The Fontan procedure provides a palliative surgical repair for complex congenital heart disease, but it is associated with many long-term problems, including liver cirrhosis, and hepatocellular carcinoma. The current suggestion from international guidance is that end-organ surveillance should be carried out, with a particular focus on regular blood tests and imaging for liver function.
In this study, retrospective analysis was performed on adult patients who had previously had a Fontan operation performed to determine the regularity of end-organ surveillance in regards to their liver function covering the three calendar years from 2016 to 2018, and the first six months of 2019.
Eighty-six patients were identified in South Wales monitored by the adult congenital heart disease unit. We found that the number of investigations performed in the first six months of 2019 was comparable to other calendar years in their entirety. Liver function tests had been performed in 57% of patients throughout 2018, with only 8% having had an alpha-fetoprotein taken, and only 9% having had imaging of the liver performed. Over the course of their lifetime, 97% of patients had had a liver function blood test performed at some point, with 17% having had an alpha-fetoprotein taken, and 49% having their liver imaged.
In conclusion, end-organ surveillance is an important follow-up for patients with a Fontan circulation, with guidelines proposing yearly blood test and imaging investigations. This study shows the opportunities to improve surveillance in this group of patients to highlight the development of liver cirrhosis, and/or hepatocellular carcinoma.
A Fontan procedure is a surgical connection between the systemic venous return and the pulmonary artery performed in complex congenital heart disease where there is only one functioning ventricle.1 Most commonly, tricuspid atresia, pulmonary atresia (with intact ventricular septum), hypoplastic left heart syndrome, and a double inlet ventricle are the congenital heart defects palliated by a Fontan procedure.2
Problems associated with a Fontan procedure include cardiac arrhythmias, ventricular dysfunction, lymphatic dysfunction, protein losing enteropathy, venous thrombosis, plastic bronchitis, liver cirrhosis, and increased risk of developing hepatocellular carcinoma (HCC).3
Long-term follow-up of patients with a Fontan operation have demonstrated the risk of developing liver cirrhosis, with 10-, 20-, and 30-year freedom from cirrhosis of 99%, 94%, and 57%, respectively, on investigation of 195 patients.4 Autopsy data from patients having undergone the Fontan procedure demonstrated cardiac cirrhosis in four of the nine patients, with one of these four patients having a hepatic adenoma, and a further patient having developed HCC.5
The proposed mechanism for the development of liver cirrhosis, and, hence, the risk of developing HCC, is elevated central venous pressure and reduced hepatic venous flow leading to chronic congestion in the liver.6 This hepatic venous congestion leads to the development of hepatic fibrosis. Given the complication of liver cirrhosis and HCC, proposed surveillance strategies have been considered to periodically assess end-organ function.
A 2018 report from the American College of Cardiology (ACC)/American Heart Association (AHA),7 advises that “it is reasonable to perform biochemical and haematological testing on an annual basis for liver and renal function”, as well as stating that “imaging of the liver (ultrasonography, CMR [cardiac magnetic resonance imaging], CT [computed tomography]), [is] reasonable in adults after Fontan palliation”, although no timeframe for monitoring is given.
Recently, the use of transient elastography (TE) as a non-invasive investigation for liver stiffness has been hypothesised as a surveillance tool for liver disease in the Fontan population, given that the current gold standard of defining severity in these patients is with liver biopsy.8 Although there was a correlation between the time from Fontan procedure being performed and the liver stiffness score on TE, there was no correlation between the severity of liver pathology found on routine liver biopsy of the cohort and the stiffness measured with TE.
The South Wales and South West Congenital Heart Disease Network has developed guidance for the timeline of monitoring,9 which suggests that annual monitoring of blood tests should be performed, including full blood count, coagulation profile, urea and electrolytes, ferritin, liver function tests (LFTs), gamma glutamyl transpeptidase (GGT) and alpha-fetoprotein (AFP). The network also suggests yearly liver ultrasound and yearly TE.
By using the ‘Cardiobase’ software, a list of patients with reference to a Fontan circulation who were 16 years or older were exported from this system. To confirm the correct patients had been identified from this export function, each patient was individually searched using the ‘Welsh Clinical Portal’ system to view cardiology clinic letters and determine if these patients had had a Fontan operation.
The Welsh Clinical Portal software was then used to investigate the number of patients who had LFT and AFP blood tests and liver imaging performed in each calendar year. Magnetic resonance imaging (MRI) or ultrasound (USS) abdomen were accepted as modalities of imaging for the liver in this study.
The audit of Fontan patients was performed on 1 July 2019, and focused on the first half of 2019, and the previous three calendar years of results for each patient. While extracting these data, it was also noted whether each patient had ever had the investigation in their lifetime.
Data were collected for each health board in South Wales (Cardiff & Vale, Aneurin Bevan, Cwm Taf, Abertawe Bro Morgannwg and Hywel Dda University Health Boards), and overall data were then combined to produce data for all of South Wales. Since undertaking the audit, Cwm Taf and Abertawe Bro Morgannwg University Health Boards have now become Cwm Taf Morgannwg University Health Board and Swansea Bay University Health Board, due to a change in borders and services in this region. This has not had any impact on the way that results could be viewed through the Welsh Clinical Portal. Data have been grouped by the pre-existing health board arrangement, as this was the geographical case when these tests were performed.
One hundred and twenty-one patients’ information was exported from the Cardiobase software. After analysis of these patients, 33 were found to be expectant mothers whose offspring were anticipated to need a Fontan circulation after birth. Unfortunately, two patients with a Fontan circulation in South Wales had deceased in the previous five years, and were subsequently removed from analysis. Therefore, 86 patients remained in the final analysis (table 1).
Table 1. Baseline characteristics of Fontan circulation patients across South Wales, as well as separated into each health board
|Number (%)||86 (100%)||25 (29%)||20 (23%)||16 (19%)||15 (17%)||10 (12%)|
|Mean age, years||25.02||26.28||26.20||23.94||25.27||20.90|
|Days since last clinic||373||389||418||361||357||289|
|Key: ABMUHB = Abertawe Bro Morgannwg University Health Board; ABUHB = Aneurin Bevan University Health Board; CAVUHB = Cardiff & Vale University Health Board; CTUHB = Cwm Taf University Health Board; HDUHB = Hywel Dda University Health Board|
The analysis of tests carried out in the first half of 2019 demonstrated that of the 86 patients in South Wales, 40 (47%) had LFTs taken, eight (9%) had an AFP taken, and 11 (13%) had liver imaging performed. A similar proportion of patients had these tests performed in 2018, with 49 (57%) having their LFTs taken, seven (8%) having an AFP, and eight (9%) had liver imaging.
In 2017, we found that 41 (48%) of patients had LFTs performed, three (3%) had an AFP, and 11 (13%) had liver imaging. The investigations from the patients in South Wales from 2016 showed that 40 (47%) had LFTs taken, three (3%) had an AFP taken, and 12 (14%) had liver imaging performed.
When data were analysed for whether the patients had ever had these investigations performed, it was found that 83 patients (97%) had LFTs performed, 15 (17%) had had an AFP taken, and 42 (49%) had liver imaging.
No data were found using the Welsh Clinical Portal to suggest that TE had been performed on any of the patients identified.
From these results, we noted a low overall number of yearly investigations. Encouragingly, there was a comparable number of investigations performed in the first half of 2019 alone, as well as a slight upward trend in the proportion of patients receiving a yearly AFP. Given that we began the data collection for this study throughout the first few months of 2019, this may have increased staff awareness of the requirement for these investigations, leading to the increased proportion of investigations performed in 2019.
By accessing patient investigations using the Welsh Clinical Portal, we noted the incidental finding that many of the LFTs were not performed as an elective, outpatient investigation, but instead performed in the accident and emergency (A&E) or medical assessment unit (MAU) of the patients’ local hospitals. The events leading to these admissions was not investigated as part of this project, so no conclusions can be drawn regarding whether these tests were performed relating to the underlying congenital heart disease.
Further work, published in 2019, investigated the non-invasive assessment of Fontan liver physiology,10 and demonstrated that, in patients with liver biopsy performed for Fontan surveillance, fibrosis severity did not correlate with MRI, CT, or TE findings, nor did it correlate with laboratory investigations for liver fibrosis.
Despite this, a publication by the AHA in 20193 (published after the collection of these data) suggests a group of basic, in-depth and investigational tests for the monitoring of liver function. The ‘basic’ tests listed are ‘complete metabolic profile’ (a grouped term to describe LFTs, urea and electrolytes, calcium, chloride and glucose), platelet count, GGT, prothrombin time (PT) (or international normalised ratio [INR]), total serum cholesterol and abdominal liver USS.
The ‘in-depth’ investigations are AFP, liver imaging (CT or MRI), liver elastography (USS or MRI) and FibroSure biomarkers (a further grouped term which combines the results from alpha2-macroglobulin, haptoglobulin, apolipoprotein A1, GGT, and total bilirubin). The only investigational surveillance test listed was liver biopsy. This publication suggests it is reasonable to consider end-organ system surveillance testing every one to two years in Fontan patients older than 18 years.
Liver biopsy remains the gold standard investigation for liver fibrosis,10 but is an invasive investigation with risk of bleeding, particularly given the number of Fontan patients prescribed oral anticoagulation and/or antiplatelet therapy. Therefore, further studies are required to investigate improved methods of non-invasive monitoring of end-organ complications in this patient group.
Assessment of liver function in the Fontan patient group, be it with non-invasive laboratory investigations, liver biopsy, or imaging techniques, is important for the early identification of serious pathology, such as liver cirrhosis, fibrosis or the development of HCC. Despite the important advancements in the monitoring of Fontan-associated liver disease, management for these patients exhibiting liver dysfunction remains difficult.
There are no current medical therapies available for the treatment of liver fibrosis in Fontan circulation patients.11 In particular, utilisation of medications targeting the renin–angiotensin system for liver fibrosis patients have not been investigated in the Fontan-associated liver disease group. Outcomes of organ transplantation are only available from a small series of case reports detailing both combined heart–liver transplantation (CHLT),12 or heart transplantation alone.13,14
Published reports of CHLT document three patients who have all survived to two-,
three-, and five-year follow-up at the time of publication. A further study14 has reported encouraging outcomes from heart transplantation alone, with reversal of liver cirrhosis of congestive cause after heart transplantation. Data collected from Fontan patients undergoing heart transplantation13 showed that there was no significant difference in one-year mortality for patients with diagnosed cirrhosis prior to transplant, compared with non-cirrhotic patients. There are rare reports of ventricular assist devices being used as a bridge to heart transplantation in the failing Fontan circulation,15 but no current studies have been performed to investigate whether there is a reversal of liver function with the use of these devices.11
Given the current advice from AHA, we aim to improve the proportion of patients receiving yearly blood tests and imaging investigations. We are currently developing a booklet for Fontan patients so that these necessary investigations can be ‘checked off’ each year, improving adherence to these guidelines. Our aim is to involve a referral system to local hepatology services, to refer patients who demonstrate deranged LFTs, or any evidence of fibrosis or other abnormality on abdominal USS, so that any hepatic complications of their Fontan circulation is flagged up quickly.
- The long-term complications of a Fontan procedure include health problems such as cardiac arrhythmias, ventricular dysfunction, and liver cirrhosis, which may lead to hepatocellular carcinoma
- International guidelines provide some advice that end-organ surveillance should be carried out at regular intervals to monitor liver function, and the development of liver cirrhosis and hepatocellular carcinoma
- We found low overall yearly investigations performed in our cohort for liver surveillance, and no transient elastography was performed
- Keeping surveillance investigations at regular intervals for this at-risk group of patients will involve education of staff, as well as quality improvement interventions where possible
Conflicts of interest
According to the NHS Health Research Authority, this study is not considered research and, therefore, did not require ethical approval.
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