Improves Liver Biochemistry Research Articles

Ductopenia related liver sarcoidosis

Sarcoidosis is a systemic granulomatous disease which may involve many organs. In approximately 95% of patients there is liver involvement, with noncaseating hepatic granulomas occurring in 21 to 99% of patients with sarcoidosis. Liver involvement is usually asymptomatic and limited to mild to moderate abnormalities in liver biochemistry. The occurrence of jaundice in sarcoidosis is rare; extensive imaging procedures and the examination of liver biopsies permit a precise diagnostic. Ductopenia associated with sarcoidosis has been reported in less than 20 cases and can lead to biliary cirrhosis and liver- related death. We report here on a case of ductopenia-related sarcoidosis in which primary biliary cirrhosis and extrahepatic cholestasis have been carefully excluded. The patient follow up was 8 years. Although ursodesoxycholic acid appears to improve liver biochemistry it does not preclude the rapid occurrence of extensive fibrosis. A review of the literature of reported cases of ductopenia related to sarcoidosis is provided.

Ursodeoxycholic acid in primary sclerosing cholangitis: meta‐analysis of randomized controlled trials

The effect of ursodeoxycholic acid (UDCA) treatment on survival and liver histological progression of primary sclerosing cholangitis (PSC) remains uncertain. The aim of the present study was to evaluate the effect and safety of UDCA in PSC. Electronic databases including Medline, Embase, Cochrane controlled trials register, Web of Science and PubMed (updated to January 2009) and manual bibliographical searches were carried out. A meta-analysis of all randomized controlled trials (RCT) comparing UDCA with placebo or no treatment was carried out. Eight RCT including 465 patients were assessed. UDCA could significantly improve liver biochemistry, but had no effect on pruritus and fatigue. Meta-analysis of the included RCT showed UDCA had no significant effect on the incidence of death, liver transplantation, and death and/or liver transplantation. However, a significant difference for the incidence of histological improvement was found between the two groups (odds ratio [OR], 9.19; 95% CI: 0.98, 86.15; P = 0.05). Meta-analysis also indicated a reduction trend of histological deterioration and an improvement trend of cholangiographic changes. These trends were constant in the sensitivity analyses. The meta-analysis found that UDCA can improve liver biochemistry and there is a trend towards improvement in liver histology and cholangiography, but has no effect on survival free of transplantation.

Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis

A longitudinal, cohort study was performed to characterize the clinical features of patients with small-duct primary sclerosing cholangitis (PSC) occurring with and without inflammatory bowel disease (IBD) and to determine the influence of IBD and the effect of ursodeoxycholic acid (UDCA) therapy on the course of the liver disease. Forty-two patients with small-duct PSC (14 women and 28 men; mean age, 36.7 +/- 13.3 years) were followed for up to 24.9 years. At presentation, prevalence of signs of liver disease (none versus 35%, P = 0.002), gastroesophageal varices (5% versus 30%, P = 0.03), and stage III/IV disease (9% versus 45%, P = 0.008) were lower in those with IBD versus those without IBD. During follow-up, 6 patients underwent liver transplantation, and another died of cirrhosis. Using the Cox proportional hazard analysis, concomitant IBD was not associated with liver death or transplant, whereas the revised Mayo risk score for PSC was the only prognostic factor associated with liver-related outcomes (relative risk, 6.47; 95% confidence interval, 1.75-137.5). UDCA (13-15 mg/kg/day) therapy for an average of 40 months showed biochemical improvement (P < 0.001) in UDCA-treated patients, while no significant change occurred in untreated patients. UDCA therapy had no effect on delaying progression of disease (relative risk, 0.95; 95% confidence interval, 0.38-2.36). Small-duct PSC often is recognized at an early stage in patients with IBD; however, IBD has no impact on long-term prognosis. Although UDCA therapy improves liver biochemistries, it may not delay disease progression during the short period of treatment.

Long-Term Effects of Mid-Dose Ursodeoxycholic Acid in Primary Biliary Cirrhosis: A Meta-analysis of Randomized Controlled Trials

The effect of ursodeoxycholic acid (UDCA) treatment on survival and liver histological progression of primary biliary cirrhosis (PBC) remains uncertain. The aim of this study is to assess the long-term efficacy of mid-dose UDCA treatment for PBC. Electronic databases including Medline, Embase, Cochrane controlled trials register, Science Citation Index, and PUBMED (updated to Nov 2005), and manual bibliographical searches were conducted. A meta-analysis of all long-term randomized controlled trials (RCTs) comparing mid-dose UDCA with placebo or no treatment was performed. Seven RCTs and six reports of their extended follow-up including 1,038 patients were assessed. UDCA could significantly improve liver biochemistry, but had no effect on pruritus and fatigue. UDCA could delay the progression of PBC, especially for early-stage patients. Meta-analysis of the seven RCTs including their extended follow-up showed a significant reduction of the incidence of liver transplantation (OR 0.65, p = 0.01), and a marginally significant reduction of the rate of death or liver transplantation (fixed-effect model: OR 0.76, p = 0.05; random-effect model: OR 0.77, p = 0.3) in the UDCA group, except death (OR 1.01, p = 1). In the sensitivity analyses, which included studies administrating placebo as control, long-term studies (> or = 48 months), or large size studies (total number of patients > or = 100), we all found long-term treatment with UDCA could significantly reduce the incidence of liver transplantation, and death or liver transplantation. Long-term treatment with mid-dose UDCA can improve liver biochemistry and survival free of liver transplantation in patients with PBC. In addition, UDCA therapy can delay the histological progression in the early-stage patients.

Adeno-associated virus-mediated heme oxygenase-1 gene transfer suppresses the progression of micronodular cirrhosis in rats

To test the hypothesis that enhancement of the activity of heme oxygenase can interfere with processes of fibrogenesis associated with recurrent liver injury, we investigated the therapeutic potential of over-expression of heme oxygense-1 in a CCl(4)-induced micronodular cirrhosis model. Recombinant adeno-associated viruses carrying rat HO-1 or GFP gene were generated. 1x 10(12) vg of adeno-associated viruses were administered through portal injection at the time of the induction of liver fibrosis. Conditioning the rat liver with over-expression of HO-1 by rAAV/HO-1 significantly increased the HO enzymatic activities in a stable manner. The development of micronodular cirrhosis was significantly inhibited in rAAV/HO-1-transduced animals as compared to controls. Portal hypertension was markedly diminished in rAAV/HO-1-transduced animals as compared to controls, whereas there are no significant changes in systolic blood pressure. This finding was accompanied with improved liver biochemistry, less infiltrating macrophages and less activated hepatic stellate cells (HSCs) in rAAV/HO-1-transduced livers. Enhancement of HO activity in the livers suppresses the development of cirrhosis.

Multifocal Nodular Non-Alcoholic Steatohepatitis (NASH)

Introduction: Insulin sensitizers have been reported to improve liver biochemistry and histology in patients with NASH. Rarely fatty lesions in liver can be multifocal and nodular, and mimic metastatic disease to the liver. We describe a patient with multifocal nodular NASH who's radiological and biochemical abnormalities resolved with rosiglitazone. Case: A 59-year-old white female with metabolic syndrome underwent CT scan of her liver to evaluate abnormal transaminases. This revealed a hypodense mass with a size of 10.5 cm in maximum diameter in left lobe with multifocal nodular lesions in the right lobe of liver. This was initially concerning for malignant disease. However MRI suggested multifocal nodular fatty liver. A laparoscopic liver biopsy was nevertheless elected. The liver surface had yellowish discoloration with fibrotic changes. Biopsy showed changes consistent with NASH and early fibrosis. The patient was started on vitamin E 400 IU daily. At 6 months there was no change in CT scan findings. Rosiglitazone 4 mg twice a day was added and vitamin E was continued. Six months later her hemoglobin A1C improved from 6.7% to 6.1%. Her fasting glucose and insulin levels improved. She was able to improve her body mass index from 29.3 to 26.6. Transaminases normalized. A repeat CT scan done after 6 months of rosiglitazone showed resolution of multifocal nodular fatty liver lesions. Conclusion: This case illustrates that multifocal nodular fatty liver can mimic metastatic disease to the liver. Rosiglitazone resulted in improvement in insulin resistance and dramatic resolution of nodular fatty lesions on CT scan.

Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis

Background/Aims: The mortality of patients with severe acute alcoholic hepatitis (AH) remains high, leading to interest in the use of extracorporeal liver support. The molecular adsorbents recirculating system (MARS) is a liver support device based upon a hollow fibre module in which the patient's blood is dialyzed across an albumin-impregnated membrane. The aim of this paper is to assess the safety, efficacy and feasibility of using MARS in patients with severe AH. Methods: Eight patients (all encephalopathic; hepatorenal syndrome: Type 1, five patients; Type 2, two patients) were treated with MARS. Clinical, biochemical and haemodynamic assessments were done. Results: Five patients were discharged from hospital, and four are alive at 3 months of follow-up, compared with an estimated survival of about 20%. There were significant improvement in serum bilirubin ( P=0.008), creatinine ( P=0.02), prothrombin time ( P=0.04), and grade of encephalopathy ( P=0.05). Sustained improvements in mean arterial pressure, systemic vascular resistance and cardiac output were observed. Thrombocytopaenia was the only MARS-related adverse event observed. Conclusions: MARS resulted in improved liver biochemistry, cardiovascular haemodynamics, renal function and encephalopathy in patients with severe AH, with an apparent reduction in mortality. On this basis, a multi-centre, randomized clinical trial has been initiated.

Interferon for acute hepatitis C.

Acute hepatitis C virus (HCV) infection progresses to chronicity in the majority of patients. In order to prevent the progression to chronic disease, several studies have assessed interferon in patients with acute hepatitis C. The aim of this review was to assess the efficacy of interferon in acute HCV infection. We searched MEDLINE, the Cochrane Controlled Trials Register, and the abstracts of the American Association for the Study of Liver Diseases (June 2001). We also contacted pharmaceutical companies to obtain unpublished trials. Randomised clinical trials comparing interferon with placebo or no treatment, and published as an article, abstract, or letter were selected. No language limitations were used. Two reviewers independently assessed trial quality and extracted data. The following endpoints were analysed: normalization of alanine aminotransferase (ALT) activity at the end of treatment (biochemical ETR); sustained ALT normalization at the end follow-up (biochemical SR); disappearance of serum HCV RNA by polymerase chain reaction assay at the end of treatment (virologic ETR) and at the end of follow-up (virologic SR). Histologic data and adverse events were also recorded. Assessment of drug efficacy used the methods of Peto and Der Simonian and Laird. Six randomised trials involving 206 patients with acute hepatitis C met the inclusion criteria. Four trials assessing interferon alfa-2b in 141 patients, all with transfusion-acquired acute hepatitis C, were included. They demonstrated no significant heterogeneity in the outcomes assessed. When compared with no treatment, interferon alfa-2b was associated with an increase in the rates of virologic ETR and SR by 45% (95% CI 31-59%, P < 0.00001) and 29% (95% CI 14-44%, P = 0.0002), respectively. The virologic ETR was 42% (95% CI: 30-56%) in the interferon alfa-2b group versus 4% (95% CI 0-13%, P < 0.00001) in the control group. At the end of follow-up, a virologic SR was seen in 32% (95% CI 21-46%) of interferon-treated patients versus only 4% (95% CI 0-13%, P = 0.00007) of controls. The tolerability of therapy, or the impact of interferon alfa-2b on hepatic histology, was not reported. Two trials assessed interferon beta in a total 65 patients. The efficacy of interferon beta could not be assessed, however, due to heterogeneity of these trials. Interferon alfa is effective in improving biochemical outcomes and achieving sustained virologic clearance in patients with transfusion-acquired acute hepatitis C. The effect on long-term clinical outcomes could not be assessed due to limitations in the current data.

Metabolism and effects on cholestasis of isoursodeoxycholic and ursodeoxycholic acids in bile duct ligated rats

Isoursodeoxycholic acid (isoUDCA), the 3β-epimer of ursodeoxycholic acid (UDCA), may have pharmaceutical potential because of its similar hydrophilicity and in vitro cytoprotection as compared with UDCA. We compared metabolism and effects on cholestasis of UDCA and isoUDCA in experimental cholestasis in rats. Cholestasis was induced by bile duct ligation. For bile flow and biliary bile acid analysis, UDCA or isoUDCA were infused intraduodenally. For the study of chronic effects, chow was supplemented with 2.5 g/kg UDCA or isoUDCA for 3 weeks. Sham-operated animals served as controls. IsoUDCA became completely converted to UDCA in the liver. Choleresis and biliary bile acids were the same after the intraduodenal administration of either compound. Oral administration of UDCA or isoUDCA significantly improved liver biochemistry but not clinical and histological parameters in chronic cholestasis. The decrease of serum cholic acid in control animals was more pronounced after isoUDCA (−93%) than after UDCA (−76%). Only after UDCA, this decrease was compensated by increases of UDCA, β-muricholic acid (MCA), and Δ 22-β-MCA. Our results show that isoUDCA has the same effect on choleresis and liver biochemistry as UDCA. IsoUDCA features pro-drug characteristics of UDCA and causes compared to the latter lower serum bile acid concentrations in non-cholestatic animals.

MECHANISM OF HEPATOPROTECTIVE ACTION OF BILE SALTS IN LIVER DISEASE

Ursodeoxycholic acid (UDCA) improves liver enzymes and in many instances liver histology in cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. Besides classic cholestatic diseases, UDCA also improves liver biochemistry in alcoholic liver disease and in chronic viral hepatitis C. The main target of UDCA treatment, however, is cholestasis, and consequently the mechanisms responsible for the beneficial effects in these diseases are of interest, and are discussed in detail in this article.

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

Objective: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. Methods: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. Results: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) ( p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p ≤ 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. Conclusion: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Review article: glycyrrhizin as a potential treatment for chronic hepatitis C.

Chronic hepatitis C is a slowly progressive liver disease that may evolve into cirrhosis with its potential complications of liver failure or hepatocellular carcinoma. Current therapy with alpha-interferon is directed at viral clearance, but sustained response is only achieved in 20-40% of patients without cirrhosis, and less than 20% in patients with cirrhosis who have the greatest need for therapy. Treatment for those who do not respond to anti-viral therapy is highly desirable. In Japan glycyrrhizin has been used for more than 20 years as treatment for chronic hepatitis. In randomized controlled trials, glycyrrhizin induced a significant reduction of serum aminotransferases and an improvement in liver histology compared to placebo. Recently, these short-term effects have been amplified by a well-conducted retrospective study suggesting that long-term usage of glycyrrhizin prevents development of hepatocellular carcinoma in chronic hepatitis C. The mechanism by which glycyrrhizin improves liver biochemistry and histology are undefined. Metabolism, pharmacokinetics, side-effects, and anti-viral and hepatoprotective effects of glycyrrhizin are discussed.

Single or multiple dose ursodeoxycholic acid for cholestatic liver disease: biliary enrichment and biochemical response

Background: Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance. Aim: The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated. Methods: Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg −1 day −1) in a single dose at bed time ( n=13) or in three divided gifts with meals ( n=14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between. Results: Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean±SEM) was 40.1±2.4 in the single dose group vs 40.8±2.8 in the multiple dose group ( p=NS) and was positively correlated with biochemical improvement (AP: r=0.47, p=0.02; GGT: r=0.58, p=0.002; ASAT: r=0.67, p=0.002; ALAT: r=0.52, p=0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens. Conclusion: Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.