tretinoin and Liver-Cirrhosis--Alcoholic

More than 18 million adults in the United States abuse alcohol, a prevalence 5 times higher than that of hepatitis C. Chronic alcohol use of greater than 80 g/day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) approximately 5-fold; alcohol use of less than 80 g/day is associated with a nonsignificant increased risk for HCC. The risk for HCC in decompensated alcohol induced cirrhosis approaches 1% per year. The risk does not decrease with abstinence, and HCC can occur in a noncirrhotic liver. Alcohol use in chronic hepatitis C doubles the risk for HCC as compared with the risk in hepatitis C alone. Furthermore, there may be synergism between alcohol and hepatitis C in the development of HCC, and in these patients HCC may occur at an earlier age and the HCC may be histologically more advanced. Studies in the United States and Italy suggest that alcohol is the most common cause of HCC (accounting for 32%-45% of HCC). The mechanisms by which alcohol causes HCC are incompletely understood, but may include chromosomal loss, oxidative stress, a decreased retinoic acid level in the liver, altered DNA methylation, and genetic susceptibility. Alcohol use is increasing in many countries, suggesting that alcohol will continue to be a common cause of HCC throughout the world.

Topics: Alcohol Drinking; Carcinoma, Hepatocellular; Chromosome Aberrations; DNA Methylation; Hepatitis C, Chronic; Humans; Incidence; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Oxidative Stress; Risk Factors; Tretinoin; United States

Patients with alcoholic liver disease (ALD) have vitamin A (VA) deficiency and an enhanced immune response associated with disease severity. All-trans retinoic acid (ATRA), a VA-active metabolite, has anti-inflammatory effects and its deficiency could contribute to the exacerbated proinflammatory reaction. The aim of this study was to investigate the effects of ATRA/VA deficiency and supplementation on the monocyte response in ALD.. Vitamin A and ATRA plasma levels were quantified in ALD patients and healthy subjects (HS). The in vitro effect of ATRA on lipopolysaccharide (LPS)-induced TNF-α production by human peripheral blood mononuclear cells (PBMC) was assessed by ELISA and RT-PCR. The activation pattern of peritoneal macrophages (PerMΦ) and circulating monocytes isolated from VA-deficient mice and ALD patients, respectively, was evaluated by flow cytometry, quantification of TNF-α and NO2 production.. Alcoholic liver disease patients (n = 85) showed plasmatic VA deficiency that was correlated with scores of severity and with the hepatic venous pressure gradient. ATRA levels correlated significantly with VA levels. In vitro, ATRA pretreatment decreased the overproduction of TNF-α by LPS-stimulated PBMC of ALD patients. In vivo, VA deficiency in mice was associated with increased activation of PerMΦ, while oral ATRA supplementation normalized it.. For the first time, we show that VA/ATRA deficiencies in ALD patients are associated with disease severity. Furthermore, our data strongly suggest that the VA deficiency observed in ALD patients might participate in the pathophysiology of the disease by priming immune cells, and that ATRA supplementation could downregulate the deleterious proinflammatory state in cirrhosis and might thus be of therapeutic use.

Topics: Adult; Aged; Animals; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Down-Regulation; Female; Humans; Lipopolysaccharides; Liver Cirrhosis, Alcoholic; Macrophage Activation; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Middle Aged; Monocytes; RNA, Messenger; Tretinoin; Tumor Necrosis Factor-alpha; Vitamin A; Vitamin A Deficiency

Of 26 patients hospitalized with mild to moderate alcohol-associated cirrhosis, 14 had dark-adaptation abnormalities consistent with marginal vitamin-A status. The response of dark adaptation and the plasma retinol transport proteins, retinol-binding protein and prealbumin, was studied in 12 of these patients after daily oral vitamin-A supplements of 3300 microgram. Vitamin-A supplementation was associated with significant (p less than 0.05-0.005) improvement in dark adaptation and increased plasma concentrations of retinyl esters, retinol, and retinol-binding protein. Thus in patients with cirrhosis and marginal vitamin-A status, supplemental vitamin-A therapy appears to stimulate retinol-binding protein release from the liver. This enhancement of plasma retinol transport and delivery of retinol to peripheral tissues such as the retina is one of several factors that may serve to optimize vitamin-A nutritional status in patients with cirrhosis.

Topics: Dark Adaptation; Esters; Humans; Liver Cirrhosis, Alcoholic; Liver Function Tests; Male; Middle Aged; Prealbumin; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Tretinoin; Vitamin A; Zinc