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Increased hepatic vascular resistance is the primary factor in the development of portal hypertension. Metformin ameliorates vascular cells function in several vascular beds. Our study was aimed at evaluating the effects, and the underlying mechanisms, of metformin on hepatic and systemic hemodynamics in cirrhotic rats and its possible interaction with the effects of propranolol (Prop), the current standard treatment for portal hypertension. CCl4-cirrhotic rats received by gavage metformin 300 mg/kg or its vehicle once a day for 1 wk, before mean arterial pressure (MAP), portal pressure (PP), portal blood flow (PBF), hepatic vascular resistance, and putative molecular/cellular mechanisms were measured. In a subgroup of cirrhotic rats, the hemodynamic response to acute Prop (5 mg/kg iv) was assessed. Effects of metformin ±Prop on PP and MAP were validated in common bile duct ligated-cirrhotic rats. Metformin-treated CCl4-cirrhotic rats had lower PP and hepatic vascular resistance than vehicle-treated rats, without significant changes in MAP or PBF. Metformin caused a significant reduction in liver fibrosis (Sirius red), hepatic stellate cell activation (α-smooth muscle actin, platelet-derived growth factor receptor β polypeptide, transforming growth factor-βR1, and Rho kinase), hepatic inflammation (CD68 and CD163), superoxide (dihydroethidium staining), and nitric oxide scavenging (protein nitrotyrosination). Prop, by decreasing PBF, further reduced PP. Similar findings were observed in common bile duct ligated-cirrhotic rats. Metformin administration reduces PP by decreasing the structural and functional components of the elevated hepatic resistance of cirrhosis. This effect is additive to that of Prop. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs clinical evaluation. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Cardiovascular risk factors (CVRF) lead to systemic endothelial dysfunction. It has been suggested that in cirrhosis, cardiovascular risk is low and systemic endothelial function is enhanced. However, there is no prospective study evaluating the relationship between cardiovascular risk and systemic endothelial function in cirrhosis, which was investigated here.METHODS:In 47 patients with cirrhosis (33 males; median Child-Pugh score 8; median age 55 years), we evaluated: laboratory parameters, hepatic and systemic hemodynamics, CVRF, 10-year global cardiovascular risk by Framingham score, and presence of carotid plaques. Systemic endothelial dysfunction was investigated non-invasively by flow-mediated dilatation (FMD) of the brachial artery by ultrasound and defined as FMD <10%.RESULTS:Cardiovascular risk (median 7%) was low in 25%, moderate in 26%, moderately high in 40%, and high in 9%. Fifty-three percent of patients had systemic endothelial dysfunction. Systemic endothelial dysfunction (low FMD) increased in parallel with CV risk (linear trend P=0.039) and was higher in patients overweight or obese. Conversely, FMD increased in parallel with Child-Pugh/Mayo Clinic Model for End-stage Liver Disease (MELD) score, bilirubin, serum sodium, plasma renin activity, leukocyte count, platelet count, and with lower arterial pressure, suggesting that enhanced FMD is a feature of advanced liver failure and inflammation. Cardiovascular risk, bilirubin, leukocyte count, and arterial pressure remained independently associated with systemic endothelial dysfunction.CONCLUSIONS:CV risk was not low in our studied patients with cirrhosis, and systemic endothelial dysfunction was frequent in this population. In cirrhosis, similar to general population, cardiovascular risk impaired systemic FMD, although liver failure attenuated endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is involved in the pathogenesis of endothelial dysfunction and is also present in patients with cirrhosis. Intrahepatic endothelial dysfunction plays a major role, increasing hepatic vascular resistance and promoting portal hypertension (PH). In addition, β-adrenergic agonists and insulin share several intracellular signaling pathways. Thus IR may influence the response to β-blockers. This study aimed at evaluating the relationship between IR and hepatic hemodynamics in patients with cirrhosis and with the portal pressure response to acute β-blockade. Forty-nine patients with cirrhosis and PH were included. Hepatic and systemic hemodynamics were measured, and IR was estimated by using the updated homeostasis model assessment (HOMA)-2 index. Patients with HOMA-2 > 2.4 were considered IR. In patients with hepatic venous pressure gradient (HVPG) ⩾ 10 mmHg) [clinically significant PH (CSPH)], hemodynamic measurements were performed again 20 min after intravenous propranolol. Mean HOMA-2 index was 3 ± 1.4. Fifty-seven percent of patients had IR. A weak correlation between HOMA-2 index and HVPG was observed. Eighty-six percent of patients had CSPH. HOMA-2 index was an independent predictor of CSPH. However, in patients with CSPH, the correlation between HOMA-2 index and HVPG was lost. HVPG, but not IR, predicted the presence of esophageal varices. Response to propranolol was not different between patients with or without IR. In nondiabetic patients with cirrhosis, HOMA-2 index is directly associated with the presence of CSPH and indirectly with varices, but does not allow either grading HVPG or predicting its response to propranolol. [ABSTRACT FROM AUTHOR]

Background: New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients.Methods: A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated.Results: Patients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8-9.2; P = 0.004).Conclusions: In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness. [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with cirrhosis and small hepatocellular carcinoma with normal bilirubin and hepatic venous pressure gradient (HVPG) <10mmHg have >70% 5-year survival after hepatic resection. On the contrary, patients with HVPG ⩾10mm Hg (clinically significant portal hypertension, CSPH) frequently develop decompensation following surgery, with around 50% 5-year survival. Liver stiffness (LS) evaluation by transient elastography might non-invasively identify CSPH. We investigated the usefulness of LS predicting CSPH in patients with compensated cirrhosis and potentially resectable liver tumors. Methods: Ninety-seven consecutive Child-Pugh A patients with potentially resectable liver tumors referred for HVPG measurement were prospectively evaluated. In fasting conditions LS was measured before the hemodynamic study. Results: HVPG could be measured in all patients, whereas LS could not be measured in 18 (18.5%) obese patients. In the 79 patients with valid LS, 32 (40.5%) had CSPH; mean HVPG was 8.8±4.7mmHg. Mean LS was 18.4±12.3kPa. LS showed a moderate correlation with HVPG (r=0.552; p <0.001). LS<13.6kPa had high sensitivity (91%) but low specificity (57%) excluding CSPH. Conversely, LS>21kPa had low sensitivity (53%) and high specificity (91%) predicting CSPH. 35% of patients had LS between 13.6 and 21kPa (“grey zone”). Conclusions: These data suggest that in real-life scenarios half of patients with potentially resectable liver nodules can be non-invasively classified as having or not CSPH by LS. However, in the remaining half, LS is either not applicable or inaccurate. In this last population HVPG is still a non replaceable method to detect CSPH. [ABSTRACT FROM AUTHOR]

Background & Aims: Both transient elastography (TE) and left lobe liver surface (LLS) ultrasound may non-invasively detect cirrhosis (LC). We aimed to examine the diagnostic value of these methods in patients with a suspicion but not a definite diagnosis of cirrhosis. Methods: We enrolled 90 patients with clinical suspicion of cirrhosis and a strong co-existing differential diagnosis requiring further invasive evaluation. They underwent hepatic venous pressure gradient (HVPG) measurement±transjugular liver biopsy, LLS and TE. Images of LLS were digitally post-processed to obtain a numerical value (quantitative LLS, qLLS). TE<12kPa was considered to exclude LC, ⩾18kPa diagnosed LC, and 12–18kPa indeterminate. Technical failures were considered ‘indeterminate’. Diagnosis of cirrhosis was confirmed by histology (84%) or by clinical data and HVPG⩾10mm Hg. Diagnostic accuracy was evaluated by positive and negative likelihood ratios (+LR and −LR). Results: Cirrhosis was diagnosed in 44 patients. There were 14 technical failures with TE and 1 with LLS (p =0.001). TE and LLS had similar diagnostic accuracy but gave complementary information: TE was mildly more accurate than LLS to rule out LC (−LR: 0.08 vs. 0.10), while it was less accurate to rule it in (+LR 5.05 vs. 11.15). Their combination offered the best diagnostic performance (+LR 9.15; −LR 0.06). Conclusions: LLS is more technically applicable than TE. In patients with clinical suspicion of cirrhosis, LLS is the best non-invasive method to diagnose cirrhosis, while TE is preferable to rule it out. The combination of both holds the best diagnostic accuracy. [Copyright &y& Elsevier]