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PubMed2006

New therapies in hepatitis C virus and chronic liver disease: antifibrotics.

Fibrotic liver disease occurs after any of the various forms of injury to the liver. Fibrosis is a critical factor leading to hepatic dysfunction and portal hypertension and its complications. The fibrogenic cascade is complex but leads to accumulation of extracellular matrix proteins, followed by nodular fibrosis, tissue contraction, and alteration in blood flow. A critical concept emerging is that activation of effector cells, which produce extracellular matrix, underlies the fibrogenic process. The aggregate data has not only helped lead to an understanding of the pathophysiologic basis of hepatic fibrogenesis, but it has also provided an important context with which to base novel antifibrotic therapy.

Colchicine↗
PubMed2002

Current status in the surgical management of adult polycystic liver disease.

INTRODUCTION: In patients with adult polycystic liver disease (APLD), there is considerable debate surrounding the most effective way of managing symptomatic cysts. Conservative approaches like percutaneous aspiration or cyst fenestration are associated with low morbidity but high recurrence rates. Conversely, liver resection and hepatectomy with orthotopic liver transplantation is drastic and associated with high morbidity and mortality rates. Our aim is to review the current understanding of liver cystogenesis in these patients and the therapeutic options available in order to provide a rationale guide to management of this intriguing condition. METHODS: This article summarises the findings of published papers in major international journals indexed on MEDLINE on APLD using the key words--adult polycystic liver disease, liver cysts, fenestration, liver resection, liver transplantation and polycystic kidney disease. The period of search includes papers between 1965 and 2000. RESULTS: Published studies have suggested a 'two-hit' hypothesis to explain the development of liver cysts in patients with APLD. This will provide the rationale for future management. Meanwhile, the indications, pitfalls and results of the various therapeutic options are reviewed. Management of symptoms has to be tailored to the underlying severity of the liver cystic disease, co-morbidity and procedural risks and recurrence rates. CONCLUSION: Good long-term relief of symptoms can be achieved with the correct procedure at acceptable morbidity and mortality rates. We have provided guidelines on the various options available to enable a structured approach to the management of APLD.

Adult↗
PubMed1994

Leucocyte adhesion molecules and alcoholic liver disease.

The causative agent of alcoholic liver disease is self-evident although the pathogenesis of the liver damage is not well understood. There is increasing evidence from both animal experiments and human studies that inflammation triggered in response to alcohol or its metabolites is important in the tissue damage and fibrosis of alcoholic liver disease. Both alcoholic hepatitis and alcoholic cirrhosis are characterized by inflammation of the liver, although the nature of the inflammatory infiltrate differs between the two diseases. The activation of leucocytes, their migration into tissue and subsequent interaction with target cells are all dependent on regulated adhesion. Therefore, leucocyte adhesion molecules and their counter-receptors will play a crucial role in determining the nature and activity of leucocytes infiltrating the liver in alcoholic liver disease. Evidence is now emerging that suggests roles for particular adhesion pathways in two aspects of the inflammatory response in alcoholic liver disease, (1) leucocyte recruitment to the liver, and (2) cell-mediated hepatocyte damage. It is important that these pathways are defined since therapy aimed at blocking leucocyte adhesion molecules might provide an effective future therapy for selected patients with alcoholic liver disease.

Animals↗
PubMed2004

Searching for coeliac disease in patients with non-alcoholic fatty liver disease.

BACKGROUND: A non-negligible percentage of patients with non-alcoholic fatty liver disease, a leading cause of hepatic progressive disorder related to insulin resistance, have no metabolic risk factors, and abnormal intestinal permeability has been suggested to be involved in the pathogenesis of the liver damage. Coeliac disease, a curable disorder characterised by inflammatory mucosal damage, may show hepatic histological features similar to steatohepatitis. Conflicting data have been reported on the prevalence of coeliac disease in non-alcoholic steatohepatitis. AIM: To search for coeliac disease in a series of patients with non-alcoholic fatty liver disease by screening with anti-tissue transglutaminase and anti-endomysium antibodies. PATIENTS AND METHODS: Fifty-nine consecutive patients with hypertransaminasemia and non-alcoholic fatty liver disease, 38 (64%) with steatohepatitis. Anti-endomysium antibodies were assayed by indirect immunofluorescence, IgA anti-tissue transglutaminase by ELISA. Patients who tested positive underwent HLA DQ typing and endoscopy. RESULTS: Tissue transglutaminase antibodies were positive in six (10%) patients and anti-endomysium in two (3.4%); only two (3.4%), positive for both anti-endomysium positive and anti-transglutaminase, resulted to have coeliac disease based on histological findings. After 6 months of gluten-free diet, liver enzymes normalised. CONCLUSIONS: The prevalence of silent coeliac disease is 3.4% in patients with non-alcoholic fatty liver. The inclusion of anti-endomysium antibodies test in studying patients with non-alcoholic fatty liver and persistent biochemical abnormalities has to be taken into account, since positivity for tissue transglutaminase antibodies, in the absence of confirmatory anti-endomysium antibodies, is not sufficient to perform diagnostic endoscopy.

Adult↗
PubMed2005

The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.

BACKGROUND: The frequent association of nonalcoholic fatty liver disease with components of the metabolic syndrome such as obesity, hyperglycemia, dyslipidemia, and hypertension is well known. However, no prospective study has examined the role of the metabolic syndrome in the development of this disease. OBJECTIVE: To characterize the longitudinal relationship between the metabolic syndrome and nonalcoholic fatty liver disease. DESIGN: A prospective observational study. SETTING: A medical health checkup program in a general hospital. PARTICIPANTS: 4401 apparently healthy Japanese men and women, 21 to 80 years of age, with a mean body mass index (BMI) of 22.6 kg/m2 (SD, 3.0). MEASUREMENTS: Alcohol intake was assessed by using a questionnaire. Biochemical tests for liver and metabolic function and abdominal ultrasonography were done. Modified criteria of the National Cholesterol Education Program Adult Treatment Panel III were used to characterize the metabolic syndrome. RESULTS: At baseline, 812 of 4401 (18%) participants had nonalcoholic fatty liver disease. During the mean follow-up period of 414 days (SD, 128), the authors observed 308 new cases (10%) of nonalcoholic fatty liver disease among 3147 participants who were disease-free at baseline and who completed a second examination. Regression of nonalcoholic fatty liver disease was found in 113 (16%) of 704 participants who had the disease at baseline and who completed a second examination. Men and women who met the criteria for the metabolic syndrome at baseline were more likely to develop the disease during follow-up (adjusted odds ratio, 4.00 [95% CI, 2.63 to 6.08] and 11.20 [CI, 4.85 to 25.87], respectively). Nonalcoholic fatty liver disease was less likely to regress in those participants with the metabolic syndrome at baseline. LIMITATIONS: Ultrasonography may lead to an incorrect diagnosis of nonalcoholic fatty liver disease in 10% to 30% of cases and cannot distinguish steatohepatitis from simple steatosis. Self-reported alcohol intake may cause bias. Because all of the participants were Japanese, generalizability to non-Japanese populations is uncertain. CONCLUSIONS: The metabolic syndrome is a strong predictor of nonalcoholic fatty liver disease.

Adult↗
PubMed2005

Clinical significance of abnormal lipoprotein patterns in liver diseases.

We analyzed lipids in liver diseases by agarose gel electrophoresis, and differential staining and simultaneous analysis of the cholesterol (Chol) and triglyceride (TG) fractions. Liver diseases were classified into chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and metastatic liver cancer, and each fraction was compared among these diseases. Atypical patterns that were unclassifiable according to the WHO classification of hyperlipidemia phenotypes were classified, and their clinical importance was evaluated. With progression of the pathologic conditions of CH, LC, and HCC, the T-Chol level, each Chol fraction, and the TG fraction decreased while the LDL-TG fraction increased. Metastatic liver cancer showed a lower HDL-fraction level but higher levels of the other parameters than HCC. When the subjects were classified into survivors and patients who died, the HDL fraction level in HCC and metastatic liver cancer, and the LDL level in LC and metastatic liver cancer differed between survivors and patients who died. Phenotypes of hyperlipidemia also differed among diseases, and atypical patterns were frequently observed in patients who died. There were 6 atypical patterns, of which 4 (slow alpha HDL, abnormal LDL, Lp-X, and Lp-Y) were associated with liver diseases. Slow alpha HDL appeared during slight bile stagnation and was accompanied by increases in the apo E level and the HDL particle size. Abnormal LDL appeared with severe liver dysfunction; a TG peak appeared at the position of LDL, and the HDL and VLDL fractions were negligible. Lp-X was a Chol-rich band, occurring on the cathode side of LDL in the presence of marked bile stagnation such as that in obstructive jaundice, and was accompanied by appearance of abnormal LDL. Lp-Y was similar to Lp-X in terms of mobility and associated diseases but contained Chol and TG. Abnormal LDL, Lp-X, and Lp-Y were often observed in patients with poor outcomes. Lipid analysis in liver diseases by this method showed results reflecting the pathologic conditions and may be clinically useful.

Carcinoma, Hepatocellular↗
PubMed1990

HLA phenotypes and gene polymorphisms in juvenile liver disease associated with alpha 1-antitrypsin deficiency.

Chronic liver disease affects up to 20% of children with alpha 1-antitrypsin deficiency owing to the PiZZ genotype. Previous observations of a familial occurrence and abnormal immune responses to liver antigens in these patients suggests that immunoregulatory genes may be involved in the pathogenesis of liver damage. We have identified HLA phenotypes and class II (HLA-DR) gene polymorphisms in 140 white PiZZ subjects, of whom 92 (83 index patients) had liver disease, and 206 first-degree relatives. DR3* was present in 35 of 75 (46.7%) unrelated patients with liver disease compared with 5 of 28 (17.8%) patients without (p less than 0.01) and 23 of 100 controls (p less than 0.001). DR4 was increased in patients without liver disease; it was present in 17 of 28 (60.7%) compared with 29 of 75 (38.7%) patients with liver disease (p less than 0.05) and 36 of 100 controls (p less than 0.025). Using Southern blot analysis with HLA-DRB and DQB DNA probes, we identified two polymorphisms of DR3, only one (Dw25) of which is raised in PiZZ individuals with liver disease (9 of 55: 16.4%) compared with 1 of 23 (4.4%) without and 2 of 52 (3.9%) controls (p less than 0.05). Analysis of the segregation of HLA haplotypes in 77 families revealed no concordance for liver disease with HLA in those with affected sibships, indicating that, although DR3-Dw25 is associated with liver disease in alpha 1-antitrypsin deficiency, other factors must play a pathogenic role.

Adolescent↗
PubMed2005

Regional variation and use of exception letters for cadaveric liver allocation in children with chronic liver disease.

The Pediatric End-Stage Liver Disease (PELD) score was designed to reduce subjectivity in liver allocation and to advantage patients with a higher probability of waiting list mortality. The aims of this study were to determine the impact of PELD implementation for children with chronic liver disease and to assess whether PELD met its goal of standardization of liver allocation for children. This study used data reported to the United Network for Organ Sharing (UNOS) registry for children with chronic liver disease receiving primary cadaveric liver transplant between January 2000 and December 2001 (pre-PELD) and March 2002 and July 2003 (PELD). PELD reduced the percentage of children transplanted while in an intensive care unit and as status 1. A calculated PELD score was used for allocation in only 52% of recipients. Thirty percent were status 1 at transplant and PELD scores granted by exception were used for allocation in 18% of patients. There was regional variation in PELD score at allocation and use of exception scores with a significant relationship between PELD score and percentage of exception cases. Regional variation suggests that PELD has not resulted in standardization of listing practices in pediatric liver transplantation.

Cadaver↗
PubMed2003

Serum selenium levels in alcoholic liver disease.

BACKGROUND: The pathomechanism of liver damage in chronic alcoholic liver disease has not been fully elucidated yet. It seems undoubted that one of the mechanisms of alcohol-induced liver damage involves free radical reactions leading to peroxidation of proteins and lipids. The most important defense mechanisms are associated with the activity of antioxidative enzymes, among which glutathione peroxidase (GSH-Px), belonging to so-called 'free radical scavengers' should be mentioned. Selenium, regarded as a bioelement, is present in GSH-Px. Involved in numerous redox reactions, it belongs to the factors protecting the organism from oxidative shock. The aim of the study was to determine the selenium levels in blood serum of chronic alcohol abusers and to find potential correlations with the parameters of liver damage. MATERIAL/METHODS: The study was carried out in a group of 25 subjects (21 males, 4 females), treated in the Clinic or Outpatient Department of Hepatology for chronic alcoholic liver disease. At the time of the study, the patients had abstained from drinking for a period from one month to a year. Selenium was determined with atomic absorption spectroscopy method, using the hydride generation technique. The control group consisted of 11 males and 7 females. RESULTS: Statistical analyses of the control group indicated a significantly higher blood serum selenium level in males than in females. The patients demonstrated elevated aminotransferase activity, normal Falk, markedly increased GGTP. Mean INR was 1.4 and albumin concentration 3.3 g/l. Blood serum selenium levels in male patients were significantly lower in comparison with normal values. The analysis of correlations between some liver function parameters and selenium levels demonstrated a positive correlation between the levels of albumin and selenium. Serum selenium level was inversely proportional to ALAT activity. No correlations between selenium levels and INR levels, or GGTP activity were found. CONCLUSIONS: 1. Serum selenium levels differ in male and female populations. In healthy men, the level of Se in the serum is higher. 2. Antioxidative activity measured by serum Se level is low in men with chronic alcoholic liver disease (during the abstinence period). 3. Increased selenium level in the hair may indicate the presence of certain antioxidative reserve, which requires further studies.

Case-Control Studies↗
PubMedDate not supplied

Hypermanganesemia in long-term intravenous nutrition and chronic liver disease.

BACKGROUND: Hypermanganesemia and cholestatic liver disease are both recognized complications of long-term IV nutrition. Manganese is primarily excreted in bile, and recent studies have indicated that manganese toxicity may play a role in the pathogenesis of IV nutrition-associated cholestasis. METHODS: Whole blood and plasma manganese concentrations were measured in patients receiving long-term home IV nutrition (HIN, n = 30). Whole blood manganese concentrations also were measured in patients with chronic liver disease (CLD, n = 10) and control subjects (n = 10). RESULTS: Whole blood manganese concentrations of all CLD patients were within the reference interval (73 to 210 nmol/L) and were not different from those of the control group (151 +/- 44 nmol/L, CLD vs 155 +/- 35 nmol/L, control; not significant), despite the presence of cholestasis. In contrast, whole blood manganese concentration was increased (>210 nmol/L) in 26 patients, and plasma manganese concentration increased (>23 nmol/L) in 23 of the patients receiving HIN. None of the patients exhibited neurologic signs of manganese toxicity. There was no correlation between whole blood manganese concentrations and markers of cholestasis, IV manganese intake, or duration of HIN. However, plasma manganese concentration correlated both with average weekly IV manganese intake (r = .44, p = .02) and with gamma-glutamyl transferase (r = .43, p = .02) and alkaline phosphatase activities (r = .55, p = .003). CONCLUSIONS: Cholestatic liver disease does not appear to contribute to increased whole blood manganese concentrations in patients not receiving HIN. Plasma manganese concentrations in patients receiving HIN reflect recent manganese exposure and impaired excretion where cholestasis is present. The lack of relationship between plasma and whole blood manganese concentrations suggests that factors other than manganese intake and excretion affect intracellular concentrations.

Adult↗
PubMed1992

Pregnancy in patients with chronic liver disease.

The pregnant patient with established chronic liver disease presents a unique situation in medicine. Although neither the pregnancy nor the liver disease is likely to specifically worsen the other, the combination can result in fatal complications for mother and infant. Fertility is decreased in patients with advanced liver disease and may provide a degree of protection for many patients who would be at increased risk should they become pregnant; however, pregnancy may occur even with advanced liver disease, and it is necessary to anticipate and plan for possible complications of the specific hepatic disease encountered. Counseling prior to pregnancy is the best policy, with consideration to transplantation prior to childbearing or to sterilization if it is more appropriate. Most problems associated with advanced liver disease are managed as in the nonpregnant patient; however, variceal bleeding may be a particularly difficult problem, and management here may necessitate portacaval shunt surgery.

Budd-Chiari Syndrome↗
PubMed2006

Liver disease selectively modulates cytochrome P450--mediated metabolism.

BACKGROUND: The liver plays a significant role in drug metabolism; thus it would be expected that liver disease may have a detrimental effect on the activity of cytochrome P450 (CYP) enzymes. The extent to which the presence and severity of liver disease affect the activity of different individual drug-metabolizing enzymes is still not well characterized. The purpose of this study was to assess the effect of liver disease on multiple CYP enzymes by use of a validated cocktail approach. METHODS: The participants in this investigation were 20 patients with different etiologies and severity of liver disease and 20 age-, sex-, and weight-matched healthy volunteers. Liver disease severity was categorized by use of the Child-Pugh score. All participants received a cocktail of 4 oral drugs simultaneously, caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and chlorzoxazone, as in vivo probes of the drug-metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, and CYP2E1, respectively. The primary end points were measurements of specific CYP metabolism indexes for each enzyme. RESULTS: Mephenytoin metabolism was significantly decreased in both patients with mild liver disease (Child-Pugh score of 5/6) (-63% [95% confidence interval (CI), -86% to -40%]; P = .0003) and patients with moderate to severe liver disease (Child-Pugh score >6) (-80% [95% CI, -95% to -64%]; P = .0003). In comparison with control subjects, the caffeine metabolic ratio was 69% lower (95% CI, -85% to -54%; median, 0.14 versus 0.62; P = .0003), the debrisoquin recovery ratio was 71% lower (95% CI, -96% to -47%; median, 0.10 versus 0.65; P = .012), and the chlorzoxazone metabolic ratio was 60% lower (95% CI, -91% to -29%; median, 0.21 versus 0.83; P = .0111) in patients with moderate to severe liver disease. All 4 drugs showed significant negative relationships with the Child-Pugh score. CONCLUSIONS: CYP enzyme activity is differentially affected by the presence of liver disease. We propose that the data can be explained by the "sequential progressive model of hepatic dysfunction," whereby liver disease severity has a differential effect on the metabolic activity of specific CYP enzymes.

Administration, Oral↗
PubMed2001

Pharmacokinetics of roxatidine acetate in patients with chronic liver disease.

BACKGROUND AND AIM: Patients with liver disease are prone to develop peptic ulceration and often receive H(2)-receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H(2)-receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H(2)-receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease. METHODS: Blood samples were obtained from 11 patients with chronic hepatitis, 11 patients with cirrhosis and six healthy subjects. Under fasting conditions, 75 mg of roxatidine acetate was administered orally, and plasma roxatidine levels were determined sequentially from 3 to 12 h. Relationships between pharmacokinetic variables and each parameter related to hepatic functions were also investigated. RESULTS: There was no difference in the pharmacokinetic variables and serum levels of roxatidine between chronic hepatitis and healthy controls. In contrast, in cirrhosis, serum roxatidine levels were significantly higher than those in chronic hepatitis and normal control. Half-life, the area under the plasma concentration-time curve and clearance in cirrhosis were also significantly longer, bigger and smaller than those in chronic hepatitis and healthy controls, respectively. The half-life became longer and the clearance became smaller in parallel with the progression of liver disease. Serum levels of hyaluronate and gamma-glutamyl transpeptidase showed a good correlation with half-life, clearance and elimination rate. A good correlation between creatinine clearance and elimination rate was found. CONCLUSION: Pharmacokinetics of roxatidine acetate is affected by hepatic function, and the dosage of roxatidine acetate for patients with liver disease, especially cirrhosis, should be modified.

Administration, Oral↗
PubMedDate not supplied

Alcohol dehydrogenase: an autoantibody target in patients with alcoholic liver disease.

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.

Adult↗
PubMed1999

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.

Animals↗
PubMed1998

Consumption of 'country liquor' and its relation to alcoholic liver disease in Mumbai.

The amount of alcohol intake required for the development of liver disease has been determined in Western populations; corresponding figures in Indians, many of whom consume locally brewed liquors, are not known. We studied 328 patients from a public hospital in Mumbai who admitted to regular alcohol consumption, to determine the pattern of alcohol consumption and its relation to liver disease. Liver disease was more common in those who consumed illicitly-brewed as compared to licit liquor. Daily drinking, volume of consumption > 200 ml per day, and duration of drinking > 14 years were each significantly more common in those with liver disease. A cumulative intake of > 2000 ml. years, calculated as the product of volume (ml per day) and duration (years), was a reliable cut-off level for association with liver disease (sensitivity 65%, specificity 77%) and cirrhosis (sensitivity 70%, specificity 59%). The content of alcohol in these liquors, estimated in 23 samples, ranged from 23-36.1 g/100 ml, being lower in the illicit liquors. Thus, in Mumbai, alcoholic liver disease occurs more commonly with consumption of illicit liquor (despite its lower alcohol content); liver involvement appears earlier and with lower consumption levels than in the West.

Adult↗