Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways

Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall.Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen activated protein kinase (MAPK) activation, though the molecular mechanisms of this process are poorly understood. Here we report that tribbles-1, a recently described modulator of MAPK activation controls vascular smooth muscle cell proliferation and chemotaxis via the Jun Kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The activity of this kinase is dependent on tribbles-1 levels, whilst the activation and the expression of MKK4/SEK1 is not. In addition, tribbles-1 expression is elevated in human atherosclerotic arteries compared to non-atherosclerotic controls, suggesting that this protein may pay a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology

Liver transplantation reverses hypergammaglobulinemia in patients with chronic hepatic failure

Introduction: Sparse data are available about the effect of therapy methods on antibody levels in patients with liver failure. The aim of this study was to determine serum immunoglobulin concentrations in patients with chronic hepatic failure (CHF), acute- (ALF), or acute-on-chronic liver failure (ACLF) and to evaluate the impact of MARS treatment or liver transplantation (LT) on antibody levels. Materials and methods: We followed ten patients with ALF, twelve with ACLF and 18 with CHF. Eight patients with ALF and seven with ACLF underwent MARS therapy, whereas the rest received LT. 13 healthy volunteers served as controls. Serum antibody concentrations were measured using ELISA-technique. Results: Median serum levels of IgA, IgG and IgM were significantly increased in patients with CHF compared to ALF or controls (P < 0.02, P < 0.01, and P < 0.01). IgM and IgG concentrations were also significantly elevated in patients with CHF compared to ACLF (IgM, 3.7 vs. 1 g/L, P < 0.001; IgG, 8.7 vs. 3.1 g/L, P = 0.004). Immediately after LT a significant decrease of IgA (6.9 vs. 3.1 g/L, P = 0.004), IgG (8.7 vs. 5.1 g/L, P = 0.02) and IgM (3.7 vs. 1.8 g/L, P = 0.001) was detected in patients with CHF and antibody levels further decreased the days after LT reaching levels comparable to healthy individuals. MARS treatment had no apparent effect on the immunoglobulin profile in patients with ALF or ACLF. Conclusion: We provide evidence that LT reverses hypergammaglobulinemia in patients suffering from CHF within one day, which could be explained to a reconstituted hepatic antibody clearance, whereas MARS treatment has no immediate effect on immunoglobulin levels

Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis

Background and aims Vitamin D deficiency is frequent in patients with cirrhosis. The aims of this study were to evaluate the relation of vitamin D status to portal hypertension, degree of liver dysfunction and survival. Methods Patients with cirrhosis who have been tested for 25-OH-vitamin D levels were retrospectively included. Vitamin D deficiency was defined as 25-OH-vitamin D levels <10ng/ml. ChildPugh score, model for end-stage liver disease (MELD) and available hepatic venous pressure gradient (HVPG) were recorded. Mortality was documented during follow-up. Results A total of 199 patients were included. Prevalence of vitamin D deficiency (<10ng/ml) was 40% (79/199), with 14% in ChildPugh stage A, 39% in ChildPugh stage B and 47% in ChildPugh stage C (p = 0.001). Vitamin D deficiency was more common in patients with clinically significant portal hypertension (CSPH, HVPG 10mmHg) than in patients without (43.5% vs. 24.4%, p = 0.025). Significantly more deaths were observed in patients with vitamin D deficiency (32.9%, 26/79 vs. 13.3%, 16/120; p = 0.001). COX regression found presence of hepatocellular carcinoma (p < 0.001; HR: 5.763 95%CI:2.18315.213), presence of CSPH (p = 0.026; HR: 5.487 95%CI: 1.22624.55) and ChildPugh stage C (p = 0.003; HR:5.429 95%CI: 1.77116.638) as independent risk factors for mortality. Furthermore we could show a tendency towards group vitamin D deficiency being an independent risk factor (p = 0.060; HR: 1.86 95%CI:0.9743.552). Conclusions Vitamin D levels progressively decrease in more advanced Child stages and in patients with increasing HVPG. Vitamin D deficiency might be a valuable predictor of mortality in cirrhosis.(VLID)349856

Erectile dysfunction in cirrhosis is impacted by liver dysfunction, portal hypertension, diabetes and arterial hypertension

Background Although several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function5 (IIEF5) is a wellvalidated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis. Methods In this prospective study, erectile dysfunction was defined as: absent (>21 IIEF5points), mild (1221) and severe (511). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded. Results Among n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 9 years; model for endstage liver disease score (MELD): 12.7 3.9; ChildPugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mildtomoderate and moderatetosevere erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). ChildPugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, betablocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.1634.85]; P = .033), diabetes (OR: 7.40 [1.3141.75]; P = .023), MELD (OR: 1.19 [1.031.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.0021.23]; P = .045) were independent risk factors for the presence of erectile dysfunction. Conclusion About twothirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.(VLID)483927

Hepatology Research / Dysbalanced sex hormone status is an independent predictor of decompensation and mortality in patients with liver cirrhosis

Aims Endocrinological abnormalities, including low testosterone levels, are prevalent in cirrhosis. We assessed sexual hormone status in regard to hemodynamic abnormalities and its impact on hepatic decompensation and survival. Methods Males with cirrhosis were prospectively included in this study since 2010. Sexual hormones including bioavailable testosterone, total testosterone, luteinizing hormone, folliclestimulating hormone, prolactin, and sex hormonebinding globulin as well as ChildPugh score, Model for Endstage Liver Disease (MELD) score, and hepatic venous pressure gradient were recorded. Sarcopenia was also assessed in patients with available computed tomography scans. Clinical followup for hepatic decompensation, liver transplantation, and death was recorded until May 2017. Results One hundred fourteen male cirrhotic patients were included: age 55 9.4 years, MELD 13.5 (range, 720.7). Etiologies were alcoholic liver disease in 61(53.5%) patients, viral in 30 (26.3%) patients, and other in 23 (20.2%). ChildPugh scores were A in 32 (28.1%) patients, B in 48 (42.1%), and C in 34 (29.8%). Levels of bioavailable testosterone and total testosterone decreased with advanced ChildPugh score (P 12 mmHg). Median bioavailable testosterone (0.25 ng/mL [0.071.7] vs. 0.97 ng/mL [0.152.74)]; P = 0.017) and total testosterone levels (1.28 ng/mL [0.257.32] vs. 4.32 ng/mL [0.4313.47]; P = 0.031) were significantly lower in sarcopenic patients. Median followup was 13 months (0.275 months) and liverrelated events were recorded in 46 patients (40.4%; death, 31 [27.2%]). Low total testosterone was associated with an increased risk for hepatic decompensation and/or death, even after adjusting for ChildPugh score, MELD, and other relevant factors (ChildPugh score model: hazard ratio 2.503, 95% confidence interval, 1.2145.157, P = 0.013; MELD model: hazard ratio 3.065, 95% confidence interval, 1.5236.169, P = 0.002). Conclusion In parallel to increasing severity of cirrhosis, levels of testosterone decline whereas prolactin levels increase. However, low testosterone levels are independently associated with a higher risk for hepatic decompensation and mortality.(VLID)341392