Primary Prevention of Bleeding from Oesophageal Varices

Variceal bleeding is the most serious complication of patients with cirrhosis and portal hypertension. Mortality related to variceal bleeding has been falling in recent years but is still considered among the leading causes of death in these patients. Therefore, the issue of primary prophylaxis of variceal bleeding is an important one. In the pre-primary prophylaxis setting (prevention of formation/growth of varices) all cirrhotics should be screened for varices at diagnosis although there is no currently indication for treating patients in order to prevent the formation of varices. Areas requiring further study include the natural history of low-risk varices and treatment possibilities for the decrease or the prevention of the development and/or the progression of varices. Patients with small varices could be treated with beta-blockers, which have been proved effective in reducing the risk of first variceal bleeding in patients with medium and large oesophageal varices. Endoscopic band ligation seems to be more effective in recent trials, but concerns have been raised regarding its safety. Further, studies are required to clarify whether the use of the combination of band ligation and beta-blockers is better than each treatment alone. The future aim is to improve current medical therapy taking into consideration the cost-effectiveness and the quality of life

Ursodeoxycholic acid improves bilirubin but not albumin in primary biliary cirrhosis: further evidence for nonefficacy.

BACKGROUND/AIM: In randomised controlled trials (RCTs) of ursodeoxycholic acid (UDCA), although serum bilirubin is frequently reduced, its effect on disease progression and mortality is unclear. As serum albumin is an established independent prognostic marker, one might expect less deterioration of serum albumin values in a UDCA-treated group. We therefore modelled the typical evolution of serum bilirubin and albumin levels over time in UDCA-untreated patients and compared it with the observed levels in UDCA RCTs. METHODS: Multilevel modelling was used to relate the evolution of serum albumin to serum bilirubin and time since patient referral. For each considered RCT, the derived model was used to predict the relationship between final mean serum albumin and bilirubin concentration, adjusted for mean serum albumin at referral and followup duration. RESULTS: Five RCTs were eligible in terms of available data, of which two had long followup. In all trials, serum albumin did not significantly differ between UDCA- and placebo-treated patients, despite the UDCA effect on serum bilirubin. Therefore, there is no evidence over time for changes or maintenance of albumin levels for UDCA-treated patients above the levels predicted for placebo-treated patients. CONCLUSIONS: Our findings suggest that UDCA does not alter serum albumin in a way that is consistent with its effect on serum bilirubin. Therefore, reductions in serum bilirubin of UDCA-treated PBC do not parallel another validated and independent prognostic marker, further questioning the validity of serum bilirubin reduction with UDCA as a surrogate therapeutic marker

Optimal therapy of chronic hepatitis B: how do I treat HBeAg-positive patients?

Current agents for the treatment of chronic hepatitis B (CHB) can be classified into interferon- (standard or pegylated) (IFN) and nucleos(t)ide analogues (NAs). IFN therapy has the advantage of a finite duration (48weeks) with a chance for durable sustained off-treatment response in HBeAg positive CHB patients. However, these benefits are limited to approximately 30% of HBeAg positive patients, while parenteral administration and potential side effects are common patient concerns. Thus, patients who can benefit from IFN therapy must be carefully selected and monitored. Recently, stopping rules for IFN non-responders were developed based on 12-week HBsAg levels. NAs are currently used in most CHB patients. They are administered in one tablet daily and can be used in all patients with excellent tolerability and a good safety profile. The current first-line options, entecavir (ETV) and tenofovir (TDF), are highly potent with a minimal risk of resistance during long-term monotherapy. Prolongation of entecavir or tenofovir maintains the initially high virological remission rates in adherent HBeAg positive patients and modifies the long-term outcomes. The need for a long-term, perhaps indefinite, treatment duration is the main limitation of ETV or TDF, which may sometimes be safely discontinued in HBeAg positive patients who achieve stable HBeAg seroconversion. Since there will always be safety concerns and family planning issues with long-term therapy, NAs should be used carefully particularly in young HBeAg positive patients with minimal-mild liver disease

HBeAg-negative chronic hepatitis B: why do I treat my patients with pegylated interferon-alfa?

HBeAg-negative chronic hepatitis B (CHB) is the most frequent and aggressive type of CHB. The current therapeutic options for CHB include pegylated-interferon-alfa (PEG-IFN) and nucleos(t)ide analogues (NAs). NAs are well-tolerated and safe agents that effectively inhibit viral replication, but they should be given as long-term, probably lifelong therapy, in particular in HBeAg-negative CHB. Thus, the finite, usually 48-week, duration is the main advantage of PEG-IFN, providing sustained virological responses (SVR) off-therapy in approximately one-fourth of patients with HBeAg-negative CHB and often leading to HBsAg loss. However, the limited efficacy is the main factor restricting the use of PEG-IFN in CHB and therefore identifying the predictors of response is of great clinical importance. No reliable baseline predictors of response to PEG-IFN have been identified to date, but certain studies have identified satisfactory predictors of post-PEG-IFN response using on-treatment serological markers, mostly HBsAg levels. In particular, in HBeAg-negative CHB patients mostly with genotype D a lack of decline in HBsAg levels and a lack of decrease in HBV DNA levels 2 log10 copies/ml at week-12 has a nearly 100% negative predictive value for SVR off-treatment and is now recommended as a stopping rule for early discontinuation of ineffective PEG-IFN. Prolonging PEG-IFN therapy to 96weeks seems to provide higher SVR rates but the application and efficacy of this approach requires further study. The combination of PEG-IFN with NAs, mostly lamivudine, has not resulted in any therapeutic benefit so far, but newer combined approaches with PEG-IFN and NA(s) are currently under study

Gastrointestinal and liver side effects of drugs in elderly patients

It is expected that the percentage of people >60 years of age will be 22% worldwide by the year 2050. Multi-morbidity and polypharmacy are common in individuals during old age, while adverse drug reactions are at least twice as common in the elderly compared to younger adults. Publications related to drug side effects are rather rare in this age group since most clinical trials exclude patients >75-80 years of age. Gastrointestinal adverse drug reactions studied in the elderly include non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulant-induced gastrointestinal tract mucosal injuries. Malabsorption, diarrhoea and constipation are common side effects of laxatives, antibiotics, anticholinergics and calcium channel blockers. Drug (amoxycilin/clavulanic acid, isoniazide, nitrofurantoin, diclifenac and methotrexate)-induced hepatotoxicity in the elderly is four times more common than in younger adults and may simulate almost all known liver disorders. Further clinical studies are needed to investigate gastrointestinal and hepatic side effects of drugs in elderly patients. (C) 2010 Elsevier Ltd. All rights reserved

Recent Advances in Cirrhotic Cardiomyopathy

Cirrhotic cardiomyopathy, a cardiac dysfunction presented in patients with cirrhosis, represents a recently recognized clinical entity. It is characterized by altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, in particular prolongation of the QT interval. Several mechanisms seem to be involved in the pathogenesis of cirrhotic cardiomyopathy, including impaired function of beta-receptors, altered transmembrane currents, and overproduction of cardiodepressant factors, like nitric oxide, tumor necrosis factor alpha, and endogenous cannabinoids. Diastolic dysfunction is the first manifestation of cirrhotic cardiomyopathy and reflects the increased stiffness of the cardiac mass, which leads to delayed left ventricular filling. On the other hand, systolic incompetence is presented later, is usually unmasked during pharmacological or physical stress, and predisposes to the development of hepatorenal syndrome. The prolongation of QT is found in about 50 % of cirrhotic patients, but rarely leads to fatal arrhythmias. Cirrhotics with blunted cardiac function seem to have poorer survival rates compared to those without, and the risk is particularly increased during the insertion of transjugular intrahepatic portosystemic shunt or liver transplantation. Till now, there is no specific treatment for themanagement of cirrhotic cardiomyopathy. New agents, targeting to its pathogenetical mechanisms, may play some role as future therapeutic options

Variceal bleeding in primary biliary cirrhosis patients: a subgroup with improved prognosis and a model to predict survival after first bleeding.

BACKGROUND: Varices are a late complication in primary biliary cirrhosis (PBC). However, patients without clinical jaundice do bleed from varices; whether their prognosis differs is unknown. AIM: Evaluate PBC patients, particularly those with bilirubin 34 micromol/l (P=0.001, log rank test). Hazard ratios (95% confidence intervals) for independent predictors of mortality after bleeding were: age 1.02 (1-1.05), log10 bilirubin 4.64 (2.56-8.41), ascites 2.13 (1.29-3.51) and hepatic encephalopathy 2.72 (1.56-4.74). CONCLUSION: Variceal bleeding complicates histologically advanced PBC. A distinct subgroup with near normal bilirubin and lower alkaline phosphatase first presents with variceal bleeding in 50% of cases and has a better prognosis than jaundiced PBC variceal bleeders

Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit

Background. HCV infection and transfusional iron overload in Thalassemic patients may result in liver disease. HCV treatment in Thalassemia has raised safety concerns.Aim. Estimate effectiveness and tolerability of interferon-based therapy in HCV-infected Thalassemic patients.Material and methods. Over a 12-year period, consecutive patients with β Thalassemia major (TM) and chronic hepatitis C received treatment. Liver biopsy, HCV-RNA and genotyping were performed beforehand. Sustained virological response (SVR) was defined as negative HCV-RNA 6 months post-treatment. Forty eight patients (26 M-22 F, mean age 39.8) were enrolled. Twenty nine patients were treated with conventional interferon alpha (IFNa) for 48 weeks (group A). Nineteen patients (10 naïve-9 previously IFNa experienced) received pegylated interferon (PEG-IFN) (group B).Results. HCV-1 was found in 44%, HCV-2 in 14%, HCV-3 in 23% and HCV-4 in 19%. Group A: ten patients (38.5%) achieved SVR, 2 (7.5%) relapsed and 17 (54%) were non responders. Group B: five (28%) achieved SVR, 8 (44%) relapsed and 6 (28%) never responded. High HCV-RNA levels, genotype 1 and advanced liver fibrosis were independently associated with no response. Four patients (3 treated with IFNα, 1 with PEG-IFN) had to discontinue treatment due to complications.Conclusions. The response rate of IFN monotherapy in multi-transfused, HCV-infected Thalassemic patients is not inferior to that in non-multi-transfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting

Frequency and Severity of Cirrhotic Cardiomyopathy and Its Possible Relationship with Bacterial Endotoxemia

Background The cardiac dysfunction presented in cirrhotic patients is already known as cirrhotic cardiomyopathy. The pathogenesis of this entity is not fully understood. Aims The aim of this study was to evaluate the frequency and characteristics of cirrhotic cardiomyopathy and to investigate the possible role of bacterial endotoxemia on its aggravation. Methods Forty-five cirrhotics were studied by a tissue Doppler imaging echocardiography at rest and after stress. The diagnosis of left ventricular diastolic dysfunction was based on the latest guidelines of the American Society of Echocardiography, whereas its severity was defined by the E/e’av ratio. Endotoxemia was estimated by measuring the serum levels of lipopolysaccharide-binding protein (LBP) and cytokines. Results None of the patients had systolic dysfunction, but 17/45 (37.8 %) had a diastolic one. Patients with grade II diastolic dysfunction had significantly longer QTc (p = 0.049), larger left atrium volume (p = 0.013), higher Brain Natriuretic Peptide levels (p = 0.007) and higher LBP levels (p = 0.02), compared to those with normal cardiac function, without differences in the systemic hemodynamics and the cytokines’ levels. Moreover, the severity of diastolic dysfunction as reflected by the E/e’av. was significantly correlated with the LBP levels (p = 0.002). On the multivariate analysis, the LBP was independently associated with the presence of diastolic dysfunction. Conclusions Cirrhosis is commonly complicated by cardiac dysfunction. Patients with severe cirrhotic cardiomyopathy have higher LBP levels, which are significantly correlated with the degree of diastolic dysfunction. Our findings support a potential role of bacterial endotoxemia on the aggravation of cardiomyopathy in cirrhotic patients