Ursodeoxycholic acid, a dihydroxyl bile acid normally present in human beings in minimal amounts, becomes incorporated into the bile salt pool when taken orally. In cholestasis, bile acids are retained in the liver and are hepatotoxic. Ursodeoxycholic acid is the least-known hepatotoxic bile acid, has choleretic properties and is reported to benefit patients with chronic cholestasis. In a nationwide Canadian controlled trial, 222 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (14 mg/kg/body wt/day) or placebo for 24 mo. Only patients with a diagnosis confirmed by liver biopsy and serum positive for antimitochondrial antibodies were enrolled; 88% were symptomatic on entry. The primary outcome measure was percent change in total serum bilirubin from baseline to final follow-up. Treated patients (111) and controls (111) were comparable with regard to age, gender, biochemical parameters and liver histological condition. Although treatment was not associated with any improvement in symptoms, ursodeoxycholic acid therapy caused the bilirubin to fall significantly within the first 3 mo of therapy (p < 0.001). Significant falls in serum alkaline phosphatase, aminotransferases, cholesterol and IgM levels were also noted in the treated group. Improvement in some histological features was observed but there was no difference between the groups in the number of patients who reached the endpoints of death or liver transplantation. Ursodeoxycholic acid, given to patients with primary biliary cirrhosis, leads to an improvement in serum markers of cholestasis. A larger sample size is needed to determine whether ursodeoxycholic acid therapy has a beneficial effect on the survival of patients with primary biliary cirrhosis.
-Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Elevated plasma homocysteine (Hcy) concentration is associated with other cardiovascular risk factors. We previously reported that Hcy stimulated cholesterol biosynthesis in HepG2 cells. In the present study, we investigated the underlying mechanisms of Hcy-induced hepatic cholesterol biosynthesis in an animal model. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a highmethionine diet for 4 wk. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were significantly increased in livers of hyperhomocysteinemic rats. There were marked hepatic lipid accumulation and an elevation of plasma cholesterol concentration in hyperhomocysteinemic rats. Three transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element-binding protein (CREB), and nuclear factor Y (NF-Y) were activated in livers of hyperhomocysteinemic rats. Upon Hcy treatment of hepatocytes, there was a significant increase in HMG-CoA reductase mRNA expression in these cells. The activation of SREBP-2, CREB, and NF-Y preceded the increase in HMG-CoA reductase expression in Hcy-treated cells. Pretreatment of hepatocytes with inhibitors for transcription factors not only blocked the activation of SREBP-2, CREB, and NF-Y but also attenuated Hcy-induced HMG-CoA reductase mRNA expression. These results suggested that hyperhomocysteinemia-induced activation of SREBP-2, CREB, and NF-Y was responsible for increased cholesterol biosynthesis by transcriptionally regulating HMG-CoA reductase expression in the liver leading to hepatic lipid accumulation and subsequently hypercholesterolemia. In conclusion, the stimulatory effect of Hcy on hepatic cholesterol biosynthesis may represent an important mechanism for hepatic lipid accumulation and cardiovascular disorder associated with hyperhomocysteinemia.homocysteine; 3-hydroxy-3-methylglutaryl coenzyme A reductase; cAMP response element-binding protein; sterol regulatory elementbinding protein-2; nuclear factor Y HYPERHOMOCYSTEINEMIA, an elevation of blood homocysteine (Hcy) concentration, is considered an independent risk factor for cardiovascular and cerebrovascular disorders (7,37,48). The mechanisms responsible for hyperhomocysteinemia-associated cardiovascular disorders are still under investigation.
Hepatitis B virus (HBV) infections continue to occur in adult hemodialysis units. A possible contributing factor is the presence of occult HBV (serum hepatitis B surface antigen [HBsAg] negative but HBV DNA positive). Two hundred forty-one adult hemodialysis patients were screened for occult HBV. HBV DNA testing was performed by real-time polymerase chain reaction (PCR) with 2 independent primer sets (core promoter and surface). Two (0.8%) of the 241 patients were HBsAg positive. Of the remaining 239 HBsAgnegative patients, 9 (3.8%) were HBV DNA positive. Viral loads in these individuals were low (10 2 -10 4 viral copies/mL). Seven of the 9 (78%) were nt 587 mutation (sG145R mutant) positive. Demographic, biochemical, and HBV serological testing did not help to identify those with occult HBV. In conclusion, the prevalence of occult HBV in adult hemodialysis patients in this North American urban center is approximately 4 to 5 times higher than standard HBsAg testing would suggest. The majority of these infections are associated with low viral loads and a high prevalence of the sG145R mutant. Finally, the demographic, biochemical, and/or serological features of HBV DNA-positive subjects do not distinguish these individuals from the remainder of the dialysis patient population. (HEPATOLOGY 2004; 40:1072-1077.) D espite the development of an effective hepatitis B virus (HBV) vaccine and extensive infection control guidelines, HBV infections continue to occur in dialysis units throughout North America and Europe. 1-3 Based on the results of hepatitis B surface antigen (HBsAg) testing, the incidence of such infections is thought to be 0.05%-1% per year. 4 However, this likely represents an underestimate of the true incidence, as the use of more sensitive monoclonal-based assays for HBsAg detection increase positive findings in dialysis patients by 120%. 5 The relatively low acceptance and response rates to the HBV vaccine among dialysis patients likely contributes to ongoing transmission, as does the need for vaccine boosts to maintain antibody to HBsAg (anti-HBs) at protective levels. 4,6 -8 Additional contributing factors include "breakdowns" in the application of universal and/or dialysis-specific infection control measures. 4,7,9 With the development of specific and sensitive polymerase chain reaction (PCR)-based testing for HBV DNA, the presence of occult HBV infection (HBV DNA positivity in the setting of negative serum HBsAg) represents yet another possible explanation for ongoing transmission.To date, few studies have documented the prevalence of occult HBV infection in renal dialysis patients. In 3 small studies of 33, 5, and 67 HBsAg-negative dialysis patients, 50%, 40%, and 0%, respectively, were HBV DNA positive. 10 -12 Of note, the majority of HBV DNApositive individuals in these studies had serological evidence of previous HBV infection (HBV seropositive), but as many as 39% were HBV seronegative.The present study documents the prevalence of HBV DNA positivity in a large, North American renal dialys...
Determining the longitudinal molecular evolution of hepatitis B virus (HBV) is difficult due to HBV's genomic complexity and the need to study paired samples collected over long periods of time. In this study, serial samples were collected from eight hepatitis B virus e antigen-negative asymptomatic carriers of HBV genotype B in 1979 and 2004, thus providing a 25-year period to document the long-term molecular evolution of HBV. The rate, nature, and distribution of mutations that emerged over 25 years were determined by phylogenetic and linear regression analysis of full-length HBV genome sequences. Nucleotide hypervariability was observed within the polymerase and pre-S/S overlap region and within the core gene. The calculated mean number of nucleotide substitutions/site/year (7.9 ؋ 10 ؊5 ) was slightly higher than published estimates (1.5 ؋ 10 ؊5 to 5 ؋ 10 ؊5 ). Nucleotide changes in the quasispecies population did not significantly alter the molecular evolutionary rate, based on linear regression analysis of evolutionary distances among serial clone pre-S region sequences. Therefore, the directly amplified or dominant sequence was sufficient to estimate the putative molecular evolutionary rate for these long-term serial samples. On average, the ratio of synonymous (d S ) to nonsynonymous (d N ) substitutions was highest for the polymerase-coding region and lowest for the core-coding region. The low d S /d N ratios observed within the core suggest that selection occurs within this gene region, possibly as an immune evasion strategy. The results of this study suggest that HBV sequence divergence may occur more rapidly than previously estimated, in a host immune phase-dependent manner.Determination of the molecular evolution of hepatitis B virus (HBV) involves an understanding of the accumulated sequence changes to the viral genome and the observed mutation rate over a long period. Determining the rate of sequence change is difficult due to the complex organization of the HBV genome, which involves multiple coding and regulatory functions within overlapping open reading frames (16). Two-thirds of the viral genome codes for multiple proteins, and thus a synonymous change in one open reading frame results in a nonsynonymous change in the overlapping open reading frame. In this way, it is believed that HBV genome evolution is "constrained" in order to maintain essential protein functions (22).Since HBV replication involves an error-prone reverse transcription step, the rate of nucleotide change during replication is higher than that found for other DNA viruses and is more similar to the rate observed for the slower-evolving RNA viruses (21, 24). The rate of HBV evolution in hepatitis B virus e antigen (HBeAg)-positive individuals has been estimated to be 1.5 ϫ 10 Ϫ5 to 5 ϫ 10 Ϫ5 nucleotide substitutions per site per year (1,13,24,29). However, the mutation rate or total accumulated number of mutations appears to be higher in HBeAgnegative patients (11, 33), suggesting that the host immune response plays an importan...
C ellular oxidative stress is one of the factors responsible for the propagation of liver diseases, such as hepatitis, cirrhosis, and hepatoma. 1 Several primary antioxidant defense systems such as superoxide dismutase (SOD), catalase, glutathione (GSH), and glutathione peroxidase are present intracellularly. These systems scavenge reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, lipid peroxides, and free radicals. Exposure to oxidative stress may, however, deplete the cellular antioxidant capacity. Therefore, other antioxidant defense systems are expected to play an important role in oxidative stress.Liver fatty acid binding protein (L-FABP) is a 14-kd protein found abundantly in the cytoplasm and the nucleus of hepatocytes. 2,3 L-FABP is very likely to be an effective endogenous antioxidant, because it has high affinity and capacity to bind long-chain fatty acid oxidation products. 4,5 Hepatocyte L-FABP concentration could be as high as 0.4 mmol/L, 6 and it contains a large number of reducing amino acid residues (1 cysteine and 7 methionine residues) in its molecular structure. With an accessible volume enclosed by the molecular surface of L-FABP of 28,600 Å 3,7 the concentration of total methionine residues in L-FABP could be as high as approximately 400 mmol/L. Methionine and cysteine amino acids are regarded as cellular scavengers of activated xenobiotics and
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