Endocrinol Metab.  2013 Mar;28(1):41-45. 10.3803/EnM.2013.28.1.41.

Tumor Necrosis Factor-alpha as a Predictor for the Development of Nonalcoholic Fatty Liver Disease: A 4-Year Follow-Up Study

• Seo YY
• Cho YK
• Bae JC
• Seo MH
• Park SE
• Rhee EJ
• Park CY
• Oh KW
• Park SW
• Lee WY

• KMID: 1805944
• DOI: http://doi.org/10.3803/EnM.2013.28.1.41

Abstract

BACKGROUND
Tumor necrosis factor (TNF)-alpha is associated with insulin resistance and systemic inflammatory responses. The aim of this study was to investigate the relationship between TNF-alpha and the development of nonalcoholic fatty liver disease (NAFLD) in a longitudinal study.
METHODS
Three hundred and sixty-three apparently healthy subjects (mean age, 40.5+/-6.1 years; male, 57.6%) without NAFLD were enrolled in 2003. Anthropometric and laboratory measurements were performed. The participants were grouped into tertiles according to their serum TNF-alpha levels from samples taken in 2003. At a 4-year follow-up, we compared the odds ratios (ORs) of the development of NAFLD according to the tertiles of TNF-alpha levels measured in 2003.
RESULTS
At the 4-year follow-up, the cumulative incidence of NAFLD was 29.2% (106/363). The group that developed NAFLD had higher levels of TNF-alpha than those in the group without NAFLD (3.65+/-1.79 pg/mL vs. 3.15+/-1.78 pg/mL; P=0.016). When the 2003 serum TNF-alpha levels were categorized into tertiles: incidence of NAFLD observed in 2007 was significantly higher with increasing tertiles (22.6%, 35.8%, and 41.5%, respectively; P<0.05). The risk of developing NAFLD was significantly greater in the highest tertile of TNF-alpha than in the lowest tertile after adjusting for age, smoking, and BMI (OR, 2.20; 95% confidence interval, 1.12 to 4.01; P<0.05).
CONCLUSION
Higher serum TNF-alpha levels in subjects without NAFLD were associated with the development of NAFLD. The results of study might suggest a pathologic role of inflammation in NAFLD.

Keyword

Inflammation; Non-alcoholic fatty liver disease; Tumor necrosis factor-alpha

MeSH Terms

Fatty Liver
Follow-Up Studies
Humans
Incidence
Inflammation
Insulin Resistance
Male
Odds Ratio
Smoke
Smoking
Tumor Necrosis Factor-alpha
Fatty Liver
Smoke
Tumor Necrosis Factor-alpha

Reference

1. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001. 21:17–26.

2. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999. 116:1413–1419.

3. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. 1994. 107:1103–1109.

4. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006. 40:Suppl 1. S17–S29.

5. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993. 259:87–91.

6. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003. 112:1785–1788.

7. Poniachik J, Csendes A, Diaz JC, Rojas J, Burdiles P, Maluenda F, Smok G, Rodrigo R, Videla LA. Increased production of IL-1alpha and TNF-alpha in lipopolysaccharide-stimulated blood from obese patients with non-alcoholic fatty liver disease. Cytokine. 2006. 33:252–257.

8. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004. 40:46–54.

9. Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, Ohata K, Nagaoka S, Matsumoto T, Takii Y, Kusumoto K, Nakamura M, Komori A, Yano K, Yatsuhashi H, Eguchi K, Ishibashi H. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int. 2006. 26:39–45.

10. Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Faga E, Pacini G, De Michieli F, Rabbione L, Premoli A, Cassader M, Pagano G. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005. 42:1175–1183.

11. Kim YC, Cho YK, Lee WY, Kim HJ, Park JH, Park DI, Sohn CI, Jeon WK, Kim BI, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Kim SW, Ryu SH. Serum adipocyte-specific fatty acid-binding protein is associated with nonalcoholic fatty liver disease in apparently healthy subjects. J Nutr Biochem. 2011. 22:289–292.

12. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985. 28:412–419.

13. Bluher M. Clinical relevance of adipokines. Diabetes Metab J. 2012. 36:317–327.

14. Peraldi P, Spiegelman BM. Studies of the mechanism of inhibition of insulin signaling by tumor necrosis factor-alpha. J Endocrinol. 1997. 155:219–220.

15. Diehl AM. Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis. 2004. 8:619–638.

16. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005. 54:2939–2945.

17. Endo M, Masaki T, Seike M, Yoshimatsu H. TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood). 2007. 232:614–621.

18. Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004. 99:1946–1952.

19. Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol. 2003. 15:539–543.

20. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, Mullen KD, Cooper JN, Sheridan MJ. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002. 123:745–750.