Linda Pasta

Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices : an analysis of data and prognostic factors in 589 patients from four randomized clinical trials

BACKGROUND The value of beta-adrenergic-antagonist drug therapy for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices is uncertain, both positive and negative study results having been reported. METHODS In this study, we analyzed data on individual patients from four randomized, controlled trials to assess the efficacy of this treatment. Of the 589 patients studied, 286 received a beta-adrenergic-antagonist drug (propranolol in 203 and nadolol in 83) and 303 received placebo. RESULTS After two years, the mean (+/- SE) percentage of patients who had had no upper gastrointestinal bleeding was 78 +/- 3 percent in the beta-adrenergic-antagonist treatment group and 65 +/- 3 percent in the control group (P = 0.002). The percentage of patients without fatal bleeding was 90 +/- 2 percent in the treatment group and 82 +/- 3 percent in the control group (P = 0.01). The percentage of patients surviving after two years was 71 +/- 3 percent in the treatment group and 68 +/- 3 percent in the control group (P = 0.34). After age and severity of cirrhosis were taken into account, the survival rate was better in the treatment group (P = 0.09). The percentage of surviving patients who had had no bleeding after two years was 62 +/- 3 percent in the treatment group and 53 +/- 3 percent in the control group (P = 0.04). Both propranolol and nadolol prevented a first episode of bleeding. Severe cirrhosis and especially the presence of ascites were associated with bleeding (P less than 0.001) and death (P less than 0.001) in both groups. The efficacy of beta-adrenergic-antagonist therapy in the prevention of bleeding (P less than 0.001) and of fatal bleeding (P = 0.004) and in the prevention of bleeding or death (P = 0.005) was the same after adjustment for cause and severity of cirrhosis, ascites, and size of varices. CONCLUSIONS Propranolol and nadolol are effective in preventing first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity.

Competing risks and prognostic stages of cirrhosis: a 25‐year inception cohort study of 494 patients

Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice.

Beta-Adrenergic–Antagonist Drugs in the Prevention of Gastrointestinal Bleeding in Patients with Cirrhosis and Esophageal Varices

BACKGROUND The value of beta-adrenergic-antagonist drug therapy for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices is uncertain, both positive and negative study results having been reported. METHODS In this study, we analyzed data on individual patients from four randomized, controlled trials to assess the efficacy of this treatment. Of the 589 patients studied, 286 received a beta-adrenergic-antagonist drug (propranolol in 203 and nadolol in 83) and 303 received placebo. RESULTS After two years, the mean (+/- SE) percentage of patients who had had no upper gastrointestinal bleeding was 78 +/- 3 percent in the beta-adrenergic-antagonist treatment group and 65 +/- 3 percent in the control group (P = 0.002). The percentage of patients without fatal bleeding was 90 +/- 2 percent in the treatment group and 82 +/- 3 percent in the control group (P = 0.01). The percentage of patients surviving after two years was 71 +/- 3 percent in the treatment group and 68 +/- 3 percent in the control group (P = 0.34). After age and severity of cirrhosis were taken into account, the survival rate was better in the treatment group (P = 0.09). The percentage of surviving patients who had had no bleeding after two years was 62 +/- 3 percent in the treatment group and 53 +/- 3 percent in the control group (P = 0.04). Both propranolol and nadolol prevented a first episode of bleeding. Severe cirrhosis and especially the presence of ascites were associated with bleeding (P less than 0.001) and death (P less than 0.001) in both groups. The efficacy of beta-adrenergic-antagonist therapy in the prevention of bleeding (P less than 0.001) and of fatal bleeding (P = 0.004) and in the prevention of bleeding or death (P = 0.005) was the same after adjustment for cause and severity of cirrhosis, ascites, and size of varices. CONCLUSIONS Propranolol and nadolol are effective in preventing first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity.

MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, and prothrombin G20210A in hepatocellular carcinoma with and without portal vein thrombosis

We studied thrombophilic genetic factors (TGFs) MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, prothrombin G20210A as risk factors in 94 patients with HCC with and without portal vein thrombosis (PVT), compared with 214 patients with liver cirrhosis (LC) with and without PVT and 94 healthy controls (HC). The OR (95% CI) for MTHFR C677TT with HCC was 3.85 (1.55–7.39) vs. HC. The OR for PAI1 4G-4G in HCC, was 2.87 (1.27–6.55) vs. HC. Also prothrombin G20210A was significantly more frequent among HCC, mainly in patients with PVT, while V Leiden factor was equally distributed among HCC and HC. Differences were more significant in patients with associated PVT. These findings suggest that frequently TGFs are needed for patients to be at risk of HCC and PVT. We conclude that in all patients with chronic liver disease TGF screening should be performed to individuate patients at risk of HCC and PVT.

Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population

The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and Prothrombin 20210A, were studied as risk factors in 865 Caucasian patients with liver cirrhosis, consecutively enrolled from June 2008 to January 2014. A total of 582 HCV, 80 HBV, 94 alcohol, (82 with more than one etiologic factor) and 191 cryptogenic patients with liver cirrhosis had been consecutively enrolled; 243 patients showed portal vein thrombosis (PVT). At least one of the above THRGFs was present in 339/865 patients (39.2%). PAI-1 4G-4G and MTHFR 677TT were the most frequent THRGFs, statistically significant in patients with alcohol, cryptogenic liver cirrhosis, and PVT: respectively 24 and 28, 50 and 73, and 65 and 83 (all chi-square tests>3.84, and p values<0.05). Two logistic regression analysis, using PAI-1 4G-4G and MTHFR 677TT, as dependent variable, confirmed the independent significant relationship of these THRGFs with alcohol, cryptogenic liver cirrhosis and PVT. PAI 1 and MTHFR 677 genotypes, deviated from those expected in populations in Hardy-Weinberg equilibrium (all p values<0.05), in the subgroups of patients with alcohol, cryptogenic liver cirrhosis and presence of PVT. Our study shows the pivotal role of PAI-1 4G-4G and MTHFR 677TT in patients with alcohol, cryptogenic liver cirrhosis, and PVT, in a Caucasian population. In conclusion, thrombo and fibro-genetic mechanisms of PAI-1 4G-4G and MTHFR 677TT, could have a role in the development of liver cirrhosis, mainly in patients without HCV and HBV, and PVT.

Thrombophilic Genetic Factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A in Noncirrhotic Portal Vein Thrombosis and Budd-Chiari Syndrome in a Caucasian Population.

Thrombophilic genetic factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A were studied as risk factors in 235 Caucasian subjects: 85 patients with abdominal thrombosis (54 with portal vein thrombosis (PVT) and 31 with Budd-Chiari syndrome (BCS) without liver cirrhosis or hepatocellular carcinoma) and 150 blood bank donors. Seventy-five patients with PVT/BCS showed associated disease or particular clinical status (46 PVT/29 BCS): 37 myeloproliferative neoplasm (20 PVT/17 BCS), 12 abdominal surgery (10 PVT/2 BCS), 10 contraception or pregnancy (6 PVT/4 BCS), 7 abdominal acute disease (6 PVT/1 BCS), and 9 chronic disease (4 PVT/5 BCS); ten patients did not present any association (8 PVT/2 BCS). PAI-14G-4G, MTHFR677TT, and V Leiden 506Q were significantly frequent (OR 95% CI and χ 2 test with P value) in abdominal thrombosis; in these patients PAI-14G-4G and MTHFR677TT distributions deviated from that expected from a population in the Hardy-Weinberg equilibrium (PAI-1: χ 2 = 13.8, P < 0.001; MTHFR677: χ 2 = 7.1, P < 0.01), whereas the equilibrium was respected in healthy controls. V Leiden Q506 and Prothrombin 20210A were in the Hardy-Weinberg equilibrium both in patients with abdominal thrombosis and healthy controls. Our study shows an important role of PAI-14G-4G and MTHFR677TT in abdominal thrombosis without liver cirrhosis or hepatocellular carcinoma.

A Randomised Controlled Trial of Propranolol for the Prevention of Initial Bleeding in Cirrhotic Patients with Portal Hypertension

SummaryThe preliminary analysis of a multicentre, randomised, single-blind trial of propranolol for prophylaxis of first bleeding in cirrhosis is reported.174 consecutively-chosen patients with large oesophageal varices were randomly assigned to either propranolol, in doses which reduced the resting heart rate by 25% (85 patients), or to vitamin K (89 patients). 25 patients had to be withdrawn from treatment with propranolol because of poor tolerance.The 30-month cumulative proportion of patients free of bleeding was 74% in the propranolol group and 63% in the vitamin K group; corresponding survival figures were 59% and 74%, respectively. These differences were not statistically significant. A retrospective analysis, according to the presence of ascites at randomisation showed that a significantly higher proportion of patients without ascites in the propranolol group were free of bleeding compared with those in the control group (87% vs 64%; p=0.023). No significant differences were found in patients with ascites at randomisation. Length of survival was not significantly affected by treatment in any subgroup, although it was shorter in ascitic patients given propranolol than in controls (33% vs 63%; p=0.07).If confirmed on a longer follow-up, these results suggest that propranolol could prevent primary variceal haemorrhage in patients with well-compensated cirrhosis.

Clinical states of cirrhosis and competing risks

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

MTHFR C677T homozygous as risk factor for complications after OLT for cryptogenic cirrhosis.

To the Editors, We read with interest the paper of Duclos-Vallée et al. (1) on the diagnosis of the so-called cryptogenic cirrhosis (CC); in this study 3 of 28 transplanted patients with CC showed incomplete septal cirrhosis (ISC) and vascular liver disease on histological re-evaluation of native liver. We have recently studied 10 patients who received an ortotopic liver transplant (OLT) because of CC, who may add useful information to the data reported by Duclos-Vallée. These 10 patients were part of a consecutive series of 56 patients with CC enrolled from January 2000 to January 2006; patients with known metabolic diseases, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune causes of liver cirrhosis (LC), celiac disease, antiphospholipid syndrome and neoplastic diseases other than hepatocellular carcinoma (HCC) were excluded. The diagnosis of CC was biopsy proven in 35 cases, and diagnosed on the presence of compatible physical signs, laboratory and ultrasound findings in 21 patients; all of this second group had oesophageal varices. All patients were negative for HBsAg and hepatitis B virus markers, hepatitis C virus (HCV), alcohol consumption >80 g/day. Six patients with superimposed HCC were included in the study. The study was planned to examine the role of thrombophilic genetic factors V Leiden Q506, prothrombin G20210A, MTHFR C677TT and PAI-1 4G/4G as risk factors for portal vein thrombosis (PVT) and Budd-Chiari syndrome (BCS) in CC. Diagnosis of PVT was accepted when unambiguous diagnostic evidence (endoluminal material and the absence of flow or presence of cavernous transformation) for extra-hepatic PVT was detected by proper imaging techniques (Doppler ultrasound, computerized tomography or magnetic resonance imaging). Diagnosis of BCS was accepted when there was unambiguous evidence for hepatic venous outflow obstruction from the level of the small hepatic veins to the entrance of the inferior vena cava into the right atrium, as detected by proper imaging techniques (Doppler ultrasound, computerized tomography or magnetic resonance imaging or venography). All patients signed an informed consent and the study conformed to the ethical guidelines of the 1975 Helsinki Declaration. Among the 10 patients with OLT for CC, two had ISC confirmed on native liver, all with venous portal lesions, according to the criteria used by Duclos-Vallée et al. (1). The immunosuppressive regimen of all the 10 transplanted patients was tacrolimus and prednisolone; no one patient was treated with folate or vitamin B. No one of these patients showed PVT or BCS before OLT. Demographic and clinical characteristics of the patients were the following: gender M/F: 7/3; median age: 43 yr (range 19–64); all patients before OLT were in Child-Pugh C class; oesophageal varices absent/small/large: 0/4/6; previous bleeding episodes: 6. Survival and development of acute rejection (AR), chronic rejection (CR), PVT and BCS was recorded in all patients after OLT. Median followup after OLT was 24 months (range 12–108). No one showed Leiden factor; one patient with prothrombin G20210A heterozygous, four MTHFR C677T homozygous and two PAI-1 4G/ 4G were found; no patient showed the association of more than one thrombophilic factor. Among patients with MTHFR C677T homozygous, one developed AR and three CR; three of these four patients also developed PVT; the patient with AR was re-transplanted without subsequent relevant events. Clin Transplant 2006: 20: 796–798 DOI: 10.1111/j.1399-0012.2006.00564.x Copyright a Blackwell Munksgaard 2006

Second study shows that octreotide may prevent early rebleeding in cirrhosis

EDITOR—Jenkins et al have reported a randomised trial showing that long term subcutaneous octreotide together with sclerotherapy significantly reduces the risk of recurrent bleeding from oesophageal varices in liver cirrhosis.1 In a double blind placebo controlled pragmatic trial we have found that a 15 day course of subcutaneous octreotide was effective in preventing early rebleeding in cirrhosis. After acute bleeding of the upper digestive tract had been controlled, 262 consecutive patients with cirrhosis were randomised to receive octreotide 100 μg subcutaneously three times a day for 15 days (n=131) or …