SOX9 in biliary atresia: New insight for fibrosis progression

Background:Liver fibrosis is a hallmark determinant of morbidity in biliary atresia(BA)even in successfully operated cases.Responsible factors for this rapid progression of fibrosis are not completely defined.Aberrant expression of the transcription factor SOX9 and hepatic progenitor cells(HPCs)proliferation have roles in fibrogenesis in cholestatic disorders.However,they were not investigated sufficiently in BA.We aimed to delineate the relation of SOX9 and HPCs to fibrosis and its progression in BA.Methods:Forty-eight patients with BA who underwent an initial diagnostic liver biopsy(LB)and consequent intraoperative LB were recruited and compared to 28 cases with non-BA cholestasis that had an LB in their diagnostic workup.Liver fibrosis,tissue SOX9 and HPC expressions were studied in both BA and non-BA-cholestasis cases.Liver fibrosis,SOX9,and HPCs’dynamic changes in BA cases were assessed.Relation of fibrosis and its progression to SOX9 and HPCs in BA was assessed.Results:SOX9 and HPCs in ductular reaction(DR)form were expressed in 100%of BA and their grades increased significantly in the second biopsy.The rapidly progressive fibrosis in BA,represented by fibrosis grade of the intraoperative LB,correlated significantly to SOX9-DR and HPC-DR at the diagnostic(r=0.420,P=0.003 and r=0.405,P=0.004,respectively)and the intraoperative(r=0.460,P=0.001 and r=0.467,P=0.001,respectively)biopsy.On the other hand,fibrosis,SOX9-DR,and HPC-DR were significantly lower in non-BA cases at a comparable age(P<0.001,P=0.006,and P=0.014,respectively).Conclusions:Fibrosis in BA is rapidly progressive within a short time and is significantly correlated to SOX9 and HPCs.Assessment of targeting SOX9 and HPCs on fibrosis progression is warranted.

Serum ferritin in neonatal cholestasis: A specific and active molecule or a non-specific bystander marker?

Background: Serum ferritin(SF) and consequently hepatic iron have long been considered important in liver fibrosis progression. They have been studied in different liver diseases with no previous reports in neonatal cholestasis(NC). This study aimed to measure SF in different etiologies of NC and investigate its relation to hepatic iron and fibrosis. Methods: SF was measured in 75 infants, including 50 with NC and 25 with sepsis. SF was compared between these two groups. Biochemical parameters, hepatic iron grades, and liver fibrosis and other histopathological characteristics and correlated with SF were assessed in NC group. Finally, a comparison between intrahepatic cholestasis and obstructive etiology was performed. Results: SF was elevated in NC(1598 ± 2405 ng/mL) with no significant difference from those with sepsis( P = 0.445). NC and sepsis constituted augmenting factors leading to more elevation of SF(2589 ± 3511 ng/mL). SF was significantly correlated with hepatic iron grades( r = 0.536, P < 0.0 0 01) and a cut-off value of 803.5 ng/mL can predict higher grades( ≥ grade 3) of iron deposition with sensitivity of 100%, specificity of 70% and accuracy of 85%. Moreover, SF was significantly higher( P < 0.0 0 01) in those with intrahepatic cholestasis(2602 ± 3154 ng/mL) and their prevalent pathological findings of giant cell transformation( P = 0.009) and hepatocyte swelling( P = 0.023) than those with obstructive etiology(672 ± 566 ng/mL) and their prevalent pathological findings of ductular proliferation( P = 0.003) and bile plugs( P = 0.002). SF was unrelated to the grade of liver fibrosis( P = 0.058). Conclusions: SF is non-specifically elevated in NC, with positive correlation to hepatic iron grades. SF ≥ 803.5 ng/mL can predict higher grades( ≥ grade 3) of hepatic iron. However, an active role of increased SF and hepatic iron in disease progression remains questionable.