Liver fibrosis and accelerated immune dysfunction (immunosenescence) among HIV-infected Russians with heavy alcohol consumption - an observational cross-sectional study.

BACKGROUND: The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. METHODS: ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing CD28-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. RESULTS: Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. CONCLUSIONS: Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.

Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine.

With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4α binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4α-mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6.

Selenium glutathione peroxidase: some aspects in man.

The levels of activity of selenium glutathione peroxidase (GSH-Px) in animals, in circulating blood cells, and in pathologic conditions in man are reviewed. The results are discussed in relation to circulating lipoperoxides and to selenium supplementation.

Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.

BACKGROUND: Attention has long been drawn to the potentially harmful effects of coffee on health, however recent epidemiological studies have suggested unexpected, possibly beneficial effects of coffee against the occurrence of alcoholic liver cirrhosis and upon serum liver enzyme levels. METHODS: We examined the potential inverse association between coffee drinking and serum concentrations of gamma-glutamyltransferase (GGT) and aminotransferases, with special reference to interaction with alcohol consumption, in a cross-sectional study involving 12687 health examinees (7398 men and 5289 women) aged 40-69 years from over 1000 workplaces in Nagano prefecture in central Japan. Those who had a history of liver disease and/or serum aminotransferases exceeding the normal range were excluded. Possible confounding effects of alcohol consumption, body mass index, cigarette smoking, and green tea consumption were controlled through multivariate analyses. RESULTS: Increased coffee consumption was strongly and independently associated with decreased GGT activity among males (P trend < 0.0001); the inverse association between coffee and serum GGT was more evident among heavier alcohol consumers (P < 0.0001), and was absent among non-alcohol drinkers. Among females, however, coffee was only weakly related to lower GGT level. Similar inverse associations with coffee and interactions between coffee and alcohol intake were observed for serum aspartate aminotransferase and alanine aminotransferase. Intake of green tea, another popular source of caffeine in Japan, did not materially influence the liver enzyme levels. CONCLUSIONS: Our results suggest that coffee may inhibit the induction of GGT in the liver by alcohol consumption, and may possibly protect against liver cell damage due to alcohol.

Choline acetyltransferase and acetylcholinesterase activities are unchanged in brain in human and experimental portal-systemic encephalopathy.

Activities of choline acetyltransferase, acetylcholinesterase and butyrylcholinesterase were studied in the frontal cortex, temporal cortex, cerebellum and caudate nucleus obtained at autopsy from eight alcoholic cirrhotic patients who died in hepatic coma and from an equal number of age-matched subjects free from hepatic, neurological or psychiatric disorders. Activities of these enzymes were unaltered in the brains of cirrhotics compared to controls. Choline acetyltransferase and cholinesterase activities were also studied in the cerebral cortex, cerebellum, brain stem and striatum of rats four weeks following portacaval anastomosis and their sham-operated controls. Portacaval-shunting did not cause any statistically significant differences in the activities of choline acetyltransferase, acetyl or butyrylcholinesterases. These results argue against a presynaptic cholinergic lesion in human and experimental portal-systemic encephalopathy.

Changes in cytochromes P-450, 2E1, 2B1, and 4A, and phospholipases A and C in the intragastric feeding rat model for alcoholic liver disease: relationship to dietary fats and pathologic liver injury.

The influence of dietary fat and alcohol on hepatic microsomal levels of cytochromes P-450 2E1, 2B, and 4A; phospholipases A and C; and UDP-glucuronosyltransferase was studied in the intragastric feeding rat model for alcoholic liver injury. Eight groups of animals were evaluated. Control and ethanol fed rats received either saturated fat or corn oil and were killed after 2 weeks and 1 month of feeding. All animals were pair-fed by continuous infusion of liquid diet through permanently implanted gastric cannulas. Alcoholic liver injury developed only in the corn oil-ethanol-fed groups and was manifest by 1 month. Livers were subjected to the following analyses: pathologic evaluation of liver injury; levels of cytochromes P-450 2E1, 2B, and 4A protein and mRNA; aniline hydroxylase activity; and phospholipase A and C and UDP-glucuronosyltransferase activities. Ethanol-induced increases in cytochromes P-450 2E1 and 2B protein determined by Western blotting were greatest in the corn oil-ethanol-fed group, which developed pathologic changes in the liver. Cytochromes P-450 2E1 and 2B1 mRNA levels were unaffected, suggesting that posttranscriptional mechanisms are responsible for the increase in the corresponding P-450 proteins. In contrast, cytochrome P-450 4A levels were higher in the saturated fat-ethanol groups compared with the corn oil-ethanol groups. Phospholipase A and phospholipase C levels were higher in the corn oil-ethanol groups compared with pair-fed dextrose controls and the saturated fat-ethanol groups. UDP-glucuronosyltransferase levels declined with time in the ethanol-fed groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine.

UNLABELLED: Phosphatidylethanolamine N-methyltransferase participates in the synthesis of membrane phosphatidylcholine. Its activity was reported to be decreased in patients with alcoholic cirrhosis, but it is not known whether this is a consequence of the cirrhosis or precedes it. This question was studied in a baboon model of alcohol-induced fibrosis. Phosphatidylethanolamine N-methyltransferase activity was measured in sequential percutaneous needle liver biopsies by the conversion of phosphatidylethanolamine to phosphatidylcholine, using radioactive S-adenosylmethionine as a methyl donor. Chronic alcohol consumption (1-6 years) significantly decreased hepatic phospholipid and phosphatidylcholine levels and reduced phosphatidyl-ethanolamine N-methyltransferase activity even before the development of fibrosis. These effects were prevented or attenuated by supplementing the diet with 2.8 g/1000 kcal of a preparation rich in dilinoleoyl phosphatidylcholine, a highly bioavailable phosphatidylcholine species. There were significant (p < 0.001) correlations between phosphatidylethanolamine N-methyltransferase activity and both hepatic phosphatidylcholine (r = 0.678) and total phospholipid (r = 0.662). CONCLUSIONS: 1. Alcohol consumption diminishes phosphatidylethanolamine N-methyltransferase activity prior to the development of cirrhosis and decreases the hepatic content of its product, namely phosphatidylcholine, a key component of cell membranes. This may promote hepatic injury and possibly trigger fibrosis. 2. Phosphatidylcholine administration ameliorates the ethanol-induced decrease in phosphatidylethanolamine N-methyltransferase activity and corrects phospholipid and phosphatidylcholine depletions, thereby possibly contributing to the protection against alcoholic liver injury.

Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers.

The hepatoprotective and immunomodulatory effects of silymarin and amino-imidazol-carboxamid-phosphate were studied in 60 patients with compensated alcoholic cirrhosis of the liver in a one month double blind clinical trial. Treatment with both drugs normalized the elevated levels of aspartate aminotransferase, alanine aminotransferase and serum bilirubin, markedly reduced the high level of gamma-glutamyl transferase, increased lectin-induced lymphoblasttransformation, decreased the percentage of CD8+ cells and suppressed lymphocytotoxicity. None of these changes occurred in the placebo-treated group. Thus the hepato-protective effects of silymarin and amino-imidazol-carboxamid-phosphate are accompanied by changes in parameters of cellular immunoreactivity of the treated patients.

Effect of free radical scavengers on superoxide dismutase (SOD) enzyme in patients with alcoholic cirrhosis.

The in vitro and in vivo effects of three hepatoprotective antioxidants (silymarin, (+)cyanidanol-3 and 4-amino-5-imidazole-carboxamide-phosphate) on the expression and activity of superoxide dismutase (SOD) enzyme were studied in erythrocytes and lymphocytes from patients with alcoholic cirrhosis. In vitro incubation with the drugs in a concentration corresponding to the usual therapeutic dosage markedly increased (i) the SOD expression of lymphocytes as measured by flow-cytofluorimetry following staining with monoclonal anti-Cu, Zn-SOD-antibody and FITC-conjugated anti-mouse Ig, as well as (ii) erythrocyte and lymphocyte SOD activities. In vivo treatment also restored the originally low SOD activity and expression of the patients' lymphocytes and erythrocytes. The data indirectly suggest that antioxidant activity might be one of the important factors in the hepatoprotective action of these agents.

Red blood cell transketolase activity and the effect of thiamine supplementation in patients with chronic liver disease.

Biochemical evidence of thiamine deficiency was found in 58% of patients with chronic liver disease, the incidence being higher in alcoholic than in non-alcoholic patients. Daily supplementation with high doses of thiamine hydrochloride (200 mg/day) for one week restored levels of thiamine pyrophosphate (TPP), the active co-enzyme form of thiamine, to normal in all cases. Such supplementation also stimulated synthesis of the TPP dependent enzyme transketolase. Because of the essential role of TPP as a co-factor in intermediary metabolism, it is concluded that high doses of thiamine should be included in the routine nutritional management of patients with severe chronic liver disease.

Aminopyrine breath test in alcoholic liver disease and in patients on enzyme-inducing drugs.

The 14C-aminopyrine breath test was used to measure liver function in 14 normal subjects, 16 patients with alcoholic cirrhosis, 14 alcoholics without cirrhosis, and 29 patients taking a variety of drugs. The normal value for the breath test was 8.6 +/- 1.5%, whereas it was significantly lower (5.1 +/- 3.8%) in patients with alcoholic cirrhosis. Higher than normal values were found in some alcoholic patients without cirrhosis and in patients receiving enzyme-inducing drugs, such as phenobarbitone. There was a significant correlation between serum gamma-glutamyltransferase and breath test in these groups. Some patients with alcoholic cirrhosis may also be capable of enzyme induction.