Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome.

BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS2 analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. RESULTS: 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. CONCLUSIONS: Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity.

Vinyl Chloride Metabolites Potentiate Inflammatory Liver Injury Caused by LPS in Mice.

Vinyl chloride (VC) is a ubiquitous environmental contaminant for which human risk is incompletely understood. We have previously reported that high occupational exposure to VC directly caused liver damage in humans. However, whether VC may also potentiate liver injury from other causes is not known. C57Bl/6J mice were administered chloroethanol (CE), a major metabolite of VC, and lipopolysaccharide (LPS) 24 h after CE. Samples were harvested for determination of liver damage, inflammation, and changes in carbohydrate and lipid metabolism. In mice, CE exposure alone caused no detectable liver damage. LPS exposure caused inflammatory liver damage, oxidative stress, lipid accumulation, and glycogen depletion; the effect of all of these variables was potentiated by CE pre-exposure. In vitro experiments suggest that VC metabolite chloroacetaldehyde (CAA) directly damages mitochondria, which may explain the sensitization effect observed in vivo Moreover, co-exposure of cells to CAA and TNFα caused increased cell death, supporting the hypothesis of sensitization by VC metabolites. Taken together, these data demonstrate that exposure to VC/metabolites at levels that are not overtly hepatotoxic can potentiate liver injury caused by another hepatotoxicant. This serves as proof-of-concept that VC hepatotoxicity may be modified by an additional metabolic stress such as endotoxemia, which commonly occurs in acute (eg, sepsis) and chronic (eg, NAFLD) diseases.

Role of Cytochrome P450 Monooxygenase in Carcinogen and Chemotherapeutic Drug Metabolism.

The purpose of this chapter is to provide insight into which human cytochromes P450 (CYPs) may be involved in metabolism of chemical carcinogens and anticancer drugs. A historical overview of this field and the development of literature using relevant animal models and expressed human CYPs have provided information about which specific CYPs may be involved in carcinogen metabolism. Definition of the biochemical properties of CYP activity came from several groups who studied the reaction stoichiometry of butter yellow and benzo[α]pyrene, including their role in induction of these enzyme systems. This chapter will list as much as is known about the human CYPs involved in carcinogen and anticancer drug metabolism, as well as summarize studies with rodent CYPs. A review of three major classes of anticancer drugs and their metabolism in humans is covered for cyclophosphamide, procarbazine, and anthracycline antibiotics, cancer chemotherapeutic compounds extensively metabolized by CYPs. The emerging information about human CYP gene polymorphisms as well as other enzymes involved in foreign compound metabolism provides considerable information about how these genetic variants affect carcinogen and anticancer drug metabolism. With information available from individual's genomic sequences, consideration of populations who may be at risk due to environmental exposure to carcinogens or how to optimize their cancer therapy regimens to enhance efficacy of the anticancer drugs appears to be an important field of study to benefit individuals in the future.

Treating Every Needle in the Haystack: Hyperammonemic Encephalopathy and Severe Malnutrition After Bariatric Surgery-A Case Report and Review of the Literature.

Neurologic complications are not uncommon following bariatric surgery. Hyperammonemic encephalopathy (HAE) due to an acquired or unmasked urea cycle deficit is among the rarest of these. Pediatric nutrition support specialists are familiar with recognizing urea cycle deficits, but adult specialists may not be. Here we present a case of a patient initially misdiagnosed with cirrhosis who presented with recurrent HAE 4 years after Roux-en-Y gastric bypass. She was diagnosed with a proximal urea cycle deficit and severe protein calorie malnutrition. The patient recovered with specialized nutrition and medical support targeting this condition. A literature review indicates multiple fatalities from this condition, indicating the importance of early diagnosis and appropriate nutrition support.

Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice.

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that are detectable in the serum of all American adults. Amongst PCB congeners, PCB 153 has the highest serum level. PCBs have been dose-dependently associated with obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in epidemiological studies. OBJECTIVE: The purpose of this study is to determine mechanisms by which PCB 153 worsens diet-induced obesity and NAFLD in male mice fed a high-fat diet (HFD). METHODS: Male C57BL6/J mice were fed either control or 42% milk fat diet for 12 weeks with or without PCB 153 coexposure (50 mg/kg ip ×4). Glucose tolerance test was performed, and plasma and tissues were obtained at necropsy for measurements of adipocytokine levels, histology and gene expression. RESULTS: In control diet-fed mice, addition of PCB 153 had minimal effects on any of the measured parameters. However, PCB 153 treatment in high-fat-fed mice was associated with increased visceral adiposity, hepatic steatosis and plasma adipokines including adiponectin, leptin, resistin and plasminogen activator inhibitor-1 levels. Likewise, coexposure reduced expression of hepatic genes implicated in ß-oxidation while increasing the expression of genes associated with lipid biosynthesis. Regardless of diet, PCB 153 had no effect on insulin resistance or tumor necrosis factor alpha levels. CONCLUSION: PCB 153 is an obesogen that exacerbates hepatic steatosis, alters adipocytokines and disrupts normal hepatic lipid metabolism when administered with HFD but not control diet. Because all US adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts human obesity/NAFLD.

Toxicant-associated steatohepatitis.

Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.

Nutrition therapy of the severely obese, critically ill patient: summation of conclusions and recommendations.

This report compiles the conclusions and recommendations for nutrition therapy of the obese, critically ill patient derived by the group of experts participating in this workshop on obesity in critical care nutrition. The recommendations are based on consensus opinions of the group after review of the current literature. Obesity clearly adds to the complexity of nutrition therapy in the intensive care unit (ICU). Obesity alters the incidence and severity of comorbidities, tolerance of the prescribed regimen, and ultimately patient outcome through the course of hospitalization. Although the basic principles of critical care nutrition apply to the obese ICU patient, a high-protein, hypocaloric regimen should be provided to reduce the fat mass, improve insulin sensitivity, and preserve lean body mass. The ideal enteral formula should have a low nonprotein calorie to nitrogen ratio and have a variety of pharmaconutrient agents added to modulate immune responses and reduce inflammation.

Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers.

OBJECTIVE: Cytokeratin 18 (CK18) is a novel serologic biomarker for occupational liver disease. The purpose of this study is to determine the prevalence of CK18 elevation in elastomer/polymer workers exposed to acrylonitrile, 1,3-butadiene, and styrene. METHODS: A total of 82 chemical workers were evaluated. Cytokeratin 18 was determined by enzyme-linked immunosorbent assay and proinflammatory cytokines were measured by multi-analyte chemiluminescent detection. RESULTS: Thirty-nine percent (32 of 82) had elevated CK18 levels, which were not explained by alcohol or obesity, except in potentially four cases. The pattern of CK18 elevation was consistent with toxicant-associated steatohepatitis (TASH) in the majority of cases (78%). Tumor necrosis factor α, interleukin-6, interleukin-8, monocyte chemotactic protein-1, and plasminogen activator inhibitor-1 were increased in these workers compared with those with normal CK18 levels. CONCLUSIONS: These results suggest a high prevalence of occupational liver disease and TASH in elastomer/polymer workers with elevated proinflammatory cytokines.

Micronutrient-related neurologic complications following bariatric surgery.

Nearly two thirds of American adults are either overweight or obese. Accordingly, bariatric surgery experienced explosive growth during the past decade. Current estimates place the worldwide volume of bariatric procedures at greater than 300,000 cases annually. Micronutrient deficiencies are well-described following bariatric surgery, and they may present with devastating and sometimes irreversible neurologic manifestations. Clinical symptoms range from peripheral neuropathy to encephalopathy, and are most commonly caused by thiamine, copper, and B(12) deficiencies.

Toxicant-associated steatohepatitis in vinyl chloride workers.

UNLABELLED: Although nonalcoholic steatohepatitis (NASH) is typically associated with obesity, it has also been reported to occur in lean individuals exposed to industrial chemicals. Occupational exposure to vinyl chloride (VC) is a well-documented risk factor for hemangiosarcoma, but has not previously been associated with steatohepatitis. Here we evaluate liver biopsies from 25 nonobese, highly exposed VC workers for steatohepatitis. Next, we evaluate associated metabolic and cytokine abnormalities in affected workers controlled by 26 chemical workers with no to minimal VC exposures, and 11 unexposed, healthy volunteers. Among highly exposed VC workers the prevalence of steatohepatitis was 80%. Of these, 55% had fibrosis and four had hemangiosarcoma. We have coined the term toxicant-associated steatohepatitis (TASH) to describe this condition, which was not explained by obesity or alcohol. Although mean serum transaminases were normal in TASH, total cytokeratin 18, but not the caspase-cleaved fragment, was elevated. Despite the absence of obesity, workers with TASH had insulin resistance with reduced adiponectin levels. TASH was also associated with markedly elevated serum tumor necrosis factor alpha and interleukins 1beta, 6, and 8. Serum antioxidant activity was reduced in TASH. CONCLUSION: TASH occurred frequently in these nonobese VC workers with high cumulative exposures and normal liver enzymes. Elevated total cytokeratin 18 suggested the presence of necrotic cell death in TASH and may be a useful serologic biomarker. TASH was further characterized by insulin resistance, elevated proinflammatory cytokines, and impaired antioxidant defenses. The threshold VC exposure and the role of other chemical agents in TASH are as yet unknown.

Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial.

UNLABELLED: Based on animal studies and pilot studies in humans, betaine, a methyl donor for the remethylation of homocysteine, may be a therapeutic agent for nonalcoholic steatohepatitis (NASH). We evaluated the safety and efficacy of betaine for patients with NASH and whether betaine positively modified factors postulated to be "second hits" and underlying mechanisms of NASH. We conducted a randomized placebo-control study of 55 patients with biopsy-proven NASH who received either oral betaine (20 g daily) or placebo for 12 months. Pre- and posttreatment variables were analyzed using the paired t test or Wilcoxon rank test. Treatment groups were comparable at baseline. Of the 35 patients (17 betaine, 18 placebo) who completed the study, 34 patients (16 betaine, 18 placebo) underwent posttreatment liver biopsy. Patients randomized to betaine had a decrease in steatosis grade. No intra- or intergroup differences or changes in nonalcoholic fatty liver disease activity score or fibrosis stage were noted. Elevations of insulin, glucose, and proinflammatory cytokines and the reduced antioxidant status noted in NASH patients did not improve with betaine therapy. The antiinflammatory agent adiponectin was significantly reduced in both groups and did not change with therapy. Lastly, S-adenosylhomocysteine was approximately twice normal and was not reduced by betaine therapy. CONCLUSION: Compared to placebo, betaine did not improve hepatic steatosis but may protect against worseningsteatosis [corrected]. High-dose betaine supplementation failed to reduce S-adenosylhomocysteine and did not positively affect any of the second hit mechanisms postulated to contribute to NASH that we studied. Although betaine has been proven effective in treating hepatic steatosis in several animal models, translating novel therapeutic options noted in animal studies to humans with NASH will prove challenging.