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PubMedDate not supplied

Mitochondrial glutathione depletion in alcoholic liver disease.

Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMedDate not supplied

The liver. Part 4: chronic liver disease.

Chronic liver disease and associated signs and symptoms present a challenge for clinical management as liver failure affects all body systems. While this part of the series concentrates on the physical symptoms of chronic liver disease, it needs to be remembered that these can also have many far-reaching implications for the patients' psychosocial well-being.

Adult↗
PubMed1998

Soluble complement receptor type 1 (sCR1) in chronic liver diseases: serum levels at different stages of liver diseases.

Complement receptor type 1 (CR1) is an integral membrane protein of many haematopoietic cells and plays an important role in the clearance of complement-associated immune complexes, favouring their transport to liver and spleen macrophages. A small amount of soluble CR1 (sCR1) is also found in plasma and might originate directly from release of leucocytes and other circulating cells. In previous studies, an increase in serum sCR1 level has been observed in liver cirrhosis and end-stage renal failure. High levels have also been found in patients with some haematologic malignancies. sCR1 serum levels were measured using a specific double sandwich ELISA assay. The present study demonstrates the correlation between mean serum sCR1 concentrations and disease severity in patients with chronic liver disease. In patients with liver cirrhosis, grouped according to the Child-Pugh classification, sCR1 rose as liver function decreased. The presence of neoplastic growth in the liver apparently does not play a role in the increase of sCR1. Serum sCR1 was not elevated in other solid malignancies. Since sCR1 accumulates in liver diseases, evaluation of its serum levels could be useful as a liver function test.

Carcinoma, Hepatocellular↗
PubMed1991

Coagulation activation in liver diseases.

In liver disorders alterations of the coagulation system are mainly due to a reduced synthesis of coagulation proteins. In addition, an enhanced intravascular consumption of coagulation factors is discussed controversely in liver diseases. By measuring factor IXiAT- and TAT-complexes we tried to find out, whether coagulation activation in liver patients leads to activation of the complete coagulation cascade followed by DIC or whether in some diseases a futile partial coagulation activation develops. In all liver diseases examined, elevated factor IXiAT-complexes were demonstrated, while TAT-complexes were only elevated in chronic active hepatitis, metabolic decompensated liver cirrhosis and in patients suffering from end stage liver disease. We conclude that all liver diseases examined lead to an activation of the coagulation cascade. A complete activation followed by DIC only occurs in patients with very severe liver disorders.

Antithrombin III↗
PubMed1994

The prognosis and outcome of alcoholic liver disease.

Alcoholic liver disease evolves from fatty change through alcoholic hepatitis to alcoholic cirrhosis. Its development is associated with an excess mortality both in relation to the presence of liver disease and to other complications of alcohol abuse. In the majority of patients fatty liver is a benign lesion which will reverse completely following abstinence from alcohol. Continued drinking is associated with the eventual development of cirrhosis in approximately 20% of individuals. Survival rates of 70% are reported both at 2 years and at 10 years. Alcoholic hepatitis is a precirrhotic lesion; progression to cirrhosis is observed more commonly in women, in individuals with severe disease and in those who continue to drink. Thirty-day mortality rates of less than 20% are observed in patients with mild to moderate disease but exceed 40% in individuals with severe liver injury. Corticosteroids may improve short term survival in a small subgroup of patients with severe alcoholic hepatitis. Survival rates of 55 to 60% are reported both at 2 years and at 10 years. Survival is significantly reduced in women and in the elderly and is adversely affected by the presence of severe liver injury, evolution to cirrhosis and continued drinking. Two-thirds of patients with alcoholic cirrhosis present with decompensated disease; 15% will develop hepatocellular carcinoma. Survival rates at 5 years vary from zero to 80%; 60 to 90% of individuals die of their liver disease. Survival is adversely affected by the presence of decompensated disease, superimposed alcoholic hepatitis, continued drinking and the development of hepatocellular carcinoma. The advent of hepatic transplantation, which has a 5-year survival rate in excess of 70%, will influence these survival figures.

Carcinoma, Hepatocellular↗
PubMed1991

Natural killer activity of human liver-derived lymphocytes in various liver diseases.

Liver-derived lymphocytes were isolated from 40 human livers with end-stage liver disease that were removed at the time of orthotopic liver transplantation. In addition, 10 resection specimens or whole livers removed from patients with liver cancer and seven normal livers (unused donor organs) were studied as controls. Liver-derived lymphocytes were isolated from enzymatically digested tissue by gradient centrifugation and adherence to plastic. Their phenotypical characteristics were studied by two-color flow cytometry, and effector cell function was determined in 4-hr 51Cr-release assays against a natural killer-sensitive target, K562 (natural killer activity), natural killer-resistant Daudi line (lymphokine-activated killer activity) and by P815 line with or without phytohemagglutinin to assess lectin-dependent cellular cytotoxicity. Liver-derived lymphocytes isolated from normal liver contained equal proportions of T and natural killer lymphocytes (mean natural killer/T ratio = 0.7). CD3-CD56+CD16- natural killer cells were the main natural killer subset present in liver-derived lymphocytes, in contrast to the predominant natural killer phenotype in the circulation (CD56+CD16+). Control liver-derived lymphocytes had levels of cytotoxicity significantly greater than those of the normal peripheral-blood lymphocytes against all three targets. In contrast, liver-derived lymphocytes isolated from organs with advanced liver disease differed markedly in the natural killer/T cell ratio and levels of liver-derived lymphocyte cytotoxicity. Liver-derived lymphocytes obtained from hepatocellular carcinoma or rejecting allografts treated by immunosuppressive therapy had virtually no cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

[Skin changes in liver diseases].

The liver is the second largest organ in the human body. An association between the skin and the liver has been recognized for centuries. Indeed, there is not always a correlation between the severity of the liver disease and the skin changes and they often are not specific. Several types of interaction between the skin and the liver are encountered: 1. Liver disease may cause skin changes. 2. The skin and the liver may be involved by the same pathologic process. 3. Skin disease may cause-liver abnormalities. 4. The liver may be damaged by drugs used to treat skin disease. In the following, the first two conditions are discussed.

Diagnosis, Differential↗
PubMed2000

Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation.

OBJECTIVE: Osteoporosis is frequently found in patients with cholestatic liver disease (primary biliary cirrhosis/primary sclerosing cholangitis) and chronic viral hepatitis. There is limited information about the long-term effect of liver transplantation (OLT) on bone metabolism. The aim of this study was to investigate the effect of liver transplantation on bone metabolism in patients with cholestatic and viral liver diseases. METHODS: We randomly recruited 193 patients with chronic viral hepatitis or cholestatic liver diseases. Bone density (Z-score) and markers of bone metabolism (intact parathyroid hormone [iPTH], PTH 70-84, osteocalcin, procollagen, telopeptide, and vitamin D) were determined before and at time points (< and > 24 months) post-OLT. RESULTS: Before OLT, bone density (Z-score) was decreased in patients with cholestatic (-1) and viral (-0.4) liver diseases. In both groups bone density continued to decrease in the periods up to and more than 24 months after OLT. In the cholestatic group, bone density decreased significantly compared to pre-OLT (p < 0.05) and to the viral hepatitis group (p < 0,001). Markers of bone metabolism showed that after OLT, bone metabolism was enhanced and shifted versus bone resorption. Immunosuppressive drug therapy (glucocorticoids, cyclosporin, FK 506) directly correlated with increased bone metabolism post-OLT. CONCLUSIONS: Bone loss is a long-term problem after OLT, particularly in patients with cholestatic liver diseases. Drug therapy is a main factor of bone loss. Pre- and post-OLT therapy to reduce bone loss is recommended.

Adult↗
PubMed1988

Cryptogenic chronic liver disease and serum or liver hepatitis B virus markers. Their possible correlations and etiologic significance.

In an attempt to evaluate a possible correlation between cryptogenic chronic liver disease and a present or past hepatitis B virus (HBV) infection, we studied 17 patients with hepatitis B surface antigen (HBsAg)-negative, nonalcoholic chronic liver disease; 9 of them were positive for serum HBsAg detected by a solid-phase enzyme immunoassay with monoclonal antibody (M-EIA) and 8 were negative for the same marker. Liver hepatitis B core antigen (HBcAg), studied by an indirect immunofluorescence technique, was present in 55.5% of the patients positive for serum HBsAg by M-EIA. In the same group of patients, liver HBV-DNA was found in 66.6% of the patients. On the other hand, only 1 patient without serum positivity for HBsAg by M-EIA was positive for liver HBcAg and HBV-DNA. None of our patients showed serum positivity for HBV-DNA sequences. We conclude that HBV infection may be a possible cause of cryptogenic chronic liver disease; this HBV-related, HBsAg-negative chronic liver disease seems to have no viral replication or undetectable levels of HBV-DNA in serum. HBsAg, detected by a monoclonal assay, seems to be a suitable marker to identify this subgroup of patients with HBsAg-negative chronic liver disease.

Antibodies, Monoclonal↗
PubMed2004

Diagnosis and therapy of alcoholic liver disease.

Alcoholic liver disease (ALD) presents considerable challenges to clinicians. Screening for alcohol abuse and alcoholism should be routine and repeated annually with close attention to signs and symptoms of liver disease. In patients with evidence of liver dysfunction or injury, consideration should be given to performance of liver biopsy for diagnosis and prognosis and prior to initiation of medication with the potential for significant side effects. Therapy depends on the spectrum of pathological liver injury: alcoholic fatty liver, alcoholic hepatitis, and cirrhosis. Abstention is the foundation of therapy for an alcohol problem. Alcoholic fatty liver should improve with abstention, but the similarity to the pathogenesis of nonalcoholic fatty liver and potential for progressive injury merits consideration of lipotropic agents. The continuing mortality, poor acceptance of corticosteroids, and identification of tumor necrosis factor-alpha (TNF-alpha) as an integral component has led to studies of pentoxifylline and, recently, anti-TNF antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidant therapy of alcoholic cirrhosis has significant promise but will require large clinical trials.

Adrenal Cortex Hormones↗
PubMed1997

Growth factors in children with end-stage liver disease before and after liver transplantation: a review.

Growth failure is a common observation in children with end-stage liver disease (ESLD). The liver is an important endocrine organ producing potent anabolic growth factors such as IGF-I (insulin-like growth factor-I) and its major binding-proteins, called IGFBP-1, -2 and -3. Circulating IGF-I and IGFBP-3 levels are low in children with chronic liver failure despite increased GH secretion. This discrepancy suggests that GH resistance is present in chronic liver failure and is mainly due to the associated malnutrition. The advent of orthotopic liver transplantation (OLT) has dramatically improved the life expectancy of children with ESLD. Nevertheless, the growth of 15-20% of the children in recent studies remains poor after successful transplantation. Several factors such as age and height deficit at the time of OLT, etiology of the liver disease and graft function as well as the dose and mode of administration of glucocorticoids have been implicated in the lack of complete catch-up growth following surgery. Few studies have explored the possibility that anomalies in the GH-IGF-I cascade could explain growth retardation. However, it is unlikely that major anomalies of the GH-IGF-I axis contribute to impaired growth. Treatment with GH alone or in combination with IGF-I before or after OLT may improve the growth of children. Randomized multi-center studies are needed to address this issue.

Child↗
PubMed2004

Recent Advances in Alcoholic Liver Disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease.

A significant body of evidence indicates that endotoxemia and endotoxin-mediated hepatocellular damage play a crucial role in the pathogenesis of alcoholic liver disease. A close correlation between endotoxemia and the severity of alcohol-induced liver injury is supported by a number of clinical and experimental studies. Elevated intestinal permeability appears to be the major factor involved in the mechanism of alcoholic endotoxemia and the pathogenesis of alcoholic liver disease. Ethanol and its metabolic derivatives, acetaldehyde in particular, alter intracellular signal-transduction pathways leading to the disruption of epithelial tight junctions and an increase in paracellular permeability to macromolecules. Studies addressing the mechanisms of such epithelial disruption and the protective factors that prevent ethanol and acetaldehyde-mediated disruption of epithelial tight junctions are critically important in the investigations toward the search of preventive and therapeutic strategies for alcoholic liver disease.

Animals↗
PubMed1998

Allograft rejection after liver transplantation for autoimmune liver diseases.

Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.

Adult↗
PubMed1995

Effect of alcohol use on allograft rejection rates after liver transplantation for alcoholic liver disease.

Alcoholic liver disease is a major cause of liver disease and has become an ever-increasing indication for liver transplantation (LTx). Follow-up studies have reported a higher rate of alcohol recidivism in patients transplanted for alcoholic hepatitis, compared with those transplanted for endstage alcohol-associated cirrhosis. It is assumed widely that recurrent alcohol use is associated with reduced compliance with immune suppression and, as a result, an increased risk of graft rejection and loss. To assess this question, 209 alcoholic patients transplanted for either alcoholic hepatitis with cirrhosis or cirrhosis alone between January 1, 1986 and December 31, 1991 were followed, with a mean follow-up of 4.4 +/- 0.6 years. There were 175 episodes of acute cellular rejection (ACR) that occurred in 137 patients, for an overall rejection rate of 83.7% or at a rate of 1.25 episodes/patient with rejection. The rate of ACR was three times as great in those who remained alcohol-abstinent (2.24 episodes/patient), compared with those who admitted to continued alcohol use (0.75 episodes/patient) (p < 0.01). A total of 33 episodes of chronic rejection occurred in 26 patients, for an overall rate of 12.4%. As was the case for ACR, the chronic rejection rate was greater among those who were continuously alcohol-abstinent, compared with those who intermittently used alcohol after successful LTx. There were no differences in the mean FK 506 or cyclosporin A levels in the groups with and without a rejection episode at the time the rejection episode was documented by liver biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Autonomic dysfunction in chronic liver disease.

Chronic liver disease is accompanied by a number of circulatory changes including impairment of cardiovascular autonomic reflexes. This occurs irrespective of the aetiology of liver disease, increases in prevalence and severity with worsening hepatic function, and is related at least in part to an autonomic neuropathy. Parasympathetic abnormalities predominate and, although largely subclinical, they may play a role in the altered fluid homeostasis and neurohumoral disturbances associated with cirrhosis. On prospective follow up, the presence of autonomic impairment was associated with a five-fold increased mortality, largely from sepsis and variceal haemorrhage. Defective responses to such stressful events as a result of an afferent defect could possibly explain these findings. Further studies are required to evaluate the natural history of this complication, and determine if it is reversible with improvement in hepatic function or after liver transplantation.

Autonomic Nervous System Diseases↗