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PubMed1983

Lipoprotein metabolism in liver disease.

Liver disease is associated with abnormalities in plasma lipids and lipoprotein structure and metabolism. These abnormalities are not specific for the type of liver disease. The severity of the changes does, however, parallel the severity of the liver disease. Lipoprotein abnormalities may also have prognostic significance; but there is no good correlation between the abnormalities in plasma lipoproteins and more standard liver-function tests. Due to the marked derangements that occur in lipoproteins, liver disease provides a useful model to study lipoprotein metabolism.

Apolipoproteins↗
PubMed2004

Factor VIII expression in liver disease.

Liver disease is associated with markedly elevated plasma factor VIII (FVIII) levels, whereas the synthesis of many other coagulation factors and proteins is reduced. In order to define the mechanism of FVIII increase, we have determined the expression levels of FVIII, both at mRNA and protein level, in patients with liver disease who underwent partial liver resection. In addition, the expression of von Willebrand factor (VWF) and low density lipoprotein receptor-related protein (LRP), proteins known for their ability to modulate FVIII plasma levels, were examined. Tissue samples for RNA extraction were obtained from 4 patients with cirrhosis, 9 patients with liver failure without cirrhosis and 6 patients with liver metastasis of a colon or rectum carcinoma (control group). In patients with liver cirrhosis hepatic FVIII and LRP mRNA levels were significantly lower than controls (p < or = 0.010), while VWF mRNA was significantly higher (p < or = 0.050). Immunohistochemical analysis revealed that cellular VWF protein distribution was also increased in cirrhotic livers compared to liver tissue from patients with non-cirrhotic liver disease. In cirrhotic tissue enlarged portal veins appeared to overgrow FVIII producing sinusoidal endothelial cells. Similarly, the number of LRP-producing cells appeared to be lower in cirrhotic tissue than in controls. The plasma concentration of both FVIII and VWF was significantly higher in patients with cirrhosis than control subjects (p = 0.038 and 0.010 respectively). These results demonstrate that elevated plasma FVIII levels in liver cirrhosis are associated with increased hepatic biosynthesis of VWF and decreased expression of LRP, rather than increased FVIII synthesis.

Adult↗
PubMed2003

Parenteral nutrition associated liver disease.

Liver disease is relatively common during parenteral nutrition (PN). Cholestasis predominates in infants, and ranges in severity from mild increases in plasma conjugated bilirubin to progressive liver failure that results in death of the patient. Severity of liver disease depends primarily on the magnitude of the underlying intestinal problem that indicated PN. Transient ileus resulting from a non-intestinal disorder usually results in trivial, self-limited liver injury. Removal of a large segment of the intestinal tract because of necrotizing enterocolitis or a congenital malformation predicts a more prolonged course with a guarded prognosis, particularly when initially complicated by sepsis. Pathogenesis of PN-associated liver disease is not completely understood. There is no proven treatment short of ending PN through adaptation of remnant intestine or intestinal transplantation, with or without a concurrent liver graft. Effective interventions that are less radical than transplantation are needed. Research that includes prospective trials of novel therapies in PN-associated liver disease is the key to improving outcome.

Humans↗
PubMed2002

Nutrition management in chronic liver disease.

Liver has a central role in nutritional homeostasis and any liver disease leads to abnormalities in nutrient metabolism and subsequent malnutrition. All children with chronic liver disease (CLD) must undergo a periodic nutritional assessment--medical history, anthropometry esp. skinfold thickness and mid-arm circumference, and biochemical estimation of body nutrients. Nutritional rehabilitation is catered to the individual child but generally the caloric intake is increased to 130% of RDA by adding glucose polymers and/or MCT oil (coconut oil) with essential fatty acid supplementation (sunflower oil). The enteral route is preferred and occasionally nasogastric and/or nocturnal feeding are required to ensure an adequate intake. Proteins rich in branched chain amino acids are given in moderation (2-3 gm/kg/day) in compensated cirrhotics unless encephalopathy occurs when protein restriction may be necessary (1 gm/kg/day). Fat-soluble vitamins are supplemented in large quantities esp. in cholestasis along with other vitamins and minerals. Dietary therapy is the mainstay of management of some metabolic liver diseases and may be curative in disorders like galactosemia, fructosemia and glycogen storage disorders. Pre and postoperative nutritional support is an important factor in improving survival after liver transplantation.

Cholestasis↗
PubMed1989

The role of transplantation in liver disease.

Liver transplantation is rapidly emerging as the most effective treatment pathway for a growing number of acute and chronic liver disease states. Indications and contraindications to transplant are undergoing continuous revision and clarification as experience is accrued in the expanding number of treatment centers. For some disorders such as primary biliary cirrhosis, sclerosing cholangitis, and chronic active hepatitis with cirrhosis, the role of transplantation in patient management is obvious. For other hepatic diseases such as primary hepatic neoplasm, clear definition of the role of transplantation is likely to await development of improved early diagnostic techniques and more effective chemotherapy regimens. Standardization of the technical aspects of liver transplant and recent advances in graft preservation have led to reduction in the logistical problems that previously plagued this complex therapy. Refinements in immunosuppression with the introduction of cyclosporine and monoclonal antibody therapy have extended chances for survival and contributed to considerable improvement in quality of life following transplant. Further extension of transplantation as a treatment option to individuals with liver disease will require the concerned effort of the primary care or referral physician in the early recognition and management of patients with liver disease.

Adult↗
PubMed2005

Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease.

Liver disease in alpha-1-antitrypsin (alpha1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial- and ER-caspase activation, and nuclear factor kappaB (NFkappaB) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of alpha1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective proliferative advantage. Further, this paradigm may apply to other genetic and infectious liver diseases that are predisposed to hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed1984

Antithrombin III metabolism in patients with liver disease.

Liver diseases are associated with complex haemostasis defects, in which platelets, coagulation, and fibrinolysis may all be affected. The low plasma concentrations of clotting factors often found can be the result of many changes such as impaired synthesis, increased catabolism due to intravascular coagulation, or alternate distribution. In this study, we investigated the metabolism of purified human antithrombin III(AT III) labelled with 125I in 25 patients with histologically established liver disease and in nine control subjects. The results showed that, in general, low plasma concentrations of AT III in liver cirrhosis are not due to consumption in the central compartment but rather to altered transcapillary flux ratio. Such altered transcapillary flux ratios may already exist even with normal plasma AT III concentrations. Altered ratios are not only found for coagulation proteins but also for albumin and thus may be a general phenomenon of liver disease. In micronodular cirrhosis the alpha phase, the transcapillary efflux (k1, 2) and influx (k2, 1) were significantly increased compared with the normal subjects.

Antithrombin III↗
PubMed2006

Kupffer cells and alcoholic liver disease.

Liver disease is a major cause of illness and death worldwide. A central component in the complex network leading to the development of alcoholic liver disease is the activation of Kupffer cells by endotoxin and other soluble mediators. Alcohol consumption induces a state of "leaky gut increasing plasma and liver endotoxin levels. When Kupffer cells become activated, they interact with a complex of proteins located on the extracellular membrane signaling to produce a wide array of soluble factors, including cytokines, chemokines, growth factors, cyclooxygenase and lipoxygenase metabolites, and reactive oxygen species such as superoxide anion, hydrogen peroxide, and nitric oxide, all of which provide physiologically diverse and pivotal paracrine effects on all other liver cell types and, ultimately, liver injury. Kupffer cells are also central to the liver homeostatic response to injury as upon cellular degenerative changes, they immediately respond to the insult and release mediators to orchestrate inflammatory and reparative responses. Thus, the homeostatic responses are initiated by Kupffer cell-derived mediators at the cellular level and underlie the liver s defense and reparative mechanisms against injury. In order to understand better the role of Kupffer cells in the onset of liver injury, animal models in which Kupffer cells are inactivated, and cell culture settings (e.g. co-cultures) are being used with promising results that advance our understanding of alcoholic liver disease.

Animals↗
PubMed1999

Liver diseases.

Liver diseases in the elderly often reflect an age-associated decrease in the capacity to respond to metabolic and infectious insults. Because the geriatric population is growing rapidly, physicians can expect to encounter an increasing number of older patients with liver disease. In this article, the authors discuss the clinical manifestations of the most common liver diseases seen in the geriatric population.

Aged↗
PubMed1989

Alcoholic liver disease.

Liver injury may develop in some people who consume alcohol. The pathogenesis of liver damage in such subjects remains obscure. Major histopathologic features of alcohol-associated liver injury include steatosis, steatonecrosis, and cirrhosis. The clinical manifestations of alcoholic liver disease are nonspecific and range from asymptomatic hepatomegaly to stigmata of portal hypertension with advanced parenchymal failure. The severity of the clinical presentation and the degree of aminotransferase elevation correlate poorly with the liver histopathology, particularly in patients who continue to drink alcohol. Short-term mortality of such patients is best predicted by a composite of clinical and laboratory parameters that are influenced by alcohol consumption as well as by liver disease. Long-term prognosis is determined by residual damage to vital organs (that is, whether or not cirrhosis has developed) and whether or not the patient continues to drink. Current therapy of alcoholic liver disease includes abstinence and correction of nutritional deficiencies. Other therapies are experimental and are best utilized in the setting of controlled clinical trials.

Alcoholism↗
PubMedDate not supplied

A randomized trial of solvent/detergent-treated and standard fresh-frozen plasma in the coagulopathy of liver disease and liver transplantation.

BACKGROUND: Virus inactivation of pooled fresh-frozen plasma (FFP) by the solvent/detergent (SD) method results in a loss of approximately 20 percent of factor VIII. This study aimed to assess the efficacy of SD-treated plasma in correcting the coagulopathy associated with liver disease and liver transplantation. STUDY DESIGN AND METHODS: Forty-nine patients with coagulation deficits due to liver disease, who required FFP for invasive procedures or liver transplantation, were randomly assigned to receive either FFP or SD-treated plasma. Patients were assessed for side effects, correction of coagulopathy over 24 hours, and seroconversion for viral markers 6 to 18 months after treatment. RESULTS: In the liver disease group, equal correction of clotting factors and partial thromboplastin time was seen with FFP and SD-treated plasma, with a similar return to baseline values over 24 hours. There was greater correction of the International Normalised Ratio in patients receiving SD-treated plasma (p = 0.037), but this patient group had higher baseline values than recipients of FFP (p = 0.024). Liver transplant patients also showed equivalent correction of coagulopathy with the same dose of FFP and SD-treated plasma. The use of other blood components during transplantation was identical in the two treatment groups. No seroconversions were seen for HIV or hepatitis B or C virus. One patient who had received FFP seroconverted for human parvovirus B19. Apparent seroconversion for hepatitis A virus seen at 9 to 13 months in four other patients was probably due to detection of passively transferred antibodies, as later testing of these patients gave negative results. Minor side effects were rare in both groups. CONCLUSION: SD-treated plasma is an efficacious source of coagulation factors for patients with liver disease who are undergoing biopsy or transplantation. Assessment of seroconversion for viral markers in recipients of plasma-derived products and plasma components should include consideration of the possibility that passively transferred antibodies were detected.

Adult↗
PubMed1993

Clinical pharmacokinetics of newer antibacterial agents in liver disease.

Liver disease may produce significant, albeit highly variable, effects on the pharmacokinetic behaviour of antibiotics in serum. Drug disposition may be altered through several pathophysiological mechanisms including reduced hepatobiliary clearance, and modifications in the volume of distribution induced by albumin synthesis deficiency or portal hypertension-related ascites. Antibacterial agents are not affected by potential alteration in hepatic first-pass effects. Only liver cirrhosis-induced effects on serum pharmacokinetics of antibiotics have been extensively studied, unlike those possibly produced by other forms of liver disease. In liver cirrhosis, pharmacokinetic alterations of nearly all beta-lactam or quinolone agents appear not to be marked enough to require dosage adjustment, provided that renal function stays normal. Adaptation in therapeutic schedule, however, is warranted for those drugs that are substantially cleared by the hepatobiliary system, namely mezlocillin, clindamycin, erythromycin, pefloxacin, enoxacin, antituberculous agents or nitroimidazole derivatives. Special caution should also be exercised when using aminoglycosides or vancomycin because of the wide interpatient variability of their pharmacokinetic disposition and their toxic potential. When renal function is impaired and there is an increased volume of distribution due to ascites, as frequently observed in severe liver insufficiency, the elimination half-life of most antibiotics is markedly prolonged, resulting in potential side effects due to drug accumulation. Accordingly, dosage adjustment applies to all drugs. In this regard, it should be remembered that delineating the dosage guidelines for a given antibiotic on the basis of reported pharmacokinetic parameters in patients with liver cirrhosis is awkward and probably of limited value. This pattern is ascribed to large interpatient variability in the active hepatic cell mass, the degree of portal hypertension and the alteration of serum binding capacity. Furthermore, there is no way of predicting accurately the extent of liver insufficiency in an individual patient. Dosage reduction is thus done empirically in most cases. Whenever possible, direct measurements of serum antibiotic concentrations should be the reasonable approach to manage antibiotic therapy in this kind of clinical condition.

Animals↗
PubMed1986

Immunohistochemical studies on structural changes of the hepatic lobules in chronic liver diseases.

Liver biopsy specimens were examined immunohistochemically to clarify structural changes of the hepatic lobules in chronic liver diseases. In normal liver carbohydrate antigen 19-9 was located in the biliary ductular epithelium, whereas factor VIII-related antigen was observed in the endothelium of portal veins, hepatic arteries, and central veins. This antigen was not detected in the sinusoidal endothelium. In contrasts, monoclonal antibody OKM5 was reactive with the sinusoidal endothelium but was unreactive with the endothelium of the portal blood vessels or central veins. In chronic active hepatitis and liver cirrhosis, both carbohydrate antigen 19-9 positive biliary ductular cells and factor VIII-related antigen positive endothelial cells were not only observed in the enlarged portal area but also extended into the parenchyma. They were occasionally accompanied by fibers. These findings suggest that fibrosis, ductular epithelial, and blood vascular proliferation in the portal space and their invasion into the parenchyma might gradually cause structural changes of the hepatic lobules in chronic liver disease.

Antigens↗
PubMed2004

Apoptosis and necrosis in liver disease.

Liver cell injury and cell death is a prominent feature in all liver disease processes. During the last 5-10 years, most research activities focused almost exclusively on evaluating apoptotic cell death and the corresponding intracellular signaling pathways. Although this effort led to substantial progress in our understanding of the mechanisms of apoptosis, it also created substantial confusion regarding the predominant mode of cell death and the relevance of apoptosis in a variety of liver disease models, as discussed in this review for acetaminophen and troglitazone hepatotoxicity, obstructive cholestasis and viral hepatitis. Part of the problem is related to the fact that there is no specific assay or parameter, with the exception of morphological changes in vivo, which allows the unequivocal distinction between apoptosis and oncotic necrosis. In addition, some aspects of the signaling pathways are similar. Therefore, to make progress in identifying relevant pharmacological intervention strategies to prevent or attenuate human liver disease processes, it is of critical importance to apply several different experimental approaches and analyze as many parameters as possible. In addition, positive controls for the assumed process should be used whenever possible and mechanisms of cell injury should only be investigated in model systems relevant for the human pathophysiology.

Animals↗
PubMed1990

Extrahepatic cell membrane lipid abnormalities and cellular dysfunction in liver disease.

Liver disease is associated with characteristic changes in the lipid composition of the surface coat of plasma lipoprotein particles. Cholesterol and lecithin molecules accumulate as hepatic secretion of lecithin-cholesterol acyltransferase decreases, and the arachidonate content, the precursor for eicosanoid production, is also reduced. By exchange and equilibration processes, such abnormal circulating lipoproteins should tend to induce corresponding changes in cell membrane lipid composition; studies in both human and experimental liver disease confirm that this does occur and that it is wide-spread. The correct functioning of membrane proteins, which serve as receptors or are responsible for enzymatic and transport processes, is most commonly dependent on the fluidity of their lipid bilayer matrix. Because cholesterol enrichment of biomembranes reduces bulk lipid fluidity, it can be predicted that extrahepatic membrane dysfunction might be a general feature of severe liver disease. This concept is supported by increasing experimental evidence and, as a consequence, it is proposed that many of the cellular disturbances and metabolic abnormalities accompanying hepatic disease result from, or are exacerbated by, lipoprotein-induced changes in membrane lipid composition and function. Importantly, this mechanism also suggests that drugs which can fluidise membranes, such as S-adenosyl-L-methionine (SAMe), might help ameliorate cellular dysfunction.

Humans↗
PubMedDate not supplied

Mechanisms of hemolysis in liver disease.

Liver disease, particularly alcoholic cirrhosis, is associated with a number of interesting chemical changes which result in structural and metabolic abnormalities of the erythrocyte membrane leading to microscopically observable cell shape changes and hemolytic anemia varying from very mild to potentially lethal. Increase in unesterified serum cholesterol owing to lecithin cholesterol acyl transferase (LCAT) deficiency in cirrhosis leads to expansion of the lipid bilayer and macrocytosis without megaloblastic changes in precursors. Substitutions of phosphatidyl choline (PC) moieties in the erythrocyte lipid bilayer lead to echinocytes (disaturated PC) or to stomatocytes (diunsaturated PC). In some patients, high density lipoprotein (HDL) abnormalities lead to erythrocyte surface changes causing rapid formation of echinocytes. The rapidity and reversibility of these changes suggest blockade of metabolic transport channels critical to the maintenance of erythrocyte membrane shape. Metabolic changes involving vitamin E deficiency leading to lipid peroxidation and pyruvate kinase instability leading to adenosine triphosphate (ATP) reduction have also been invoked to explain hemolysis associated with acute liver damage. The most severe hemolysis in liver disease is associated with acanthocytes (spur cells) and a marked imbalance in cholesterol-phospholipid ratio. These patients usually have hypersplenism, as well as rigid erythrocyte membrane transformations which are irreversible. Any of the other erythrocyte membrane shape changes described appear to be reversible if the liver disease abates, but they too may become irreversible if bits of projecting membrane are repeatedly removed by the macrophages of an enlarged spleen.

Erythrocyte Deformability↗