number of patients followed up beyond 30 years after surgery was very small (n=21) and this was a small proportion of the total number included in the study. Reasons for this were not provided.
  3. Only 79% of patients included in the study had fibrosis indices calculated, why was this so low?
  4. Certain factors were not taken into account such as alcohol intake or sub-type of the Fontan circulation, e.g., Atrio-pulmonary, lateral tunnel, extra-cardiac.

Comment: Five yearly liver assessment seems relatively infrequent in Fontan patients. Most places would do this every 1-2 years.