Focus: Nutrition and Enviromental Toxin
Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition

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Abstract

More than 20% of Americans have nonalcoholic fatty liver disease (NAFLD), and this is, by far, the leading cause of abnormal liver enzymes in the United States. Nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD, can proceed to cirrhosis and even hepatocellular carcinoma. These liver diseases represent the hepatic component of the metabolic syndrome, and this spectrum of liver disease represents a major health problem both in the United States and worldwide. Hepatic steatosis is closely linked to nutrition, including obesity, possibly high-fructose corn syrup consumption and consumption of certain types of fats. There are a variety of second insults or “hits” that appear to transform simple steatosis into NASH, with some of these second hits including certain proinflammatory cytokines, oxidative stress and possibly industrial toxins. In certain underdeveloped countries, it appears likely that industrial toxins play a role in NASH, and there is increasing interest in the potential interaction of industrial toxins and nutrients. Moreover, optimal therapy for NAFLD appears to include lifestyle modification with exercise, diet and weight loss. Certain nutrients may also be of benefit. Important areas for future research are the effect(s) of nutritional supplements on NAFLD/NASH and the effects of industrial toxins.

Introduction

Obesity-associated fatty liver disease was first described by Westwater and Fainer [1] nearly 50 years ago. However, little progress was made until 1979, when Adler and Schaffner [2] described fatty liver, hepatitis and cirrhosis mimicking alcoholic liver disease in a group of overweight patients often with diabetes and lipid abnormalities. The following year, Ludwig et al. [3] coined the term nonalcoholic steatohepatitis to describe similar pathologic findings in a group of obese, often diabetic, female patients with abnormal liver function tests. Since then, the term nonalcoholic fatty liver disease (NAFLD), has been used to describe a larger spectrum of steatotic liver disease, generally associated with the metabolic syndrome [4], [5].

NAFLD is defined by clinicopathologic criteria [4], [5], [6]. Clinically, patients do not consume significant quantities of alcohol (generally defined as no more than two drinks per day). Pathologically, several patterns of disease exist, which resemble alcoholic liver disease. The sine qua non of NAFLD is macrovesicular steatosis or fatty liver. If this condition exists in isolation, the patient is said to have simple steatosis or nonalcoholic fatty liver (NAFL). The majority of patients seem to tolerate this condition well and likely have limited progression to cirrhosis [6], [7]. However, some patients with steatosis develop superimposed necroinflammatory activity with a nonspecific inflammatory infiltrate, hepatocyte ballooning with Mallory's hyaline and, sometimes with fibrosis, called nonalcoholic steatohepatitis (NASH) (Table 1). Some of these patients will develop cirrhosis, which may become complicated by hepatocellular carcinoma and die of a liver-related cause. This article will review the epidemiology, clinical presentation, pathogenesis and treatment of NAFLD, with a focus on nutrition and potential nutritional and environmental interactions contributing to the disease.

Section snippets

Epidemiology

NAFLD is now the most common liver disease in the United States and possibly worldwide. Furthermore, the number of affected patients is growing rapidly, and the disease has reached epidemic proportions. NAFLD is the hepatic manifestation of the metabolic syndrome, and it is important to first examine the epidemiology of obesity, the metabolic syndrome and other contributing factors such as high-fructose corn syrup and saturated fat consumption. Occupational exposure to petrochemicals may

Clinical features and prognosis

Although NAFLD may present at any stage, including cirrhosis with hepatocellular carcinoma, the most common presentation is in the asymptomatic, nondrinking patient with mildly elevated transaminases (ALT usually greater than aspartate aminotransferase [AST]). Patients will generally have associated metabolic comorbidities such as obesity, the metabolic syndrome, diabetes and dyslipidemia. Middle-aged males are most commonly affected, and Hispanics seems to be at particularly high risk, while

Mechanisms

The mechanisms leading to NASH are likely to be multiple. Certainly, the development of hepatic steatosis in experimental animals can be caused by many factors. In patients with NASH, it is felt that there is a baseline of steatosis plus some other insult, the so-called 2-hit theory [5], [26]. Some of the likely second hits include oxidative stress, mitochondrial dysfunction, abnormal methionine metabolism, insulin resistance and industrial toxins (of particular interest for this article).

Overview

The type of treatment and its aggressiveness depend on the severity of the liver disease, as well as related comorbidities. For example, patients with decompensated cirrhosis may require liver transplantation to prevent death, while patients with simple steatosis may require only lifestyle modifications because they are at low risk for progression. Treatment becomes more complicated for patients with biopsy-proven NASH, particularly those with fibrosis or asymptomatic cirrhosis. Aggressive,

References (106)

  • J.A. Marrero et al.

    NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States

    Hepatology

    (2002)
  • C.A. Matteoni et al.

    Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity

    Gastroenterology

    (1999)
  • H. Cortez-Pinto et al.

    Non-alcoholic steatohepatitis: from cell biology to clinical practice

    J Hepatol

    (2006)
  • A.J. Sanyal et al.

    Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities

    Gastroenterology

    (2001)
  • Y. Sumida et al.

    Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease

    J Hepatol

    (2003)
  • M.G. Emery et al.

    CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease

    Hepatology

    (2003)
  • K. Schulze-Osthoff et al.

    Cytotoxic activity of TNF is mediated by early damage of mitochondrial functions

    J Biol Chem

    (1992)
  • A. Dela Pena et al.

    NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis

    Gastroenterology

    (2005)
  • M. Kugelmas et al.

    Cytokines and NASH: effects of lifestyle modification and vitamin E

    Hepatology

    (2003)
  • J. Crespo et al.

    Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients

    Hepatology

    (2001)
  • L. Valenti et al.

    Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in non-alcoholic fatty liver disease

    Gastroenterology

    (2002)
  • R.K. Chawla et al.

    Plasma cysteine, cystine, and glutathione in cirrhosis

    Gastroenterology

    (1984)
  • J.M. Mato et al.

    S-adenosylmethionine synthesis: molecular mechanisms and clinical implications

    Pharmacol Ther

    (1997)
  • C. Ji et al.

    Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice

    Gastroenterology

    (2003)
  • A.J. Barak et al.

    Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats

    J Nutr

    (2003)
  • G. Marchesini et al.

    Association of nonalcoholic fatty liver disease with insulin resistance

    Am J Med

    (1999)
  • H. Cortez-Pinto et al.

    Non-alcoholic fatty liver: another feature of the metabolic syndrome?

    Clin Nutr

    (1999)
  • A. Koteish et al.

    Animal models of steatohepatitis

    Best Pract Res Clin Gastroenterol

    (2002)
  • J. Bjorkegren et al.

    Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury

    J Biol Chem

    (2002)
  • T. Rozman et al.

    Relationship of body weight to disposition of hexachloronbenzene

    Toxicol Lett

    (1983)
  • T. Ueno et al.

    Therapeutic effects of restricted diet and exercise in obese patients with fatty liver

    J Hepatol

    (1997)
  • T. Andersen et al.

    Hepatic effects of dietary weight loss in morbidly obese subjects

    J Hepatol

    (1991)
  • A.R. Tovar et al.

    Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats

    J Lipid Res

    (2005)
  • C.E. Ruhl et al.

    Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States

    Gastroenterology

    (2005)
  • J.E. Lavine

    Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study

    J Pediatr

    (2000)
  • A.J. Sanyal et al.

    A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis

    Clin Gastroenterol Hepatol

    (2004)
  • C.J. McClain et al.

    S-adenosylmethionine, cytokines and alcoholic liver disease

    Alcohol

    (2002)
  • Z. Song et al.

    S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice small star, filled

    J Nutr Biochem

    (2003)
  • J.M. Mato et al.

    S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial

    J Hepatol

    (1999)
  • S.A. Craig

    Betaine in human nutrition

    Am J Clin Nutr

    (2004)
  • A.J. Barak et al.

    Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats

    J Nutr

    (2003)
  • J. Ludwig et al.

    Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease

    Mayo Clin Proc

    (1980)
  • S.G. Hubscher

    Role of liver biopsy in the assessment of non-alcoholic fatty liver disease

    Eur J Gastroenterol Hepatol

    (2004)
  • C.L. Ogden et al.

    Prevalence of overweight and obesity in the United States, 1999–2004

    JAMA

    (2006)
  • E.S. Ford et al.

    Increasing prevalence of the metabolic syndrome among U.S. adults

    Diabetes Care

    (2004)
  • S. Solga et al.

    Dietary composition and nonalcoholic fatty liver disease

    Dig Dis Sci

    (2004)
  • E.T. Kennedy et al.

    Dietary-fat intake in the US population

    J Am Coll Nutr

    (1999)
  • B.A. Neuschwander-Tetri et al.

    Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone

    Hepatology

    (2003)
  • A. Michailova et al.

    A comparative assessment of liver function in workers in the petroleum industry

    Int Arch Occup Environ Health

    (1998)
  • J.L. Barberino et al.

    Liver changes in workers at an oil refinery and in a reference population in the state of Bahia, Brazil

    Rev Panam Salud Publica

    (2005)
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    This work was supported by NIH grants R21 AA015611 (Deaciuc), K01 AA015344-01A1 (Song), R01AA014371 (Barve), R37AA010762 (McClain), R01AA010496 (McClain), R01AA15970 (McClain), R01DK071765 (McClain) and the Veterans Administration (McClain).

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