NONALKOLİK KARACİĞER YAĞLANMASI VE STEATOHEPATİT

Abstract

Nonalkolik karaciğer yağlanması (NAFLD), artık dünyada en yaygın karaciğer hastalığı olarak kabul edilmektedir. Bu, basit steatozdan steatohepatite, son dönem karaciğer hastalığına (siroz) ve hepatoselüler karsinoma kadar gidebilen farklı derecedeki durumlar için kullanılan genel bir isimdir. Bu durum sıklıkla metabolik sendromun özelliklerini gösterir ve insülin rezistansı ile ilişkilidir. Hastalık asemptomatik karaciğer enzim yüksekliğinden siroza ve karaciğer yetersizliğinin komplikasyonlarına kadar değişik şekillerde görünmektedir. Bu derlemede NAFLD etiyolojisi, patogenezi, tanısı ve tedavi yaklaşımları tartışılmıştır.

Keywords

• Nonalkolik karaciğer yağlanması (NAFLD), nonalkolik steatohepatit (NASH), insülin rezistansı, inflamasyon

References

1. Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 96: 2711-2717, 2001.
2. Adams LA, Talwalkar JA. Diagnostic evaluation of nonalcoholic fatty liver disease. J Clin Gastroenterol 40: 34-38, 2006.
3. Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 99: 2365-2368, 2004.
4. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30: 1356-1362, 1999.
5. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12: 141-179, 1994.
6. Barzilai N, Wang J, Massilon D, Vuguin P, Hawkins M, Rossetti L. Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Invest 100: 3105-3110, 1997.
7. Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 31: 384, 1999.
8. Belfort R, Harrison SA, Brown K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355: 2297-307, 2006.

9. Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, Banner BF. Non-alcoholic steatohepatitis and iron: increasied prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 31: 421-429, 1999.
10. Brunt EM. Pathologist's point of view: Grading and staging the histologic lesions of nonalcoholic steatohepatitis. Do they tell us about the future? In: Tozun N, Avsar E, eds. Non Alcoholic Fatty Liver Disease - EASL 2003 President's Premeeting Syllabus 41-56, 2003.
11. Campbell JM, Hunt TK, Karam JH, Forsham PH. Jejunoileal bypass as a treatment of morbid obesity. Arch Intern Med 137: 602-610, 1977.
12. Curzio M, Esterbauer H, Dianzani MU. Chemotactic activity of hydroxyalkenals on rat neutrophils. Int J Tissue React 7: 137-142, 1985.
13. Day C, James O. Steatohepatitis: A tale of two “hits”? [editorial]. Gastroenterology 114: 842, 1998.
14. Day CP. Pathogenesis of steatohepatitis. Best Practice and Research Clinical Gastroenterology 16: 663-678, 2002.
15. Deushi M, Nomura M, Kawakami A, Haraguchi M, Ito M, Okazaki M, Ishii H, Yoshida M. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett 581: 5664-5670, 2007.
16. Dixon JB, Bhathal PS, O'Brien PE. Weight loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histologic improvement. Obes Surg 16: 1278-1286, 2006.
17. Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, Del Vecchio Blanco C, Loguercio C. A new silybin-vitamin E-phospholipid complex improves insulin resistance and liver damage in patients with non-alcoholic fatty liver disease: preliminary observations. Gut 55:901-902, 2006.
18. Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, Colombo M. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 56: 968-973, 2007.
19. Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 23: 1643-1647, 2006.
20. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology 49: 80-86, 2009.
21. Hirose A, Ono M, Saibara T, Nozaki Y, Masuda K, Yoshioka A, Takahashi M, Akisawa N, Iwasaki S, Oben JA, Onishi S. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 45: 1375-1381, 2007. 22. Hortander JC, Kwo PY, Cummings OW, Koukoulis G. Atorvastatin for the treatment of NASH. Gastroenterology 120: 544, 2001.
22. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor in human obesity and insulin resistance. J Clin Invest 95: 2409-2415, 1995.
23. Huang MA, Greenson JK, Chao C. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 100: 1072-1081, 2005.
24. Iijima H, Moriyasu F, Tsuchiya K, Suzuki S, Yoshida M, Shimizu M, Sasaki S, Nishiguchi S, Maeyama S. Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis. Hepatol Res 37: 722-730, 2007. 26. Karcaaltincaba M, Akhan O. Imaging of hepatic steatosis and fatty sparing. Eur J Radiol 61: 33–43, 2007.
25. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-spesific overexpression of lipoprotein lipase causs tissuespesific insulin resistance. Proc Natl Acad Sci 98: 7522-7527, 2001.
26. Kiyici M, Gulten M, Gurel S, Nak SG, Dolar E, Savci G, Adim SB, Yerci O, Memik F. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 17: 713-718, 2003.
27. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23: 1464-1467, 1996.
28. Lee KS, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 96: 2461-2468, 1995.
29. Letteron P, Fromenty B, Terris B, Degott C, Pessayre D. Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. J Hepatol 24: 200-208, 1996.
30. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298: 1180-1188, 2007.
31. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39: 770-778, 2004.
32. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55: 434-438, 1980.
33. Maher JJ. Cytokines: Overview. Semin Liv Dis 19: 109-115, 1999.
34. Marubbio AT Jr, Buchwald H, Schwartz MZ, Varco R. Hepatic lesions of central pericellular fibrosis in morbid obesity, and after jejunoileal bypass. Am J Clin Pathol 66: 684-691, 1976.
35. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis 8: 521-533, 2004.
36. Nair S, Diehl AM, Perrillo RP. Metformin in non-alcoholic steatohepatitis (NASH): efficacy and safety – a preliminary report. Gastroenterology 122: 4, 2002.
37. Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 20: 23-28, 2004.
38. Neuroschwander-Tetri BA. Fatty liver and the metabolic syndrome. Curr Opin Gastroenterol 23: 193-198, 2007.
39. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38: 1008-1017, 2003.
40. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356: 2457-2471, 2007.
41. Oh MK, Winn J, Poordad F. Diagnosis and Treatment of Non-alcoholic Fatty Liver Disease. Aliment Pharmacol Ther 28: 503-522, 2008.
42. Palmentieri B, de Sio I, La Mura V, Masarone M, Vecchione R, Bruno S, Torella R, Persico M. The role of bright liver echo pattern on ultrasound B-mod examination in the diagnosis of liver steatosis. Dig Liver Dis 38: 485-489, 2006.
43. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 99: 1408-1413, 1990.
44. Park SH, Kim PN, Kim KW, Lee SW, Yoon SE, Park SW, Ha HK, Lee MG, Hwang S, Lee SG, Yu ES, Cho EY. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology 239: 105-112, 2006.
45. Parola M, Pinzani M, Casini A, Albano E, Poli G, Gentilini A, Gentilini P, Dianzani MU. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun 194: 1044-1050, 1993.
46. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39: 188-196, 2004.
47. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E, Grimaldi A, Poynard T; LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: One-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135: 100-110, 2008.
48. Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol 22: 634-638, 2007.
49. Scheen AJ. Cannabinoid-1 receptor antagonists in type-2 diabetes. Best Pract Res Clin Endocrinol Metab 21: 535-553, 2007.
50. Schreuder TC, Verwer BJ, van Nieuwkerk CM, Mulder CJ. Nonalcoholic fatty liver disease: An overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol 14: 2474-2486, 2008.
51. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288: 462-468, 2005.
52. Talwalkar JA, Kurtz DM, Schoenleber SJ, West CP, Montori VM. Ultrasound-based transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 5: 1144-1146, 2007.
53. Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int 26: 1015-1017, 2006.
54. Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, Yesilova Z, Gulsen M, Dagalp K. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 19: 537-544, 2004.
55. Wang RT, Koretz RL, Yee HF Jr. Is weight reduction an effective therapy for nonalcoholic fatty liver? A systematic review. Am J Med 115: 554-559, 2003.
56. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12: 1106-1110, 1990.
57. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinalbacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor in the pathogenesis of non-alcoholic steatohepatitis. Gut 48: 206-211, 2001.
58. Yakaryilmaz F, Guliter S, Savas B, Erdem O, Ersoy R, Erden E, Akyol G, Bozkaya H, Ozenirler exercise in obese patients with fatty liver. J Hepatol 27: 103-107, 1997.
59. S. Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study. Intern Med J 37: 229-35, 2007.
60. Yılmaz Y, Dolar E, Ulukaya E, Akgoz S, Keskin M, Kiyici M, Aker S, Yilmaztepe A, Gurel S, Gulten M, Nak SG. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol 13: 837-844, 2007.
61. Yokohama S, Tokusashi Y, Nakamura K, Tamaki Y, Okamoto S, Okada M, Aso K, Hasegawa T, Aoshima M, Miyokawa N, Haneda M, Yoneda M. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J Gastroenterol 12: 322-6, 2006.
62. Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, Hasegawa T, Tokusashi Y, Miyokawa N, Nakamura K. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 40: 1222-1225, 2004.
63. Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, Oren R. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 4: 639-644, 2006.