Julio Vorobioff

Increased Blood Flow Through the Portal System in Cirrhotic Rats

Portal venous pressure is the result of the interplay between portal venous blood flow and the vascular resistance offered to that flow. Whether portal hypertension is maintained only by an increased portal venous resistance or also by an increased blood flow within the portal venous system is still open to speculation. To resolve these differences, splanchnic and systemic hemodynamics were evaluated in cirrhotic rats, induced by CCl4. Blood flow and portal-systemic shunting were measured by radioactive microsphere techniques. All cirrhotic rats had portal hypertension (portal venous pressure 13.5 +/- 1.1 vs. 9.0 +/- 0.5 mmHg, in normal control rats; p less than 0.01), but portal-systemic shunting in cirrhosis (31% +/- 13% vs. 0.2% +/- 0.02%; p less than 0.05) was variable, ranging from 1% to 97%. Portal venous inflow, the total blood flow within the portal system, was increased in cirrhotic rats (5.75 +/- 0.04 vs. 4.52 +/- 0.36 ml/min per 100 g; p less than 0.05). Total splanchnic arterial resistance was reduced in cirrhotic rats (3.3 +/- 0.2 vs. 5.8 +/- 0.5 dyn X s X cm-5 X 10(5); p less than 0.01). Portal venous resistance, however, was not abnormally elevated in cirrhotic rats (4.6 +/- 0.5 vs. 4.7 +/- 0.5 dyn X s X cm-5 X 10(4), p = NS). Splanchnic hemodynamics in cirrhotic rats demonstrate that portal hypertension is maintained, at least in part, by a hyperdynamic portal venous inflow. The hemodynamic data in cirrhotic rats provided evidence that supports the role of an increased portal blood flow in portal hypertension and gives a quantitative definition of splanchnic hemodynamics in intrahepatic portal hypertension.

Prevention of portal hypertension: From variceal development to clinical decompensation

Pharmacological treatment of portal hypertension (PH) has been exclusively devoted to gastroesophageal varices–related events at different frameworks, including prophylactic, emergency, or preventive therapy. The goals of treatment are to avoid the first bleeding episode, stop active bleeding, and prevent bleeding recurrence, respectively. The objective of preprimary prophylaxis (PPP) is to avoid variceal development, and therefore it necessarily deals with patients with cirrhosis at earlier stages of the disease. At these earlier stages, nonselective beta‐blockers (NSBBs) have been ineffective in preventing the development of varices and other complications of PH. Therefore, treatment should not rely on NSBB. It is possible that, at these earlier stages, etiological treatment of liver disease itself could prevent progression of PH. This review will focus mainly on early treatment of PH, because, if successful, it may translate into histological‐hemodynamic improvements, avoiding not only variceal development, but also other PH‐related complications, such as ascites and portosystemic encephalopathy. Moreover, the advent of new therapies may allow not only the prevention of the complications of PH, but also the chance of a substantial degree of regression in the cirrhotic process, with the possible prevention of hepatocellular carcinoma (HCC). (Hepatology 2015;61:375–381)

The Spectrum of Nimesulide-Induced-Hepatotoxicity. An Overview

Nimesulide is the unique molecule of the sulphonanilides class of non-steroidal antiinflammatory drugs [NSAIDs]: Nimesulide has analgesic, anti-pyretic, potent anti-inflammatory activities and very good gastro-intestinal [GI] tolerability. Therapeutic action is multifactorial, including cyclooxigenase-2 (COX-2) inhibition, scavenging of free radicals and inhibition of various pathways of inflammation. Nimesulide is oxidatively metabolised via liver cytochromes P450. Several unproven hepatotoxicy-predisposing-factors thought to be present in rheumatologic patients have been linked to a higher incidence of hepatic reactions in this sub-population. However, the molecular mechanism underlying hepatotoxicy remains to be elucidated. Nimesulide has been associated over two decades with reports of severe liver damage. The clinical presentation of nimesulide-related-hepatoxicity includes, malaise, pruritus, a wide range of ALT/AST elevation, and an average 4 fold elevation of alkaline phosphatase and GGT. Liver biopsy shows a predominance of hepatocellular involvement, less frequently cholestatic and mixed patterns. Both, the hepatitis pattern and the mixed-type combining cholestatic jaundice, might evolve into fulminant hepatic failure. However, the incidence of nimesulide-inducedhepatotoxicity is not homogeneous across the medical literature. Indeed, most of the countries find it to be comparable to that of other NSAIDs, while a significant higher hepatotoxicity is suggested by reports from Finland, Ireland and Argentina. Our series in Argentina comprising 43 cases is worrisome particularly because it evidences a significant proportion of severe forms. In the present work we analyze the epidemilogical characteristics of nimesulide-induced-hepatotoxicity and we describe the clinical and histologic spectrum of nimesulide-associated-liver damage based on the comparison of our series of 43 cases and worldwide published observations in the pertinent medical literature.

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America

Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real‐clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real‐world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child‐Pugh B at baseline and one patient died due to multi‐organ failure. Follow up HCV‐RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child‐Pugh A cirrhosis in non‐European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child‐Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.

Octreotide Enhances Portal Pressure Reduction Induced by Propranolol in Cirrhosis: A Randomized, Controlled Trial

BACKGROUND:In vitro, octreotide potentiates vasoconstriction in isolated, preconstricted, mesenteric arterial vessels. In cirrhotic patients, portal pressure (HVPG) reduction induced by propranolol is partly due to splanchnic vasoconstriction.AIM:To evaluate HVPG effects of octreotide administration in cirrhotic patients receiving long-term propranolol.PATIENTS AND METHODS:A randomized, controlled trial. First study: a total of 28 patients were studied at baseline and 30 and 60 minutes after octreotide (200 μg) (N = 14) or placebo (N = 14) and then treated with propranolol for approximately 30 days (106 ± 5 mg/day). Second study: after baseline evaluation patients received octreotide or placebo as they were assigned to in the first study and measurements repeated 30 and 60 minutes later.RESULTS:In the first study baseline HVPG was 18.7 ± 0.9 mmHg and decreased to 17.1 ± 1.1 mmHg and 17.1 ± 1.0 mmHg (both P < 0.05 vs baseline) at 30 and 60 minutes after octreotide, respectively. Eight patients decreased their HVPG after octreotide. In the second study baseline HVPG was 15.6 ± 1.3 mmHg (P < 0.01 vs baseline HVPG in first study) and decreased to 14.1 ± 1.2 mmHg and 14.1 ± 1.3 mmHg (25.7 ± 5% lower than baseline HVPG in the first study, P < 0.01) (both P < 0.05 vs baseline) at 30 and 60 minutes after octreotide, respectively. Nine patients (2 responders/7 nonresponders to propranolol) decreased their HVPG after octreotide. Octreotide effects may be mediated by potentiation and additive mechanisms.CONCLUSIONS:Octreotide enhances HVPG reduction induced by propranolol in cirrhotic patients.

Hepatic venous pressure gradient: the facts

Many of the clinical complications of cirrhosis are the direct consequences of the elevation of portal venous pressure (PVP). Portal hypertension is defined as a PVP of greater than the normal 5–10 mmHg. The degree of portal hypertension has been shown to correlate with the severity of liver disease, both functionally1 and histologically2, 3. However, direct portal venous measurement is invasive and cannot be routinely performed. As a surrogate, hepatic venous pressure gradient (HVPG) has been widely accepted as a measurement for PVP. The ease and safety of HVPG measurement has made it a valuable tool not only in the research arena, but also more and more in clinical practice.

Consensus Statements: Changing Scenarios: Prevention of Decompensation

Successful cure of the etiologic agent in chronic liver disease may improve both liver structure and function, and this could translate into a portal pressure reduction (1b;A).

Endoscopic Band Ligation in Primary Prophylaxis

The Baveno V meeting concluded that either nonselective beta-blockers (NSBB) or endoscopic band ligation (EBL) may be recommended to prevent the first variceal bleeding in patients with medium or large varices, the final decision being based on several specific considerations. Further studies and meta-analyses focused on the “specific considerations” leading to the best decision considering that good quality trials failed to show any significant difference between the two therapies in variceal bleeding, bleeding-related mortality, and all-cause mortality. The main conclusions arising from these studies are the following: (1) NSBB must be administered at high doses (>75 mg/day) to be as effective as EBL, and (2) potential adverse events are higher when using NSBB, but those complicating EBL are far more serious, leading to death in some cases. Thus, EBL must be used in patients with intolerance or contraindications to NSBB as well as in those patients developing refractory ascites or SBP, in whom NSBB may aggravate the circulatory dysfunction. In the remaining patients, the decision must be personalized according to patient’s situation.