Monocarboxylate Transporter 1 (MCT1) in Liver Pathology.

Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in hepatocyte homeostasis, as well as drug handling. However, there is no available information about the impact of liver pathology on the transporter levels and function. The study was aimed to quantify SLC16A1 mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography-tandem mass spectrometry (LC---MS/MS)) in the livers of patients diagnosed, according to the standard clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to Child-Pugh score. Downregulation of SLC16A1/MCT1 levels was observed in all liver pathology states, significantly for ALD. The progression of liver dysfunction, from Child-Pugh class A to C, involved the gradual decline in SLC16A1 mRNA and MCT1 protein abundance, reaching a clinically significant decrease in class C livers. Reduced levels of MCT1 were associated with significant intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1 abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all studied liver pathologies. Overall, the study demonstrates that SLC16A1/MCT1 is involved in liver pathology, especially in ALD.

Recurrence of Hepatocellular Carcinoma After Liver Transplantation: A Single-Center Experience.

BACKGROUND There is a worldwide increase in use of liver transplantation (LT) for treatment of hepatocellular carcinoma (HCC). We analyzed our experience with LT for HCC to determine long-term and recurrence-free survival, accuracy of imaging diagnosis of HCC compared to the explant pathology, recurrence rate of HCC, and predictors of recurrence. MATERIAL AND METHODS The whole explant was examined by the same pathologist and compared with the baseline diagnosis established according to clinical, laboratory, and radiological data. A group of patients with pathologically confirmed HCC was characterized, with special attention to etiology, survival, recurrence, and diagnostic accuracy of imaging techniques. RESULTS Among 718 patients transplanted from 2000 to 2018 in our center, HCC was found in 166 explanted livers. In 42 cases the clinical diagnosis of HCC was not accurate, being either false positive or negative; however, the specificity and sensitivity of CT/MRI in HCC recognition was 97.87% and 88.24%, respectively. Five- and 10-year survival was 81.27% and 66.57%, respectively, and it was inferior to the overall survival. The recurrence rate was 9.6% with a median time to recurrence of 14 months and a median survival time of 9 months. Poor differentiation of HCC and HCV etiology of the baseline disease, but not previous DAA treatment, were the risk factors of HCC recurrence. CONCLUSIONS Adherence to strictly defined selection criteria for LT in HCC patients guarantees the success of LT in HCC treatment.

[Dynamics of the pathomorphological changes in cirrhotic liver in own material]. / Dynamika zmian patomorfologicznych w marskosci watroby--obserwacje wlasne.

Cirrhosis is widely regarded as being irreversible end stage of many different chronic liver diseases. Recent studies have demonstrated that fibrosis end even cirrhosis may regress. In fact liver cirrhosis is a dynamic process involving hepatocellular injury, increased extracellular matrix synthesis, lobular structure distortion and nodular regeneration. The analysis of 157 patients with chronic hepatitis B or C who had at least two biopsies shown that liver fibrosis sometimes decreased but evident cirrhosis was reversible very rarely. The differences between patients HBV+ and HCV+ were not statistically significant.

Nuclear factor erythroid 2-like 2 (Nrf2) expression in end-stage liver disease.

The transcription factor Nrf2, encoded by NFE2L2 gene is a key regulator of cellular defense against oxidative and electrophilic stress, also governing the expression of many phase II detoxification enzymes. Nrf2 is negatively regulated by KEAP1 protein. Recent studies have shown that Nrf2 might also constitute an important mediator of inflammatory processes. In the current study the expression of Nrf2 in livers from patients with end-stage liver disease has been investigated. Surgical specimens were obtained from explanted livers of 24 patients with end-stage liver disease of different etiology. Control samples were obtained from nontumoral liver tissue from 6 patients with metastatic liver tumors. Nrf2 expression was evaluated by means of qRT-PCR, Western-blot and immunohistochemical staining. KEAP1 gene expression was investigated at mRNA level. The expression of the NFE2L2 gene was decreased in all groups of end-stage liver disease samples as compared with the controls (mean 0.470±1.20 of the value observed in the control samples, p=0.003). Decreased values of NFE2L2/KEAP1 mRNA ratio were also observed in end-stage liver disease groups (0.60±0.24 of the value observed in the control samples, p=0.019). The results were generally confirmed in Western-blot and immunohistochemical analysis of Nrf2 protein. Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. Treatment of HepG2 cells with pro-inflammatory cytokines resulted in significant decrease of GSTA1, NFE2L2 and GCLC expression, while the exposure had no significant influence on KEAP1, HMOX1, and NQO1 mRNA levels. Nrf2 deficiency may be one of the factors underlying impaired liver function in detoxification processes. It remains to be established in further studies if the observed decrease of Nrf2 expression is just a result of liver cirrhosis or is primary, playing a role in disease pathogenesis.

Expression of genes involved in xenobiotic metabolism and transport in end-stage liver disease: up-regulation of ABCC4 and CYP1B1.

BACKGROUND: Expression of drug-metabolizing enzymes and drug transporters in liver is mainly regulated by a system of nuclear receptors. The aim of the current study was to investigate the expression of nuclear receptors, as well as these enzymes and transporters, in liver samples from patients suffering from end-stage liver disease of various etiologies (HCV infection, alcohol liver disease, and primary sclerosis cholangitis). METHODS: Gene expression was measured using quantitative real-time PCR with surgical specimens from livers of patients with end-stage liver disease, and non-tumoral liver tissue that served as control. RESULTS: Our study confirmed that the expression of most phase I enzymes is suppressed in end-stage liver disease, and is correlated with a decrease in NR1I2 and NR1I3, the main regulators of xenobiotic metabolism. While mRNA levels of phase II enzymes were generally unchanged, some ABC transporters were up-regulated. The most spectacular increases in expression were observed with ABCC4 (MRP4) - at the mRNA level, and CYP1B1 - at both the mRNA and protein levels. We also demonstrated that IL-6 can induce CYP1B1 expression independently of CYP1A1, in a human hepatocellular liver carcinoma cell line. CONCLUSIONS: As CYP1B1 is an enzyme which converts various substrates into carcinogenous metabolites, its overexpression in liver may be one of the factors increasing the risk of hepatic cancers in patients with liver disease. CYP1A1 and CYP1B1 are often referred to as model AHR target genes, but CYP1A1 was down-regulated in diseased liver samples. This points to the existence of differences in regulation of these two genes.