Nina Kimer

Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy

Rifaximin is recommended for prevention of hepatic encephalopathy (HE). The effects of rifaximin on overt and minimal HE are debated.

The continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathy

Existing tests for minimal/covert hepatic encephalopathy (m/cHE) are time- and expertise consuming and primarily useable for research purposes. An easy-to-use, fast and reliable diagnostic and grading tool is needed. We here report on the background, experience, and ongoing research regarding the continuous reaction times (CRT) method. The method has been in clinical use for decades in Denmark for the stated purpose. The method is a 10-minutes, computerised registration of a series of motor reaction times to an auditory stimulus, with results reported as the CRTindex (50 percentile/(90–10) percentile) as a parameter of reaction time variability. The index is a measure of alertness stability and is used to assess attention and cognition deficits. The CRTindex identifies half of patients in a Danish cohort with chronic liver disease, as having m/cHE, a normal value safely precludes HE, it has a broad outcome span reflecting the degree of brain impairment, it shows no learning effect, and it is independent on age and gender. The CRTindex is, therefore, a candidate tool for routine screening, detecting, grading, and monitoring m/cHE. Still, however, further methodological and clinical validation trials are required and are currently being conducted.

Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C: systematic review and meta-analysis of randomised controlled trials

Objectives To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C. Design Systematic review and meta-analyses of randomised controlled trials. Prospective cohort studies were included in sensitivity analyses. Data Sources Eligible trials were identified through electronic and manual searches. Study Selection Eight randomised controlled trials comparing antiviral therapy (interferon or pegylated interferon alone or with ribavirin) versus placebo or no intervention were included. Data extraction and synthesis Two independent reviewers assessed the methodological quality of studies and extracted data. Random effects meta-analyses were performed. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate sources of intertrial heterogeneity, the risk of bias and the robustness of the results after adjusting for multiple testing. Results Random effects meta-analysis showed that antiviral therapy reduced the risk of HCC (81/1156 vs 129/1174; risk ratio 0.53, 95% CI 0.34 to 0.81). In subgroup analyses, antiviral therapy was more beneficial (test for subgroup differences p=0.03) in virological responders (0.15, 0.05 to 0.45) than in non-responders (0.57; 0.37 to 0.85). No evidence of bias was seen in regression analyses. Sequential analysis confirmed the overall result. The sensitivity analyses showed that the cohort studies found that antiviral therapy reduced the risk of HCC. There was clear statistical evidence of bias in the cohort studies (p=0.02). Conclusions Antiviral therapy may reduce the risk of HCC in hepatitis C-related fibrosis and cirrhosis. The effect may be seen irrespective of the virological response, but is more pronounced among virological responders compared with non-responders.

Beta-blockers in cirrhosis and refractory ascites: a retrospective cohort study and review of the literature

Abstract Objective. It is currently discussed if beta-blockers exert harmful effects and increase mortality in patients with cirrhosis and refractory ascites. In this study, we provide an overview of the available literature in this field in combination with a retrospective analysis of 61 patients with cirrhosis and refractory ascites in a tertiary unit. Material and methods. We performed a systematic search of literature in May 2014. In addition, 61 patients with cirrhosis and ascites were identified and followed from development of refractory ascites until death or end of follow-up. Results. Fourteen trials (9 trials on propranolol, 1 case-control study and 4 retrospective analyses) were identified. One trial suggested an increased mortality in patients treated with beta-blockers and refractory ascites. The results of the remaining trials were inconclusive. No increase in mortality among beta-blocker-treated patients was found in the present retrospective analysis. Conclusions. Treatment with beta-blockers may increase mortality in patients with cirrhosis and refractory ascites. However, the current evidence is sparse and high-quality studies are warranted to clarify the matter.

Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy.

Hepatic encephalopathy is a complex disease entity ranging from mild cognitive dysfunction to deep coma. Traditionally, treatment has focused on a reduction of ammonia through a reduced production, absorption, or clearance. Rifaximin is a nonabsorbable antibiotic, which reduces the production of ammonia by gut bacteria and, to some extent, other toxic derivatives from the gut. Clinical trials show that these effects improve episodes of hepatic encephalopathy. A large randomized trial found that rifaximin prevents recurrent episodes of hepatic encephalopathy. Most patients were treated concurrently with lactulose. Trials have varied greatly in design, outcomes, and duration of treatment regimes. Although a number of retrospective studies have indicated that long-term treatment with rifaximin is safe and possibly beneficial, high quality trials are needed to further clarify efficacy and safety of long-term treatment with rifaximin and evaluate effects of combination therapy with lactulose and branched-chain amino acids for patients with liver cirrhosis and hepatic encephalopathy.

New vasoactive peptides in cirrhosis: organ extraction and relation to the vasodilatory state.

Patients with cirrhosis have substantial circulatory imbalance between vasoconstrictive and vasodilating forces. The study of circulatory vasoactive peptides may provide important pathophysiological information. This study aimed to assess concentrations, organ extraction and relations to haemodynamic changes in the pro‐peptides copeptin, proadrenomedullin and pro‐atrial natriuretic peptide (proANP) in patients with cirrhosis.

Cameron lesions: an often overlooked cause of iron deficiency anaemia in patients with large hiatal hernias

Cameron lesions are linear gastric ulcers or erosions on the mucosal folds at the diaphragmatic impression in patients with a large hiatal hernia. The lesions are associated with occult bleeding and development of chronic iron deficiency anaemia, but are often overlooked during routine endoscopy. We present two patients with known hiatal hernias in who repeated endoscopic examinations had not been able to identify a source of bleeding. In both cases, typical Cameron lesions were found either by repeat gastroscopy or by capsule endoscopy. Treatment with high-dose proton pump inhibitor and iron supplement was initiated.

Advances in the treatment of portal hypertension in cirrhosis

ABSTRACT Non-selective beta-blockers and handling of esophageal varices has been key elements in the treatment of portal hypertension in recent decades. Liver vein catheterization has been essential in diagnosis and monitoring of portal hypertension, but ongoing needs for noninvasive tools has led to research in areas of both biomarkers, and transient elastography, which displays promising results in discerning clinically significant portal hypertension. Novel research into the areas of hepatic stellate cell function and the dynamic components of portal hypertension has revealed promising areas of treatment modalities, targeting intestinal decontamination, angiogenesis, inflammation and oxidative stress. Future studies may reveal if these initiatives lead to developments of new drugs for treatment of portal hypertension.

The Royal Free Hospital Cirrhosis Glomerular Filtration Rate: Validation in a Danish Cohort

Although renal impairment is a frequent complication in cirrhosis, accurate determination of renal function in the decompensated patient remains challenging. Assessment of glomerular filtration rate (GFR) can be performed by 51-chromium-ethylene diamine tetraacetic acid (Cr-EDTA), which is considered the gold-standard technique, but is technically challenging and expensive. We read with great interest the article recently published in HEPATOLOGY by Kalafateli et al. The researchers developed and validated a new algorithm (Royal Free Hospital cirrhosis GFR 5 RFH cirrhosis GFR) for estimating GFR in the patient with cirrhosis. The investigators found that this algorithm was more accurate in estimating GFR than current equations. In a randomized, controlled trial, we recently measured GFR with use of Cr-EDTA in 54

Letter: the effects of rifaximin in hepatic encephalopathy - authors' reply

jects. However, liver cirrhosis significantly affects the pharmacokinetics of this drug, with systemic absorption markedly increased in these patients compared to controls. Indeed, plasma concentrations as high as 10 ng/mL have been observed in cirrhotics, with levels being even higher in those patients with Child–Pugh C disease, compared to only 1 ng/mL in controls. This could be a cause for concern, particularly when a daily, long-life therapy is proposed for chronic disorders, such as HE prevention. Therefore, a note for caution should be considered before suggesting long-term therapy with rifaximin for the prevention of HE in cirrhotics, and further studies are warranted to assess its actual safety. Of note, a significant increase in serum potassium and sodium concentrations has been reported during rifaximin therapy. This could be a matter for concern in cirrhotic patients with these electrolyte disturbances also being involved in the development of HE. At the same time, some concerns with both possible infection and bacterial resistance induction during rifaximin therapy should be also considered, particularly when long-term treatment is suggested. Following 6 months of rifaximin therapy, two cases of Clostridium difficile infection were found in the rifaximin group, despite this antibiotic being active against such a bacterium, while no case occurred in the placebo group. Therefore, a note of caution should be considered, particularly when long-term antibiotic therapy is suggested. Rifaximin markedly reduced faecal bacterial counts during oral intake, but the effect was short-lasting since the bacterial population recovered within 1–2 week after the end of treatment. Therefore, a rapid disappearance of resistant bacteria was observed after stopping a short course rifaximin treatment but no data are available for long-term therapy. Of note, anaerobic bacteria, especially the Gram-negative rods, regained sensitivity to rifaximin more slowly than aerobic species. Finally, Candida albicans, which has been implicated in the pathogenesis of antibiotic-associated diarrhoea, was isolated from the faecal samples of 20% of patients given 1200 mg of rifaximin daily. Therefore, it has been suggested that rifaximin therapy could be used as a rescue therapy in addition to disaccharides in those cirrhotics who experienced HE during disaccharides therapy. While waiting for further safety data, caution should be used in adding rifaximin therapy in the very short term, disclosing to the patients both the benefit and potential risks.