Treatment of portal vein thrombosis in cirrhosis: a multicenter real life cοhort study.

BACKGROUND: Portal vein thrombosis (PVT) is a common complication of cirrhosis and can be a cause or consequence of liver disease progression. It is unclear whether PVT treatment is affecting clinical outcomes in cirrhotics. METHODS: This is a multicenter study of cirrhotics with PVT, initially retrospectively and thereafter prospectively registered in a data base. We studied the impact of PVT treatment on this population for efficacy, safety and the impact on survival. In survival analysis Mantel-Cox and Wilcoxon-Breslow-Gehan tests were used. A P value of <0.05, was considered significant. For statistical computations the STATA 12.1 was used. RESULTS: Seventy-six patients were included (76% decompensated, median MELD score 12 and Child-Pugh score 7), 47% with concomitant HCC. Fifty-one patients with PVT were treated with Vitamin-K antagonists or Low-Molecular-Weight Heparin. Patients were followed up for at least 6 months after PVT diagnosis, or until death or transplantation. PV patency after 6 months was not statistically different between patients receiving or not anticoagulation (complete-partial recanalization 27.4% of treated vs. 20% of untreated, P=0.21). Median survival was statistically worse between patients treated with anticoagulation than those untreated (10 vs. 15 months, P=0.036). Less portal hypertensive bleeding and less decompensation rates were found in treated cirrhotics vs. untreated (45.8% vs. 54.2%, P=0.003 and 78% vs. 80.9%, P=0.78, respectively). Patients with HCC had worse survival when treated vs. untreated (P=0.047). CONCLUSIONS: In our cohort of cirrhotics with PVT, treatment was feasible with acceptable side effects, but without meaningful clinical benefits.

Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis.

Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota. In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of potentially pathogenic bacteria (i.e., gram negative species) and a decrease in autochthonous familiae. Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences. We therefore described the features of the complex interaction between gut microbiota and cirrhotic host, the so called "gut-liver axis", with a particular attention to the acquired risk of bacterial translocation, systemic inflammation and the relationship with systemic infections in the cirrhotic patient. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.

Endogenous heparinoids detected by anti-Xa activity are present in blood during acute variceal bleeding in cirrhosis. A prospective study.

BACKGROUND & AIMS: Endogenous heparinoids have been detected by thromboelastography and quantified by clotting based anti-Xa activity assays in patients with cirrhosis, but their presence in variceal bleeding has not been established yet. METHODS: Clotting based anti-Xa activity was measured in A) 30 cirrhotics with variceal bleeding, B) 15 non-cirrhotics with peptic ulcer bleeding, C) 10 cirrhotics without infection or bleeding, and D) 10 cirrhotics with hepatocellular carcinoma (HCC). RESULTS: Anti-Xa activity was not detected in ulcer bleeders or in cirrhotics without infection or bleeding but was present in seven (23%) variceal bleeders (median levels: 0.03 u/mL (0.01-0.07)) and was quantifiable for 3 days in six of seven patients. Four of seven variceal bleeders with anti-Xa activity present had HCC (p=0.023). Age, creatinine, platelet count and total infections the second day from admission were significantly correlated with the presence of measureable anti-Xa levels (p=0.014, 0.032, 0.004 and 0.019, respectively). In the HCC group, anti-Xa activity was present in three patients (30%) [median levels: 0.05 u/mL (0.01-0.06)]. CONCLUSIONS: In this study, variceal bleeders and 30% of the patients with HCC had endogenous heparinoids that were detected by a clotting based anti-Xa activity assay, whereas there was no anti Xa activity present in patients with cirrhosis without infection, or bleeding or HCC, nor in those with ulcer bleeding. Thus, the anti Xa activity is likely to be a response to bacterial infection and/or presence of HCC in cirrhosis.

Beta-blockers in liver cirrhosis.

Since the original description of the effectiveness of ß-blockers in lowering the portal pressure and therefore the risk of variceal bleeding, more than 500 articles in the English literature on the use of non selective ß-blockers (NSBB) in cirrhosis have been published. The use of NSBB in pre-primary prophylaxis of variceal bleeding is currently not indicated. In primary prophylaxis, patients with high risk small varices or large/medium varices should receive primary prophylaxis either with NSBB or with endoscopic band ligation if there are contraindications to NSBB. For secondary prophylaxis the current recommendation is to receive a combination of NSBB and endoscopic variceal ligation. In addition to lowering portal pressure, NSBB can also reduce bacterial translocation, potentially exerting multiple beneficial effects which go beyond the reduction of bleeding risk. Carvedilol is a NSBB with intrinsic anti-α(1)-adrenergic activity, possibly more effective than propranolol in lowering portal hypertension. A potential harmful effect of propranolol in patients with cirrhosis with refractory ascites deserves further confirmation. NSBB remain the cornerstone of therapy in cirrhotic patients with portal hypertension.

Management of varices in cirrhosis.

INTRODUCTION: Acute variceal bleeding is a medical emergency and one of the main causes of mortality in patients with cirrhosis. Timely and effective treatment of the acute bleeding episode results in increased survival, and appropriate prophylactic treatment can prevent bleeding or rebleeding from varices. AREAS COVERED: We discuss the prevention of development and growth of varices, the primary and secondary prophylaxis of bleeding, the treatment of acute bleeding, and the management of gastric varices. We systematically reviewed studies, without time limits, identified through Medline and searches of reference lists, and provide an overview of the evidence underlying the -treatment options in the management of varices in cirrhosis. EXPERT OPINION: The management of variceal hemorrhage relies on nonspecific interventions (e.g., adequate fluid resuscitation, airway protection) and on specific interventions. These are routine prophylactic antibiotics, vasoactive drugs and endoscopic treatment. Procedures such as the placement of a Sengstaken-Blakemore tube or a transjugular intrahepatic portosystemic shunt (TIPS) can be lifesaving. The primary and secondary prophylaxis of bleeding is based on nonselective beta-blockers and endoscopy, even though TIPS or, less frequently, surgery have a role in selected cases.

Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No.

Portal hypertension (PH) is a severe complication of liver cirrhosis. Measurement of the degree of portal hypertension is usually performed by measuring the hepatic venous pressure gradient (HVPG) which is the difference between the free hepatic venous pressure (FHVP) and the wedged hepatic venous pressure (WHPG). The HVPG accurately reflects the degree of PH in the majority of liver diseases. PH is defined by an increase of HVPG values above the normal upper limit of 5 mm Hg, while clinically significant PH is defined by an HVPG to ≥10 mm Hg. Although measurement of HVPG potentially has several applications, in clinical practice its major use has been related to the assessment of hemodynamic response to pharmacological therapy, in order to evaluate the efficacy of treatment and to predict the risk of rebleeding from esophageal varices. When properly performed, HVPG is a reliable, safe and good predictive tool in the management of portal hypertension. However, the need for appropriate equipment, sufficient and reliable operators and costs, have discouraged its use outside Liver Units specifically devoted to the clinical management of portal hypertension. This has diminished its applicability. Combining its use with transjugular liver biopsy and using the prognostic value of HVPG may help encourage its use.

Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study.

OBJECTIVES: Bacterial translocation seems to precede the occurrence of overt bacterial infection in patients with cirrhosis. The presence of bacterial DNA in blood and ascites correlates with bacterial translocation and is frequent in patients with advanced cirrhosis without overt infection. Our aim was to search for bacterial DNA in patients with cirrhosis both with and without ascites, and to study its correlation with abnormal intestinal motility or permeability and the presence of bacterial overgrowth. METHODS: Blood and ascites samples were obtained on day 1, and blood samples were taken twice a day for the following 3 days. Bacterial DNA was assayed by polymerase chain reaction using universal primers for rRNA 16 s. Oro-caecal transit time and bacterial overgrowth were assessed with Lactulose H(2) breath testing. Intestinal permeability was assessed by determining urinary lactulose and mannitol excretion with high performance liquid chromatography. RESULTS: We studied seven patients (six were male, age range was 42-78 years). Aetiology was alcohol in four, HCV in two, HBV in one; ascites was present in four and Child-Pugh grade was A in four and B in three. All patients had increased intestinal permeability, six had decreased transit time and one had bacterial overgrowth. In only one patient (with ascites), polymerase chain reaction was positive for bacterial DNA both in ascites and serum for all 4 days on which samples were taken. CONCLUSION: Increased intestinal permeability and abnormal motility were frequent without evidence of bacterial translocation in cirrhosis even without ascites. They are likely to be facilitators for bacterial translocation and thus precede it.

Terlipressin therapy for renal failure in cirrhosis.

OBJECTIVES: Renal failure is common in cirrhosis frequently due to hepatorenal syndrome (HRS). Terlipressin and albumin improve renal function with a trend to prolong survival in HRS, but prognostic factors with therapy have been poorly studied. METHODS: Forty-five cirrhotics seen consecutively in a single centre with renal failure defined as oliguria/anuria and/or rising creatinine and no response to volume loading, without intrinsic renal disease, sepsis, gastrointestinal bleeding [median Child-Pugh score 12(8-14)/Model for End-Stage Liver Disease 29(10-40)], had intravenous terlipressin and albumin and were audited retrospectively classified into three groups: group 1 HRS type 1 (15), group 2 HRS type 2 (11) and group 3(19): not fulfilling HRS 1 or 2 criteria. Baseline median creatinine was 1.7 (0.9-5.46) mg/dl and 30 (67%) had creatinine greater than 1.5 mg/dl. All 45 patients had initial colloid/albumin and 31 continued terlipressin (2-4 mg/day) for a median 8 (2-76) days. RESULTS: Improvement in serum creatinine occurred in 23 (51%) [(1.3 mg/dl (0.6-3.9)] compared with baseline [1.7 mg/dl (0.92-3.75)] (P<0.001). In the multivariate analysis a greater reduction in creatinine between baseline and day 4 (95% confidence interval, odds ratio: 0.25) was associated with improved survival at 6 weeks. CONCLUSION: Albumin and terlipressin improve renal failure in the absence of sepsis in cirrhosis independently of whether HRS criteria are fulfilled or not. Improvement at 4 days of therapy is associated with better survival. Randomized studies are needed for oliguria and rising creatinine in cirrhotics even if HRS criteria are not fulfilled.

Heparin effect on thromboelastography after transjugular intrahepatic portosystemic shunt procedure.

OBJECTIVE: In patients with cirrhosis and bacterial infection there is impaired coagulation and a heparin effect on thromboelastography (TEG). Our aim was to assess the presence of a heparin effect on heparinase I-modified TEG in patients before and after transjugular intrahepatic portosystemic shunt (TIPS). Our hypothesis was that, given the presence of a portosystemic gradient of endotoxaemia, and the role of endotoxaemia on the release of heparinoids, the inflow of portal blood after TIPS might reveal heparinoids through a heparin effect on TEG. MATERIAL AND METHODS: Blood samples for heparinase I-modified TEG were taken before, 1 h after, 6 h after and the morning after TIPS, with further daily samples being taken until any TEG changes had reverted to baseline. A heparin effect was defined as an improvement of > or =20% in a TEG variable after addition of heparinase I. RESULTS: We studied 10 patients (six males, mean age 48.8 years, mean Child score 8.8). The aetiology of liver disease was alcohol in six patients, Budd-Chiari syndrome in two, and hepatitis C virus and cryptogenic cirrhosis in one each. Indications for TIPS were recurrent variceal bleeding in four patients, refractory ascites or hydrothorax in four and Budd-Chiari syndrome in two. There was a statistically significant worsening in TEG parameters after TIPS placement. In eight patients a heparin effect appeared after TIPS and disappeared within 24-48 h. CONCLUSIONS: We report the appearance of a transient heparin effect in systemic venous blood after TIPS in patients with cirrhosis or Budd-Chiari syndrome, suggesting the presence of heparinoid substances in the portal venous system in these patients.

TIPS for refractory ascites: a single-centre experience.

PURPOSE: Transjugular intrahepatic portosystemic shunt (TIPS) has been reported superior to large-volume paracentesis for refractory ascites, but post-TIPS encephalopathy is a major complication. We intended to assess the outcome of limited diameter TIPS on ascites control, mortality, and encephalopathy in patients with refractory ascites at our centre. METHODS: TIPS was successfully performed on 56 patients. Initial stent dilatation was to 6 mm, if there was a reduction in portal pressure gradient (PPG) >25%, further dilatation was not proposed. RESULTS: Either complete or partial response was obtained in 58%, 81%, 83%, and 93% of patients at 1, 3, 6, and 12 months, respectively. Mortality was 10%, 29%, 37%, and 50% at 1, 3, 6, and 12 months, respectively. In 27 patients (48%), a new episode of encephalopathy developed, but only 6 (22%) were grade III or IV and 23 (85%) responded quickly to treatment. CONCLUSIONS: The results of our study confirm the efficacy of TIPS for refractory ascites. The use of narrow-diameter dilatation without aiming at lowering the PPG below a certain threshold might simplify the procedure and the follow-up for these patients.