Clinical features of alcoholic hepatitis in latinos and caucasians: A single center experience.

Aim: To study differences of presentation, management, and prognosis of alcoholic hepatitis in Latinos compared to Caucasians.

Methods: We retrospectively screened 876 charts of Caucasian and Latino patients who were evaluated at University of California Davis Medical Center between 1/1/2002-12/31/2014 with the diagnosis of alcoholic liver disease. We identified and collected data on 137 Caucasians and 64 Latinos who met criteria for alcoholic hepatitis, including chronic history of heavy alcohol use, at least one episode of jaundice with bilirubin ≥ 3.

Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model.

Wilson disease (WD), a genetic disorder affecting copper transport, is characterized by hepatic and neurological manifestations with variable and often unpredictable presentation. Global DNA methylation in liver was previously modified by dietary choline in tx-j mice, a spontaneous mutant model of WD. We therefore hypothesized that the WD phenotype and hepatic gene expression of tx-j offspring could be modified by maternal methyl supplementation during pregnancy.

Effects of Nonpurified and Choline Supplemented or Nonsupplemented Purified Diets on Hepatic Steatosis and Methionine Metabolism in C3H Mice.

Background: Previous studies indicated that nonpurified and purified commercially available control murine diets have different metabolic effects with potential consequences on hepatic methionine metabolism and liver histology.

Methods: We compared the metabolic and histological effects of commercial nonpurified (13% calories from fat; 57% calories from carbohydrates with 38 grams/kg of sucrose) and purified control diets (12% calories from fat; 69% calories from carbohydrates with ∼500 grams/kg of sucrose) with or without choline supplementation administered to C3H mice with normal lipid and methionine metabolism. Diets were started 2 weeks before mating, continued through pregnancy and lactation, and continued in offspring until 24 weeks of age when we collected plasma and liver tissue to study methionine and lipid metabolism.

Ethnic differences in presentation and severity of alcoholic liver disease.

Background: The frequency of alcoholic liver disease (ALD), including alcoholic steatosis, hepatitis, and cirrhosis, varies significantly by ethnicity.

Methods: With the goal to assess the role of ethnicity in determining the age of onset and severity of ALD and to compare the risk factors for its progression among ethnic groups, we conducted a retrospective chart review of all patients with ALD who were admitted or were followed as outpatients at University of California Davis Medical Center between 2002 and 2010. After excluding HBsAg- and HIV-positive subjects, we reviewed the charts of 791 patients with ALD including 130 with alcoholic fatty liver, 154 with alcoholic hepatitis, and 507 with alcoholic cirrhosis.

Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease.

Background: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks).

Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation.

Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse.

Background: Alcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism.

Methods: To investigate the phenotypic and epigenetic consequences of altered methionine metabolism in this disease, we studied the effects of 4-week intragastric EtOH feeding with and without the methyl donor betaine in cystathionine beta synthase (CβS) heterozygous C57BL/6J mice.

Results: The histopathology of early ASH was induced by EtOH feeding and prevented by betaine supplementation, while EtOH feeding reduced and betaine supplementation maintained the hepatic methylation ratio of the universal methyl donor S-adenosylmethionine (SAM) to the methyltransferase inhibitor S-adenosylhomocysteine (SAH).

Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease.

Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD.

Alcoholic liver disease patients treated with S-adenosyl-L-methionine: an in-depth look at liver morphologic data comparing pre and post treatment liver biopsies.

Background: The objective of this study is to assess if there were any changes in liver biopsies after treatment with S-adenosyl-L-methionine(SAMe) in alcoholic liver disease patients.

Methods: Liver biopsies of 14 patients were randomized for SAMe treatment at week 0 (biopsy #1) and at 24 weeks (biopsy #2). Patients received 1.

Folate, alcohol, and liver disease.

Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of ALD with particular focus on ethanol-induced alterations in methionine metabolism, which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions.

B-Vitamin dependent methionine metabolism and alcoholic liver disease.

Convincing evidence links aberrant B-vitamin dependent hepatic methionine metabolism to the pathogenesis of alcoholic liver disease (ALD). This review focuses on the essential roles of folate and vitamins B6 and B12 in hepatic methionine metabolism, the causes of their deficiencies among chronic alcoholic persons, and how their deficiencies together with chronic alcohol exposure impact on aberrant methionine metabolism in the pathogenesis of ALD. Folate is the dietary transmethylation donor for the production of S-adenosylmethionine (SAM), which is the substrate for all methyltransferases that regulate gene expressions in pathways of liver injury, as well as a regulator of the transsulfuration pathway that is essential for production of glutathione (GSH), the principal antioxidant for defense against oxidative liver injury.

Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease.

Unlabelled: Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson's disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related to liver injury, levels of SAHH, SAH, DNA methyltransferases genes (Dnmt1, Dnmt3a, Dnmt3b), and global DNA methylation in the tx-j mouse (tx-j), an animal model of WD. Findings were compared to those in control C3H mice, and in response to Cu chelation by penicillamine (PCA) and dietary supplementation of the methyl donor betaine to modulate inflammatory and methylation status.

Vitamin-dependent methionine metabolism and alcoholic liver disease.

Emerging evidence indicates that ethanol-induced alterations in hepatic methionine metabolism play a central role in the pathogenesis of alcoholic liver disease (ALD). Because malnutrition is a universal clinical finding in this disease and hepatic methionine metabolism is dependent upon dietary folate and vitamins B-6 and B-12, ALD can be considered an induced nutritional disorder that is conditioned by alcohol abuse. The present review describes the etiologies of these 3 vitamin deficiencies in ALD and how they interact with chronic ethanol exposure to alter hepatic methionine metabolism.

S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial.

Background: S-adenosyl-L-methionine (SAM) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione, the main cellular antioxidant. Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases (ALDs). The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24-week trial.

Aberrant hepatic methionine metabolism and gene methylation in the pathogenesis and treatment of alcoholic steatohepatitis.

The pathogenesis of alcoholic steatohepatitis (ASH) involves ethanol-induced aberrations in hepatic methionine metabolism that decrease levels of S-adenosylmethionine (SAM), a compound which regulates the synthesis of the antioxidant glutathione and is the principal methyl donor in the epigenetic regulation of genes relevant to liver injury. The present paper describes the effects of ethanol on the hepatic methionine cycle, followed by evidence for the central role of reduced SAM in the pathogenesis of ASH according to clinical data and experiments in ethanol-fed animals and in cell models. The efficacy of supplemental SAM in the prevention of ASH in animal models and in the clinical treatment of ASH will be discussed.

Impaired homocysteine transsulfuration is an indicator of alcoholic liver disease.

Background & Aims: Although abnormal hepatic methionine metabolism plays a central role in the pathogenesis of experimental alcoholic liver disease (ALD), its relationship to the risk and severity of clinical ALD is not known. The aim of this clinical study was to determine the relationship between serum levels of methionine metabolites in chronic alcoholics and the risk and pathological severity of ALD.

Methods: Serum levels of liver function biochemical markers, vitamin B6, vitamin B12, folate, homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, alpha-aminobutyrate, glycine, serine, and dimethylglycine were measured in 40 ALD patients, of whom 24 had liver biopsies, 26 were active drinkers without liver disease, and 28 were healthy subjects.

Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse.

Unlabelled: We tested the hypothesis that the pathogenesis of alcoholic liver injury is mediated by epigenetic changes in regulatory genes that result from the induction of aberrant methionine metabolism by ethanol feeding. Five-month-old cystathionine beta synthase heterozygous and wild-type C57BL/6J littermate mice were fed liquid control or ethanol diets by intragastric infusion for 4 weeks. Both ethanol-fed groups showed typical histopathology of alcoholic steatohepatitis, with reduction in liver S-adenosylmethionine (SAM), elevation in liver S-adenosylhomocysteine (SAH), and reduction in the SAM/SAH ratio with interactions of ethanol and genotype effects.

Quantitative lipid metabolomic changes in alcoholic micropigs with fatty liver disease.

Background: Chronic ethanol consumption coupled with folate deficiency leads to rapid liver fat accumulation and progression to alcoholic steatohepatitis (ASH). However, the specific effects of alcohol on key liver lipid metabolic pathways involved in fat accumulation are unknown. It is unclear whether lipid synthesis, lipid export, or a combination of both is contributing to hepatic steatosis in ASH.

Postnatal ontogeny of intestinal GCPII and the RFC in pig.

In humans and pigs, hydrolysis of dietary polyglutamyl folates is carried out by intestinal brush border folate hydrolase [glutamate carboxypeptidase II (GCPII)], whereas the transport of the monoglutamyl folate derivatives occurs via the intestinal brush border reduced folate carrier (RFC). The study objective was to measure the expression of intestinal GCPII and RFC during postnatal development of pigs and their effects on plasma and liver folate concentrations. Duodenum, jejunum, ileum, liver, and plasma samples were collected from female Yorkshire pigs at birth, 24 h, 1 wk, 3 wk, and 6 mo (n=6 at each time point).

Perspectives on obesity and sweeteners, folic acid fortification and vitamin D requirements.

This review summarizes three controversial areas of clinical practice that were discussed in many articles that appeared in the American Journal of Clinical Nutrition during the author's tenure as editor in chief. Controversy 1-obesity and high-fructose corn syrup. The increased frequency of obesity in the US is paralleled by increasing annual consumption of high-fructose corn syrup, an extracted sweetener that is routinely added to soft drinks and to many processed foods in the US diet.

Interactive effects of COMT Val108/158Met and MTHFR C677T on executive function in schizophrenia.

Schizophrenia is characterized by heritable deficits in executive function. Two common, functional polymorphisms, catechol-O-methyltransferase (COMT) Val108/158Met and methylenetetrahydrofolate reductase (MTHFR) C677T, have separately been associated with executive function performance in schizophrenia. Given the closely related biochemistry of MTHFR and COMT, it is plausible that the T and Val alleles act synergistically to impair executive function.

M-30 and 4HNE are sequestered in different aggresomes in the same hepatocytes.

M-30 and 4HNE adducts are two markers of active liver disease. M-30 is a serologic marker and 4HNE adducts are histologic markers. M-30 is a marker for apoptosis because it is a fragment of cytokeratin-18 left over from proteolysis by caspase 3.

Cloning of a pig homologue of the human lactoferrin receptor: expression and localization during intestinal maturation in piglets.

The presence of a small intestinal lactoferrin receptor (SI-LfR) has been suggested in the pig, but remains to be identified. LfR has been suggested to play a key role in the internalization of lactoferrin (Lf) and to facilitate absorption of iron bound to Lf. The aim of this study was to identify the pig SI-LfR cDNA, determine its mRNA and protein expression during different stages of intestinal development.

Relations of glutamate carboxypeptidase II (GCPII) polymorphisms to folate and homocysteine concentrations and to scores of cognition, anxiety, and depression in a homogeneous Norwegian population: the Hordaland Homocysteine Study.

Background: Glutamate carboxypeptidase II (GCPII) encodes for intestinal folate hydrolase and brain N-acetylated alpha-linked acidic dipeptidase. Previous studies provided conflicting results on the effect of the GCPII 1561C-->T polymorphism on folate and total homocysteine (tHcy) concentrations.

Objective: We aimed to determine the potential effects of 2 polymorphisms of GCPII on plasma folate and tHcy concentrations, cognition, anxiety, and depression in a large aging cohort of Norwegians enrolled in the Hordaland Homocysteine Study.

Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium.

This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione concentrations and the SAM-SAH ratio; increasing cytochrome P4502E1 activation and lipid peroxidation; up-regulating endoplasmic reticulum stress markers, including sterol regulatory element-binding protein-1, and proapoptotic gene caspase-12; and decreasing global DNA methylation.