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PubMedDate not supplied

Hepatocyte proliferation and apoptosis in relation to oxidative damage in alcohol-related liver disease.

In alcohol-related liver disease, free radicals play a part in the pathogenesis of liver damage and may influence cell turnover. The aims of this study were to correlate lipid peroxidation, antioxidant defence and iron metabolism with cell proliferation and apoptosis in alcoholic liver injury, and also in comparison with virus-related liver disease. In 45 patients [10 with chronic alcoholic liver damage (CALD), 24 with HCV-related (HCV) and 11 with HBV-related chronic hepatitis (HBV)], and 10 control subjects, we investigated serum ferritin, liver tissue iron, cysteine, reduced/oxidized glutathione, malondialdehyde, histology with hepatocyte proliferation and the apoptotic index. Ferritin, iron levels and malondialdehyde were significantly higher in HCV and CALD than in HBV, and malondialdehyde correlated with both iron and ferritin. Glutathione levels were significantly lower in CALD than in HCV, HBV and control subjects, whereas cysteine levels were significantly higher. The apoptotic index was slightly lower in CALD, with apoptosis occurring more frequently in the centrilobular area, while CALD had fewer proliferating hepatocytes, both overall and in the periportal and centrilobular areas. This study confirms that chronic alcohol intake: (1) induces more peroxidative damage, which correlates with iron loading; (2) reduces antioxidant defence, lowering reduced glutathione liver availability; (3) induces an accumulation of cysteine, a glutathione precursor/metabolite in the liver, probably due to gamma-glutamyltransferase induction; (4) correlates with a lesser extent and different distribution of hepatocyte proliferation and apoptosis than in viral liver damage. This last finding may explain the different types of liver cirrhosis deriving from alcoholic liver damage and the lower cancer risk.

Adult↗
PubMed1999

[The usefulness of transjugular hepatic biopsy in the evaluation of liver disease in candidates for heart transplantation].

Heart transplantation is a universally accepted procedure in the treatment of terminal heart diseases. However, the presence of advanced liver disease in the potential receptors represents a contraindication for heart transplantation. On the other hand, the true diagnosis of liver disease not secondary to heart disease may be difficult requiring confirmatory liver biopsy. Nonetheless, percutaneous liver biopsy may be difficult to perform due to presence of coagulation alterations, marked dilatation of the hepatic veins, etc. The aim of this study was to evaluate the efficacy and safety of transjugular hepatic biopsy in the presence of severe coagulopathy in potential heart transplantation receptors with suspicion of liver disease and contraindication of percutaneous liver biopsy. Over a 9-year period, 350 potential heart transplantation patients were evaluated. In 23 patients (6.7%) transjugular hepatic biopsy was performed with aspiration needle followed by a hemodynamic study in 17 cases. The transjugular hepatic biopsy was completed in 22 cases (95.6%) with adequate material for the diagnosis being obtained in 21 (91.3% of the total cases indicated). Histologic study showed significant inflammatory infiltrates or alteration of the hepatic architecture in 4 patients (18%), all being positive for some viral markers (AgHBs or anti-HCV). The obtaining of a certain histologic diagnosis modified the consideration of liver disease as a definitive contraindication and allowed the performance of heart transplantation in 17 patients (73.9%). No complications were observed in association with the procedure. The transjugular hepatic biopsy is a feasible, effective and safe alternative for obtaining liver tissue in patients under evaluation for heart transplantation with suspicion of severe liver disease. The establishment of a correct histologic diagnosis may modify the clinical decision in an important number of patients.

Biopsy↗
PubMed1981

Influence of range of renal function and liver disease on predictability of creatinine clearance.

Several formulas for predicting creatinine clearance (Ccr) are used for adjusting drug dosages but limited data are available on their accuracy in patients with significant renal impairment or concurrent disease. We measured 144 Ccr in 103 patients and compared results using four predictive methods. Of nine common diseases in these patients, liver disease was associated with a large (p less than 0.02) prediction error (overprediction). After data from eight patients with liver disease were removed, there was good overall correlation between predicted and measured Ccr (r2 = 0.91 for each method) but only two of the methods (I and IV) were consistently accurate in all ranges of renal function. Methods for predicting Ccr should not be used in patients with liver disease.

Adolescent↗
PubMed1997

Review: molecular approaches to inherited liver disease. Focus on Wilson disease.

Although infectious agents account for a large proportion of liver disease, inherited forms of liver disease, often treatable, must not be overlooked. New approaches to the cloning of disease genes are allowing an increased understanding of the basic defect of human diseases. Identification of disease genes can have practical applications for diagnosis, can provide information on prognosis and can lead to new therapies. This review focuses on selected inherited liver diseases and the knowledge to be gained from molecular studies. Three genetic diseases affecting the liver, Wilson disease, haemochromatosis and alpha 1-antitrypsin deficiency, are selected as examples of current approaches to the study of genetic liver disease.

Hemochromatosis↗
PubMed1978

Hepatotoxicity in patients with liver disease.

The biochemical and physiological disturbances caused by liver disease may enhance the toxicity of drugs. Besides alterations in liver blood flow and drug binding, a decreased rate of drug metabolism is an important phenomenon. Studies with phenazone, a model drug, demonstrates that the rate of microsomal drug metabolism is related to the degree of metabolic hepatic impairment. Individual dosage adjustments in patients with liver disease are complicated for many drugs, because of the counteracting influences of a decreased hepatic blood clearance and an increased free fraction of drug which may enhance drug metabolism and drug action. Moreover, many drugs owe part of their pharmacological action to active metabolites formed in the liver. Finally, little is known about altered receptor sensitivity in patients with liver disease. Non-predictable hepatotoxic reactions appear not to occur more frequently in patients with liver disease than in other patients. However, hepatotoxicity may be masked by the liver disease or by the intake of ethanol.

Chemical and Drug Induced Liver Injury↗
PubMed1990

Hepatic alcohol dehydrogenase activity in alcoholic subjects with and without liver disease.

Alcohol dehydrogenase activity was measured in samples of liver tissue from a group of alcoholic and non-alcoholic subjects to determine whether decreased liver alcohol dehydrogenase activity is a consequence of ethanol consumption or liver damage. The alcoholic patients were classified further into the following groups: control subjects with no liver disease (group 1), subjects with non-cirrhotic liver disease (group 2), and subjects with cirrhotic liver disease (group 3). The non-alcoholic subjects were also divided, using the same criteria, into groups 4, 5, and 6, respectively. The analysis of the results showed no significant differences when mean alcohol dehydrogenase activities of alcoholic and non-alcoholic patients with similar degrees of liver pathology were compared (groups 1 v 4, 2 v 5, and 3 v 6. Alcohol dehydrogenase activity was, however, severely reduced in patients with liver disease compared with control subjects. Our findings suggest that alcohol consumption does not modify hepatic alcohol dehydrogenase activity. The reduction in specific alcohol dehydrogenase activity in alcoholic liver disease is a consequence of liver damage.

Alcohol Dehydrogenase↗
PubMed2004

Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease.

BACKGROUND AND AIMS: The adverse effect of acute hepatitis A in chronic liver disease is well known. The outcome of acute hepatitis E in chronic liver disease has not been extensively studied. The present study aimed to examine the clinical profile and outcome of patients with chronic liver disease and hepatitis E virus (HEV) superinfection, and the seroprevalence of hepatitis A and E infections in patients with chronic liver disease and controls in India. METHODS: A retrospective study of patients with chronic liver disease and acute icteric hepatitis E was performed. Acute hepatitis E was diagnosed by immunoglobulin (Ig)M ELISA. Seroprevalence studies were carried out using IgG ELISA in 100 patients with chronic liver disease and 79 age- and sex-matched controls. RESULTS: From June 2001 to December 2002, nine patients with chronic liver disease were found to have superinfection with HEV. Out of these, six patients died of advanced liver failure. The etiology of liver disease was Wilson's disease in six, hepatitis B virus in one, autoimmune in one and cryptogenic in one case. The seroprevalence of hepatitis A was 99 and 100% and 56 and 21% for HEV in cases and controls, respectively. CONCLUSIONS: Acute HEV in patients with chronic liver disease has a grave prognosis. Wilson's disease was the most common cause of chronic liver disease complicated by acute HEV. Seroprevalence studies showed that 44% of patients with chronic liver disease were at risk of developing hepatitis E. Hepatitis E vaccine, when available, is indicated for use in this group.

Acute Disease↗
PubMed2004

Drug-induced liver disease in 2003.

Drug-induced liver disease remains an important topic of concern for all prescribers as well as drug manufacturers. The withdrawal of troglitazone (Rezulin) and bromfenac (Duract) a few years ago remains fresh in the minds of regulatory authorities as well as clinicians and researchers who are focusing renewed attention on ways to better understand mechanisms of injury to predict and avert serious drug-induced liver disease in the future from drugs under development as well as existing agents known to cause liver injury. As in past years, this review describes new and first-time reports of various aspects of drug-induced liver disease for several classes of compounds, including herbal products (such as kava kava), reviews the risk factors seen with antiretroviral and antituberculosis agents among others. It provides a sampling of experimental hepatoprotection studies that may hold the key to treatment and prevention of drug-induced liver disease in the future and discusses the ongoing approaches to be taken to restrict the availability of acetaminophen that have proved successful in reducing the number of overdoses, deaths, and liver transplantations from this drug in the United Kingdom. Given the fact that acetaminophen is the single most important cause of acute liver failure here and abroad, such efforts to limit its use seem appropriate for other nations as well.

Journal Article↗
PubMed2006

The epidemiology of nonalcoholic fatty liver disease in adults.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that has been shown to progress to cirrhosis and hepatocellular carcinoma. This article reviews the prevalence of NAFLD and the factors associated this disorder, and with the more advanced stages of NAFLD, including nonalcoholic steatohepatitis (NASH) and fibrosis. In the general population, the estimated prevalence ranges from 3% to 24%, with most estimates in the 6% to 14% range. NAFLD is extremely common among patients undergoing bariatric surgery, ranging from 84% to 96%. In these patients, 25% to 55% have NASH, 34% to 47% have fibrosis, and 2% to 12% have bridging fibrosis or cirrhosis. NAFLD appears to be most strongly associated with obesity, and insulin resistance states including diabetes and with other features of the metabolic syndrome, such as high triglycerides and low HDL. It appears to be more common in men, and it increases with increasing age and after menopause. Some data suggest that Mexican Americans are more likely to have NAFLD and blacks are less likely compared with non-Hispanic whites. More advanced stages of NAFLD are associated with older age, higher body mass index, diabetes, hypertension, high triglycerides, and/or insulin resistance. An AST/ALT ratio greater >1 may also indicate more severe disease. Although hepatocellular carcinoma can occur in the setting of NAFLD, the risk factors for hepatocellular carcinoma in the setting of NAFLD have not been established. More prospective studies are needed to determine the true risk factors for the development and progression of NAFLD to help identify patients at highest risk who might benefit from treatment trials.

Carcinoma, Hepatocellular↗
PubMed1999

Effect of schistosomiasis and hepatitis on liver disease.

Infection with hepatitis C virus (HCV) has become the most important public health problem in Egypt. In Egypt, viral hepatitis along with infection with Schistosoma mansoni is the major cause of chronic liver disease and liver cirrhosis. Although HCV infection is highly prevalent in Egypt, very little information is available on the distribution of the different genotypes of HCV. Our aims in this study were first to determine the prevalence of viral and parasite infections in patients with chronic liver disease and then to assess the distribution of HCV genotypes in these patients. In the present study, 151 individuals (50 with chronic liver disease, 51 with chronic diseases of organs other than the liver, and 50 apparently healthy persons) were investigated. The last 2 groups served as control groups. These individuals were subjected to routine liver function tests and detection of serum antibodies to bilharziasis, hepatitis B surface antigen (HBsAg), and HCV. Furthermore, the presence of hepatitis G virus (HGV) and HCV in the serum samples were tested for by a reverse transcription polymerase chain reaction (RT-PCR). Prevalence of different genotypes of HCV in patients positive for HCV were determined by RT-PCR using type-specific primers. Results of the study revealed that 84, 74, 12, and 20% of patients with chronic liver disease were positive for Schistosoma mansoni, HCV, HBsAg, and HGV, respectively, as compared to 51, 43.1, 2, and 4% of patients with other chronic diseases and 22, 6, 0, and 0% of apparently healthy individuals. One hundred percent of patients with chronic liver disease, 72.5% of those with other diseases, and 26% of normal controls were shown to have at least one of the studied infectious agents. Two or more of the agents were highly coincident in patients with chronic liver disease. In Egypt, HCV genotype 4a is highly prevalent, where it contributed 85% of the tested samples in comparison to 10, 2.5, and 2.5% for subtypes 1b, 2a, and 3a, respectively. In conclusion, these results suggest that in Egypt, HCV along with schistosomal parasite infection is the major risk factor for chronic liver disease. In most Egyptian patients, HCV genotype 4 is highly prevalent.

Adult↗
PubMed1998

Cobalamin (vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease.

OBJECTIVE: We wanted to know if alterations in plasma cobalamin (B12) concentration and B12 carriers, e.g., holotranscobalamins (holo TC), occur in blood and liver tissue from patients with severe alcoholic liver disease. Our purpose was to test the hypothesis that liver disease may disrupt B12 distribution. METHOD: Total B12, as well as B12 bound to transcobalamin I, II, III (holo TC), were measured to determine their concentration in plasma and in liver tissue; Poteriochromonas malhamensis--a protozoan reagent served to measure only metabolically active (true) B12. Total B12 as distributed in holo TC in plasma and liver tissue of healthy subjects (controls) were compared to patients with severe alcoholic liver disease. RESULTS: Severe liver disease initiates highly elevated B12 levels in plasma and a lowered liver tissue total B12 concentration. The percent of B12 distributed to holo TC II is significantly depleted during liver disease. In contrast, holo TC I and III are elevated in plasma during liver disease and contain more B12 than controls. Total B12 and B12 distributed to TC are lower in diseased liver tissue. CONCLUSION: Severe alcoholic liver disease involves leakage of total B12 from liver tissue into the plasma. Holo TC I and III concentration increases in plasma; this preserves the high plasma B12 from being excreted. However, plasma holo TC II B12 distribution is decreased, indicating that there is a depression of exogenous B12 entering the plasma and tissues. In severe liver disease, liver tissue B12 binding and storage by TC is disrupted and causes B12 to leak out of the liver into the circulation. Eventually liver disease could produce enough severe tissue B12 deficits to cause metabolic dysfunction despite elevated plasma total B12. Elevation of plasma B12, accompanied by a lowering of holo TC II distribution, seemed to be a useful index of liver disease severity suggesting preventive treatment.

Humans↗
PubMed2004

Combined 'en bloc' liver and pancreas transplantation in patients with liver disease and type 1 diabetes mellitus.

Liver disease alters the glucose metabolism and may cause diabetes, but this condition is potentially reversible with liver transplantation (LTx). Type 1 diabetes mellitus may be coincidentally present in a LTx candidate and immunosuppressive drugs will aggravate diabetes and make its management more difficult for posttransplant. In addition, diabetes negatively influences outcome after LTx. Therefore, the question arises as to why not transplanting the pancreas in addition to the liver in selected patients suffering from both liver disease and Type 1 diabetes. We report two cases of en bloc combined liver and pancreatic transplantation, a technique originally described a decade ago in the treatment of upper abdominal malignancies but rarely used for the treatment of combined liver disease and Type 1 diabetes. Both recipients are currently liver disease-free and insulin-free more than 2 and 4 years posttransplant, respectively. Surgical, medical and immunological aspects of combined liver-pancreas transplantation are discussed in the light of the existing relevant literature.

Adult↗
PubMed2003

Immunogenicity and safety of hepatitis A vaccine in children with chronic liver disease.

BACKGROUND: Acute hepatitis A superimposed on chronic liver disease has been associated with a more severe course of disease and development of fulminant hepatitis. The aim of this study was to evaluate the immunogenicity and safety of an inactivated hepatitis A virus vaccine in children with chronic liver disease. PATIENTS AND METHODS: This was an open, prospective, and controlled trial with 89 anti-HAV negative children between 1 and 16 years of age studied at a pediatric liver disease and transplantation referral center. Inactivated HAV vaccine (Havrix), from GlaxoSmithKline Biologicals containing 720 Elisa units of alum-adsorbed hepatitis A antigen per 0.5 ml dose was used. Thirty-four pediatric patients with chronic liver disease (mean age: 7.0 +/- 4.86 years) and 55 healthy controls (mean age: 4.8 +/- 2.7 years) received two doses of Havrix vaccine in months zero and six. Seroconversion and anti-HAV titers expressed as geometric mean titers (GMT) in mIU/ml were measured at months one and seven, by a modified Hepatitis A virus antibodies (HAVAB) assay. RESULTS: Seroconversion rates at four weeks after primary immunization were 76% and 94% and the GMT 107.77 and 160.77 mIU/ml in the patient and control groups, respectively. One month after second dose the seroconversion rates were 97% and 100% in the groups with GMT of 812.40 and 2,344.90 mIU/ml. Both doses were well tolerated with no significant adverse events observed. Local injection-site symptoms were the most common reactions reported in both groups. CONCLUSION: Although GMTs were significantly lower in children with chronic liver disease compared to healthy controls, the overall seroconversion rates were not different. Hepatitis A virus vaccine was safe, well-tolerated, and immunogenic in children with chronic liver disease.

Adolescent↗
PubMed1999

Cholesterol-derived hydroperoxides in alcoholic liver disease.

Human liver samples from 33 patients were collected at autopsy (controls, n = 9; fatty liver, n = 12; liver cirrhosis, n = 12), and samples homogenized. Lipids extracted with chloroform and methanol were injected into the octyl column of a high-performance liquid chromatograph with post-column chemiluminescence. Liquid chromatography-mass spectrometry was developed to identify 7-hydroperoxycholest-5-en-3 beta-ol (7-OOH). We found that two cholesterol-derived hydroperoxides, 7 alpha-hydroperoxycholest-5-en-3 beta-ol (7 alpha-OOH) and 7 beta-hydroperoxycholest-5-en-3 beta-ol (7 beta-OOH), are present in significantly elevated amounts (12.4 and 25.0 nmol/g tissue, respectively) in lipid extracts from alcoholic fatty liver, but not in extracts from alcoholic cirrhotic liver. 7 alpha-OOH and 7 beta-OOH are early intermediates produced during free radical-mediated cholesterol oxidation and can serve as molecular indicators of chain peroxidative damage in cell membranes. This is the first demonstration of 7 alpha-OOH and 7 beta-OOH accumulations in human liver, and it is presumed to reflect greater oxidative stress pathology in alcoholic fatty liver.

Adult↗
PubMed2002

Variant estrogen receptors and their role in liver disease.

The liver presents estrogen receptors alpha and beta. As for breast cancer, a variant form of estrogen receptor alpha transcript (ER) has been described in hepatocellular carcinoma (HCC). It is derived by an exon 5-deleted transcript (vER), which lacks the hormone-binding domain of the receptor but, being intact in the DNA-binding domain, maintains constitutive transcriptional activity. HCCs presenting vER have an extremely aggressive clinical course and are unresponsive to the antiestrogen tamoxifen. On the other hand, megestrol, a drug able to block both the wild type and the variant form of ER, influence the clinical course of HCC presenting vER. The presence of vER is associated with elevated cancer cell proliferation rate.

Apoptosis↗
PubMed1980

Serum glutathione S-transferase activity in liver diseases.

Assay conditions of human liver glutathione S-transferase and its activity in human serum from liver disease patients were investigated. One mmol/l reduced glutathione, and 1 mmol/l-1-chloro-2,4-dinitrobenzene, pH 6.5, were used for the measurement, because of the very low non-enzymatic conjugation. Glutathione S-transferase activity was inhibited by bilirubin, but this inhibition was counteracted by the presence of a low concentration of albumin. The normal human serum glutathione S-transferase activity was 5.2 +/- 2.4 I.U./l (mean +/- S.D.), and was not influenced by any differences of age, sex or leukocyte count. A significant increase in serum enzyme activity was noted in cases of acute hepatitis with GPT exceeding 200 I.U./l, primary hepatoma and metastatic liver cancer. Some of the cases with fulminant hepatitis showed extremely high values. The degree of correlation between serum glutathione S-transferase and GOT or GPT was high in acute hepatitis, with GOT or GPT exceeding 200 I.U./l, in fulminant hepatitis, primary hepatoma and gall stones, while in chronic hepatitis and liver cirrhosis it was low. In cases of acute hepatitis and fulminant hepatitis, the disappearance of serum glutathione S-transferase from the blood was much faster than that of GOT and GPT. Serum glutathione S-transferase measurements will provide new and unique information for the diagnosis of acute liver diseases.

Adult↗
PubMedDate not supplied

Carbohydrate-deficient transferrin in alcoholics with liver disease.

To assess the relationship between carbohydrate-deficient transferrin (CDT) and alcoholic liver disease, we measured the ratio of carbohydrate-deficient transferrin to total transferrin (rCDT) in 32 male alcoholics with liver disease (Child-Pugh class A, 8; B, 11; C, 13) and 14 male alcoholics without clinically evident liver disease. Twenty of 32 with liver disease and six of 14 without clinically apparent liver disease had recent abstinence. The 32 patients with liver disease were assessed, in addition to the Child-Pugh class, using a linear prognostic score, the Combined Clinical and Laboratory Index (CCLI). Transferrin and CDT were measured by isocratic anion exchange chromatography and a radio-immunoassay. When the total group (n = 46) was divided into those with recent abstinence (n = 26) and those without (n = 20), the rCDT was lower in the abstainers than non-abstainers (0.7 +/- 0.6 vs 2.9 +/- 2.4, P < 0.005). Similarly, abstainers with liver disease (n = 20) had a significantly lower rCDT than non-abstainers (n = 12) with liver disease (0.7 +/- 0.7 vs 3.5 +/- 2.8, P < 0.005). The rCDT in the 20 abstaining patients with liver disease did not differ significantly between Child-Pugh classes. Furthermore, there was no correlation between the CCLI and rCDT (r = 0.05). We conclude that the relationship between rCDT and alcohol abuse is not appreciably altered by the presence of clinically severe liver disease in male alcoholics.

Alcoholism↗
PubMed1977

Liver disease in renal transplant recipients.

Significant liver disease developed in 14 patients after renal transplantation. Nine patients had morphologic and functional evidence of chronic active hepatitis. In general, these patients had few symptoms of liver disease, even though the course of chronic active hepatitis was progressive. Despite large doses of prednisone, cirrhosis ultimately developed in five patients. The cause of chronic active hepatitis could not be related to azathioprine or methyldopa therapy because there was no perceptible change in the course of liver disease after treatment with these drugs was stopped. Three patients were persistently positive for hepatitis B surface antigen. Isolated instances of granulomatous hepatitis (Mycobacterium kansasii) and of prolonged intrahepatic cholestasis were encountered in patients with chronic active hepatitis. Two patients had acute cytomegalovirus hepatitis. There was one episode each of fulminant herpes simplex hepatitis and severe fatty metamorphosis.

Adolescent↗