Gastroenterology
Volume 135, Issue 6 , Pages 1860-1862, December 2008

The Natural History of Nonalcoholic Fatty Liver Disease: Insights From Children and Mice

  • Rexford S. Ahima

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Rexford S. Ahima, MD, PhD, University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, 712A Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104. fax: 215-573-5809

University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, Pennsylvania

published online 11 November 2008.

Article Outline

 

See “Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis” by Patton HM, Lavine JE, Van Notta ML, et al, on page 1961; and “Development of nonalcoholic steatohepatitis in insulin-resistant liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule mutant mice” by Lee SJ, Heinrich G, Fedorova L, et al, on page 2084.

Nonalcoholic fatty liver disease (NAFLD) affects 20%–30% of adults in developed countries.1 NAFLD includes a range of abnormalities from simple steatosis to nonalcoholic steatohepatitis (NASH; Figure). Steatosis is frequently associated with obesity, characterized by fat accumulation in the liver without inflammation and considered benign.1 NASH occurs in 2%–3% of NAFLD cases, is characterized by steatosis, inflammation, hepatocellular ballooning, and pericellular fibrosis, and can progress to cirrhosis and hepatocellular carcinoma.1 Individuals with NAFLD are often asymptomatic. The diagnosis typically follows abnormal liver function tests in patients with the “metabolic syndrome,” associated with visceral adiposity, insulin resistance, impaired glucose tolerance or type 2 diabetes, dyslipidemia, and increased cardiovascular risk. In the absence of excessive alcohol consumption, infections and other causes of liver damage, an elevation of serum alanine aminotransferase (ALT) is suggestive of NAFLD. Serum ALT levels in NAFLD are positively related to waist circumference, hyperinsulinemia, and insulin resistance; however, aspartate aminotransferase (AST) can be higher than ALT after the development of cirrhosis.1, 2

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  • Figure. 

    Schematic diagram showing the development of NAFLD. Obesity is associated with increased adipose mass and insulin resistance, lipolysis, hepatic fatty acid uptake, and excessive triglyceride formation. De novo hepatic lipogenesis is also increased in obesity. Hepatic steatosis is very common in obesity, but only a subset of affected individuals develop NASH or fibrosis.

NAFLD was first described in children in the 1980s.3 As in adults, pediatric NAFLD is associated with obesity and insulin resistance.3, 4 In the United States National Health and Nutrition Examination Survey (1999–2004), the prevalence of elevated ALT levels (>30 U/l) was 7.4% among white adolescents, 11.5% among Mexican American adolescents, and 6% among black adolescents.4 Elevated ALT levels were more common in males (12.4%) than females (3.5%), in agreement with reports in other populations.4, 5, 6 Fatty liver may be visualized using abdominal ultrasound, computed tomography, or magnetic resonance imaging, but these techniques do not distinguish the various stages of NAFLD. Thus, the definitive diagnosis of NAFLD requires liver biopsy. The histopathologic features of NASH differs between adults and children.3 NASH in adults is characterized by steatosis, ballooning degeneration of hepatocytes, Mallory bodies, polymorphonuclear leukocyte infiltration surrounding hepatocytes in the perivenular areas, and pericellular fibrosis. In contrast, pediatric NASH is characterized by minimal ballooning of hepatocytes and Mallory bodies, and mononuclear infiltration mostly in the periportal areas.

Given the high prevalence of obesity in children and the potential for NASH to progress to cirrhosis, there is urgent need for diagnostic tools, preferably noninvasive, to identify children at risk for NASH.3, 7 Liver biopsy is the gold standard for diagnosing NASH, but this approach is impractical for screening large numbers of patients and carries the risk of severe complications. Measurement of serum aminotransferase levels is simple and logical, but this biomarker has not been validated against the histologic staging of NAFLD. The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is a prospective study involving 8 centers across the United States, aimed at understanding the pathogenesis, natural history, prognosis, and treatment of NAFLD.8, 9 In this issue of Gastroenterology, children (aged 6–17 years) were analyzed to identify the clinical and biochemical parameters that predict the histology and severity of NAFLD.9 Liver biopsies were obtained within 6 months of collecting clinical data. Among 176 children, increasing levels of AST and γ-glutamyl transferase (GGT) were associated with the severity of NASH. Increasing AST levels and white cell count, and decreasing hematocrit levels, were associated with the severity of fibrosis. AST was superior to ALT for distinguishing the histologic patterns of NAFLD. However, it is noteworthy that ALT was ≥60 U/l in ≥50% of the participants; therefore, the associations among ALT, AST, and NAFLD histology in this particular study may not apply to others.9 Higher smooth muscle antibody titers were associated with NAFLD. Body mass index was not predictive of the severity of fibrosis in NAFLD, although higher insulin levels were predictive of fibrosis.9 Although the biomarkers lacked the discriminative power to detect NAFLD severity, the findings in this study could potentially be used in initial evaluation of NAFLD in obese children. Overall, the work of the NASH CRN is a critical step in the search for biomarkers related to NAFLD. Further work is needed to determine the importance of adipocyte hormones, cytokines, lipid metabolites, and other circulating factors associated with insulin resistance, oxidative stress, and inflammation.10

Insulin resistance increases lipolysis is adipose tissue, resulting in hepatic fatty acid influx and triglyceride formation.10, 11 Hyperinsulinemia also increases de novo hepatic lipogenesis in obesity.11 The “2-hit” hypothesis of NAFLD suggests that steatosis is a prerequisite for NASH, but it is possible that triglyceride accumulation actually protects the liver from the harmful effects of fatty acid metabolites.12, 13 Efforts to delineate the molecular relationship between steatosis and NASH have suffered from the absence of animal models showing metabolic features of human NAFLD. Normal rodents do not spontaneously develop NASH. Methionine-choline–deficient (MCD) diet causes oxidative injury, steatohepatitis, and fibrosis, but MCD diet also decreases weight and enhances insulin sensitivity.14 Lepob/ob mice with congenital leptin deficiency or Leprdb/db and fa/fa rats with loss-of-function mutations of the leptin receptor develop severe insulin resistance, steatosis, and NASH on an MCD diet.15, 16 However, leptin plays important roles in immunity and fibrosis; hence, the disruption of leptin signaling in these animals may alter the pathogenesis of NAFLD. Lipodystrophic mice develop severe insulin resistance and steatosis but lack inflammatory changes and fibrosis consistent with NASH.17

Lee et al, in this issue of Gastroenterology, describe NAFLD in mice expressing a mutant form of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1) which prevents insulin clearance by the liver.18, 19 L-SAAC1 mice develop insulin resistance, late-onset obesity, and hyperlipidemia.19 Because CEACAM1 inhibits inflammation after T-cell activation, the authors hypothesized that L-SAAC1 mice would develop NASH.18 In agreement, L-SAAC1 mice on a regular (low-fat) diet exhibited mild serum ALT elevation, steatosis, and fibrotic changes in the liver.19 Although wild-type and L-SAAC1 mice became obese after consuming a high-fat (Western) diet, only L-SAAC1 mice developed severe steatohepatitis, associated with elevated levels of tumor necrosis factor-α, and activation of nuclear factor-κB.19 Lipid peroxidation, hepatocellular necrosis, apoptosis, and fibrosis were also prominent in the livers of obese L-SAAC1 mice.

These findings demonstrate that key metabolic features of human NAFLD can be reproduced in L-SAAC1 mice by feeding them a high-fat diet.19 However, the “permissive factors” mediating the effects of high-fat diet in L-SAAC1 mice are unknown. Furthermore, it is uncertain whether CEACAM1 is involved in human NAFLD. Despite these shortcomings, the L-SAAC1 mouse is a unique mouse for studying the natural history of NAFLD, and the molecular mechanisms linking insulin resistance to steatosis, inflammation, and fibrosis.

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References 

  1. Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond). 2008;115:141–150
  2. Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–798
  3. Roberts EA. Pediatric nonalcoholic fatty liver disease (NAFLD): a ”growing” problem?. J Hepatol. 2007;46:1133–1142
  4. Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999–2004. Gastroenterology. 2007;133:1814–1820
  5. Chan DF, Li AM, Chu WC, et al. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord. 2004;28:1257–1263
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  8. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321
  9. Patton HM, Lavine JE, Van Natta ML, et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis (NASH). Gastroenterology. 2008;135:1961–1971
  10. Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2006;91:4753–4761
  11. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–838
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  13. Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–1374
  14. Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol. 2004;40:47–51
  15. Rinella ME, Elias MS, Smolak RR, et al. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res. 2008;49:1068–1076
  16. Ota T, Takamura T, Kurita S, et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology. 2007;132:282–293
  17. Shimomura I, Hammer RE, Richardson JA, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 1998;12:3182–3194
  18. Lee SJ, Heinrich G, Fedorova L, et al. Development of non-alcoholic steatohepatitis in insulin resistant L-SACC1 mice. Gastroenterology. 2008;135:2084–2095
  19. DeAngelis AM, et al. Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism. Diabetes. 2008;57:2296–2303

 The author discloses no conflicts.

PII: S0016-5085(08)01984-7

doi:10.1053/j.gastro.2008.11.004

Refers to article:

  • Editorial Accompanies ArticleLinking Article with CGHAdditional Online Content Available Clinical Correlates of Histopathology in Pediatric Nonalcoholic Steatohepatitis , 04 September 2008

    Heather M. Patton, Joel E. Lavine, Mark L. Van Natta, Jeffrey B. Schwimmer, David Kleiner, Jean Molleston, Nonalcoholic Steatohepatitis Clinical Research Network
    Gastroenterology December 2008 (Vol. 135, Issue 6, Pages 1961-1971.e2)

  • Editorial Accompanies Article Development of Nonalcoholic Steatohepatitis in Insulin-Resistant Liver-Specific S503A Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Mutant Mice , 22 August 2008

    Sang Jun Lee, Garrett Heinrich, Larisa Fedorova, Qusai Y. Al–Share, Kelly J. Ledford, Mats A. Fernstrom, Marcia F. McInerney, Sandra K. Erickson, Cara Gatto–Weis, Sonia M. Najjar
    Gastroenterology December 2008 (Vol. 135, Issue 6, Pages 2084-2095)

Gastroenterology
Volume 135, Issue 6 , Pages 1860-1862, December 2008

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