Invited Commentary: The Hunt for Mechanistic Origins of Liver Fibrosis in the Fontan Circulation

Abstract

Liver disease in the presence of a Fontan circulation has become an important focus of investigation. Biopsy studies using quantitative collagen-specific staining techniques demonstrate variable degrees of liver fibrosis present by early adolescence in all subjects evaluated. Fortunately, despite these histopathological changes, liver functional performance remains relatively preserved in the vast majority, and particularly in the young. However, the magnitude of fibrosis increases with advancing age, and adults with a Fontan circulation are more likely to have cirrhosis than are children. Alarming as well is the increased risk of hepatocellular carcinoma in young adults, potentiated by a progressively fibrotic liver that is under sustained, continuous physiological duress. Liver health is at risk even in the most well-functioning Fontan circulation. What causes Fontan-associated liver disease (FALD)? At the face of it, there are strong parallels to the congestive hepatopathy of rightsided heart failure. Increased venous pressure and hepatic congestion likely play important roles as physiological stressors but are unlikely to explain the whole story, and the answer may not be as simple as we think. Reports suggest that liver fibrosis may precede Fontan surgery and the degree of liver disease (ie, magnitude of fibrosis) is not directly linked to the magnitude of elevated venous pressure. Downstream of the liver, structural aspects of the Fontan circuit (ie, Fontan pathway, branch pulmonary arteries) may influence impedance to hepatic venous egress upstream and may contribute to hepatic congestion. Evans and colleagues approach this concept by studying anatomical variants and their association with a biopsy-derived fibrosis score, published in this issue of the World Journal for Pediatric and Congenital Heart Surgery. They found a higher liver fibrosis score in individuals with a univentricular heart of right ventricular morphology and a greater degree of fibrosis in those with, as compared to without, a pulmonary artery stent, controlling for Fontan duration and age at liver biopsy. A pulmonary artery stent indicates a history of branch pulmonary artery stenosis which may reflect a period of increased impedance to hepatic venous egress and thus increased hepatic congestion. In support of this notion, magnetic resonance imaging studies performed an average of six years prior to liver biopsy show that early left pulmonary artery stenosis is associated with greater magnitude of liver fibrosis at later biopsy. But why would right ventricular morphology be a risk factor? Mechanical features as identified by Evans et al are important; however, other factors may play a role. The variability and heterogeneity of FALD suggests that the etiology is complex and multifactorial. Indeed, a different perspective may be warranted to promote better understanding. We propose that the Fontan circulatory state itself promotes a predilection toward organ fibrogenesis, with genetic variation influencing the process. Importantly, fibrosis is not limited to the liver but is also seen within the myocardium, and although not extensively studied to date, we suspect within the kidney as well. Single ventricle heart disease—the substrate anomaly and the treatment strategy it entails—may be associated with a state of overall systemic fibrogenesis, induced by dysregulation of biological processes and influenced by specific genetic variants. A number of candidate regulatory processes that influence fibrogenesis are worth exploring in the Fontan circulation. Hypoxia and mechanotransduction (pressure leading to mechanical strain and deformational influences on cells) are high on the list as both mechanisms promote stellate ganglion cells to transform into fibroblasts and lay down collagen via transforming growth factor b1 (TGFb1). A growing body of evidence strongly suggests that the renin– angiotensin–aldosterone (RAA) system participates in fibrogenesis in the liver and other organs. Several studies indicate that angiotensin II mediates liver fibrosis through activation of hepatic stellate cells and by stimulating TGFb1 release via angiotensin receptors, and aldosterone induces fibrosis in heart, liver, and kidney through direct fibroblast activation. It is hard to imagine that the RAA system is not highly dysregulated in the Fontan circulation, yet to date there is surprisingly little research defining the presence or magnitude of dysregulation and its clinical impact. Elevations in circulating renin levels as well as angiotensin and aldosterone have been well described. In addition, serum amino-terminal procollagen type III, a biomarker of ventricular fibrogenesis, is associated with increased levels of serum renin, angiotensin II, and aldosterone after Fontan operation. However, direct imaging to quantify the relationship between fibrotic burden in the heart or in any other organ and biomarkers of RAA system has not been performed. For quite some time, there were high expectations in our field as investigators looked at ventricular performance and exercise capacity in Fontan patients while exploring the utility of angiotensin-converting enzyme inhibition. Disappointingly, no impact was found. Fibrogenesis, however, may be a better target outcome measure. The serotonin regulatory system is an additional target candidate ripe for exploration as a potential mechanism of fibrogenesis. Serotonin is an important regulatory molecule that influences the central nervous system and other organs. Serotonin directly promotes activation of fibroblasts via serotonin receptor 2A or 2B receptor signaling and downstream upregulation of TGFb1 and related pro-fibrotic events. Thus, serotonin is believed to play a central role in fibrogenesis in a number of conditions. Hepatic stellate cells express key regulatory components of the serotonin system, enabling them to respond in a pro-fibrogenic manner. Platelet serotonin release is one of the primary mechanisms of wound healing. Vascular damage and dysfunction with release of serotonin from the dense granules of activated platelets strongly induces extracellular matrix production via activation of serotonin receptors in a TGFb1-dependent manner. Vascular dysfunction present in a Fontan circulation makes the serotonin system a strong candidate for dysregulation with potential for promoting fibrogenesis, yet it has not been studied at all in patients with single ventricle heart disease.