Intrahepatic vascular changes in non-alcoholic fatty liver disease : potential role of insulin-resistance and endothelial dysfunction

Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, antiinflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review

Position Specific Anthropometry and Throwing Velocity of Elite female Water Polo Players.

This study was conducted with the following aims: (a) to describe the effect of playing position on anthropometrics and throwing velocity in elite female water polo players and (b) to observe any relationships between anthropometric parameters and throwing velocity. To achieve these aims, we analyzed a total of 46 female elite players (age: 22.5 ± 5.1 years; height: 172.0 ± 6.9 cm, body mass: 67.4 ± 7.5 kg) members of the top 4 teams of the Spanish Honour Division women league (21 offensive wings players, 17 center, and 8 goalkeepers). Wings were significantly shorter and had smaller arm spans than goalkeepers and center players. Goalkeepers demonstrated longer forearm lengths than wing and center players. No other significant differences were evident between positions in terms of anthropometric, strength, or throwing velocity variables The somatotype of the offensive wing players was mesomorphic, whereas centers were endomorph (classified as endomesomorphic). Height, arm span, muscular mass, biepicondylar breadth of the humerus, arm girth (relaxed and tensed), and forearm girth were related to throwing velocity. In conclusion, only a small number of anthropometric differences exist between players of different positions in elite female water polo. Shorter players with smaller arm spans may be better suited to the wings, whereas athletes with longer forearms may be better suited to the goalkeeper position. Taller, more muscular athletes with wider arm spans, broader humeri, and wider arms (relaxed and flexed) tended to throw with increased velocity. Trainers should focus on increasing the modifiable characteristics (muscle mass and arm girths) that contribute to throwing velocity in this population.Actividad Física y Deport

Medical management of variceal bleeding in patients with cirrhosis

Bleeding from gastroesophageal varices is a frequent and often deadly complication of cirrhosis. The key factor in the natural history of esophageal varices is increased portal pressure, which in cirrhosis is due to the combination of increased hepatic vascular resistance and increased portal collateral blood flow. The maintenance and aggravation of this situation leads to the progressive dilation of the varices and thinning of the variceal wall, until the tension exerted by the variceal wall exceeds the elastic limit of the vessel, leading to variceal hemorrhage. Mortality from a variceal bleeding episode has decreased in the last two decades from 40% to 20% due to the implementation of effective treatments and improvement in the general medical care. Initial treatment should include adequate fluid resuscitation and transfusion to maintain the hematocrit at 25% to 30%, and prophylactic antibiotics (norfloxacin or amoxicillin-clavulanic acid). It is currently recommended that a vasoactive drug be started at the time of admission. Drug therapy may be started during transferal to hospital by medical or paramedical personnel and maintained for up to five days to prevent early rebleeding. Terlipressin, a vasopressin derivative, is the preferred agent because of its safety profile and proven efficacy in improving survival. Somatostatin is as effective as terlipressin, but may require higher than the usually recommended dosage. Octreotide is effective in conjunction with endoscopic therapy, but is the second choice because it has not been shown to reduce mortality. Vasopressin may be used where terlipressin is not available, but should be given in combination with transdermal nitroglycerin. Endoscopic elastic band ligation is the recommended endoscopic treatment, but injection sclerotherapy is still employed in many centres for active variceal bleeding. Failures of medical therapy (drugs plus endoscopic therapy) should undergo a second course of endoscopic therapy before proceeding to transjugular intrahepatic portosystemic shunt or, in rare occasions, to portosystemic shunt surgery. Administration of recombinant activated factor VII may decrease the number of treatment failures among patients with advanced liver failure (Child-Pugh class B and C)

Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis

OBJECTIVES: A reduction in hepatic venous pressure gradient (HVPG) of 6520% of baseline or to 6412 mmHg (responders) is associated with a reduced risk of first variceal bleeding. The aim of this study was to evaluate whether this protective effect is maintained in the long term and if it extends to other portal hypertension complications. METHODS: Seventy-one cirrhotic patients with esophageal varices and without previous variceal bleeding who entered into a program of prophylactic pharmacological therapy and were followed for up to 8 yr were evaluated. All had two separate HVPG measurements, at baseline and after pharmacological therapy with propranolol \ub1 isosorbide mononitrate. RESULTS: Forty-six patients were nonresponders and 25 were responders. Eight-year cumulative probability of being free of first variceal bleeding was higher in responders than in nonresponders (90%vs 45%, p= 0.026). The lack of hemodynamic response and low platelet count were the only independent predictors of first variceal bleeding. Additionally, reduction of HVPG was independently associated with a decreased risk of spontaneous bacterial peritonitis (SBP) or bacteremia. No significant differences in the development of ascites, hepatic encephalopathy, or survival were observed. CONCLUSIONS: The hemodynamic response in cirrhotic patients is associated with a sustained reduction in the risk of first variceal bleeding over a long-term follow-up. Reduction of HVPG also correlate with a reduced risk of SBP or bacteremia

Prognosis of acute variceal bleeding : is being on beta-blockers an aggravating factor? A short-term survival analysis

Non-selective beta-blockers (NSBB) are widely used since they have been proved effective in the prophylaxis of acute variceal bleeding (AVB). However, still a significant proportion of patients experience AVB whilst on treatment with NSBB and their impact on prognosis of AVB is unknown. The present study aimed at assessing the effect of being on prophylactic therapy with NSBB on 5-day failure and 6-week mortality of cirrhotic patients admitted with AVB. 142 patients were included: 49 patients were receiving prophylactic therapy with NSBB (NSBB group) and 93 patients were not (control group). There were some differences in the baseline characteristics between the groups: higher proportion of alcoholic etiology and active alcoholism (37% vs. 10%), higher platelets count and lower hematocrit at admission in the control group. However, the severity of AVB and initial treatment were similar. 5-day failure occurred in 20% of patients (14% in NSBB vs. 24% in controls; p = 0.27). The adjusted OR for 5-day failure under NSBB was 2.46; 95% CI: 0.53-11.37; p=0.25. Nineteen patients (13%) died and 2 had liver transplantation within 6-weeks. The probability of survival at 6 weeks was 96% in the NSBB group and 82% in the control group (p=0.02). After adjusting by propensity score and model for end-stage liver disease (MELD) score, the NSBB adjusted OR for 6-week mortality was 0.38; 95% CI: 0.05- 2.63; p=0.32. The estimated association between NSBB with both 5-day failure and 6-week mortality was homogenous across all MELD spectrums

Insulin resistance and liver microcirculation in a rat model of early NAFLD

Background & Aims: Insulin contributes to vascular homeostasis in peripheral circulation, but the effects of insulin in liver microvasculature have never been explored. The aim of this study was to assess the vascular effects of insulin in the healthy and fatty liver. Methods: Wistar rats were fed a control or a high fat diet (HFD) for 3 days, while treated with a placebo, the insulin-sensitizer metformin, or the iNOS inhibitor 1400W. Vascular responses to insulin were evaluated in the isolated liver perfusion model. Insulin sensitivity at the sinusoidal endothelium was tested by endothelium-dependent vasodilation in response to acetylcholine in the presence or absence of insulin and by the level of liver P-eNOS after an insulin injection. Results: Rats from the HFD groups developed liver steatosis. Livers from the control group showed a dose-dependent hepatic vasodilation in response to insulin, which was blunted in livers from HFD groups. Metformin restored liver vascular insulin-sensitivity. Pre-treatment with insulin enhanced endothelium-dependent vasodilation of the hepatic vasculature and induced hepatic eNOS phosphorylation in control rats but not in HFD rats. Treatment with metformin or 1400W restored the capacity of insulin to enhance endothelium dependent vasodilation and insulin induced eNOS phosphorylation in HFD rats. Conclusions: The administration of a HFD induces insulin resistance in the liver sinusoidal endothelium, which is mediated, at least in part, through iNOS upregulation and can be prevented by the administration of metformin. Insulin resistance at the hepatic vasculature can be detected earlier than inflammation or any other sign of advanced NALFD

Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase

Background & Aims Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia. Methods All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests. Results At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser1176. This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress. Conclusions iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection

Right atrial pressure is not adequate to calculate portal pressure gradient in cirrhosis: a clinical-hemodynamic correlation study

Hepatic venous pressure gradient (HVPG), the difference between wedge and free hepatic venous pressure, is the preferred method for estimating portal pressure. However, it has been suggested that hepatic atrial pressure gradient (HAPG) - the gradient between wedge hepatic venous pressure and right atrial pressure (RAP) - might better reflect variceal hemodynamics. The aim of this study was to (1) investigate whether HAPG with nonselective beta-blockers correlates with prognosis in cirrhotic patients with portal hypertension at baseline and during treatment; (2) compare the prognostic value of HAPG with that of HVPG; and (3) investigate the agreement between portoatrial gradient (PAG) and portocaval gradient (PCG) in patients with transjugular intrahepatic portosystemic shunt (TIPS). We included 154 cirrhotic patients with varices with a complete hemodynamic study at baseline and on chronic treatment for primary (n = 71) or secondary (n = 83) prophylaxis for bleeding and 99 patients with TIPS. All patients were followed for up to 2 years; portal hypertensive-related bleeding and bleeding-free survival were analyzed. HVPG was equal or lower than HAPG in all patients (23.2 mm Hg; P 12 mm Hg, which may have induced unnecessary overdilation of the TIPS. Conclusion: The excellent prognostic information provided by HVPG response to drug therapy is lost if HAPG response is considered. RAP should not be used for the calculation of portal pressure gradient in patients with cirrhosis