Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of methionine to S-adenosylmethionine is depressed in alcoholics. Its repletion opposes alcoholic liver cirrhosis in baboons, decreases mortality in cirrhotic patients, and opposes oxidative stress resulting from cytochrome P4502E1 (CYP2E1) induction by alcohol, ketones, and fatty acids. Their excess causes alcoholic and nonalcoholic steatohepatitis. CYP2E1 is also induced in Kupffer cells, promoting their activation and release of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. The TNF-alpha inhibitor pentoxifylline decreased mortality from alcoholic hepatitis. Polyenylphosphatidylcholine (PPC), an antioxidant phosphatidylcholine mixture extracted from soybeans, 50% of which consists of the highly bioavailable dilinoleoylphosphatidylcholine, restores phospholipids of the damaged membranes and reactivates their enzymes, including phosphatidylethanolamine methyltransferase, needed for phospholipid regeneration. In baboons, PPC prevented cirrhosis by stimulating collagenase and by opposing lipid peroxidation, which produces the fibrogenic hydroxynonenal. PPC was beneficial in patients with alcoholic hepatitis, and it opposed fibrosis in heavy drinkers and decreased aminotransferases in patients with hepatitis C. The antioxidant silymarin also successfully opposed alcoholic cirrhosis in baboons and in some but not all clinical trials; this effect also pertains to a-tocopherol. The anti-inflammatory corticosteroids and colchicine yielded mixed results. Finally, replacing long-chain with medium-chain triglycerides opposed the fatty liver experimentally and clinically.
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PMID:New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments. 1472 Apr 55

In patients with hepatocellular carcinoma (HCC), natural killer (NK) cell activity decreases significantly, and the reduced activity may be associated with the progression of HCC. In this study we evaluated the effects of pulsing with interleukin (IL)-2 and/or IL-12 on the activation of freshly isolated peripheral blood lymphocytes (PBL) derived from patients with HCC. PBL obtained from 9 HCC patients, 4 liver cirrhosis patients, and 9 normal subjects were cultured in the presence of IL-2 and/or IL-12. After 24 h of incubation, the levels of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha presented in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The IFN-gamma and TNF-alpha production of PBL pulsed by a combination of IL-2 and IL-12 was significantly higher than those of PBL stimulated by either IL-2 or IL-12 alone. The mRNA encoding perforin, granzyme B, as well as IFN-gamma and TNF-alpha, were markedly enhanced in PBL stimulated with a combination of IL-12 and IL-2. The pulsing procedure of IL-12 in combination with IL-2 resulted in the increase of IFN-gamma and TNF-alpha, and the expression of perforin and granzyme B mRNA in PBL obtained from HCC patients, as well as in those obtained from normal subjects. These results indicate that adoptive immunotherapy based on PBL pulsed with a combination of IL-2 and IL-12 may be a promising adjunctive strategy for HCC treatment.
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PMID:Effects of pulsing procedure of interleukin-12 in combination with interleukin-2 on the activation of peripheral blood lymphocytes derived from patients with hepatocellular carcinoma. 1472 65

There is no effective medical treatment for primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease that usually progresses to cirrhosis and liver failure. The aim of this study was to determine the safety and efficacy of etanercept, an inhibitor of tumor necrosis factor, in the treatment of PSC. Ten patients with clinically active PSC were studied. All had elevated serum alkaline phosphatase levels, cholangiograms that were diagnostic of PSC, and liver histology consistent with PSC. Five patients had elevated serum bilirubin levels, five had pruritus, eight had failed to respond to ursodiol and/or methotrexate, and six had rapidly recurring dominant bile duct strictures. Patients were to receive etanercept, 25 mg subcutaneously twice weekly, for 6 months if there were no side effects and for 1 year if there was evidence of efficacy after 6 months. Biochemical tests of liver function did not improve in any patient. Mean serum bilirubin levels increased significantly, from 2.0 to 3.6 mg/dl (P = 0.026). Two of the five patients with pruritus had resolution of pruritus during treatment with etanercept, recurrence when etanercept was stopped, and resolution when it was restarted, although there was little change in liver enzymes or bilirubin levels. There was no decrease in the rate of stricture formation and there were no side effects. Etanercept, at the dosage used, was well tolerated but not effective in the treatment of PSC. It may be helpful in treating pruritus due to cholestasis.
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PMID:A pilot study of etanercept in the treatment of primary sclerosing cholangitis. 1499 26

Insulin resistance is present in nearly all patients with liver cirrhosis, but its etiology remains unclear. Recent studies have shown that tumor necrosis factor-alpha (TNF-alpha) system is involved in the insulin resistance of human obesity. Serum concentrations of TNF-alpha, and 2 soluble TNF receptors (sTNF-RI and sTNF-RII) are increased in cirrhotic patients. This study explored whether TNF-alpha system activity was associated with insulin resistance in liver cirrhosis. A total of 26 male nondiabetic patients with liver cirrhosis (mean age, 59 +/- 3 years; body mass index, 23.7 +/- 0.4 kg/m2) and 25 male control subjects (age, 65 +/- 2 years; body mass index, 24.4 +/- 0.5 kg/m2) were studied. Serum insulin, c-peptide, TNF-alpha, sTNF-RI, and sTNF-RII concentrations were determined by immunoassay. The insulin resistance was estimated by homeostasis assessment model (HOMA IR). In cirrhotic patients, serum levels of TNF-alpha, sTNF-RI, and sTNF-RII were all higher than those in the controls, and correlated with disease severity. Also, the serum c-peptide, insulin concentrations, and the HOMA IR were higher in liver cirrhosis with comparable blood glucose to control subjects, indicating a degree of insulin insensitivity. In the whole population, there was a moderate, but statistically significant, correlation between serum sTNF-RI or sTNF-RII, and HOMA IR. Also, body mass index was associated with HOMA IR, but not related to serum TNF-alpha, and sTNF-Rs levels. In multiple regression analysis, both sTNF-RII and body mass index jointly contributed to 30% variance of HOMA IR. Our study demonstrated that elevated sTNF-RII levels were associated with insulin resistance in liver cirrhosis. The data indicated that TNF-alpha system might play a role in modulating insulin action in patients with liver cirrhosis.
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PMID:Increased serum soluble tumor necrosis factor receptor levels are associated with insulin resistance in liver cirrhosis. 1525 88

Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-alpha, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.
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PMID:Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. 1527 42

Tetrathiomolybdate, an anticopper drug, has been shown to protect mice against pulmonary fibrosis from bleomycin. Our hypothesis is that it does so by inhibiting fibrosis-inducing cytokines. Indeed, we have good evidence, not yet published, that tetrathiomolybdate inhibits pulmonary levels of transforming growth factor-beta and tumor necrosis factor-alpha expression in these bleomycin experiments. Herein, we evaluate tetrathiomolybdate's effectiveness in mitigating hepatitis and fibrosis in mice from the hepatotoxins, concanavalin A and carbon tetrachloride, and its inhibition of cytokines as a possible mechanism. In short-term experiments, concanavalin A elevated serum amino leucine transferase levels several fold, and tetrathiomolybdate completely prevented this increase. In additional experiments, tetrathiomolybdate therapy reversed the elevated serum transaminase levels despite continued concanavalin A injections, with nearly significant serum interleukin-1beta inhibition. Concanavalin A given for 12 weeks produced mild fibrosis, whereas concomitant tetrathiomolybdate treatment resulted in normal histology. Carbon tetrachloride given for 12 weeks resulted in very high serum amino leucine transferase levels, high serum transforming growth factor-beta levels, cirrhosis as seen histologically, and increase in liver hydroxyproline, a measure of fibrosis. Concomitant tetrathiomolybdate partially and significantly protected against increases in amino leucine transferase and transforming growth factor-beta, fully protected against the increase in hydroxyproline, and resulted in normal histology. In conclusion, tetrathiomolybdate protects against the hepatitis and fibrosis produced by these hepatotoxins, probably by inhibiting the excessive increase in inflammatory and fibrotic cytokines.
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PMID:Tetrathiomolybdate therapy protects against concanavalin a and carbon tetrachloride hepatic damage in mice. 1533 42

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.
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PMID:Diagnosis and therapy of alcoholic liver disease. 1534 2

To evaluate their defense level against bacterial infection of patients with liver cirrhosis, we compared the luminol-dependent chemiluminescence (CL) response of peripheral blood from 40 patients with that from 40 healthy volunteers. Small quantities of heparinized whole blood (100 microl; final dilution, 1:10) were used for phagocytes, and CL was measured on addition of nonopsonized zymosan or Escherichia coli without special opsonization. Whole blood CL in cirrhotic patients was significantly lower than that in the healthy controls. The incidence of lower CL response in patients increased as disease stage advanced. Polymorphonuclear leukocytes (PMN) from cirrhotic patients exhibited a slightly lower CL response than those from controls, but this was not statistically significant. In contrast, the CL response of monocytes in patients was significantly lower than that of controls. The opsonizing capacity of the patients' sera and ascitic fluid was also decreased. In fact, the levels of opsonins such as complement in the patients' sera and both immunoglobulins and complement in the ascitic fluids were found to be lower in cirrhotic patients. On the basis of these findings, defect of opsonophagocytic function seems to participate in the increased susceptibility to infection in cirrhotic patients. Furthermore, whole blood CL induced by nonopsonized zymosan at the onset of relatively severe bacterial infections such as sepsis, pneumonia, or spontaneous bacterial infection was less augmented in the blood of cirrhotic patients than that in noncirrhotic patients. To clarify the reason why whole blood exhibits a lower CL response in the acute phase of bacterial infections, we investigated the priming effects of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha), well-known CL activators, on the CL response of whole blood obtained from cirrhotic patients in comparison with that from healthy persons. The priming effects were significantly decreased in patients' blood when compared with that of healthy persons. These low responses of patients' blood to LPS or TNF-alpha support our finding that phagocytes are not fully activated when gram-negative bacterial infections occur.
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PMID:Opsonophagocytic dysfunction in patients with liver cirrhosis and low responses to tumor necrosis factor-alpha and lipopolysaccharide in patients' blood. 1536 59

Although cytokines and cytotoxic T lymphocytes (CTL) are among the predominant mechanisms of host defense against viral pathogens, they can induce an inflammatory response that often leads to tissue injury. Hepatitis C virus (HCV) infection, a major cause of liver-related disease, results in the induction of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and CTL activity, followed by liver injury. Although inflammation facilitates the wound healing process, chronic persistence over several decades results in scar accumulation, fibrosis and often cirrhosis. This review summarizes biological data implicating a cause-and-effect relationship between TNF-alpha levels and the progression of fibrosis in chronic HCV infections, in contrast to the role of TNF-alpha in hepatitis B virus infections. Furthermore, an overview of therapeutic approaches to halting the inflammatory cascade in individuals with chronic HCV, including the use of agents to reduce the level of TNF-alpha, is presented.
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PMID:Biomedicines to reduce inflammation but not viral load in chronic HCV--what's the sense? 1545 Jul 45

Nonalcoholic fatty liver disease (NAFLD) is the preferred term to describe the spectrum of liver damage ranging from hepatic steatosis to steatohepatitis, liver fibrosis, and cirrhosis, and it is emerging as the most common liver disease in industrialized countries. Thus, the discovery of food components that would ameliorate NAFLD is of interest. Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid, has attracted considerable attention because of its potentially beneficial biological effects both in vitro and in vivo. We tested whether dietary CLA protects Zucker (fa/fa) rats from hepatic injury. After 8 wk of feeding, hepatomegaly, hepatic triglyceride (TG) accumulation, and elevated hepatic injury markers in plasma were markedly alleviated in CLA-fed Zucker rats compared with linoleic acid-fed (control) rats. These effects were attributed in part to the enhanced hepatic activities of carnitine palmitoyltransferase, a key enzyme of fatty acid beta-oxidation, and microsomal TG transfer protein, an important factor for lipoprotein secretion due to the CLA diet. We previously reported that the severe hyperinsulinemia in control Zucker rats was attenuated in CLA-fed rats due to an enhanced level of plasma adiponectin, which improves insulin sensitivity. In the present study, the adiponectin concentration was increased and the mRNA expression of tumor necrosis factor-alpha, an inflammatory cytokine, was markedly suppressed in the liver of CLA-fed Zucker rats. We speculate that the enhanced level of liver adiponectin may prevent the development and progression of NAFLD in CLA-fed Zucker rats.
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PMID:Dietary conjugated linoleic acid alleviates nonalcoholic fatty liver disease in Zucker (fa/fa) rats. 1562 25


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