Clinical and genetic factors involved in Porto-sinusoidal vascular disorder after oxaliplatin exposure.

BACKGROUND AND AIMS: Oxaliplatin (OX) has been described as a potential etiologic agent for porto-sinusoidal vascular disorder (PSVD). Our aim was to describe the natural history of PSVD due to OX in colon cancer (CRC) and identify risk factors for its development. METHODS: We made a multicenter retrospective case-control (ratio 1:3) study with patients diagnosed of PSVD-OX. Baseline data, end of treatment, years of follow-up and diagnosis of PSVD were collected and compared to controls (without PSVD). Besides, 16 different SNPs were selected from bibliography and analyzed by genotyping in the case group to identify potential genetic risk factors. RESULTS: 41 cases were identified, with a median time to PSVD diagnosis after the end of OX of 34 months. Spleen diameter was the strongest predictor of PSVD during treatment (OR 43.94 (14.48-133.336); p < 0.0001). Additionally, thrombocytopenia (<150 × 10^9) at one year was a significant disease risk marker (OR 9.35; 95% CI: 3.71-23.58; p = 0.001). We could not establish any significant association between the selected SNPs and PSVD diagnosis. CONCLUSION: The increase of spleen diameter is the strongest predictor of PSVD in patients treated with OX for CRC. These patients could be candidates for a specific follow-up of portal hypertension-related complications.

Decompensation in Advanced Nonalcoholic Fatty Liver Disease May Occur at Lower Hepatic Venous Pressure Gradient Levels Than in Patients With Viral Disease.

BACKGROUND & AIMS: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension-related decompensation in patients with advanced NAFLD (aNAFLD). METHODS: Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels. RESULTS: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P = .019) than in the aHCV group. For any of the HVPG cutoff analyzed (<10, 10-12, or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD group than in the aHCV group. CONCLUSIONS: Patients with aNAFLD have higher prevalence of portal hypertension-related decompensation at any value of HVPG as compared with aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed.

Enfermedades vasculares del hígado. Guías Clínicas de la Sociedad Catalana de Digestología y de la Asociación Española para el Estudio del Hígado / Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver

Las enfermedades vasculares hepáticas, a pesar de su relativamente baja prevalencia, representan un problema de salud importante en el campo de las enfermedades hepáticas. Una característica común a muchas de estas enfermedades es que pueden causar hipertensión portal, con la elevada morbimortalidad que ello conlleva. Con frecuencia estas enfermedades se diagnostican en pacientes jóvenes y el retraso en su diagnóstico y/o un tratamiento inadecuado pueden reducir de forma importante la esperanza de vida. El presente artículo revisa la evidencia actual en el síndrome de Budd-Chiari, la trombosis venosa portal en pacientes no cirróticos, la hipertensión portal idiopática, el síndrome de obstrucción sinusoidal, las malformaciones vasculares hepáticas en la telangiectasia hemorrágica hereditaria, la trombosis portal en la cirrosis, otras patologías vasculares menos frecuentes como las fístulas arterioportales, así como un apartado sobre el diagnóstico por imagen de las enfermedades vasculares hepáticas y su tratamiento desde el punto de vista hematológico (estudio de la diátesis trombótica y tratamiento anticoagulante). Las recomendaciones se han realizado de acuerdo a los estudios publicados extraídos de Pubmed. La calidad de la evidencia y la intensidad de las recomendaciones fueron graduadas de acuerdo al sistema Grading of Recommendations Assessment Development and Evaluation (GRADE). Cuando no existían evidencias suficientes, las recomendaciones se basaron en la opinión del comité que redactó la guía.

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy. This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide.

The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis.

BACKGROUND: Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM: To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can predict portal hypertension in patients with cirrhosis. METHODS: We measured sCD163 and the ELF components (hyaluronic acid, tissue inhibitor of metalloproteinase-1 and procollagen-III aminopeptide) in two separate cohorts of cirrhosis patients that underwent hepatic vein catheterisation. To test the predictive accuracy we developed a CD163-fibrosis portal hypertension score in an estimation cohort (n = 80) and validated the score in an independent cohort (n = 80). A HVPG ≥10 mmHg was considered clinically significant. RESULTS: Both sCD163 and the ELF components increased in a stepwise manner with the patients' Child-Pugh score (P < 0.001, all), and also with increasing HVPG (P < 0.001). receiver operator characteristics (ROC) analyses showed that each one of the individual components predicted a HVPG >10 mmHg with AUROC's of approximately 0.80. The combined score optimised by logistic regression analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short-term mortality. CONCLUSIONS: The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted significant portal hypertension in patients with cirrhosis. This score may prove useful for screening purposes and highlights the importance of both the inflammatory and the fibrotic components of cirrhotic portal hypertension.

Pregnancy in women with portal vein thrombosis: results of a multicentric European study on maternal and fetal management and outcome.

BACKGROUND & AIMS: Women of childbearing age account for approximately 25% of patients with non-cirrhotic portal vein thrombosis (PVT). We aimed at assessing maternal and fetal outcome in pregnant women with known PVT. METHODS: We performed a retrospective analysis of the files of women with chronic PVT in three European referral centers between 1986 and 2010. RESULTS: Forty-five pregnancies, 28 (62%) treated with low molecular weight heparin, occurred in 24 women. Nine (20%) were lost before gestation week 20. Preterm birth occurred in 38% of deliveries: there were 3 births at week 24-25, 7 at week 32-36, and 26 after week 37. A term birth with a healthy infant occurred in 58% of pregnancies. Cesarean section was used in 53% of deliveries. Two women developed HELLP syndrome. A favorable outcome happened in 64% of pregnancies. Pregnancies with an unfavorable outcome were associated with a higher platelet count at diagnosis. Bleeding from esophageal varices occurred in 3 patients during pregnancy, all without adequate primary prophylaxis. Genital or parietal bleeding occurred postpartum in 4 patients, only one being on anticoagulation therapy. Thrombotic events occurred in 2 patients, none related to lower limbs or mesenteric veins. There were no maternal deaths. CONCLUSIONS: In pregnant PVT patients treated with anticoagulation on an individual basis, the rate of miscarriage and preterm birth appears to be increased. However, fetal and maternal outcomes are favorable for most pregnancies reaching gestation week 20. High platelet counts appear to increase the risk for unfavorable outcome. Pregnancy should not be contraindicated in stable PVT patients.

Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats.

Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg(-1)·day(-1)), sorafenib (1 mg·kg(-1)·day(-1)), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant (P < 0.001) and similar reduction in PP (-19 and -15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (-35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (-30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (-39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (-25 and -33%, respectively), splanchnic vascularization (-37 and -41%, respectively), liver fibrosis (38%), and hepatic neovascularization (-42 and -51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes METHODS: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4-6 weeks on medical therapy. RESULTS: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction >or=20% or

Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension.

BACKGROUND: Increased intrahepatic vascular tone in cirrhosis has been attributed to a decrease of hepatic nitric oxide (NO) secondary to disturbances in the post-translational regulation of the enzyme eNOS. NO scavenging by superoxide (O(2)(-)) further contributes to a reduction of NO bioavailability in cirrhotic livers. AIM: To investigate whether removing increased O(2)(-) levels could be a new therapeutic strategy to increase intrahepatic NO, improve endothelial dysfunction and reduce portal pressure in cirrhotic rats with portal hypertension. METHODS: Adenoviral vectors expressing extracellular superoxide dismutase (SOD) (AdECSOD) or beta-galactosidase (Adbetagal) were injected intravenously in control and CCl(4)-induced cirrhotic rats. After 3 days, liver O(2)(-) levels were determined by dihydroethidium staining, NO bioavailability by hepatic cGMP levels, nitrotyrosinated proteins by immunohistochemistry and western blot, and endothelial function by responses to acetylcholine in perfused rat livers. Mean arterial pressure (MAP) and portal pressure were evaluated in vivo. RESULTS: Transfection of cirrhotic livers with AdECSOD produced a significant reduction in O(2)(-) levels, a significant increase in hepatic cGMP, and a decrease in liver nitrotyrosinated proteins which were associated with a significant improvement in the endothelium-dependent vasodilatation to acetylcholine. In addition, in cirrhotic livers AdECSOD transfection produced a significant reduction in portal pressure (17.3 (SD 2) mm Hg vs 15 (SD 1.6) mm Hg; p<0.05) without significant changes in MAP. In control rats, AdECSOD transfection prevents the increase in portal perfusion pressure promoted by an ROS-generating system. CONCLUSIONS: In cirrhotic rats, reduction of O(2)(-) by AdECSOD increases NO bioavailability, improves intrahepatic endothelial function and reduces portal pressure. These findings suggest that scavenging of O(2)(-) might be a new therapeutic strategy in the management of portal hypertension.

Primary prophylaxis of esophageal variceal bleeding in cirrhosis.

Variceal bleeding is a common and severe complication of liver cirrhosis. The risk of bleeding increases with the size of varices, red wheal marks and disease severity. Noninvasive tests are not accurate enough for the diagnosis of varices, so all patients with cirrhosis should be screened by endoscopy. Nonselective beta-blockers (propranolol, nadolol) are indicated for primary prophylaxis in patients with medium/large varices, and for those with small varices and red signs or advanced liver failure (Child C). In such patients, beta-blockers have been shown to reduce the risk of bleeding from 25 to 15%. There is no evidence to support using beta-blockers with nitrates or spironolactone. In patients with contraindication or intolerance to beta-blockers, endoscopic band ligations are indicated.

Review article: the modern management of portal hypertension--primary and secondary prophylaxis of variceal bleeding in cirrhotic patients.

BACKGROUND: Variceal bleeding is a life-threatening complication of liver cirrhosis with a high probability of recurrence. Treatment to prevent first bleeding or rebleeding is mandatory. AIM: To provide an overview of the current knowledge on the best evidence-based therapeutic options to prevent first or recurrent bleeding from oesophageal varices in patients with cirrhosis. METHODS: For the preparation of this narrative review, we sought to analyse randomized controlled trials that examined the efficacy and side effects of pharmacological or endoscopic therapy for the primary and secondary prophylaxis of oesophageal variceal bleeding. RESULTS: Endoscopic band ligation (EBL) and nonselective beta-blockers are both effective in preventing first bleeding. Until more long-term data are available, nonselective beta-blockers should be the first treatment option because of less severe side effects. EBL is an alternative when beta-blockers are contraindicated or not tolerated. Patient preference may also be considered. For prevention of rebleeding, nonselective beta-blockers (preferably in association with isosorbide-5-mononitrate) or EBL are both effective and good alternative treatments. A combination of both treatments may be the best alternative. CONCLUSIONS: A great improvement in the prevention of variceal bleeding has emerged over the last years. However, further therapeutic options that combine higher efficacy, better tolerance and fewer side effects are needed.

Prevention of recurrent variceal bleeding.

Patients surviving a first episode of variceal bleeding have a risk of over 60% of experiencing recurrent haemorrhages within 1 year from the index episode. Because of this, all patients surviving a variceal bleeding should receive active treatments for the prevention of rebleeding. beta-Blockers+/-isosorbide-5-mononitrate and band ligation are effective in preventing recurrent bleeding and both can be used. Combination of beta-blockers+/-isosorbide-5-mononitrate and band ligation may be the best treatment to prevent rebleeding but more studies are needed to confirm this issue. In patients with recurrent variceal bleeding despite appropriate medical and endoscopic treatment, transjugular intrahepatic porto-systemic shunt is highly effective in controlling bleeding. The efficacy is not significantly different from that of shunt surgery (distal splenorenal shunt or 8mm H-graft shunt), especially since the introduction of polytetrafluoroethylene-covered stents. Therefore, in this situation, transjugular intrahepatic porto-systemic shunt using polytetrafluoroethylene stents should be the treatment of choice.

[Animal models for the study of portal hypertension]. / Modelos animales en el estudio de la hipertensión portal.

Animal models allow detailed study of the hemodynamic alterations in portal hypertension syndrome and of the molecular mechanisms involved in the abnormalities in splenic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splenic circulation and the physiopathology of hyperdynamic circulation. Moreover, models of cirrhosis allow the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow to be studied. The present review summarizes currently available animal models of portal hypertension and analyzes their relative utility in investigating the distinct disorders associated with this entity. The criteria for the choice of a particular model, depending on the specific objectives of the study, are also discussed.

Modelos animales en el estudio de la hipertensión portal / The pulmonary involvement in portal hypertension: portopulmonary hypertension and hepatopulmonary syndrome

La utilización de modelos animales permite el estudio detallado de las alteraciones hemodinámicas del síndrome de hipertensión portal y de los mecanismos moleculares implicados en las alteraciones de la circulación esplácnica y sistémica asociadas a este síndrome. Los modelos de hipertensión portal prehepática permiten el estudio de las alteraciones en la circulación esplácnica y de la fisiopatología de la circulación hiperdinámica. Los modelos de cirrosis permiten, además, el estudio de las alteraciones en la microcirculación intrahepática que conducen al aumento de resistencia al flujo portal. Esta revisión resume los modelos animales de hipertensión portal actualmente disponibles, su utilidad relativa para el estudio de los diferentes trastornos asociados a la hipertensión portal y los criterios en los que se basa la elección de un determinado modelo, atendiendo a los objetivos específicos del estudio

Animal models allow detailed study of the hemodynamic alterations in portal hypertension syndrome and of the molecular mechanisms involved in the abnormalities in splenic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splenic circulation and the physiopathology of hyperdynamic circulation. Moreover, models of cirrhosis allow the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow to be studied. The present review summarizes currently available animal models of portal hypertension and analyzes their relative utility in investigating the distinct disorders associated with this entity. The criteria for the choice of a particular model, depending on the specific objectives of the study, are also discussed

Modelos animales en el estudio de la hipertensión portal / The pulmonary involvement in portal hypertension: portopulmonary hypertension and hepatopulmonary syndrome

La utilización de modelos animales permite el estudio detallado de las alteraciones hemodinámicas del síndrome de hipertensión portal y de los mecanismos moleculares implicados en las alteraciones de la circulación esplácnica y sistémica asociadas a este síndrome. Los modelos de hipertensión portal prehepática permiten el estudio de las alteraciones en la circulación esplácnica y de la fisiopatología de la circulación hiperdinámica. Los modelos de cirrosis permiten, además, el estudio de las alteraciones en la microcirculación intrahepática que conducen al aumento de resistencia al flujo portal. Esta revisión resume los modelos animales de hipertensión portal actualmente disponibles, su utilidad relativa para el estudio de los diferentes trastornos asociados a la hipertensión portal y los criterios en los que se basa la elección de un determinado modelo, atendiendo a los objetivos específicos del estudio

Animal models allow detailed study of the hemodynamic alterations in portal hypertension syndrome and of the molecular mechanisms involved in the abnormalities in splenic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splenic circulation and the physiopathology of hyperdynamic circulation. Moreover, models of cirrhosis allow the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow to be studied. The present review summarizes currently available animal models of portal hypertension and analyzes their relative utility in investigating the distinct disorders associated with this entity. The criteria for the choice of a particular model, depending on the specific objectives of the study, are also discussed