Ferroportin-related haemochromatosis associated with novel Y64H mutation of the SCL40A1 gene

In this paper we described the first Polish patient with ferroportin disease. Hereditary haemochromatosis (HH) is a condition associated with universal iron overload, and it is divided into four types, according to the Online Mendelian Inheritance in Man (OMIM) database. Ferroportin disease represented a rare type of HH, with autosomal dominant trait of inheritance. In our patient we detected a novel mutation in the ferroportin gene, with non-classical phenotype

Shear stress-induced angiogenesis in mouse muscle is independent of the vasodilator mechanism and quickly reversible.

Aim: Is modulation of skeletal muscle capillary supply by altering blood flow due to a presumptive shear stress response per se, or dependent on the vasodilator mechanism? Methods: The response to four different vasodilators, and cotreatment with blockers of NO and prostaglandin synthesis, was compared. Femoral artery blood flow was correlated with capillary-to-fibre ratio (C:F) and protein levels of putative angiogenic compounds. Results: All vasodilators induced a similar increase in blood flow after 14 days, with a similar effect on C:F (1.62 ± 0.05, 1.60 ± 0.01, 1.57 ± 0.06, 1.57 ± 0.07, respectively, all P < 0.05 vs. control 1.20 ± 0.01). Concomitant inhibitors revealed differential effects on blood flow and angiogenesis, demonstrating that a similar response may have different signalling origins. The time course of this response with the most commonly used vasodilator, prazosin, showed that blood flow increased from 0.40 mL min−1 to 0.61 mL min−1 by 28 days (P < 0.05), dropped within 1 week after the cessation of treatment (0.54 mL min−1; P < 0.05) and returned to control levels by 6 weeks. In parallel with FBF, capillary rarefaction began within 1 week (P < 0.05), giving C:F values similar to control by 2 weeks. Of the dominant signalling pathways, prazosin decreased muscle VEGF, but increased its cognate receptor Flk-1 (both P < 0.01); levels of eNOS varied with blood flow (P < 0.05), and Ang-1 initially increased, while its receptor Tie-2 was unchanged, with only modest changes in the antiangiogenic factor TSP-1. Conclusion: Hyperaemia-induced angiogenesis, likely in response to elevated shear stress, is independent of the vasodilator involved, with a rapid induction and quick regression following the stimulus withdrawal

Characterization of Dimethylsulfoxide / Glycerol Mixtures: A Binary Solvent System for the Study of "Friction-Dependent" Chemical Reactivity

The properties of binary mixtures of dimethylsulfoxide and glycerol, measured by several techniques, are reported. Special attention is given to those properties contributing or affecting chemical reactions. In this respect the investigated mixture behaves as a relatively simple solvent and it is especially well suited for studies on the influence of viscosity in chemical reactivity. This is due to the relative invariance of the dielectric properties of the mixture. However, special caution must be taken with specific solvation, as the hydrogen-bonding properties of the solvent changes with the molar fraction of glycerol.Comment: 49 pages including appendix, 20 figures and 89 reference

Correlation between Endosonographic and Doppler Ultrasound Features of Portal Hypertension in Patients with Cirrhosis

Purpose. Endoscopic ultrasound (EUS) permits the detailed visualization of clinically significant features of portal hypertension; however, it is an invasive procedure that is not widely available. The aim of this cross-sectional study was to determine whether a correlation exists between the features of portal hypertension detected using both Doppler ultrasound and EUS in subjects with liver cirrhosis. Materials and Methods. Analyzed cohort included 42 patients who underwent a detailed Doppler ultrasound focusing on the parameters of blood flow in the portal/splenic vein as well as an endoscopic/EUS procedure that included the assessment of the size and localization of “deep” varices. Results. The size of “deep” oesophageal varices detected with EUS exhibited no correlation with the parameters assessed by Doppler ultrasound. However, the size of the “deep” gastric varices detected using EUS correlated with the time averaged maximum velocity (Tmax as well as Vmin, Vmax) for the portal vein using Doppler ultrasound and exhibited a correlation with the Vmax and Tmax for the splenic vein. No significant correlation was determined between the diameter of the azygous vein and the thickness of the gastric wall when seen on EUS versus the parameters measured with Doppler ultrasound. Conclusion. EUS provides important information regarding the features of portal hypertension, and in the case of “deep” oesophageal varices exhibits a limited correlation with the parameters detected by Doppler ultrasound. Thus, despite its invasiveness, EUS is a method that provides a reliable and unique assessment of the features of portal hypertension in patients with liver cirrhosis

A common variant in the hepatobiliary phospholipid transporter ABCB4 modulates liver injury in PBC but not in PSC : prospective analysis in 867 patients

Background: The ATP-binding cassette subfamily B member 4 (ABCB4) gene encodes the hepatic phospholipid transporter. Variants in the ABCB4 gene are associated with various cholestatic phenotypes, some of which progress to liver fbrosis and cirrhosis. The aim of our study was to investigate the role of the cholestasis-associated variant ABCB4 c.711A>T (p.I237I, rs2109505) in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Results: Two cohorts of Polish patients took part in this study. The Szczecin cohort comprised 196 patients with PBC (174 females, 38% with cirrhosis) and 135 patients with PSC (39 females, 39% with cirrhosis). The Warsaw cohort consisted of 260 patients with PBC (241 females, 44% with cirrhosis) and 276 patients with PSC (97 females, 33% with cirrhosis). Two control cohorts—150 healthy blood donors and 318 patients without liver disease, were recruited in Szczecin and in Warsaw, respectively. The ABCB4 c.711A>T polymorphism was genotyped using TaqMan assay. In both PBC cohorts, carriers of the risk variant presented more frequently with cirrhosis (Szczecin: OR=1.841, P=0.025; Warsaw: OR=1.528, P=0.039). The risk allele was associated with increased serum AST, GGT and ALP (all P<0.05) at inclusion. During the follow-up, patients in both cohorts signifcantly improved their laboratory results, independently of their ABCB4 c.711A>T genotype (P>0.05). During 8±4 years follow-up, a total of 22 patients in the Szczecin PBC group developed cirrhosis, and this risk was higher among carriers of the risk variant (OR=5.65, P=0.04). In contrast to PBC, we did not detect any association of ABCB4 c.711A>T with a liver phenotype in PSC cohorts. Conclusions: The frequent pro-cholestatic variant ABCB4 c.711A>T modulates liver injury in PBC, but not in PSC. In particular, carriers of the major allele are at increased risk of progressive liver scarring

Fine-tuning of SIRT1 expression is essential to protect the liver from cholestatic liver disease

Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1-overexpressing (SIRT oe ) and hepatocyte-specific SIRT1-KO (knockout) mice (SIRT hep–/– ) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24-norursodeoxycholic acid) was tested in BDL/SIRT oe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2 –/– ) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRT oe mice showed exacerbated parenchymal injury whereas SIRT hep–/– mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRT oe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRT hep–/– hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRT oe mice. Interestingly, both SIRT1 overexpression and hepatocyte-specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine-tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage

Melatonin Protects Cholangiocytes from Oxidative Stress-Induced Proapoptotic and Proinflammatory Stimuli via miR-132 and miR-34

Biosynthesis of melatonin by cholangiocytes is essential for maintaining the function of biliary epithelium. However, this cytoprotective mechanism appears to be impaired in primary biliary cholangitis (PBC). MiR-132 has emerged as a mediator of inflammation in chronic liver diseases. The effect of melatonin on oxidative stress and bile acid-induced apoptosis was also examined in cholangiocyes overexpressing miR506, as a PBC-like cellular model. In PBC patients the serum levels of melatonin were found increased in comparison to healthy controls. Whereas, in cholangiocytes within cirrhotic PBC livers the melatonin biosynthetic pathway was substantially suppressed even though the expressions of melatonin rate-limiting enzyme aralkylamine N-acetyltransferase (AANAT), and CK-19 (marker of cholangiocytes) were enhanced. In cholangiocytes exposed to mitochondrial oxidative stress melatonin decreased the expression of proapoptotic stimuli (PTEN, Bax, miR-34), which was accompanied by the inhibition of a pivotal mediator of inflammatory response Nf-κB-p65 and the activation of antiapoptotic signaling (miR-132, Bcl2). Similarly, melatonin reduced bile acid-induced proapoptotic caspase 3 and Bim levels. In summary, the insufficient hepatic expression of melatonin in PBC patients may predispose cholangiocytes to oxidative stress-related damage. Melatonin, via epigenetic modulation, was able to suppress NF-κB signaling activation and protect against biliary cells apoptotic signaling.This work was supported by grant no. 2015/17/B/NZ5/02541 from National Science Centre in Poland

TRAF1-C5

Background. Previous studies reported associations between specific alleles of non-HLA immunoregulatory genes and higher fatigue scores in patients with primary biliary cirrhosis (PBC). Aim. To study the relationship between variables of health-related quality of life (HRQoL) and single nucleotide polymorphisms of TRAF1-C5, a member of the tumor necrosis factor receptor family. Patients and Methods. TRAF1-C5 gene polymorphisms, rs2900180 and rs3761847, were analysed in 120 Caucasian PBCs. The HRQoL was assessed with SF-36, PBC-40, and PBC-27 questionnaires. Results. We found a negative association between TT genotype of rs2900180 and SF-36’s domains vitality (P<0.05), mental health (P<0.05), and mental component summary score (P<0.05). GG homozygotes of rs3761847 had lower vitality (P<0.05), mental health (P<0.05), mental component summary score (P<0.05) and impairment of social functioning (P<0.01). Allelic analysis has shown that T allele of rs2900180 and G allele of rs3761847 related to SF-36’s vitality (P<0.05 and P<0.01), social functioning (P<0.05 and P<0.05), mental health (P<0.01 and P<0.05), and mental component summary score (P<0.01 and P<0.05), respectively. Genotyping and allelic analysis did not reveal correlation with PBC-40 and PBC-27 domains. Conclusion. The association between rs2900180 and rs3761847 polymorphisms and HRQoL variables indicates that TRAF1 is involved in the induction of impaired QoL in PBC

Vitamin D Receptor Polymorphisms Predispose to Primary Biliary Cirrhosis and Severity of the Disease in Polish Population

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver condition characterized by the immune-mediated damage of the intrahepatic bile ducts. Polymorphisms of vitamin D receptor (VDR) are considered to contribute to its pathogenesis however their incidence varies in different populations and their potential association with the course of the disease has not been studied. In this paper we investigated the incidence and correlation of three VDR polymorphisms (BsmI, ApaI or TaqI) with various clinical, biochemical, and serological factors in a homogenous group of 143 Caucasian patients with PBC. Control group comprises 306 DNA samples from umbilical cord blood of healthy newborn children. When compared to controls, we observed a significant dominance of the b allele in the BsmI (OR = 1.69 [1.27–2.24]; P = 0.0003) and t allele in the TaqI (OR = 0.62 [0.47–0.82], P = 0.0001) in patients with PBC. Moreover the BsmI and TaqI polymorphisms were associated with the presence of advanced fibrosis/liver cirrhosis at the diagnosis of PBC. Pairwise linkage disequilibrium (LD) calculations proved that the analyzed SNPs are within an LD block (100% of LDs were D'>0.9). Our study showed, for the first time, that the analyzed polymorphisms of VRD may exert an effect on a natural history of PBC

Zaawansowana marskość wątroby - prowadzenie pacjentów oczekujących na przeszczepienie wątroby

Pacjenci z zaawansowaną marskością wątroby są kandydatami do przeszczepienia tego narządu. Proces kwalifikacji do zabiegu, obejmujący wiele różnych badań i wymagający udziału wielodyscyplinarnego zespółu specjalistów ma na celu wykluczenie czynników, które mogłyby nie tylko w istotny negatywny sposób wpłynąć na przebieg samej operacji, ale również pogorszyć rokowanie po zabiegu. Zakwalifikowani do przeszczepienia pacjenci mają najczęściej przed sobą od kilku tygodni do kilkunastu miesięcy oczekiwania na operację. W tym czasie wymagają oni ścisłej specjalistycznej opieki. Celem tego artykułu było przybliżenie podstawowych zasad postępowania w najczęstszych powikłaniach marskości u pacjentów zakwalifikowanych do przeszczepienia oraz omówienie najczęstszych błędów, jakie popełnia się w leczeniu tych chorych. Gastroenterologia Kliniczna 2010, tom 2, nr 3, 81&#8211;8