Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses.

PiZZ (Glu342Lys) α1-antitrypsin deficiency (AATD) is characterized by intrahepatic AAT polymerization and is a risk factor for liver disease development in children. The majority of PiZZ children are disease free, hence this mutation alone is not sufficient to cause the disease. We investigated Z-AAT polymers and the expression of fibrosis-related genes in liver tissues of PiZZ children with different clinical courses. Liver biopsies obtained during 1979-2010 at the Department of Paediatrics, Karolinska University Hospital, Sweden, were subjected to histological re-evaluation, immunohistochemistry and NanoString-based transcriptome profiling using a panel of 760 fibrosis plus 8 bile acid-related genes. Subjects were divided into three groups based on clinical outcomes: NCH (neonatal cholestasis, favourable outcome, n = 5), NCC (neonatal cholestasis, early cirrhosis and liver transplantation, n = 4), and NNCH (no neonatal cholestasis, favourable outcome, n = 5, six biopsies). Hepatocytes containing Z-AAT polymers were abundant in all groups whereas NCC showed higher expression of genes related to liver fibrosis/cirrhosis and lower expression of genes related to lipid, aldehyde/ketone, and bile acid metabolism. Z-AAT accumulation per se cannot explain the clinical outcomes of PiZZ children; however, changes in the expression of specific genes and pathways involved in lipid, fatty acid, and steroid metabolism appear to reflect the degree of liver injury.

Tacrolimus 4-hour monitoring in liver transplant patients is non-inferior to trough monitoring: The randomized controlled FK04 trial.

BACKGROUND: After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration-dependent, chronic kidney disease. Monitoring ciclosporin with two-hour levels reduced overexposure and led to better renal function than trough-monitoring (C0). For tacrolimus, a 4-hour level (C4) can give a reasonable approximation of total drug exposure. We evaluated whether monitoring tacrolimus in stable patients after LT by C4 was superior to C0 regarding renal function, rejection and metabolic parameters. METHODS: This open label randomized controlled trial compared C4 monitoring of tacrolimus BID (Prograft) to trough (C0) monitoring in stable LT recipients. The target range for C4 of 7.8-16 ng/ml was calculated to be comparable with target C0 of 4-8 ng/ml. Primary endpoint was the effect on renal function and secondary endpoints were the occurrence of treated biopsy-proven acute rejection, blood pressure and metabolic parameters, during 3 months of follow-up. RESULTS: Fifty patients were randomized to C0 (n = 25) or C4 (n = 25) monitoring. There was no difference in renal function between the C0 and the C4 group (p = .98 and p = .13 for CG and MDRD at 3 months). Also, the amount of proteinuria was similar (p = .59). None of the patients suffered from graft loss or was treated for rejection. Metabolic parameters did not differ between the two groups. CONCLUSION: Tacrolimus 4-hour monitoring in stable LT patients is not superior to trough monitoring, regarding the effect on renal function, but is safe for use to facilitate tacrolimus monitoring in an afternoon outpatient clinic.