Non-invasive biomarkers of Fontan-associated liver disease

Emamaullee J, Khan S, Weaver C, Goldbeck C, Yanni G, Kohli R, Genyk Y, Zhou S, Shillingford N, Sullivan PM, Takao C, Detterich J, Kantor PF, Cleveland JD, Herrington C, Ram Kumar S, Starnes V, Badran S, Patel ND. JHEP Rep. 2021 Sep 14;3(6):100362. doi: 10.1016/j.jhepr.2021.100362. eCollection 2021 Dec.PMID: 34693238


Take Home Points:

  • FALD begins earlier than first thought following Fontan completion
  • Platelet count, AST: platelet ratio, bilirubin and FIB-4 scores all correlate with the degree of fibrosis
  • Progression of FALD to bridging fibrosis or cirrhosis appears to be associated with increased mortality

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


Patients with a Fontan circulation are known to have a significantly increased likelihood of hepatic fibrosis, cirrhosis and hepatocellular carcinoma; a pattern referred to as Fontan associated liver disease (FALD). Multiple factors may contribute to the pathophysiology including chronically raised central venous pressure, hypoxia and low cardiac output.



  1. To assess the association between disease seen on biopsy and non-invasive biomarkers of FALD
  2. To assess the prevalence and associations of FALD in the Hispanic population


This was a single center study in Los Angeles. The patients were studied retrospectively and identified by local database. Cardiac catheter studies are routinely performed roughly 10 years following completion of the Fontan connection in this center and transjugular hepatic biopsies are performed at the same time. Blood test results for ALT, AST, ALP, bilirubin, GGT, blood urea nitrogen, creatinine, albumin, glomerular filtration rate, prothrombin time, full blood count and BNP taken within 6 months of the biopsy.

The pathologists who examined the biopsies were blinded to the patient’s clinical details and scored them according to the Congestive Hepatic Fibrosis Score (CHFS) where scores 0-2b were classed as less severe FALD and 3-4 more severe. This separates fibrosis alone (1-2b) from bridging fibrosis (3) and cirrhosis (4).



A total of 106 patients were included in the study: 69% were Hispanic, the mean age was 14.4 years +/- 3.5 years and 27% met criteria for obesity. The biopsy was taken an average of 10-11 years post Fontan completion. One patient experienced bleeding at the time of the biopsy and this was treated with gel foam embolization. The most common underlying pathologies were hypoplastic left heart syndrome (39%) and tricuspid atresia (17%).

One hundred and five of the 106 patients had some degree of hepatic fibrosis; 35 % had bridging fibrosis and 5.7% cirrhosis. Bridging fibrosis was associated with lower platelet count, increased AST: platelet ratio, raised bilirubin and raised FIB-4 score. Temporal change in platelet count was associated with the degree of fibrosis.

Median follow up post biopsy was 2 years. The Kaplan Meier analysis showed CHFS was associated with reduced survival (p=0.027). Seven patients died during follow up; 2 had CHFS 0-2b and the remaining 5 had CHFS of 3-4. Causes of death included complications relating to placement of epicardial pacing systems, progressive heart failure, sepsis and pulmonary hemorrhage.



  • Provided data for Hispanic patients, perhaps underrepresented in other studies
  • Provided histological images used to demonstrate the degree of fibrosis
  • Findings were consistent with existing literature
  • A range of non-invasive biomarkers were investigated in order to draw the most useful predictors

Weaknesses/ suggestions for improvement

  • The statistical significance of association between more advanced FALD and death is questionable as there were are very small number of mortalities
  • The follow up period post biopsy was short (2 years median)
  • No comparison was made between biopsy results and non-invasive modalities such as ultrasound or MRI
  • No comparison was made between cardiac factors such as ventricular impairment or atrio-ventricular valve function, and the development of FALD
  • A multi-centre study may have enhanced likelihood of identifying any racial differences in Hispanic versus Caucasian patients: do we need to be even more vigilant in either of these groups?