Liver fibrosis in biliary atresia

Abstract

Biliary atresia (BA) is the most common cholestatic liver disorder requiring liver transplantation in children. Hepatic fibrosis is not only a universal and prominent feature of BA, it is also the most important predictor of outcome following portoenterostomy (PE). Without PE, the progression of hepatic fibrosis is quite dramatic, such that liver cirrhosis is established within a few weeks after birth. Etiologies and molecular networks underpinning such an expeditious fibrogenic process have not been well established. However, immune and nonimmune factors implicated in the pathogenesis of BA, and the resultant cholestasis and oxidative stress, appear to be the main triggers of hepatic fibrosis in BA. Owing to a lack of validated noninvasive tools to monitor liver fibrosis, current prognostic models of BA entail clinical and biochemical variables reflecting liver dysfunction rather than hepatic fibrogenesis. Further work is necessary to validate the results of preliminary studies indicating a good relationship between liver fibrosis determined by transient elastography and other clinical and routinely performed biochemical parameters in pediatric patients. Although a prime candidate for a number of antifibrotic therapies on the horizon, owing to poor understanding of molecular mechanisms, a clear framework of antifibrotic targets has not been outlined in BA. Similarly, specific antifibrotic therapies have not yet been incorporated in clinical practice, limiting these measures to prompt diagnosis and PE operation, prevention and treatment of cholangitis and optimal nutritional support including the administration of fat-soluble vitamins.

Shear wave elastography helps differentiate biliary atresia from other neonatal/infantile liver diseases

“…Hepatic fibrosis is a universal feature of biliary atresia and its progression to severe fibrosis and cirrhosis early in life is unique to this disorder [6]. Although biopsy has traditionally been required to assess liver fibrosis, several recent studies in children and adults have demonstrated that US shear wave elastography (SWE) can be used to detect and quantify liver fibrosis [7][8][9].…”

Special considerations in children

“…An enigmatic characteristic of this entity is the rapid progression of fibrosis, leading to cirrhosis in the first weeks of life. A combination of genetic and environmental factors has been proposed to explain it, giving rise to a particularly intense fibrogenesis driven by an ongoing immune activation that may persist even after surgical restoration of bile flow [5,6]. After the Kasai portoenterostomy >50% of patients will clear jaundice if surgery is performed before 60 days of age but, unfortunately, almost all will already show an advanced stage of fibrosis or cirrhosis by that time (Figure 28.2) [7].…”

MicroRNAs orchestra the cellular processes driving failure of the heart

“…However, both studies relate to biliary atresia, in which occlusion of the bile duct leads to cholestasis with secondary fibrosis of the liver [38] It is therefore conceivable, that the high miR-222 levels found in these studies do not directly correlate with pro-fibrotic signaling, but rather relate to increased stellate cell proliferation with secondary effects on the degree of cholestasis and fibrosis.…”

“…Subsequently, the eIF4F complex recruits the 40S ribosomal subunit and joins with the 60S ribosomal subunit at the AUG codon to begin elongation. RISC is postulated to repress initiation of translation by competing with eIF4E to bind to the 5' terminal cap [36,37], and by blocking the association of the 60S ribosomal subunit with the 40S pre-initiation complex [38].…”

“…Decreased expression [18] and activity [27] of SERCA2a are thought to be the primary mechanisms for the impaired cardiac relaxation in the aged myocardium. In addition, age-associated alterations in proteins able to regulate SERCA2a activity, including PLB, [35][36][37][38], PKA [39], and CAMKII [40] have also been documented in the aged heart. Thus, βAR signalling plays a crucial role in maintaining a balanced calcium homeostasis and regulating cardiomyocyte contraction and relaxation, and dysregulated βAR signalling forms one of the major cellular hallmarks of the senescent myocardium.…”