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Nonalcoholic Fatty Liver and Insulin Resistance Among Petrochemical Workers
To the Editor: Insulin resistance (IR) and features of the metabolic syndrome are often associated with nonalcoholic fatty liver disease (NAFLD). Insulin resistance has been considered to be essential for the development of NAFLD.1 However, multiple mechanisms are involved in the pathogenesis of NAFLD.2 We previously described a form of NAFLD among petrochemical workers, affecting predominantly younger men, causing mild fibrosis and cholestasis.3-4 In the current study we evaluated the relationship of IR to NAFLD among petrochemical workers.
Methods
Forty petrochemical workers with the diagnosis of NAFLD who presented with abnormal alanine aminotransferase, aspartate aminotransferase, and  -glutamyltransferase levels on 3 or more determinations, were referred to the Hepatology Clinic, Federal University of Bahia, Brazil, between March 2001 and November 2003. All had a history of occupational exposure to chemicals (benzene, xylene, ethylene, dimethylformamide, vinyl chloride, and others) for at least 5 years. Patients, corroborated by family members, indicated the absence of significant ethanol consumption (>20 g/d). Those with use of other drugs and presence of hepatitis B and C virus, hemochromatosis, and autoimmune diseases were excluded. The Ethics Committee for Medical Research at Federal University of Bahia, Brazil, approved the study. All patients provided written informed consent.
Insulin resistance was determined by the homeostasis model assessment (HOMA) index5 (Method Immunolite 2000 DPC, Los Angeles, Calif). Control HOMA-IR values were obtained from 63 healthy volunteers. Insulin resistance was considered to be present when the HOMA index value was 3 or higher. The cut-off point was validated against the results of the quantitative insulin sensitivity check index (QUICKI).6 The fifth percentile (value <0.337) was used as the QUICKI cut-off point for IR. The concordance between HOMA and QUICKI classifications of IR was 100%.
The following definitions were used: obesity, body mass index greater than 30, and overweight as body mass index (calculated as weight in kilograms divided by the square of height in meters) between 25.0 and 29.9; central obesity, waist circumference greater than 102 cm (men) or greater than 88 cm (women); diabetes mellitus, fasting plasma glucose level of at least 126 mg/dL (6.99 mmol/L) on 2 separate occasions; hyperlipidemia, serum total cholesterol greater than 200 mg/dL (5.18 mmol/L), or high-density lipoprotein cholesterol concentration less than 40 mg/dL (1.03 mmol/L) in men and less than 50 mg/dL (1.29 mmol/L) in women, or low-density cholesterol greater than 130 mg/dL (3.36 mmol/L), or serum triglyceride greater than 150 mg/dL (1.69 mmol/L).
Results
Insulin resistance was absent in 29 (72.5%) of the patients with NAFLD (Table 1). Among the 11 patients (27.5%) with IR, all had hyperlipidemia, while 54.5% were obese, 72.7% were overweight, and 45.4% had diabetes. Among 29 patients without IR, 34.5% had hyperlipidemia and 27.6% were also overweight, but without central obesity. Hyperlipidemia, obesity, overweight, or diabetes were not observed in 11 (37.9%) of the patients.
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Table 1. Risk Factors for Nonalcoholic Fatty Liver Disease Among 40 Petrochemical Workers According to the Presence or Absence of Insulin Resistance (IR)
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Liver biopsy was performed on 32 (80%) of the patients (Table 2). Steatohepatitis with fibrosis was detected in 22 (68.8%) of these patients; 17 of these 22 patients (77.3%) did not have IR. All 5 patients with IR had steatohepatitis with fibrosis.
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Table 2. Histological Findings in 32 Petrochemical Workers With Nonalcoholic Fatty Liver Disease
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Comment
To our knowledge, this is the first study to evaluate IR in patients with NAFLD related to chemical exposure. The majority of patients (72.5%) did not have evidence of IR. In addition, 37.9% of these patients without IR were free of metabolic risk factors. These results indicate that, contrary to prior assumptions,1 the development of fatty liver is not invariably associated with IR, and other mechanisms may be involved. Potential sources of oxidant stress include mitochondrial injury, cytochrome P450 system induction, and peroxisomal B-oxidation.2 Such factors may also be relevant to NAFLD/nonalcoholic steatohepatitis (NASH) cases related to exposure to chemicals without IR. The absence of demonstrable IR may explain that this type of NAFLD/NASH, usually asymptomatic, presents with mild histological findings that usually improve after workers are removed from exposure.3 These findings suggest that the usual recommended measures for treating metabolic syndrome (diet and exercise, for example) may have only limited efficacy in petrochemical-related NAFLD. However, the natural history of this form of NAFLD and its relationship with co-existing metabolic syndrome deserves further investigation.
Author Contributions: Dr Cotrim had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Cotrim, Carvalho, De Freitas.
Acquisition of data: Cotrim, Siqueira, Lordelo, Rocha, De Freitas.
Analysis and interpretation of data: Cotrim, Carvalho, De Freitas.
Drafting of the manuscript: Carvalho, Siqueira, Lordelo, Rocha.
Critical revision of the manuscript for important intellectual content: Cotrim, Carvalho, De Freitas.
Statistical analysis: Carvalho, Siqueira, Lordelo, Rocha.
Obtained funding: Cotrim, Carvalho.
Administrative, technical, or material support: Cotrim, Carvalho, De Freitas.
Study supervision: Cotrim, Carvalho.
Financial Disclosures: None reported.
Funding Support: This work was supported by CEPETRO-CNPq (Brazilian Government National Research Council) research grant 464438/00-4 and FINEP (Brazilian Government Research Funding Foundation) research grant FINEP/CTPETRO 64.000.350.00.
Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Helma P. Cotrim, MD
hpcotrim{at}ufba.br
Fernando Carvalho, MD;
Ana Cristina Siqueira, MD;
Marina Lordelo;
Raquel Rocha, MSc
School of Medicine
Universidade Federal da Bahia
Luiz A. R. De Freitas, MD
CPqGM (Gonçalo Muniz Research Center)–FIOCRUZ (Osvaldo Cruz Foundation)
Bahia, Brazil
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2. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202-1219.
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4. Cotrim HP, De Freitas LA, Freitas C, et al. Clinical and histopathological features of NASH in workers exposed to chemicals with or without associated metabolic conditions. Liver Int. 2004;24:131-135.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2005;294:1618-1620.
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