Important Note: The following information is provided for your education. It should not be relied upon for personal diagnosis or treatment. If you believe that a particular therapy applies to you or someone you care about, be sure to consult a doctor before trying it.
   

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Previous Cirrhosis Research: 2002-2006   
The Cirrhosis File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Cirrhosis, click HERE.
 

Latest Research on Cirrhosis
     
Arch Intern Med. 2008 Jun 9;168(11):1188-99.
Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial.
Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, McKay A, Ait-Daoud N, Addolorato G, Anton RF, Ciraulo DA, Kranzler HR, Mann K, O'Malley SS, Swift RM; Topiramate for Alcoholism Advisory Board; Topiramate for Alcoholism Study Group.
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22908-0623, USA. bankolejohnson@virginia.edu

BACKGROUND: Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system. We sought to determine whether topiramate's antidrinking effects are bolstered by improvements in physical and psychosocial well-being. METHODS: In a 17-site, 14-week, double-blind, randomized controlled trial, we compared the effects of topiramate (up to 300 mg/d) vs placebo on physical health, obsessional thoughts and compulsions about using alcohol, and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy. RESULTS: Topiramate was more efficacious than placebo in reducing body mass index (calculated as weight in kilograms divided by height in meters squared) (mean difference, 1.08; 95% confidence interval [CI], 0.81-1.34; P < .001), all liver enzyme levels (P < .01 for all comparisons), plasma cholesterol level (mean difference, 13.30 mg/dL; 95% CI, 5.09-21.44 mg/dL; P = .002), and systolic (mean difference, 9.70 mm Hg; 95% CI, 6.81-12.60 mm Hg; P < .001) and diastolic (mean difference, 6.74 mm Hg; 95% CI, 4.57-8.90 mm Hg; P < .001) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease. Topiramate compared with placebo significantly (P < .05 for all comparisons) decreased obsessional thoughts and compulsions about using alcohol, increased subjects' psychosocial well-being, and improved some aspects of quality of life, thereby diminishing the risk of relapse and longer-term negative outcomes. Paresthesia, taste perversion, anorexia, and difficulty with concentration were reported more frequently for topiramate than for placebo. CONCLUSION: Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects.

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Ann Intern Med. 2008 Jul 15;149(2):109-22.
Meta-analysis: Combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis.
Gonzalez R, Zamora J, Gomez-Camarero J, Molinero LM, Bañares R, Albillos A.
Hospital Universitario Ramón y Cajal, Madrid, Spain.

BACKGROUND: Combining endoscopic therapy and beta-blockers may improve outcomes in patients with cirrhosis and bleeding esophageal varices. PURPOSE: To assess whether a combination of endoscopic and drug therapy prevents overall and variceal rebleeding and improves survival better than either therapy alone. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and conference proceedings through 30 December 2007. STUDY SELECTION: Randomized trials comparing endoscopic plus beta-blocker therapy with either therapy alone, without language restrictions. DATA EXTRACTION: Two reviewers independently extracted data on interventions and the primary study outcomes of overall rebleeding and mortality. Metaregression and stratified analysis were used to explore heterogeneity. DATA SYNTHESIS: 23 trials (1860 patients) met inclusion criteria. Combination therapy reduced overall rebleeding more than endoscopic therapy alone (pooled relative risk, 0.68 [95% CI, 0.52 to 0.89]; I(2) = 61%) or beta-blocker therapy alone (pooled relative risk, 0.71 [CI, 0.59 to 0.86]; I(2) = 0%). Combination therapy also reduced variceal rebleeding and variceal recurrence. Reduction in mortality from combination therapy did not statistically significantly differ from that from endoscopic (Peto odds ratio, 0.78 [CI, 0.58 to 1.07) or drug therapy (Peto odds ratio, 0.70 [CI, 0.46 to 1.06]). Effects were independent of the endoscopic procedure (injection sclerotherapy or banding). No trial-level variable associated with the effect was identified through metaregression or stratified analysis. LIMITATION: Statistically significant heterogeneity in trial quality and evidence for selective reporting and publication bias were found. CONCLUSION: A combination of endoscopic and drug therapy reduces overall and variceal rebleeding in cirrhosis more than either therapy alone.

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Clin Infect Dis. 2008 Jul 1;47(1):66-72.
Clinical significance of spontaneous Aeromonas bacterial peritonitis in cirrhotic patients: a matched case-control study.
Choi JP, Lee SO, Kwon HH, Kwak YG, Choi SH, Lim SK, Kim MN, Jeong JY, Choi SH, Woo JH, Kim YS.
Division of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

BACKGROUND: Although Aeromonas species are known to cause bacteremia in patients with cirrhosis, less is known about spontaneous bacterial peritonitis (SBP) caused by Aeromonas species in these patients. METHODS: We performed a retrospective, matched case-control study (1:2 ratio) consisting of patients presenting with SBP due to Aeromonas species from January 1997 through December 2006. Control subjects were patients with SBP caused by other organisms and were matched to the patients by age (+/- 1 year) and sex. RESULTS: We identified 43 patients with SBP due to Aeromonas species, 40 (93%) of whom had Aeromonas hydrophila infection and 3 (7%) of whom had Aeromonas sorbia infection. There were 81 control subjects, of whom 38 (47%) were infected with Escherichia coli, 25 (31%) were infected with Klebsiella species, 12 (15%) were infected with Streptococcus species, and 6 (7%) were infected with other bacteria. Baseline Child-Pugh class and model for end-stage liver disease score did not differ between groups. A significant increase in the incidence of infection during the warm season (July-September) was observed in the group with SBP due to Aeromonas species, compared with the group with SBP due to other bacteria (63% vs. 25%; P < .001). Diarrheal episodes were significantly more frequent in the group with SBP due to Aeromonas species (26% vs. 6%; P = .002). There were no statistically significant differences between groups with regard to appropriateness of initial antibiotic therapy,3-day mortality, and 30-day cumulative survival. In the group with Aeromonas infection, the in-hospital mortality rate was 23%; septic shock was the only independent prognostic factor of in-hospital mortality (odds ratio, 34.5;95% confidence interval, 1.9-640.6; P = .02). CONCLUSION: Aeromonas species should be considered to be a causative organism of SBP in cirrhotic patients presenting with diarrheal episodes during the warm season. Compared with SBP caused by other organisms, SBP due to Aeromonas species was not associated with more-advanced cirrhosis.

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Am J Gastroenterol. 2008 Jun;103(6):1399-405.
Midodrine versus albumin in the prevention of paracentesis-induced circulatory dysfunction in cirrhotics: a randomized pilot study.
Singh V, Dheerendra PC, Singh B, Nain CK, Chawla D, Sharma N, Bhalla A, Mahi SK.
Department of Hepatology, Postgraduate Insitiute of Medical Education and Research, Chandigarh, India.

OBJECTIVES: Intravenous albumin has been used to prevent paracentesis-induced circulatory dysfunction (PICD) in cirrhotics; however, its use is costly and controversial. Splanchnic arterial vasodilatation is primarily responsible for PICD. There are no reports of use of midodrine in the prevention of PICD. In this pilot study, we evaluated midodrine and albumin in the prevention of PICD. METHODS: Forty patients with cirrhosis underwent therapeutic paracentesis with midodrine or albumin in a randomized controlled trial at a tertiary center. Effective arterial blood volume was assessed by plasma renin activity. RESULTS: Plasma renin activity at baseline and at 6 days after paracentesis did not differ in the two groups (43.18 +/- 10.73 to 45.90 +/- 8.59 ng/mL/h, P= 0.273 in the albumin group and 44.44 +/- 8.44 to 41.39 +/- 10.21 ng/mL/h, P= 0.115 in the midodrine group). Two patients had an increase in plasma renin activity of more than 50% from baseline in the albumin group, and none in the midodrine group. A significant increase in 24-h urine volume and urine sodium excretion was noted in the midodrine group. Midodrine therapy was cheaper than albumin therapy. CONCLUSIONS: The study suggests that midodrine may be as effective as albumin in preventing PICD in cirrhotics, but at a fraction of the cost, and can be administered orally. Midodrine also resulted in an increase in 24-h urine volume and sodium excretion.

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Hepatology. 2008 Jun;47(6):1856-62.
Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.
Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL.
Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands.

Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-1.04; P = 0.095). During a median follow-up of 4.0 years (interquartile range, 2.0-6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P = 0.009). CONCLUSION: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC.

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Gastroenterology. 2008 May;134(6):1764-76.
Indications for liver transplantation.
O'Leary JG, Lepe R, Davis GL.
Hepatology, Department of Medicine, Baylor University Medical Center, Dallas, Texas 75246, USA.

Patients should be considered for liver transplantation if they have evidence of fulminant hepatic failure, a life-threatening systemic complication of liver disease, or a liver-based metabolic defect or, more commonly, cirrhosis with complications such as hepatic encephalopathy, ascites, hepatocellular carcinoma, hepatorenal syndrome, or bleeding caused by portal hypertension. While the complications of cirrhosis can often be managed relatively effectively, they indicate a change in the natural history of the disease that should lead to consideration of liver transplantation. Referral to a liver transplant center is followed by a detailed medical evaluation to ensure that transplantation is technically feasible, medically appropriate, and in the best interest of both the patient and society. Patients approved for transplantation are placed on a national transplant list, although donor organs are allocated locally and regionally. Since 2002, priority for transplantation has been determined by the Model of End-Stage Liver Disease (MELD) score, which provides donor organs to listed patients with the highest estimated short-term mortality.

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Gastroenterology. 2008 May;134(5):1352-9. Epub 2008 Feb 14. Comment in: Gastroenterology. 2008 May;134(5):1608-11.
Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
Martín-Llahí M, Pépin MN, Guevara M, Díaz F, Torre A, Monescillo A, Soriano G, Terra C, Fábrega E, Arroyo V, Rodés J, Ginès P; TAHRS Investigators.
Liver Unit, Hospital Clínic, University of Barcelona School of Medicine, Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Centro de Investigacíon Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.

BACKGROUND & AIMS: Hepatorenal syndrome is common in patients with advanced cirrhosis and constitutes a major problem in liver transplantation. There is no effective medical treatment for hepatorenal syndrome. METHODS: Forty-six patients with cirrhosis and hepatorenal syndrome, hospitalized in a tertiary care center, were randomly assigned to receive either terlipressin (1-2 mg/4 hour, intravenously), a vasopressin analogue, and albumin (1 g/kg followed by 20-40 g/day) (n = 23) or albumin alone (n = 23) for a maximum of 15 days. Primary outcomes were improvement of renal function and survival at 3 months. RESULTS: Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with 2 patients (8.7%) treated with albumin alone (P = .017). Independent predictive factors of improvement of renal function were baseline urine volume, serum creatinine and leukocyte count, and treatment with terlipressin and albumin. Survival at 3 months was not significantly different between the 2 groups (terlipressin and albumin: 27% vs albumin 19%, P = .7). Independent predictive factors of 3-month survival were baseline model for end-stage liver disease score and improvement of renal function. Cardiovascular complications occurred in 4 patients treated with albumin alone and in 10 patients treated with terlipressin and albumin, yet permanent terlipressin withdrawal was required in only 3 cases. CONCLUSIONS: As compared with albumin, treatment with terlipressin and albumin is effective in improving renal function in patients with cirrhosis and hepatorenal syndrome. Further studies with large sample sizes should be performed to test whether the improvement of renal function translates into a survival benefit.

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MMW Fortschr Med. 2008 Apr 10;150 Suppl 1:22-6.
[Acute renal failure in patients with liver cirrhosis--what to do? An update]
[Article in German]
Gundling F, Gülberg V, Schepp W, Mann J.
Klinik für Gastroenterologie, Hepatologie und Gastroenterologische Onkologie, Klinikum Bogenhausen, Städtisches Klinikum München GmbH, München. Felix.Gundling@gmx.de

A lot of patients suffering from liver cirrhosis show a decreased renal perfusion and glomerular filtration rate. An impaired renal function is the result of complex e.g. hemodynamic disturbances, resulting of the chronic liver disease. This explains its disposition to renal dysfunction and the higher incidence of acute renal failure in liver cirrhosis. In the case of renal failure hepatorenal syndrome, apart from prerenal, renal and postrenal causes, should be included in the differential diagnosis especially when signs of portal hypertension are apparent regarding its high mortalityand fatal prognosis requiring an immediate therapeutically approach. Special attention must be due to preventive strategies to avoid renal deterioration. This includes simple steps e.g. a careful election of medication but also an adequate therapy of infection-associated complications in patients with liver cirrhosis.

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J Viral Hepat. 2008 Mar;15(3):165-72.
Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome.
Castellares C, Barreiro P, Martín-Carbonero L, Labarga P, Vispo ME, Casado R, Galindo L, García-Gascó P, García-Samaniego J, Soriano V.
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.

Liver disease is frequently seen in HIV+ patients as a result of coinfection with hepatitis B (HBV) or C (HCV) viruses, alcohol abuse and/or exposure to hepatotoxic drugs. The aim of this study was to assess the prevalence of liver cirrhosis, its main causes and clinical presentation in HIV+ patients. Observational, cross-sectional, retrospective study of all HIV+ individuals followed at one reference HIV outpatient clinic in Madrid. Liver fibrosis was measured in all cases using transient elastometry (FibroScan((R))). All 2168 HIV+ patients on regular follow-up (76% males, 46% injecting drug users) were successfully examined by FibroScan((R)) between October 2004 and August 2006. Liver cirrhosis was recognized in 181 (overall prevalence, 8.3%), and the main aetiologies were HCV, 82.3%; HBV, 1.6%; dual HBV/HCV, 2.8%; and triple HBV/HCV/ hepatitis delta virus (HDV) infection, 6.6%. The prevalence of cirrhosis differed among patients with distinct chronic viral hepatitis: HCV, 19.2%; HBV, 6.1%; HBV/HCV, 41.7%; and HBV/HCV/HDV, 66.7%. In 12 patients with cirrhosis (6.7%), no definite aetiology was recognized. Overall, cirrhotics had lower mean CD4 counts than noncirrhotics (408 vs 528 cells/muL respectively; P = 0.02), despite similar proportion of subjects with undetectable viraemia on highly active antiretroviral therapy. Clinical manifestations of liver cirrhosis were: splenomegaly, 61.5%; oesophageal varices, 59.8%; ascites, 22.6%; encephalopathy, 12.1%; and variceal bleeding, 6.1%. Liver cirrhosis and hepatic decompensation events are relatively frequent in HIV+ individuals. Chronic HCV and alcohol abuse, but not chronic HBV, play a major role. Transient elastometry may allow the identification of a significant number of HIV+ individuals with asymptomatic liver cirrhosis.

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Gut. 2008 Feb;57(2):268-78.
Cardiovascular complications of cirrhosis.
Møller S, Henriksen JH.
Department of Clinical Physiology, 239, Hvidovre Hospital, DK-2650 Copenhagen, Denmark. soeren.moeller@hvh.regionh.dk

Cardiovascular complications of cirrhosis include cardiac dysfunction and abnormalities in the central, splanchnic and peripheral circulation, and haemodynamic changes caused by humoral and nervous dysregulation. Cirrhotic cardiomyopathy implies systolic and diastolic dysfunction and electrophysiological abnormalities, an entity that is different from alcoholic heart muscle disease. Being clinically latent, cirrhotic cardiomyopathy can be unmasked by physical or pharmacological strain. Consequently, caution should be exercised in the case of stressful procedures, such as large volume paracentesis without adequate plasma volume expansion, transjugular intrahepatic portosystemic shunt (TIPS) insertion, peritoneovenous shunting and surgery. Cardiac failure is an important cause of mortality after liver transplantation, but improved liver function has also been shown to reverse the cardiac abnormalities. No specific treatment can be recommended, and cardiac failure should be treated as in non-cirrhotic patients with sodium restriction, diuretics, and oxygen therapy when necessary. Special care should be taken with the use of ACE inhibitors and angiotensin antagonists in these patients. The clinical significance of cardiovascular complications and cirrhotic cardiomyopathy is an important topic for future research, and the initiation of new randomised studies of potential treatments for these complications is needed.

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Orphanet J Rare Dis. 2008 Jan 23;3(1):1 [Epub ahead of print]
Primary biliary cirrhosis.
Kumagi T, Heathcote JE.

ABSTRACT: Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth to seventh decades of life at time of diagnosis, and 90% are women. Annual incidence is estimated between 0.7 and 49 cases per million population and prevalence between 6.7 and 940 cases per million population (depending on age and sex). The majority of patients are asymptomatic at diagnosis, however, some patients present with symptoms of fatigue and/or pruritus. Patients may even present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. PBC is associated with other autoimmune diseases such as Sjogren's syndrome, scleroderma, Raynaud's phenomenon and CREST syndrome and is regarded as an organ specific autoimmune disease. Genetic susceptibility as a predisposing factor for PBC has been suggested. Environmental factors may have a potential causative role (infection, chemicals, smoking). Diagnosis is based on a combination of clinical features, abnormal liver biochemical pattern in a cholestatic picture persisting for more than six months and presence of detectable antimitochondrial antibodies (AMA) in serum. All AMA negative patients with cholestatic liver disease should be carefully evaluated with cholangiography and liver biopsy. Ursodeoxycholic acid (UDCA) is the only currently known medication that can slow the disease progression. Patients, particularly those who start UDCA treatment at early-stage disease and who respond in terms of improvement of the liver biochemistry, have a good prognosis. Liver transplantation is usually an option for patients with liver failure and the outcome is 70% survival at 7 years. Recently, animal models have been discovered that may provide a new insight into the pathogenesis of this disease and facilitate appreciati
on for novel treatment in PBC.

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Acta Derm Venereol. 2008;88(1):34-7.
Itch in primary biliary cirrhosis: a patients' perspective.
Rishe E, Azarm A, Bergasa NV.
Department of Medicine, Beth Israel Medical Center.

The perception of itch in primary biliary cirrhosis (PBC) is not characterized. Patients with primary biliary cirrhosis who were members of the PBCers Organization were invited to participate in an on-line survey addressing certain characteristics of their itch. Patients used their own words in the questions that asked for descriptions. A total of 238 subjects responded to the survey; of these, 231 were women, and 165 (69%) reported itch. One hundred and twenty-four patients from the 165 (75%) reported that itch preceded the diagnosis of primary biliary cirrhosis. A total of 58 from 164 (35%) respondents described their itch as "bugs crawling". Fifty-seven of 88 (64.7%) subjects reported that something cool relieved their itch, and 69 of 112 (61.6%) reported that heat worsened it. One hundred and seven of 164 (65.2%) respondents reported that the itch was worse at night. The most commonly prescribed medications were antihistamines and cholestyramine, and the most common type of medication reported as being associated with relief was antihistamine drugs. There was no systematic approach to the evaluation and treatment of itch in patients with primary biliary cirrhosis. Education on the subject of itch in primary biliary cirrhosis is warranted.

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Aliment Pharmacol Ther. 2007 Dec;26 Suppl 2:183-93.
Review article: Management of ascites and associated complications in patients with cirrhosis.
Kuiper JJ, de Man RA, van Buuren HR.
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. j.j.kuiper@erasmusmc.nl

BACKGROUND: Ascites is the most common complication of cirrhosis, associated with an expected survival below 50% after 5 years. Prognosis is particularly poor for patients with refractory ascites and for those developing complications, including spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS). AIM: To provide an evidence-based overview of the pathophysiology, diagnosis and clinical management of ascites secondary to liver cirrhosis. METHODS: Review based on relevant medical literature. RESULTS: Portal hypertension, splanchnic vasodilatation and renal sodium retention are fundamental in the pathophysiology of ascites formation. The SAAG (serum-ascites albumin gradient) allows reliable assessment of the cause of ascites. The majority of cirrhotic patients with ascites can be managed with dietary sodium restriction in combination with diuretic agents. Large volume paracentesis with albumin suppletion and TIPS are therapeutic options in patients with refractory ascites. Prophylactic antibiotics for SBP should be given in certain patient populations. CONCLUSIONS: Recent advances in the diagnosis and treatment of ascites and associated complications have improved the medical management and poor prognosis of patients with these manifestations of advanced liver disease. Early diagnosis, adequate treatment and focus on prevention of complications remain essential as well as timely referral for liver transplantation.

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J Clin Gastroenterol. 2007 Nov-Dec;41(10 Suppl 3):S300-4.
Preventing the development of varices in cirrhosis.
Garcia-Tsao G.
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA. guadalupe.garcia-tsao@yale.edu

Gastroesophageal varices are a direct consequence of portal hypertension. Nonselective beta-adrenergic blockers decrease portal pressure and are effective in preventing variceal hemorrhage. However, a large multicenter placebo-controlled trial demonstrates that nonselective beta-adrenergic blockers are not effective in preventing the development of varices and are associated with a significant rate of adverse events. This therapy is, therefore, not recommended in compensated cirrhotic patients without varices at large. In this very compensated group of patients with cirrhosis (stage 1, ie, without varices and without ascites or encephalopathy) the predictive value (both for the development of varices and for the development of clinical decompensation) of a baseline hepatic venous pressure gradient greater than 10 mm Hg is confirmed, supporting this threshold level as one that defines a clinically significant portal hypertension. Importantly, reductions in hepatic venous pressure gradient >10% are associated with a significant reduction in the development of varices, a therapeutic goal that could be achieved through the use of beta-blockers or other drugs being developed for the treatment of portal hypertension.

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J Clin Gastroenterol. 2007 Nov-Dec;41(10 Suppl 3):S318-22.
Prevention of recurrent esophageal variceal hemorrhage: review and current recommendations.
Kravetz D.
San Diego Veterans Affairs Medical Center, University of California at San Diego, San Diego, CA 92161, USA. dkravetz@ucsd.edu

Variceal rebleeding is a very frequent and severe complication in cirrhotic patients; therefore, its prevention should be mandatory. Lately several studies demonstrated that the rate of rebleeding was decreased by 40% and overall survival is improved by 20% with beta-blockers. However, this treatment presents some problems, such as the number of nonresponders and contraindications for its use. Recent trials found that the combination of beta-blockers with mononitrate of isosorbide to be superior to beta-blockade alone. Furthermore, endoscopic band ligation also shown to decrease the frequency of rebleeding, complications, and death compared with sclerotherapy and should be the preferred endoscopic treatment. In addition, the comparison between combined pharmacologic treatment with endoscopic treatment present similar rebleeding and mortality rates. More recently, the addition of nadolol to endoscopic band ligation increased the efficacy of endoscopy alone in the prevention of variceal rebleeding. These studies suggest that banding plus drugs could be the treatment of choice for the prophylaxis of rebleeding. When these treatments fail, the recommendation is to use transjugular intrahepatic portosystemic shunt (TIPS) or surgical shunts. Both treatments are effective in preventing rebleeding; however, they are associated with a greater risk of encephalopathy. The comparison of portacaval shunts with TIPS demonstrated that TIPS patients presented higher rebleeding, treatment failure, and transplantation. Another randomized controlled trial comparing distal splenorenal shunt with TIPS shows that variceal rebleeding was similar in both groups without differences in encephalopathy and mortality. The only difference observed was the higher rate of reintervention observed in the TIPS group to maintain his patency.

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Clin Lab. 2007;53(9-12):583-9.
Coagulation abnormalities in cirrhotic patients with portal vein thrombosis.
Amitrano L, Guardascione MA, Ames PR.
Gastroenterology Unit, A. Cardarelli Hospital, Naples, Italy. luamitra@tin.it

The liver has a central role in the clotting process and an altered haemostasis is common in advanced liver disease. Nevertheless, recent studies have questioned the historical belief that impaired haemostasis in liver disease means an increased risk of bleeding. Coagulation and anticoagulation mechanisms are still balanced but are set at a lower level. Platelet function and number also play a role. The prevalence of thrombotic events is similar in both cirrhotic patients and in the general population but the cirrhotic patients have an increased risk for thrombosis in the splanchnic area. Portal blood flow stasis is the main underlying change favouring thrombosis even if other local, systemic, congenital and acquired factors are present. The onset of portal vein thrombosis strongly affects the prognosis of liver cirrhosis, worsening both portal hypertension and liver function. Some of the known risk factors for venous thrombosis--G20210A mutation of prothrombin, factor V Leiden, endoscopic treatment of esophageal varices and abdominal surgery--have a specific role in the development of splanchnic thrombosis in cirrhotic patients. The knowledge of the pathophysiological aspects of portal vein thrombosis and clotting alterations in liver disease will allow determination of the indication, duration and timing of anticoagulation therapy.

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Transplantation. 2007 Nov 27;84(10):1361-3.
Liver transplantation in children with progressive familial intrahepatic cholestasis.
Englert C, Grabhorn E, Richter A, Rogiers X, Burdelski M, Ganschow R.
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Germany.

Progressive familial intrahepatic cholestasis (PFIC) is caused by mutations of the bile salt export pump or the multidrug resistance P-glycoprotein, resulting in chronic hepatic failure. Partial external diversion of bile or ileal bypass is effective in some cases and, in others, liver transplantation (OLT) is necessary. Forty-two children were included in this study. Twenty-six children suffered from PFIC type 2 and 16 from PFIC type 3. Symptoms included pruritus, cholestasis, liver cirrhosis, and growth retardation. Seventeen patients received external biliary diversion. Ten had to undergo OLT in the following course. As of this report, three of the remaining patients were on the wait list for OLT. Twenty-three children received a liver graft primarily with excellent outcome. Our data show that OLT is the option of choice in symptomatic PFIC and whenever liver cirrhosis is present. We suggest a very restrictive recommendation of external biliary diversion. However, gene therapy may be a future option for children with PFIC.

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World J Gastroenterol. 2007 Nov 14;13(42):5648-53.
Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin.
Braks RE, Ganne-Carrie N, Fontaine H, Paries J, Grando-Lemaire V, Beaugrand M, Pol S, Trinchet JC.
Department of Hepatology, Hopital Jean Verdier, Bondy 93140, France.

AIM: To assess the long-term clinical benefit of sustained virological response (SVR) in patients with hepatitis C virus (HCV) cirrhosis treated by antiviral therapy using mostly ribavirin plus interferon either standard or pegylated. METHODS: One hundred and thirteen patients with uncomplicated HCV biopsy-proven cirrhosis, treated by at least one course of antiviral treatment > or = 3 mo and followed > or = 30 mo were included. The occurrence of linical events [hepatocellular carcinoma (HCC), decompensation and death] was compared in SVR and non SVR patients. RESULTS: Seventy eight patients received bitherapy and 63 had repeat treatments. SVR was achieved in 37 patients (33%). During a mean follow-up of 7.7 years, clinical events occurred more frequently in non SVR than in SVR patients, with a significant difference for HCC (24/76 vs 1/37, P = 0.01). No SVR patient died while 20/76 non-SVR did (P = 0.002), mainly in relation to HCC (45%). CONCLUSION: In patients with HCV-related cirrhosis, SVR is associated with a significant decrease in the incidence of HCC and mortality during a follow-up period of 7.7 years. This result is a strong argument to perform and repeat antiviral treatments in patients with compensated cirrhosis.

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Eur J Gastroenterol Hepatol. 2007 Oct;19(10):846-52.
Prognostic role of the initial portal pressure gradient reduction after TIPS in patients with cirrhosis.
Biecker E, Roth F, Heller J, Schild HH, Sauerbruch T, Schepke M.
Department of Internal Medicine I, University Hospital of Bonn, University of Bonn, Sigmund-Freud-Str. 25, Bonn, Germany. erwin.biecker@helios-kliniken.de

BACKGROUND: The aim of this study was to determine the prognostic relevance of the portal pressure gradient (PPG) before and after transjugular intrahepatic portosystemic stent shunt (TIPS) insertion in patients with liver cirrhosis and recurrent oesophageal variceal bleeding. METHODS: 118 cirrhotic patients (Child A/B/C, 41/56/21; Child score, 7.7+/-2.0; baseline PPG, 21.8+/-4.7 mmHg) underwent TIPS for the prevention of variceal rebleeding. A multivariate logistic regression analysis was applied to identify the independent determinants of rebleeding and survival. The estimated rebleeding rate and the estimated survival were compared by log-rank testing. RESULTS: TIPS insertion reduced the PPG by 53.2+/-17.7%. During follow-up 21 patients suffered significant rebleeding (17.8%); bleeding-related mortality was 3.4% (four patients). The median survival [95% confidence intervals (CI)] was 48.2 (39.8; 60.8) months. The multivariate Cox model identified creatinine as the only independent predictor of survival, and the initial decrease of the PPG after TIPS as the only independent predictor of rebleeding. PPG before TIPS (21.8+/-4.7 mmHg) and the gradient at the time of rebleeding (22.0+/-2.9 mmHg) did not differ significantly. Patients with an initial decrease of the PPG after TIPS <30% were at the highest risk for rebleeding. Patients with an initial decrease of the PPG >60% rarely suffered from rebleeding. CONCLUSIONS: The initial decrease in the PPG after TIPS is a predictor for the risk of rebleeding but not for survival after TIPS. For that reason, in patients undergoing TIPS placement for the prevention of recurrent bleeding from oesophageal varices, an initial reduction of the PPG of 30-50% should be attempted.

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Scand J Gastroenterol. 2007 Oct;42(10):1238-44.
Renal function and cognitive impairment in patients with liver cirrhosis.
Kalaitzakis E, Björnsson E.
Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. evangelos.kalaizakis@vgregion.se

OBJECTIVE: Cognitive impairment is a common problem in patients with liver cirrhosis. Its pathogenesis is multifactorial and ammonia is considered to play a central role. Renal function has been shown to be important for ammonia metabolism in cirrhosis. Although renal dysfunction is common in cirrhotic patients, its effect on cognitive function is largely unexplored. MATERIAL AND METHODS: A total of 128 consecutive cirrhotic patients were prospectively evaluated for the presence of cognitive dysfunction according to the West-Haven criteria and by means of two psychometric tests. Serum creatinine, sodium and potassium as well as plasma ammonia concentrations were assessed. Glomerular filtration rate was also measured by (51)Cr- EDTA clearance in a subgroup of patients. RESULTS: Forty-one patients (32%) were found to have cognitive dysfunction (clinical evaluation and/or psychometric tests). Sixteen patients (13%) found with serum creatinine levels above reference values had cognitive dysfunction more frequently than patients with creatinine within the normal range (69% versus 31%; p = 0.001), but did not differ in aetiology or severity of cirrhosis (p >0.1). Patients with loop diuretics versus without did not differ in creatinine values (p >0.1). Multivariate analysis showed that cognitive dysfunction was related to hospital admission at inclusion in the study, international normalized ratio and serum creatinine (p <0.05 for all), but not to potassium or sodium levels. Plasma ammonia concentration was related to serum creatinine (r = 0.26, p = 0.004) and the glomerular filtration rate (r = -0.44, p = 0.023). CONCLUSIONS: Renal dysfunction seems to be related to cognitive impairment in patients with liver cirrhosis and might be implicated in the pathogenesis of hepatic encephalopathy.

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Dig Liver Dis. 2007 Sep;39 Suppl 1:S96-S101.
Antiviral treatment of HCV-related cirrhosis.
Piccinino F, Coppola N.
Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Italy.

The primary aim of antiviral therapy in HCV liver cirrhosis is to stop viral replication and, consequently, to prevent the clinical progression of fibrosis, liver decompensation and the onset of hepatocellular carcinoma. However, the results of therapy are different according to the different clinical stages of cirrhosis. In patients with bridging fibrosis or histological cirrhosis international trials have demonstrated that the sustained virological response to the highly active combination ofpegylated interferon plus ribavirin was substantially similar to that observed in subjects with chronic hepatitis C without cirrhosis. Few data are available as to the efficacy and tolerability of antiviral treatment in patients with fully developed clinical cirrhosis, with or without decompensation, and all studies to date underscore the difficulties in the management of the more frequent and severe side effects in these patients. In patients with a more severe disease who do not achieve a sustained virological response, an alternative option is to reduce or suppress inflammation and fibrosis progression with long-term suppressive therapy in the hope to prevent clinical deterioration and the onset of hepatocellular carcinoma. Three international trials are currently evaluating the use of antiviral treatment as a maintenance antiviral therapy.

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Nephrol Dial Transplant. 2007 Sep;22 Suppl 8:viii37-viii46.
Prophylaxis and treatment of recurrent viral hepatitis after liver transplantation.
Riediger C, Berberat PO, Sauer P, Gotthardt D, Weiss KH, Mehrabi A, Merle U, Stremmel W, Encke J.
University of Heidelberg, Department of Gastroenterology and Hepatology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Carina_Riediger@med.uni-heidelberg.de

Chronic hepatitis B or C can cause severe liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC). Both viral infections together especially hepatitis c virus infection (HCV) are the mayor indication for liver transplantation in Western Europe and the United States. Recurrence of hepatitis B virus (HBV) or HCV infection after orthotopic liver transplantation (OLT) plays a key role for the outcome after liver transplantation concerning patient and graft survival rates. Allograft dysfunctions, cirrhosis of the allograft and graft failure are major complications after recurrent viral hepatitis. The survival after liver transplantation for HBV-related liver disease changed dramatically during the last two decades with results today comparable with non-HBV-related liver transplantations. Availability of immunoprophylaxis with hepatitis B immunoglobulin (HBIG) as well as nucleoside/nucleotide analogues like lamivudine or adefovir in the pre- and post-transplant setting conferred to significant better results due to an efficient prophylaxis and the possibility of therapy of HBV reinfection of the allograft. New drugs such as entecavir, tenofovir and telbivudine for the treatment of chronic hepatitis B infections may offer even more opportunities in the transplant setting. In contrast, despite recent achievements in the treatment of HCV infection with pegylated interferons and ribavirin, patients with HCV cirrhosis or after liver transplantation are difficult to treat. Sustained virological response (SVR) rates in prophylactic and therapeutic approaches of HCV reinfection after OLT are only low compared to the pre-cirrhotic HCV infection. Moreover, best treatment duration and dosage of recurrent HCV infection with pegylated interferon in combination with ribavirin remains to be defined.

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Rev Med Brux. 2007 Sep;28(4):270-5.
[How to prevent complications of liver cirrhosis?]
[Article in French]
Adler M, Verset C, Moreno G.
Service de Gastro-entérologie et d'Hépato-pancréatologie, Hôpital Erasme, Bruxelles.

Liver cirrhosis is the end-stage of chronic liver disease. Even at the compensated stage complications are multiple, severe and potentially fatal which are related to liver insufficiency, portal hypertension and a pre-cancerous stage. It is now possible to diagnose cirrhosis through non invasive tools like biochemical scores and Fibroscan. It may be reversible provided adequate counselling about excessive alcohol intake and metabolic syndrome and specific treatments such as antivirals, venesection, immunosuppressive therapies are implemented. The role of the general practitioner is to diagnosis and treat cirrhosis early together with the hepatogastroenterologist. He can also, through simple means, prevent complications such as hepatocellular carcinoma, variceal bleeding, overt encephalopathy and renal failure and liver decompensation after surgery.

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Neth J Med. 2007 Sep;65(8):283-8.
Ascites in cirrhosis: a review of management and complications.
Kuiper JJ, van Buuren HR, de Man RA.
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, the Netherlands. j.j.kuiper@erasmusmc.nl

Ascites is the most common manifestation in cirrhotic patients, and is associated with a reduced survival rate. Management of ascites is primarily focused on sodium restriction and diuretic treatment to which most patients respond appropriately. For the small group of patients who do not respond sufficiently, interventions such as large volume paracentesis and transjugular intrahepatic portosystemic shunt placement should be considered. Most important in the management of cirrhotic patients with ascites is prevention of complications. Spontaneous bacterial peritonitis and hepatorenal syndrome are severe complications with a poor prognosis when not detected and treated in an early stage. In all hospitalised patients with ascites, an infection of the ascitic fluid should be ruled out. For those patients at risk of developing spontaneous bacterial peritonitis, in particular patients after a first episode and patients with gastrointestinal bleeding, antibiotic prophylaxis should be given. To prevent the hepatorenal syndrome, substitution with albumin is essential, both in patients who experience an episode of spontaneous bacterial peritonitis and in patients treated with large volume paracentesis. For those patients unresponsive to standard treatment regimens, liver transplantation may be the only suitable treatment option.

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World J Gastroenterol. 2007 Sep 28;13(36):4903-8.
Does protracted antiviral therapy impact on HCV-related liver cirrhosis progression?
Tarantino G, Gentile A, Capone D, Basile V, Tarantino M, Di Minno MN, Cuocolo A, Conca P.
Department of Clinical and Expermtal Medicine, Federico II University Medical School of Naples,Via S. Pansini, 5, Naples 80131, Italy. tarantin@unina.it

AIM: To study the outcomes of patients with compensated hepatitis C virus-related cirrhosis. METHODS: Twenty-four grade A5 and 11 grade A6 of Child-Pugh classification cirrhotic patients with active virus replication, treated for a mean period of 31.3 +/- 5.1 mo with moderate doses of interferon-alpha and ribavirin, were compared to a cohort of 36 patients with similar characteristics, without antiviral treatment. Salivary caffeine concentration, a liver test of microsomal function, was determined at the starting and thrice in course of therapy after a mean period of 11 +/- 1.6 mo, meanwhile the resistive index of splenic artery at ultra sound Doppler, an indirect index of portal hypertension, was only measured at the beginning and the end of study. RESULTS: Eight out of the 24 A5- (33.3%) and 5 out of the 11 A6- (45.45%) treated-cirrhotic patients showed a significant improvement in the total overnight salivary caffeine assessment. A reduction up to 20% of the resistive index of splenic artery was obtained in 3 out of the 8 A5- (37.5%) and in 2 out of the 5 A6- (40%) cirrhotic patients with an improved liver function, which showed a clear tendency to decrease at the end of therapy. The hepatitis C virus clearance was achieved in 3 out of the 24 (12.5%) A5- and 1 out of the 11 (0.091%) A6-patients after a median period of 8.5 mo combined therapy. In the cohort of non-treated cirrhotic patients, not only the considered parameters remained unchanged, but 3 patients (8.3%) had a worsening of the Child-Pugh score (P = 0.001). CONCLUSION: A prolonged antiviral therapy with moderate dosages of interferon-alpha and ribavirin shows a trend to stable liver function or to ameliorate the residual liver function, the entity of portal hypertension and the compensation status at acceptable costs.

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Eur J Surg Oncol. 2007 Aug 2; [Epub ahead of print]
Liver resection for HCC with cirrhosis: Surgical perspectives out of EASL/AASLD guidelines.
Capussotti L, Ferrero A, Viganò L, Polastri R, Tabone M.
Department of Surgery, Ospedale Mauriziano “Umberto I”, Largo Turati 62, 10128 Torino, Italy; Unit of Surgical Oncology, Institute for Cancer Research and Treatment, Candiolo, Italy.

EASL/AASLD guidelines clearly define indications for liver surgery for HCC: patients with single HCC and completely preserved liver function without portal hypertension. These guidelines exclude from operation many patients that could benefit from radical resection and that are daily scheduled for hepatectomy in surgical centers. Patients with large tumors or with portal vein thrombosis cannot be transplanted or treated by interstitial treatments. In selected cases liver resection may obtain good long-term outcomes, significantly better than non-curative therapies. In cases of multinodular HCC, liver transplantation is the treatment of choice within Milan criteria; patients beyond these limits can benefit from liver resection, especially if only two nodules are diagnosed: even if they have a worse prognosis, survival results after liver surgery are better than those reported after TACE or conservative treatments. EASL/AASLD guidelines excluded from operating patients with portal hypertension but data about this topic are not conclusive and further studies are necessary. Selected patients with mild portal hypertension could probably be scheduled for liver resection and, considering the shortage of donors, listing for transplantation could be avoided. In conclusion, guidelines for HCC treatment should consider good results of liver resection for advanced HCC, and indications for hepatectomy should be expanded in order not to exclude from radical therapy patients that could benefit from it.

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Hepatology. 2007 Aug 8; [Epub ahead of print]
Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: A population-based cohort study.
Jackson H, Solaymani-Dodaran M, Card TR, Aithal GP, Logan R, West J.
University of Nottingham Medical School, Division of Epidemiology and Public Health, Medical School, Queen's Medical Centre, Nottingham, United Kingdom.

There is debate over the mortality and malignancy risk in people with primary biliary cirrhosis (PBC) and whether this risk is reduced by use of ursodeoxycholic acid. To investigate this issue, we identified 930 people with PBC and 9,202 control subjects from the General Practice Research Database in the United Kingdom. We categorized regular ursodeoxycholic acid as treatment with 6 or more prescriptions and nonregular treatment as less than 6. We found a 2.7-fold increase in mortality for the PBC cohort compared with the general population [adjusted hazard ratio (HR), 2.69; 95% CI, 2.35-3.09]. In those having regular ursodeoxycholic acid (43%), the mortality increase was 2.2-fold (HR, 2.19; 95% CI, 1.66-2.87) and in those not treated 2.7-fold (HR, 2.69; 95% CI, 2.18-3.33). This apparent reduction in mortality was not explained by less severe disease in the ursodeoxycholic acid-treated group. The increased risk of primary liver cancer in ursodeoxycholic acid-treated patients was 3-fold (HR, 3.17; 95% CI, 0.64-15.62), in contrast to an 8-fold increase in those not treated (HR, 7.77; 95% CI, 1.30-46.65). Conclusion: We found that people with PBC had a 3-fold mortality increase when compared with the general population, which was somewhat reduced by regular treatment with ursodeoxycholic acid. However, the observed effect of ursodeoxycholic acid was not statistically significant. (HEPATOLOGY 2007.).

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Am J Gastroenterol. 2007 Jul;102(7):1397-405. Epub 2007 May 3.
A 3-month course of long-acting repeatable octreotide (sandostatin LAR) improves portal hypertension in patients with cirrhosis: a randomized controlled study.
Spahr L, Giostra E, Frossard JL, Morard I, Mentha G, Hadengue A.
Transplantation Unit, University Hospital, Geneva, Switzerland.

OBJECTIVE: In patients with cirrhosis, acute octreotide administration may transiently decrease the hepatic venous pressure gradient (HVPG). Information on long-term effects of octreotide is limited and controversial. We evaluated portal and systemic hemodynamics following a prolonged administration of long-acting octreotide in patients with cirrhosis. METHODS: Eighteen cirrhotic patients (alcoholic 12; age 55 yr [44-69]; Pugh's score 7.8; HVPG 17.3 mmHg [12-22]), no steatohepatitis on histology, were randomized to intramuscular octreotide 20 mg (group A) q 4 wk for 3 months or placebo (group B) in a double-blind fashion. At baseline and 3 months, we measured the HVPG, systemic hemodynamics, endothelin-1 (ET-1), and vascular endothelial growth factor (VEGF) in hepatic venous blood. RESULTS: Patients remained compensated except for one episode of infection in each group. At 3 months, the HVPG decreased in group A but not in group B (16.5 +/- 1.3 to 11.8 +/- 1.5 mmHg, P < 0.01; 18.2 +/- 1 to 17 +/- 1.1 mmHg, P= 0.4). Systemic hemodynamics and liver function remained unchanged. In group A, but not in group B, VEGF decreased (21.2 +/- 4.7 to 13.7 +/- 3.5 pg/mL, P < 0.01; 22.5 +/- 7.8 to 19.2 +/- 5.4 pg/mL, P= 0.4). ET-1 remained stable. Changes in HVPG and VEGF were correlated (r = 0.49, P < 0.05). CONCLUSIONS: Three months of long-acting octreotide in selected cirrhotic patients with portal hypertension decreases the HVPG independent of systemic hemodynamics and liver function. The decrease in VEGF blood levels suggests an improvement in splanchnic hyperemia.

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Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006000.
Azathioprine for primary biliary cirrhosis.
Gong Y, Christensen E, Gluud C.

BACKGROUND: Azathioprine is used for patients with primary biliary cirrhosis, but the therapeutic responses in randomised clinical trials have been conflicting. OBJECTIVES: To assess the benefits and harms of azathioprine for patients with primary biliary cirrhosis. SEARCH STRATEGY: Randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, The Chinese Biomedical Database, and LILACS, and manual searches of bibliographies to September 2005. SELECTION CRITERIA: Randomised clinical trials comparing azathioprine versus placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality, and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence interval (CI). Continuous outcomes were reported as weighted mean difference (WMD) or standardised mean difference (SMD). We examined the intervention effects by random-effects and fixed-effect models. MAIN RESULTS: We identified two randomised clinical trials with 293 patients. Only one of the trials was regarded as having low bias risk. Azathioprine did not significantly decrease mortality (RR 0.80, 95% CI 0.49 to 1.31, 2 trials). Azathioprine did not improve pruritus at one-year intervention (RR 0.71, 95% CI 0.28 to 1.84, 1 trial), cirrhosis development, or quality of life. Patients given azathioprine experienced significantly more adverse events than patients given no intervention or placebo (RR 2.44, 95% CI 1.14 to 5.20, 2 trials). The common adverse events were rash, severe diarrhoea, and bone marrow depression. AUTHORS' CONCLUSIONS: There is no evidence to support the use of azathioprine for patients with primary biliary cirrhosis. Researchers who are interested in performing further randomised clinical trials should be aware of the risks of adverse events.

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Cochrane Database Syst Rev. 2007 Jul 18;(3):CD005526.
Cyclosporin A for primary biliary cirrhosis.
Gong Y, Christensen E, Gluud C.

BACKGROUND: Cyclosporin A has been used for patients with primary biliary cirrhosis, but the therapeutic responses in randomised clinical trials have been heterogeneous. OBJECTIVES: To assess the beneficial and harmful effects of cyclosporin A for patients with primary biliary cirrhosis. SEARCH STRATEGY: Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, The Chinese Biomedical Database, and LILACS, and manual searches of bibliographies to June 2006. We contacted authors of trials and the company producing cyclosporin A. SELECTION CRITERIA: Randomised clinical trials comparing cyclosporin A with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality, and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and if appropriate, Peto odds ratio with 95% confidence interval (CI). Continuous outcomes were reported as weighted mean difference (WMD) or standardised mean difference (SMD). We examined intervention effects by random-effects and fixed-effect models. MAIN RESULTS: We identified three trials with 390 patients that compared cyclosporin A versus placebo. Two of them were assessed methodologically adequate with low-bias risk. Cyclosporin A did not significantly reduce mortality risk (RR 0.92, 95% CI 0.59 to 1.45), and mortality or liver transplantation (RR 0.85, 95% CI 0.60 to 1.20). Cyclosporin A significantly improved pruritus (SMD -0.38, 95% CI -0.63 to -0.14), but not fatigue. Cyclosporin A significantly reduced alanine aminotransferase (WMD -41 U/L, 95% CI -63 to -18) and increased serum albumin level (WMD 1.66 g/L, 95% CI 0.26 to 3.05). Significantly more patients experienced adverse events in the cyclosporin A group than in the placebo group, especially renal dysfunction (Peto odds ratio 5.56, 95% CI 2.52 to 12.27) and hypertension (SMD 0.88, 95% CI 0.27 to 1.48). AUTHORS' CONCLUSIONS: We found no evidence supporting or refuting that cyclosporin A may delay death, death or liver transplantation, or progression of primary biliary cirrhosis. Cyclosporin A caused more adverse events than placebo, like renal dysfunction and hypertension. We do not recommend the use of cyclosporin A outside randomised clinical trials.

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Med Klin (Munich). 2007 Jun 15;102(6):435-44.
[Nutrition in liver cirrhosis.]
[Article in German]
Gundling F, Teich N, Strebel HM, Schepp W, Pehl C.
Klinik für Gastroenterologie, Hepatologie und Gastroenterologische Onkologie, Städtisches Klinikum München GmbH, Klinikum Bogenhausen, München.

BACKGROUND: Malnutrition is highly prevalent among patients with liver cirrhosis. This includes the supply with macronutrients and micronutrients. The pathogenesis is variable and often depends on metabolic characteristics and complications of the chronic liver disease. A reduced nutritional status, i.e., protein and energy malnutrition, has prognostic significance resulting in an increased morbidity and mortality rate. The assessment of malnutrition is frequently a major problem in daily practice. CONCLUSION: A sufficient daily energy supply should be guaranteed in patients with liver cirrhosis, which is higher compared to the normal population. Furthermore, the increased turnover of amino acids requires a sufficient protein supplementation. Ascites may benefit from a restriction of daily low-salt fluid intake. Additional substitution of vitamins and trace elements is indicated when symptoms of deficiency are apparent. Associated hepatic osteopathy is a frequent complication of liver cirrhosis. Nutritional advice in patients with cirrhosis requires an individual management regarding the dominating complications of the disease.

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Expert Opin Biol Ther. 2007 Jun;7(6):785-90.
Prostacyclin in liver disease: a potential therapeutic option.
Zardi EM, Dobrina A, Amoroso A, Afeltra A.

Complex molecular and cellular mechanisms are involved in the initiation and progression of hepatic fibrosis. Recent studies have shown that hepatic stellate cells, endothelin, cytokines and prostacyclin play crucial roles in this pathology. Prostacyclin exerts vasorelaxant, antioxidant and antifibrotic properties that prevent the development of fibrosis and cirrhosis in liver diseases. In this editorial, the authors discuss some of the molecular and cellular mechanisms involved in the initiation and progression of liver fibrosis and the role played by prostacyclin in counteracting it. At the moment, however, only limited information is available from clinical studies demonstrating the effectiveness of prostacyclin in liver diseases and this makes it difficult to draw any conclusions; further efforts are necessary to verify whether prostacyclin, alone or in combination with other drugs, may be a valid therapeutic option in liver diseases.

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J Viral Hepat. 2007 Jun;14(6):371-86.
Therapeutic issues in HIV/HCV-coinfected patients.
Sulkowski MS, Benhamou Y.
Department of Medicine, Division of Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0003, USA. msulkows@jhmi.edu

The importance of treating hepatitis C virus (HCV)-associated morbidities in a growing population of patients coinfected with human immunodeficiency virus (HIV) has increased since the introduction of highly active antiretroviral therapy. As a result, investigative attention is turning to HCV-related liver disease and treatment-associated issues in coinfection. HIV/HCV-coinfected patients have higher HCV RNA loads and show more rapid progression of fibrosis than do monoinfected patients. Combination therapy with pegylated interferon plus ribavirin (RBV) is the standard of care for HCV in coinfected patients. Therapy slows fibrosis progression, but toxicity prevents identification of the most effective RBV dose. Coinfected patients have about a threefold greater risk of antiretroviral therapy-associated hepatotoxicity than patients with HIV only. Other challenges include anaemia, mitochondrial toxicity, drug-drug interactions and leucopenia. Thus, chronic hepatitis C should be treated in HIV/HCV-coinfected patients, but steps must be taken to prevent and treat potential toxicities. The first European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients was held March 2005 in Paris to address these issues. This article reviews the peer-reviewed literature and expert opinion published from 1990 to 2005, and compares results with presentations and recommendations from the Consensus Conference to best present current issues in coinfection.

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Stem Cells. 2007 May 31; [Epub ahead of print]
Stem Cell Therapy for Human Liver Cirrhosis: A Cautious Analysis of the Results.
Lorenzini S, Andreone P.
Department of Internal Medicine, Cardioangiology and Hepatology. University of Bologna, Italy.

End-stage liver disease, and in particular human liver cirrhosis, represents a worldwide health problem. Currently, liver transplant is the only effective treatment but it is affected by many problems, including relative lack of donors, operative damage, risk of rejection, and high costs. Stem cell therapy is very attractive in this setting because it has the potential to help tissue regeneration while providing minimally invasive procedures and few complications. Only a few clinical studies on the administration of bone marrow-derived stem cells to cirrhotic patients have been published up to now. Although preliminary results seem to be encouraging, the number of treated patients is too small and the study design not completely appropriate to demonstrate safety and efficacy of stem cell therapy in liver cirrhosis. Well- designed, randomized, controlled studies are needed to confirm preliminary results and eventually to clear doubts.

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Gastroenterol Nurs. 2007 Mar-Apr;30(2):102-5; quiz 105-7.
Primary sclerosing cholangitis.
Geonzon-Gonzales MR.
Orthopedic Trauma Unit, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA. alexgonzales@rcn.com

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown origin characterized by progressive inflammation, destruction, and fibrosis of the intrahepatic and extrahepatic bile ducts. The disease leads to obliteration of intrahepatic bile ducts and to biliary cirrhosis, end-stage liver disease, and portal hypertension. Primary sclerosing cholangitis commonly occurs in the presence of inflammatory bowel disease. Its exact etiology remains unknown. As a result, there is no existing effective medical management to delay or modify the progression of the disease. Ursodeoxycholic acid, the most well-studied drug for primary sclerosing cholangitis, has demonstrated promising results when used in combination with an immunosuppressant or antibiotic. To date, liver transplantation remains the only confirmed long-term treatment of primary sclerosing cholangitis, which now accounts for 6% of adult and 1% of pediatric liver transplantations in the United States. Primary sclerosing cholangitis represents an important liver disease with major morbidity and mortality.

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Dtsch Med Wochenschr. 2007 Mar 23;132(12):623-6.
[Antibiotic therapy and prophylaxis in liver cirrhosis and infection.]
[Article in German]
Appenrodt B, Sauerbruch T.
Medizinische Klinik und Poliklinik I, Universitatsklinikum Bonn, Bonn.

Bacterial infections are a well-described complication in patients with cirrhosis of the liver. The development of an infection is associated with a significantly higher mortality. The most common infection in patients with liver cirrhosis is spontaneous bacterial peritonitis (SBP), an infection of ascites without an intraabdominal focus, followed by infections of the unrinary tract, pneumonia and sepsis. Early recognition of SBP results in an early antibiotic threrapy and thus improving survival. Another important role in the development of bacterial infections in cirrhosis is gastrointestinal hemorrhage. In patients with variceal hemorrhage, infection has been shown to be associated with failure to control bleeding and with early rebleeding. For these reasons, a prompt and appropriate antibiotic therapy is important and reduces mortalitiy in cirrhotic patients with bacterial infection.

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Hepatology. 2007 Mar;45(3):569-78.
Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis.
Pockros PJ, Jeffers L, Afdhal N, Goodman ZD, Nelson D, Gish RG, Reddy KR, Reindollar R, Rodriguez-Torres M, Sullivan S, Blatt LM, Faris-Young S.
Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA 92037, USA. pockros.paul@scrippshealth.org

Interferon-gamma1b (IFN-gamma1b) is a pleiotropic cytokine that displays antifibrotic, antiviral, and antiproliferative activity. A total of 502 patients with compensated liver disease and an Ishak fibrosis score of 4-6 were randomized in a double-blind, placebo-controlled study, and 488 of these patients received subcutaneous injections of IFN-gamma1b 100 microg (group 1, n=169), IFN-gamma1b 200 microg (group 2, n=157), or placebo (group 3, n=162) 3 times a week for 48 weeks. Most patients (83.6%) had cirrhosis at baseline (Ishak score=5 or 6). Posttreatment liver biopsies were assessed in a blinded fashion for a reduction of 1 or more Ishak points (primary endpoint). Four hundred twenty patients with pretreatment and posttreatment liver biopsies were evaluable and showed no improvement in Ishak score between the 3 treatment groups (12.1%, 12.4%, and 16% of patients in groups 1, 2, and 3, respectively; P>0.05). Analysis of IFN-gamma-inducible biomarkers revealed that interferon-inducible T cell-alpha chemoattractant (ITAC), an IFN-gamma-inducible CXCR3 chemokine was an independent predictor of stable or improving Ishak score. IFN-gamma1b was well tolerated. There were similar numbers of deaths in all 3 arms (5, 5, and 4, respectively), and most were related to complications of cirrhosis. CONCLUSION: IFN-gamma1b therapy was not able to reverse fibrosis in patients with advanced liver disease for 1 year. Subgroups of patients with elevated ITAC levels and perhaps less advanced disease may be considered for future studies with IFN-gamma1b.

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Transplantation. 2007 Feb 15;83(3):351-3.
Fibrosis progression in hepatitis C positive liver recipients after sustained virologic response to antiviral combination therapy (interferon-ribavirin therapy).
Bahra M, Neumann UP, Jacob D, Langrehr JM, Berg T, Neuhaus R, Neuhaus P.
Klinik fur Allgemein-, Viszeral-, und Transplantationschirurgie, Universitatsklinikum Charite, Campus Virchow-Klinikum, Humboldt-Universitat, Berlin, Germany. marcus.bahra@charite.de

The rate of fibrosis progression was analyzed in 28 hepatitis C virus-infected liver graft recipients showing sustained virologic response after treatment with ribavirin plus either standard interferon alpha-2b (n=8), pegylated interferon alpha-2b (n=8), or pegylated interferon alpha-2a (n=12). Protocol biopsies before treatment as well as one, three, and five years after treatment showed no significant increase in mean fibrosis scores within the first three years after treatment (mean score at baseline 1.8 and at one and three years 2.0 and 2.1, respectively). Five years after cessation of treatment, the mean fibrosis score declined to 1.4 (P=0.2). Six of 28 patients (21%) showed an increase in fibrosis, five (18%) a decrease, and 17 (60%) no changes. The yearly fibrosis progression rate was 0.75 before treatment and 0.15 after antiviral treatment. Sustained virologic response is associated with a deceleration of fibrosis progression and might therefore play a major role in prevention of graft cirrhosis in hepatitis C virus-infected liver graft recipients.

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Transplant Proc. 2007 Jan-Feb;39(1):153-9.
Multimodality therapy and liver transplantation in patients with cirrhosis and hepatocellular carcinoma: 6 years, single-center experience.
Maluf DG, Stravitz RT, Williams B, Cotterell AH, Mas VR, Heuman D, Luketic V, Shiffman ML, Sterling R, Posner MP, Fisher RA.
Virginia Commonwealth University, Department of Surgery, Richmond, VA 23298, USA. dgmaluf@vcu.edu

The treatment of patients with cirrhosis and hepatocellular carcinoma (HCC) has improved dramatically over the past 10 years. We conducted a 6-year prospective study, using multimodality ablation therapy (MMT) combined with liver transplantation (LTx) for patients with cirrhosis and unresectable HCC. Subjects were classified as: group 1 (n = 35), intention to treat with MMT + LTx; group 2 (n = 16), contemporaneous LTx with "incidental" HCC on explants; group 3 (n = 94), MMT alone; and group 4 (n = 19), palliative care alone. MMT included trans-arterial chemo-embolization (54.4%), trans-arterial chemo-infusion (28.6%), and radio frequency ablation (17%). Group 1, with a mean wait time of 11.6 months pre-MELD era and 5.4 months post-MELD era, had a mean of 2.4 +/- 1.2 MMTs and achieved 1- 3-, and 5-year patient survivals of 100, 100, and 76%, respectively, which was not different from group 2 (incidental HCC), namely 93, 93, and 93%, respectively; or to a contemporaneous non-HCC LTx group: namely 84.3, 78.7, and 73.9%, respectively. Despite careful pretransplant HCC staging, 22.8% (8 of 35) group 1 subjects were understaged. Those subjects in group 1 with true T1-2 stage HCC achieved 100% cancer-free survival at 5 years. Only three cases of HCC recurrence occurred in our series, all of whom were understaged. Our data suggest that pretransplant MMT followed by timely LTx provides excellent disease-free survival at 5 years for patients with true T1-2 stage HCC and cirrhosis. Pretransplant HCC understaging contributes to posttransplant HCC recurrence after LTx.

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BMC Gastroenterol. 2007 Jan 26;7:1.
Effects of urodilatin on natriuresis in cirrhosis patients with sodium retention.
Carstens J, Gronbaek H, Larsen HK, Pedersen EB, Vilstrup H.
Research Laboratory of Nephrology and Hypertension, Aarhus University Hospital, Aarhus, Denmark. drjc@dadlnet.dk

BACKGROUND: Sodium retention and ascites are serious clinical problems in cirrhosis. Urodilatin (URO) is a peptide with paracrine effects in decreasing sodium reabsorption in the distal nephron. Our aim was to investigate the renal potency of synthetic URO on urine sodium excretion in cirrhosis patients with sodium retention and ascites. METHODS: Seven cirrhosis patients with diuretics-resistant sodium retention received a short-term (90 min) infusion of URO in a single-blind, placebo-controlled cross-over study. In the basal state after rehydration the patients had urine sodium excretion < 50 mmol/24 h. RESULTS: URO transiently increased urine sodium excretion from 22 +/- 16 micromol/min (mean +/- SD) to 78 +/- 41 mumol/min (P < 0.05) and there was no effect of placebo (29 +/- 14 to 44 +/- 32). The increase of URO's second messenger after the receptor, cGMP, was normal. URO had no effect on urine flow or on blood pressure. Most of the patients had highly elevated plasma levels of renin, angiotensin II and aldosterone and URO did not change these. CONCLUSION: The short-term low-dose URO infusion increased the sodium excretion of the patients. The increase was small but systematic and potentially clinically important for such patients. The small response contrasts the preserved responsiveness of the URO receptors. The markedly activated systemic pressor hormones in cirrhosis evidently antagonized the local tubular effects of URO.

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Gastroenterology. 2007 Jan;132(1):103-12. Epub 2006 Nov 11.
Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
Shiffman ML, Ghany MG, Morgan TR, Wright EC, Everson GT, Lindsay KL, Lok AS, Bonkovsky HL, Di Bisceglie AM, Lee WM, Dienstag JL, Gretch DR.
Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA. mshiffma@vcu.edu

BACKGROUND & AIMS: Reducing the dose of peginterferon and/or ribavirin to <80% when treating chronic hepatitis C virus has been associated with a reduction in sustained virologic response (SVR). However, prior studies did not assess the impact of reducing the dose of peginterferon independent of ribavirin or differentiate between dose reduction or interrupting or prematurely discontinuing treatment. METHODS: Nine hundred thirty-six patients with chronic hepatitis C genotype 1, advanced fibrosis, or cirrhosis (Ishak 3-6) and prior nonresponse to standard interferon +/- ribavirin were retreated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) during the lead-in phase of the HALT-C trial. The percentage of each medication actually taken during treatment was calculated. RESULTS: Reducing the total cumulative dose of peginterferon received during the first 20 weeks of treatment from full dose (> or =98%) to < or =60% reduced week 20 virologic response (W20 VR) from 35% to 12% and SVR from 17% to 5%. Reducing the dose of ribavirin from full dose (> or =98%) to < or =60% did not affect either W20 VR or SVR as long as ribavirin dosing was not interrupted for more than 7 consecutive days. Prematurely discontinuing ribavirin, even at full-dose peginterferon, reduced W20 VR to < or =19% and SVR to < or =4%. CONCLUSIONS: Reducing the peginterferon dose during the first 20 weeks of treatment reduced viral clearance and SVR. In contrast, reducing ribavirin did not affect either W20 VR or SVR as long as patients remained on full-dose peginterferon. Discontinuing ribavirin prematurely was associated with a marked decline in both VR and SVR.

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Best Pract Res Clin Gastroenterol. 2007;21(1):175-90.
Indications of liver transplantation in patients with complications of cirrhosis.
Francoz C, Belghiti J, Durand F.
Service d'Hepatologie, INSERM, Bichat Beaujon, Clichy, France.

Transplantation is the only option for reversing liver insufficiency and its complications in patients with end-stage cirrhosis. Transplantation is generally considered after the first episode of decompensation of cirrhosis, provided no specific intervention can result in a longstanding return to the compensated state. Alcohol abuse and hepatitis C virus infection are the predominant causes leading to transplantation in Western countries. In cases of alcoholic cirrhosis, a 6-month period of abstinence is needed before transplantation. Patients with hepatitis C virus infection are considered independent of viral replication, even if post-transplantation recurrence is almost constant. Conversely, in cases of hepatitis B infection, only patients without viral replication (or with extremely low viral load) are suitable candidates. Hepatocellular carcinoma represents an increasing proportion of the indications and offers excellent long-term survival. However, transplantation should be limited to patients with small tumours. HIV infection no longer represents a definitive contraindication.

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Nat Clin Pract Gastroenterol Hepatol. 2007 Jan;4(1):43-51.
Drug insight: the role of albumin in the management of chronic liver disease.
Wong F.
Department of Medicine, Toronto General Hospital, 9th floor, North Wing, Room 983, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. florence.wong@utoronto.ca

Albumin is the most abundant protein in the circulation. Its main physiologic function is to maintain colloid osmotic pressure. Better understanding of albumin's other physiologic functions has expanded its application beyond maintenance of intravascular volume. In patients with cirrhosis, albumin has been used as an adjunct to diuretics to improve the diuretic response. It has also been used to prevent circulatory dysfunction developing after large-volume paracentesis. Newer indications in cirrhotic patients include preventing hepatorenal syndrome in those with spontaneous bacterial peritonitis, and treating established hepatorenal syndrome in conjunction with vasoconstrictor therapies. The use of albumin for many of these indications is controversial, mostly because of the paucity of well-designed, randomized, controlled trials. The cost of albumin infusions, lack of clear-cut benefits for survival, and fear of transmitting unknown viruses add to the controversy. The latest indication for albumin use in cirrhotic patients is extracorporeal albumin dialysis, which has shown promise for the treatment of hepatic encephalopathy; its role in hepatorenal syndrome or acute on chronic liver failure has not been established. Efforts should be made to define the indications for albumin use, dose of albumin required and predictors of response, so that patients gain the maximum benefit from its administration.

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Curr Pharm Des. 2006;12(35):4637-47.
Vasoconstrictor therapy for hepatorenal syndrome in liver cirrhosis.
Schmidt LE, Ring-Larsen H.
Department of Hepatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. lars.schmidt@dadlnet.dk

Hepatorenal syndrome is a severe, but not uncommon complication of decompensated liver cirrhosis. In particular, the rapidly progressive form of hepatorenal syndrome (type 1) is associated with a dismal prognosis. Established hepatorenal syndrome has a spontaneous reversibility below 5%. Hepatorenal syndrome is involved in more than 50% of cirrhosis-related mortality. Thus, any treatment capable of reversing hepatorenal syndrome would be expected to reduce morbidity and mortality from liver cirrhosis. A pathophysiological hallmark of hepatorenal syndrome is arterial underfilling due to an extreme splanchnic vasodilatation. Consequently, potent vasoconstrictors capable of reversing this vasodilatation have been investigated in hepatorenal syndrome. Several vasoconstrictors including the alpha-adrenergic agonists, midodrine and noradrenalin, and the vasopressor analogues, ornipressin and terlipressin, have all been associated with a significant improvement in renal function in 57 to 100% of cases and even reversal of hepatorenal syndrome in 42 to 100% of cases. The majority of recent studies are on terlipressin. A randomized, controlled trial showed a significant effect of terlipressin on reversal of hepatorenal syndrome. The contribution of volume expansion to the beneficial effects of vasoconstrictors on hepatorenal syndrome remains to be determined. In general, reversal of hepatorenal syndrome was associated with an improved survival. However, it remains to be determined if vasoconstrictor therapy should be used in hepatorenal syndrome in general, or if it should be reserved for potential candidates for liver transplantation. In conclusion, evidence for a beneficial effect of vasoconstrictor therapy for the treatment of hepatorenal syndrome is steadily accumulating. Confirmation of the preliminary data in larger randomized, controlled trials looking at long-term survival is required.

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J Am Coll Surg. 2006 Nov;203(5):670-6. Epub 2006 Aug 17.
Recovery from liver failure after hepatectomy for hepatocellular carcinoma in cirrhosis: meaning of the model for end-stage liver disease.
Cucchetti A, Ercolani G, Cescon M, Ravaioli M, Zanello M, Del Gaudio M, Lauro A, Vivarelli M, Grazi GL, Pinna AD.
Department of Surgery and Transplantation, University of Bologna, Policlinico S Orsola-Malpighi, Bologna, Italy.

BACKGROUND: Hepatectomy for hepatocellular carcinoma in cirrhosis is followed by an impairment of liver function that can lead to patient death. The model for end-stage liver disease (MELD) is considered an index of hepatic functional reserve, and its assessment on postoperative course may properly identify individuals at risk of liver failure. STUDY DESIGN: Two hundred hepatectomies for hepatocellular carcinoma in cirrhosis were reviewed. Irreversible postoperative liver failure was defined as an impairment of liver function after hepatectomy that led to patient death or required transplantation. The MELD scores at postoperative days (POD) 1, 3, 5, and 7 were calculated and kinetics of changes investigated with t-test; logistic regression was applied to identify predictive variables of postoperative liver failure. RESULTS: Kinetics of postoperative MELD score showed an impairment of liver function between PODs 1 and 3; 185 patients in whom postoperative liver failure did not develop showed a considerable decrease in MELD score between PODs 3 and 5 (11.9+/-2.8 and 10.6+/-2.4, respectively, p<0.001). On the contrary, 15 patients, who experienced the event, showed an increase in MELD score between PODs 3 and 5 (18.2+/-3.9 and 18.3+/-3.6, respectively; p=0.845). Multivariate analysis showed preoperative MELD score (p<0.001), major hepatectomy (p=0.028), and MELD score increase between PODs 3 and 5 (p=0.011) as independent predictors of irreversible postoperative liver failure. Scores are reported as mean+/-SD. CONCLUSIONS: Recovery from liver impairment after hepatectomy for hepatocellular carcinoma in cirrhosis starts from POD 3; MELD scores increasing between PODs 3 and 5 may identify patients at risk of liver failure and represents the trigger for beginning intensive treatment or evaluating salvage transplantation.

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Dig Dis Sci. 2006 Nov;51(11):1985-91. Epub 2006 Oct 20.
Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial.
Talwalkar JA, Donlinger JJ, Gossard AA, Keach JC, Jorgensen RA, Petz JC, Lindor KD.
Division of Gastroneterology & Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. talwalkar.jayant@mayo.edu

Fatigue is a common symptom in primary biliary cirrhosis (PBC). In animal models of cholestasis, abnormalities in serotonin neurotransmission are observed with fatigue. The role of selective serotonin reuptake inhibitors in fatigue-related PBC, however, is unknown. A double-blind, placebo-controlled study design was conducted to determine the safety and efficacy of fluoxetine for the treatment of fatigue in PBC. Patients were randomized to fluoxetine, 20 mg daily, or matched placebo for 8 weeks' duration. Fatigue was assessed by the Fisk Fatigue Impact Scale (FFIS). The primary study endpoint was a > or =50% reduction in overall FFIS score at the end of treatment. Health-related quality of life (HRQL) was assessed as a secondary endpoint. Among 220 consecutively screened patients, only 18 (9%) eligible individuals were randomized to fluoxetine (n=10) or placebo (n=8) for 8 weeks. Baseline variables including median FFIS scores (52 vs 42; P=0.21) were similar between treatment arms (P > 0.05). After 8 weeks of therapy, no statistically significant change in median FFIS score was observed in the fluoxetine group. Median FFIS score in the placebo group was reduced (42 to 28), but not statistically significant. No difference in HRQL was observed between treatment arms after 8 weeks. Fourteen (78%) patients completed therapy, while four (22%) individuals withdrew from the trial. Three of the four patients had drug-related adverse events with fluoxetine. In this study, fluoxetine did not improve fatigue in PBC and was associated with adverse events.

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World J Gastroenterol. 2006 Oct 21;12(39):6331-8.
Natural history of a randomized trial comparing distal spleno-renal shunt with endoscopic sclerotherapy in the prevention of variceal rebleeding: a lesson from the past.
Santambrogio R, Opocher E, Costa M, Bruno S, Ceretti AP, Spina GP.
Unita di Chirurgia Bilio-pancreatica, Azienda Ospedaliera San Paolo-Universita degli Studi di Milano, Italy. rsantambrogio@mclink.it

AIM: To compare endoscopic sclerotherapy (ES) with distal splenorenal shunt (DSRS) in the prevention of recurrent variceal bleeding in cirrhotic patients during a long-term follow-up period. METHODS: In 1984 we started a prospective, controlled study of patients with liver cirrhosis. Long-term follow-up presents a natural history of liver cirrhosis complicated by advanced portal hypertension. In this study the effects of 2 types of treatment, DSRS or ES, were evaluated. The study population included 80 patients with cirrhosis and portal hypertension referred to our department from October 1984 to March 1991. These patients were drawn from a pool of 282 patients who underwent either elective surgery or ES during the same period of time. Patients were assigned to one of the 2 groups according to a random number table: 40 to DSRS and 40 to ES using polidocanol. RESULTS: During the postoperative period, no DSRS patient died, while one ES patient died of uncontrolled hemorrhage. One DSRS patient had mild recurrent variceal hemorrhage despite an angiographically patent DSRS and another patient suffered duodenal ulcer rebleeding. Eight ES patients suffered at least one episode of gastrointestinal bleeding: 4 from varices and 4 from esophageal ulcerations. Eight ES patients developed transitory dysphagia. Long-term follow-up was completed in all patients except for 5 cases (2 DSRS and 3 ES patients). Five-year survival rates for shunt (73%) and ES (56%) groups were statistically different: in this follow-up period and in subsequent follow-ups this difference decreased and ceased to be of statistical relevance. The primary cause of death became hepatocellular carcinoma (HCC). Four DSRS patients rebled due to duodenal ulcer, while eleven ES patients had recurrent bleeding from esophago-gastric sources (seven from varices, three from hypertensive gastropathy, one from esophageal ulcerations) and two from unknown sources. Nine DSRS and 2 ES patients developed a chronic encephalopathy; 13 DSRS and 5 ES patients suffered at least one episode of acute encephalopathy. Five ES patients had esophageal stenoses, which were successfully dilated. CONCLUSION: In a subgroup of patients with good liver function, DSRS with a correct portal-azygos disconnection more effectively prevents variceal rebleeding than ES. However, this positive effect did not influence the long-term survival because other factors (e.g. HCC) were more important in deciding the fate of the cirrhotic patients with portal hypertension.

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Cochrane Database Syst Rev. 2006 Oct 18;(4):CD000553.
Portosystemic shunts versus endoscopic therapy for variceal rebleeding in patients with cirrhosis.
Khan S, Tudur Smith C, Williamson P, Sutton R.
Queen Elizabeth Hospital, Liver Unit (Hepatobiliary Pancreatic and Liver Transplant), Metchley Lane, Edgbaston, Birmingham, West Midlands, UK. saboor.711@gmail.com

BACKGROUND: Randomised clinical trials have compared portosystemic shunting procedures with endoscopic therapy for variceal haemorrhage, but there is no consensus as to which approach is preferable. OBJECTIVES: To compare the effects of shunts (total surgical shunt (TS); distal spleno-renal shunts (DSRS) or transjugular intrahepatic porto-systemic shunts (TIPS) with endoscopic therapy (ET, sclerotherapy and/or banding) for prevention of variceal rebleeding in patients with cirrhosis. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE, conference proceedings, and the references of identified trials were searched (last search February 2004). Researchers in the field and in industry were contacted. SELECTION CRITERIA: Randomised clinical trials comparing TS, DSRS or TIPS with ET in patients who had recovered from a variceal haemorrhage and were known to be cirrhotic. DATA COLLECTION AND ANALYSIS: Data were collected to allow intention-to-treat analysis where possible. For each outcome, a pooled estimate of treatment effect (log hazard ratio for time to outcome, Peto odds ratio for binary outcomes, and differences in means for continuous outcomes) across trials was calculated. MAIN RESULTS: Twenty-two trials evaluating 1409 patients were included. All trials had problems of method. Shunt therapy compared with ET demonstrated significantly less rebleeding (OR 0.24, 95% CI 0.18 to 0.30) at the cost of significantly increased acute hepatic encephalopathy (OR 2.07, 95% CI 1.59 to 2.69) and chronic encephalopathy (OR 2.09, 95% CI 1.20 to 3.62). There were no significant differences regarding mortality (hazard ratio 1.00, 95% CI 0.82 to 1.21) and duration of in-patient stay (weighed mean difference 0.78 day, 95% CI -1.48 to 3.05). The proportion of patients with shunt occlusion or dysfunction was 3.1% (95% CI 0.4 to 10.7%) following TS (two trials), 7.8% (95% CI 3.8 to 13.9%) following DSRS (four trials), and 59% (range 18% to 72%) following TIPS (14 trials). AUTHORS' CONCLUSIONS: All shunts resulted in a significantly lower rebleeding rate at the expense of a higher incidence of encephalopathy. TIPS was complicated by a high incidence of shunt dysfunction. No survival advantage was demonstrated with any shunt.

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Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004889.
TIPS versus paracentesis for cirrhotic patients with refractory ascites.
Saab S, Nieto JM, Lewis SK, Runyon BA.
University of California Los Angeles, Medicine and Surgery, 10833 Le Conte Avenue, Los Angeles, California 90095, USA. Ssaab@mednet.ucla.edu

BACKGROUND: Refractory ascites (ie, ascites that cannot be mobilized despite sodium restriction and diuretic treatment) occurs in 10 per cent of patients with cirrhosis. It is associated with substantial morbidity and mortality with a one-year survival rate of less than 50 per cent. Few therapeutic options currently exist for the management of refractory ascites. OBJECTIVES: To compare transjugular intrahepatic portosystemic stent-shunts (TIPS) versus paracentesis for the treatment of refractory ascites in patients with cirrhosis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2006), the Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 4, 2005), MEDLINE (1950 to January 2006), EMBASE (1980 to January 2006), CINAHL (1982 to August 2004), and Science Citation Index Expanded (1945 to January 2006). SELECTION CRITERIA: We included randomised clinical trials comparing TIPS and paracentesis with or without volume expanders for cirrhotic patients with refractory ascites. DATA COLLECTION AND ANALYSIS: We evaluated the methodological quality of the randomised clinical trials by the generation of the allocation section, allocation concealment, and follow-up. Two authors independently extracted data from each trial. We contacted trial authors for additional information. Dichotomous outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). MAIN RESULTS: Five randomised clinical trials, including 330 patients, met the inclusion criteria. The majority of trials had adequate allocation concealment, but only one employed blinded outcome assessment. Mortality at 30-days (OR 1.00, 95% CI 0.10 to 10.06, P = 1.0) and 24-months (OR 1.29, 95% CI 0.65 to 2.56, P = 0.5) did not differ significantly between TIPS and paracentesis. Transjugular intrahepatic portosystemic stent-shunts significantly reduced the re-accumulation of ascites at 3-months (OR 0.07, 95% CI 0.03 to 0.18, P < 0.01) and 12-months (OR 0.14, 95% CI 0.06 to 0.28, P < 0.01). Hepatic encephalopathy occurred significantly more often in the TIPS group (OR 2.24, 95% CI 1.39 to 3.6, P < 0.01), but gastrointestinal bleeding, infection, and acute renal failure did not differ significantly between the two groups. AUTHORS' CONCLUSIONS: The meta-analysis supports that TIPS was more effective at removing ascites as compared with paracentesis without a significant difference in mortality, gastrointestinal bleeding, infection, and acute renal failure. However, TIPS patients develop hepatic encephalopathy significantly more often.
  
Previous Cirrhosis Research: 2002-2006   
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