Focus: Nutrition and Enviromental ToxinNonalcoholic fatty liver disease: predisposing factors and the role of nutrition☆
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)
- et al.
Liver impairment in the obese
Gastroenterology
(1958) - et al.
Fatty liver hepatitis and cirrhosis in obese patients
Am J Med
(1979) - et al.
Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease
J Pediatr
(2005) - et al.
Mechanisms of non-alcoholic steatohepatitis
Alcohol
(2004) - et al.
Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference
Hepatology
(2003) - et al.
AGA technical review on obesity
Gastroenterology
(2002) - et al.
Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity
Am J Clin Nutr
(2004) - et al.
Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents
J Pediatr
(2000) - et al.
The prevalence and etiology of elevated aminotransferase levels in the United States
Am J Gastroenterol
(2003) Nonalcoholic steatohepatitis: a study of 49 patients
Hum Pathol
(1989)
NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States
Hepatology
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity
Gastroenterology
Non-alcoholic steatohepatitis: from cell biology to clinical practice
J Hepatol
Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities
Gastroenterology
Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease
J Hepatol
CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease
Hepatology
Cytotoxic activity of TNF is mediated by early damage of mitochondrial functions
J Biol Chem
NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis
Gastroenterology
Cytokines and NASH: effects of lifestyle modification and vitamin E
Hepatology
Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients
Hepatology
Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in non-alcoholic fatty liver disease
Gastroenterology
Plasma cysteine, cystine, and glutathione in cirrhosis
Gastroenterology
S-adenosylmethionine synthesis: molecular mechanisms and clinical implications
Pharmacol Ther
Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice
Gastroenterology
Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats
J Nutr
Association of nonalcoholic fatty liver disease with insulin resistance
Am J Med
Non-alcoholic fatty liver: another feature of the metabolic syndrome?
Clin Nutr
Animal models of steatohepatitis
Best Pract Res Clin Gastroenterol
Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury
J Biol Chem
Relationship of body weight to disposition of hexachloronbenzene
Toxicol Lett
Therapeutic effects of restricted diet and exercise in obese patients with fatty liver
J Hepatol
Hepatic effects of dietary weight loss in morbidly obese subjects
J Hepatol
Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats
J Lipid Res
Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States
Gastroenterology
Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study
J Pediatr
A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis
Clin Gastroenterol Hepatol
S-adenosylmethionine, cytokines and alcoholic liver disease
Alcohol
S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice small star, filled
J Nutr Biochem
S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial
J Hepatol
Betaine in human nutrition
Am J Clin Nutr
Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats
J Nutr
Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease
Mayo Clin Proc
Role of liver biopsy in the assessment of non-alcoholic fatty liver disease
Eur J Gastroenterol Hepatol
Prevalence of overweight and obesity in the United States, 1999–2004
JAMA
Increasing prevalence of the metabolic syndrome among U.S. adults
Diabetes Care
Dietary composition and nonalcoholic fatty liver disease
Dig Dis Sci
Dietary-fat intake in the US population
J Am Coll Nutr
Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone
Hepatology
A comparative assessment of liver function in workers in the petroleum industry
Int Arch Occup Environ Health
Liver changes in workers at an oil refinery and in a reference population in the state of Bahia, Brazil
Rev Panam Salud Publica
Cited by (242)
Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD
2023, Journal of Ginseng ResearchEffect of Nigella sativa, atorvastatin, or L-Carnitine on high fat diet-induced obesity in adult male Albino rats
2021, Biomedicine and PharmacotherapyFructose and fructose kinase in cancer and other pathologies
2021, Journal of Genetics and GenomicsTranscript and protein marker patterns for the identification of steatotic compounds in human HepaRG cells
2020, Food and Chemical ToxicologyS-adenosyl-L-methionine (SAMe) halts the autoimmune response in patients with primary biliary cholangitis (PBC) via antioxidant and S-glutathionylation processes in cholangiocytes
2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
- ☆
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).