Top

Published in:

01-03-2010 | Review

Nonalcoholic Fatty Liver Disease: A Review and Update

Authors: Jeffrey R. Lewis, Smruti R. Mohanty

Published in: Digestive Diseases and Sciences | Issue 3/2010

Abstract

The spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from asymptomatic steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Hepatic steatosis occurs when free fatty acids, released in the setting of insulin resistance and the metabolic syndrome, are taken up by the liver. Additional biochemical insults, including oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, can result in inflammation (producing NASH) and fibrosis. Noninvasive methods (e.g., abdominal ultrasonography) are safe ways to support a diagnosis of hepatic steatosis, but advanced liver histopathologic findings including NASH and fibrosis cannot be identified without pursuing liver biopsy. Recent advances in serologic and imaging methods aim to determine severity of inflammation and fibrosis noninvasively. Currently, therapeutic options for NAFLD are limited to medications that reduce risk factors, but the future holds promise for therapies that might slow the progression of this increasingly prevalent disorder.

Maxwell JD, Sanderson I, Butler WH, Gazet JC, Pilkington TR. Hepatic structure and function after modified jejunoileal bypass surgery for obesity. Br Med J. 1977;2:726–729.PubMed

Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438.PubMed

Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231.PubMed

Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis. 2007;11:75–104. ix.PubMed

Roberts EA. Pediatric nonalcoholic fatty liver disease (NAFLD): a “growing” problem? J Hepatol. 2007;46:1133–1142.PubMed

Arun J, Clements RH, Lazenby AJ, Leeth RR, Abrams GA. The prevalence of nonalcoholic steatohepatitis is greater in morbidly obese men compared to women. Obes Surg. 2006;16:1351–1358.PubMed

Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41:372–379.PubMed

Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–1395.PubMed

Caldwell SH, Harris DM, Patrie JT, Hespenheide EE. Is NASH underdiagnosed among African Americans? Am J Gastroenterol. 2002;97:1496–1500.PubMed

10.

Stepanova M, Elariny H, Rafiq N, Afendy A, Srishord M, Younossi ZM, Baranova A, Srishord M, Chandhoke V. Differences in hepatic gene expression of caucasians and african american patients with non-alcoholic fatty liver disease (NAFLD) The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

11.

Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GK, Sollano JD. Non-alcoholic fatty liver disease in the Asia-pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol. 2007;22:778–787.PubMed

12.

Fan JG, Saibara T, Chitturi S, Kim BI, Sung JJ, Chutaputti A. What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific? J Gastroenterol Hepatol. 2007;22:794–800.PubMed

13.

Wang Z, Xia B, Ma C, Hu Z, Chen X, Cao P. Prevalence and risk factors of fatty liver disease in the Shuiguohu district of Wuhan city, Central China. Postgrad Med J. 2007;83:192–195.PubMed

14.

Lee JY, Kim KM, Lee SG, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol. 2007;47:239–244.PubMed

15.

Hsieh SD, Yoshinaga H, Muto T, Sakurai Y, Kosaka K. Health risks among Japanese men with moderate body mass index. Int J Obes Relat Metab Disord. 2000;24:358–362.PubMed

16.

Deurenberg P, Deurenberg-Yap M, Guricci S. Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obes Rev. 2002;3:141–146.PubMed

17.

Suzuki A, Abdelmalek MF, Diehl A, Guy CD. Gender-specific associations between regional anthropometric measures and hepatic fibrosis in patients with NAFLD: The 59th Annual Meeting of the American Associations for the Study of Liver Diseases. San Francisco, CA, 2008.

18.

Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.PubMed

19.

Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100.PubMed

20.

Colicchio P, Tarantino G, del Genio F, et al. Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in south Italy. Ann Nutr Metab. 2005;49:289–295.PubMed

21.

Treeprasertsuk S, Angulo P, Romero-Corral A, Lopez-Jimenez F, Somers VK. Association of adiposity, measures of metabolic dysregulation, and nonalcoholic fatty liver disease in subjects with normal body mass index: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

22.

Angulo P. Nafld, obesity, and bariatric surgery. Gastroenterology. 2006;130:1848–1852.PubMed

23.

Stranges S, Dorn JM, Muti P, et al. Body fat distribution, relative weight, and liver enzyme levels: a population-based study. Hepatology. 2004;39:754–763.PubMed

24.

Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:367–372.PubMed

25.

Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci. 2000;45:1929–1934.PubMed

26.

Furuta K, Sato S, Ishine J, Okamoto E, Tobita H, Miyake T, Ishihara S, Amano Y, Adachi K, Maruyama R, Kinoshita Y. Predictive factors for severity of liver histology in patients with non-alcoholic steatohepatitis: Usefulness of measurement of arteriosclerosis indicators: Digestive Disease Week 2008. San Diego, CA, 2008.

27.

Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005;25:1045–1050.PubMed

28.

Kim DH, Choi SY, Park EH, Yang JI, Kim W, Kim YJ, Yoon JH, Lee HS, Shin CS, Cho SH, Oh BH. Non-alcoholic fatty liver disease (NAFLD) as a risk factor of coronary heart disease; relation of NAFLD to coronary artery calcification score by multi- detector computed tomography: The 43rd Annual Meeting of the European Association for the Study of the Liver Milan, Italy, 2008.

29.

Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826.PubMed

30.

Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121.PubMed

31.

Dam-Larsen S, Franzmann M, andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755.PubMed

32.

Teli MR, James OF, Burt AD, Bennett MK, Bennett CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–1719.PubMed

33.

Chalasani N. It remains unclear whether simple steatosis is truly benign. AGA Perspectives 2008; February/March 2008.

34.

Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology. 2005;129:375–378.PubMed

35.

Tarantino G, Conca P, Riccio A, et al. Enhanced serum concentrations of transforming growth factor-beta1 in simple fatty liver: is it really benign? J Transl Med. 2008;6:72.PubMed

36.

Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.PubMed

37.

Yatsuji S, Hashimoto E, Noto H, Akahide A, Tobari M, Taniai M, Tokushige K, Shiratori K. Characteristic features and outcomes of patients with hepatocellular carcinoma in nonalcoholic steatohepatitis The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

38.

Sherman M. Recurrence of hepatocellular carcinoma. N Engl J Med. 2008;359:2045–2047.PubMed

39.

Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–845.PubMed

40.

Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–379.PubMed

41.

Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152.PubMed

42.

Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34:288–297.PubMed

43.

Honda H, Ikejima K, Hirose M, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology. 2002;36:12–21.PubMed

44.

Poniachik J, Santibañez C, Haim D, Tapia G, Araya J, Rodrigo R, Araya V, Csendes A, Burdiles P, Castillo J, Diaz J, Maluenda F, Korn O, Gutierrez L, Rojas J, Rencoret G, Ibarra J, Videla L. Enhancement in liver nuclear factor-kb (nf-kb) and activator protein 1 (ap-1) DNA binding in obese patients with non-alcoholic fatty liver disease The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

45.

Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–1295.PubMed

46.

Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2006;64:679–683.

47.

Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112:91–100.PubMed

48.

Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J Gastroenterol Hepatol. 2004;16:1095–1105.PubMed

49.

Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158–1163.PubMed

50.

Old LJ. Tumor necrosis factor (TNF). Science. 1985;230:630–632.PubMed

51.

Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–2415.PubMed

52.

Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol. 2009;51(1):212–233.PubMed

53.

Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21–29.PubMed

54.

Vendemiale G, Grattagliano I, Caraceni P, et al. Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: effect of the nutritional status. Hepatology. 2001;33:808–815.PubMed

55.

Nelson JE, Kowdley KV, Nelson JE, Kowdley KV, Yeh MM, Belt P, Wilson L. Serum ferritin is associated with the presence of NASH, increased alt, ast and histologic severity among patients with NAFLD.: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

56.

Bugianesi E, Manzini P, D’Antico S, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology. 2004;39:179–187.PubMed

57.

Graham TE, Yang Q, Bluher M, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552–2563.PubMed

58.

Grozovski M, Shatil T, Beniashvili Z, Korem S, Assy N. Retinol binding protein-4 expression is up regulated in rats with fatty liver during quiescent and regenerative state and improves with insulin sensitizing agents: The 43rh Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

59.

Wu H, Jia W, Bao Y, et al. Serum retinol binding protein 4 and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;79:185–190.PubMed

60.

Petta S, Camma C, Di Marco V, et al. Retinol-binding protein 4: a new marker of virus-induced steatosis in patients infected with hepatitis C virus genotype 1. Hepatology. 2008;48:28–37.PubMed

61.

Bluher M, Tonjes A, Stumvoll M. Does retinol-binding protein 4 cause or reflect fatty liver disease? Hepatology. 2008;48:4–6.PubMed

62.

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–1271.PubMed

63.

Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology. 2008;134:1682–1698.PubMed

64.

Pantsari MW, Harrison SA. Nonalcoholic fatty liver disease presenting with an isolated elevated alkaline phosphatase. J Clin Gastroenterol. 2006;40:633–635.PubMed

65.

Palekar NA, Naus R, Larson SP, Ward J, Harrison SA. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int. 2006;26:151–156.PubMed

66.

Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (steatotest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10.PubMed

67.

Ratziu V, Massard J, Charlotte F, et al. Diagnostic value of biochemical markers (fibrotest-fibrosure) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:6.PubMed

68.

Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854.PubMed

69.

Adams LA, MacQuillan GC, Jeffrey GP, George J, van der Poorten D, Kench JG, Rossi E, DeBoer B. Non-invasive prediction of liver fibrosis in nonalcoholic fatty liver disease: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

70.

Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–1447.PubMed

71.

Horoz M, Bolukbas C, Bolukbas FF, et al. Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis. BMC Gastroenterol. 2005;5:35.PubMed

72.

Bonnefont-Rousselot D, Ratziu V, Giral P, Charlotte F, Beucler I, Poynard T. Blood oxidative stress markers are unreliable markers of hepatic steatosis. Aliment Pharmacol Ther. 2006;23:91–98.PubMed

73.

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.PubMed

74.

Chalasani N, Crabb DW, Cummings OW, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol. 2003;98:2771–2776.PubMed

75.

Uygun A, Kadayifci A, Yesilova Z, et al. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2000;95:3584–3589.PubMed

76.

Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology. 2002;36:403–409.PubMed

77.

Abiru S, Migita K, Maeda Y, et al. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int. 2006;26:39–45.PubMed

78.

Haukeland JW, Damas JK, Konopski Z, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol. 2006;44:1167–1174.PubMed

79.

Suzuki A, Angulo P, Lymp J, Li D, Satomura S, Lindor K. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease. Liver Int. 2005;25:779–786.PubMed

80.

Pares A, Deulofeu R, Gimenez A, et al. Serum hyaluronate reflects hepatic fibrogenesis in alcoholic liver disease and is useful as a marker of fibrosis. Hepatology. 1996;24:1399–1403.PubMed

81.

Kolesnikova O, Nemtsova V, Filippovsky O. Serum hyaluronic acid, 7s domain of type iv collagen and ast/alt ratio as markers of hepatic fibrosis in patients with non-alcoholic fatty liver disease: The 43rd Annual Meeting of rhte European Association for the Study of the Liver. Milan, Italy, 2008.

82.

Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10:429–434.PubMed

83.

Schmilovitz-Weiss H, Chitty Chen C, Contreras R, Pappo C, Halpern M, Sulkes J, Braun M, Cohen M, Barak N, Tur-Kaspa R, Ben-Ari Z. The innovative serum protein n-glycans analysis predicts the extent of hepatic fibrosis in patients with nonalcoholic fatty liver disease The 58th Annual Meeting of the American Association for the Study of the Liver. Boston, MA, 2007.

84.

Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to fas mediated liver injury in mice. J Hepatol. 2003;39:978–983.PubMed

85.

Wieckowska A, Feldstein AE. Nonalcoholic fatty liver disease in the pediatric population: a review. Curr Opin Pediatr. 2005;17:636–641.PubMed

86.

Tarantino G, Conca P, Coppola A, Vecchione R, Di Minno G. Serum concentrations of the tissue polypeptide specific antigen in patients suffering from non-alcoholic steatohepatitis. Eur J Clin Invest. 2007;37:48–53.PubMed

87.

Malik R, Lai M, Bhaskar K, Nasser I, Curry M, Schuppan D, Afdhal N. Identification of biomarkers that measure disease activity in patients with nonalcoholic fatty liver disease: The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

88.

Yilmaz Y, Dolar E, Ulukaya E, et al. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol. 2007;13:837–844.PubMed

89.

Tabesh A, Duan Z, Wright EC, Loomba R, Liang T, Hoofnagle JH, Ghany MG, Kleiner DE. Serum caspase-3 generated cytokeratin 18 fragments (ck-18) as a marker for non-alcoholic steatohepatitis (NASH) and response to therapy: The 59th Annual Meeting of the American Association for Study of Liver Diseases. San Francisco, CA, 2008.

90.

Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–750.PubMed

91.

Mottin CC, Moretto M, Padoin AV, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14:635–637.PubMed

92.

Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis. 2006;38:485–489.PubMed

93.

Zelber-Sagi S, Webb M, Ratziu V, Poynard T, Halpern Z, Oren R. A comparison between the hepatorenal ultrasound index and steatotest for the non-invasive quantification of liver steatosis: The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

94.

Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705–1725.PubMed

95.

Osawa H, Mori Y. Sonographic diagnosis of fatty liver using a histogram technique that compares liver and renal cortical echo amplitudes. J Clin Ultrasound. 1996;24:25–29.PubMed

96.

Webb M, Hanny Yeshua H, Zelber-Sagie S, Santo M, Barazovski E, Katz R, Halpern Z, Oren R. A practical index for ultrasonographic quantification of liver steatosis The 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, 2007.

97.

Iijima H, Moriyasu F, Tsuchiya K, et al. Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis. Hepatol Res. 2007;37:722–730.PubMed

98.

Iijima H, Moriyasu F, Miyahara T, Yanagisawa K. Ultrasound contrast agent, levovist microbubbles are phagocytosed by kupffer cells-in vitro and in vivo studies. Hepatol Res. 2006;35:235–237.PubMed

99.

Piekarski J, Goldberg HI, Royal SA, Axel L, Axel L, Moss AA. Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease. Radiology. 1980;137:727–729.PubMed

100.

Park SH, Kim PN, Kim KW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006;239:105–112.PubMed

101.

Lee SW, Park SH, Kim KW, et al. Unenhanced CT for assessment of macrovesicular hepatic steatosis in living liver donors: comparison of visual grading with liver attenuation index. Radiology. 2007;244:479–485.PubMed

102.

Jacobs JE, Birnbaum BA, Shapiro MA, et al. Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT. AJR Am J Roentgenol. 1998;171:659–664.PubMed

103.

Fishbein M, Castro F, Cheruku S, et al. Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol. 2005;39:619–625.PubMed

104.

Longo RPP, Ricci C, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1994;5:281–285.

105.

Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–E468.PubMed

106.

Castera L, Pawlotsky JM. Noninvasive diagnosis of liver fibrosis in patients with chronic hepatitis C. MedGenMed. 2005;7:39.PubMed

107.

Takeda T, Yasuda T, Kimura M, Nakaya M, Fujii H, Nakayama Y, Sakaguchi H, Seki S. Noninvasive diagnosis of nonalcoholic steatohepatitis using elastometry The 58th Annual Meeting of the American Association for the Study of the Liver. Boston, MA, 2007.

108.

Fukuzawa Y, Kizawa S, Ohashi T, Matsumoto E, Sato K, Ayada M, Hotta N, Okumura A, Ishikawa T, Kakumu S. Efficacy of non-invasive hepatic fibrosis quantificated- evaluation by liver elasticity measurement in nonalcoholic steatohepatitis (NASH)- comparison of ultrasonic transient elastography and histopathological diagnosis: The 58th Annual Meeting of the Association for the Study of Liver Diseases. Boston, MA, 2007.

109.

Salameh N, Larrat B, Abarca-Quinones J, Leclercq I, Sinkus R, Van Beers BE. Mr elastopgraphy of dietary steatohepatitis in the rat: 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

110.

Manduca A, Oliphant TE, Dresner MA, et al. Magnetic resonance elastography: non-invasive mapping of tissue elasticity. Med Image Anal. 2001;5:237–254.PubMed

111.

Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5:1207–1213. e1202.PubMed

112.

Leen E, Goldberg JA, Angerson WJ, McArdle CS. Potential role of Doppler perfusion index in selection of patients with colorectal cancer for adjuvant chemotherapy. Lancet. 2000;355:34–37.PubMed

113.

Bellentani S, Dugoni M, Miglioli L, anderlini R, Mariano M, Borelli L, Battistini NC. Doppler perfusion index (dpi) is highly predictive of the grade of fatty liver in overweight patients with NAFLD: 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

114.

Dugoni M, Miglioli L, Borelli L, et al. Doppler perfusion index (DPI) and homa are highly predictive of fatty liver in patients with NAFLD. Dig Liver Dis. 2007;40:A39.

115.

Kakkos SK, Yarmenitis SD, Tsamandas AC, Gogos CA, Kalfarentzos F. Fatty liver in obesity: relation to Doppler perfusion index measurement of the liver. Scand J Gastroenterol. 2000;35:976–980.PubMed

116.

Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–2474.PubMed

117.

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.PubMed

118.

Campbell MS, Reddy KR. Review article: the evolving role of liver biopsy. Aliment Pharmacol Ther. 2004;20:249–259.PubMed

119.

Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236.PubMed

120.

Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906.PubMed

121.

Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–1413.PubMed

122.

Park HS, Kim MW, Shin ES. Effect of weight control on hepatic abnormalities in obese patients with fatty liver. J Korean Med Sci. 1995;10:414–421.PubMed

123.

Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004;53:413–419.PubMed

124.

Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27:103–107.PubMed

125.

Huang MA, Greenson JK, Chao C, et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005;100:1072–1081.PubMed

126.

Sato F, Tamura Y, Watada H, et al. Effects of diet-induced moderate weight reduction on intrahepatic and intramyocellular triglycerides and glucose metabolism in obese subjects. J Clin Endocrinol Metab. 2007;92:3326–3329.PubMed

127.

Bonekamp S. The effect of an exercise training intervention on hepatic steatosis The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

128.

Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation. 2002;105:804–809.PubMed

129.

Ryan MC, Abbasi F, Lamendola C, Carter S, McLaughlin TL. Serum alanine aminotransferase levels decrease further with carbohydrate than fat restriction in insulin-resistant adults. Diabetes Care. 2007;30:1075–1080.PubMed

130.

Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993–999.PubMed

131.

Le KA, Tappy L, D’Alessio DA. Mitochondrial dysfunction and insulin resistance: a matter of lifestyle? Curr Opin Clin Nutr Metab Care. 2007;10:494–497.PubMed

132.

Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology. 2009;49:306–317.PubMed

133.

Krempf M, Louvet JP, Allanic H, Miloradovich T, Joubert JM, Attali JR. Weight reduction and long-term maintenance after 18 months treatment with orlistat for obesity. Int J Obes Relat Metab Disord. 2003;27:591–597.PubMed

134.

Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281:235–242.PubMed

135.

Harrison SA, Ramrakhiani S, Brunt EM, Anbari MA, Cortese C, Bacon BR. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol. 2003;98:926–930.PubMed

136.

Hatzitolios A, Savopoulos C, Lazaraki G, et al. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol. 2004;23:131–134.PubMed

137.

Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol. 2003;12:189–192.PubMed

138.

Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 1998;63:PL113–PL117.PubMed

139.

Gary-Bobo M, Elachouri G, Gallas JF, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007;46:122–129.PubMed

140.

Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121–2134.PubMed

141.

Verdich C, Toubro S, Buemann B, Lysgard Madsen J, Juul Holst J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction. Int J Obes Relat Metab Disord. 2001;25:1206–1214.PubMed

142.

Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (glp-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43:173–181.PubMed

143.

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. 2006;26:1015–1017.PubMed

144.

Kral JG, Thung SN, Biron S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135:48–58.PubMed

145.

Klein S, Mittendorfer B, Eagon JC, et al. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology. 2006;130:1564–1572.PubMed

146.

Mathurin P, Gonzalez F, Kerdraon O, et al. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology. 2006;130:1617–1624.PubMed

147.

Antal SC. Prevention and reversal of liver damage following biliopancreatic diversion for obesity. Obes Surg. 1994;4:285–290.PubMed

148.

anderson T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese patients. J Hepatol. 1991;12:224–229.

149.

Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:519–525.PubMed

150.

Neuschwander-Tetri BA, Isley WL, Oki JC, et al. Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Ann Intern Med. 1998;129:38–41.PubMed

151.

Bailey CJ. The rise and fall of troglitazone. Diabet Med. 2000;17:414–415.PubMed

152.

Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196.PubMed

153.

Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.PubMed

154.

Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–1184.PubMed

155.

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. 2003;38:1008–1017.PubMed

156.

Balas B, Belfort R, Harrison SA, et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol. 2007;47:565–570.PubMed

157.

Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology. 2008;135:100–110.PubMed

158.

Ratziu FC, Bernhardt C, Moussalli J, Benhamou Y, Poynard T. Long-term efficacy of rosiglitazone in NASH: Results of the extension phase of the flirt-2 trial. The 59th Annual Meeting of the American Association for the Study of Liver Disease, 2008.

159.

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471.PubMed

160.

Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578–581.PubMed

161.

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. 2007;298:1180–1188.PubMed

162.

McNear S, Harrison S. Current status of therapy in nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2009;2:29–43.

163.

Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009;30:88–96.PubMed

164.

Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6:998–1003.PubMed

165.

Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–894.PubMed

166.

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. 2004;20:23–28.PubMed

167.

Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004;19:537–544.PubMed

168.

Nobili V, Manco M, Ciampalini P, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther. 2008;30:1168–1176.PubMed

169.

Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338:265–266.PubMed

170.

Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464–1467.PubMed

171.

Santos VN, Lanzoni VP, Szejnfeld J, Shigueoka D, Parise ER. A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. Braz J Med Biol Res. 2003;36:723–729.PubMed

172.

Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4:1537–1543.PubMed

173.

Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778.PubMed

174.

Detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III), 2004.

175.

Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther. 2006;23:1643–1647.PubMed

176.

Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol. 2003;17:713–718.PubMed

177.

Ekstedt M, Franzen LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: A histopathological follow-up study. J Hepatol. 2007;47:135–141.PubMed

178.

Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis. 2006;184:233–234.PubMed

179.

Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol. 1999;31:384.PubMed

180.

Daughtery K. Pravastatin-induced hepatotoxicity in a patients with fatty liver disease: a case presentation with literature review. J Pharm Pract. 2007;20:192–197.

181.

McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the national lipid association statin safety assessment task force. Am J Cardiol. 2006;97:89C–94C.PubMed

182.

Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.PubMed

183.

Chang CY, Argo CK, Al-Osaimi AM, Caldwell SH. Therapy of NAFLD: antioxidants and cytoprotective agents. J Clin Gastroenterol. 2006;40(Suppl 1):S51–S60.PubMed

184.

Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38:413–419.PubMed

185.

Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001;15:1667–1672.PubMed

186.

Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107–1115.PubMed

187.

Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–2490.PubMed

188.

Shimada M, Yoshida S, Kitamura Y, Yoshino M. The efficacy of the long-term vitamins E and C treatment for NASH: the 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

189.

Madan K, Batra Y, Gupta DS, et al. Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease. Indian J Gastroenterol. 2005;24:251–255.PubMed

190.

Song Z, Deaciuc I, Zhou Z, et al. Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. Am J Physiol Gastrointest Liver Physiol. 2007;293:G894–G902.PubMed

191.

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. 2001;96:2711–2717.PubMed

192.

Miglio F, Rovati LC, Santoro A, Setnikar I. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung. 2000;50:722–727.PubMed

193.

Abdelmalek MF, Lindor KD, Cave MC, Falkner KC, Khan R, McClain CJ. High-dose betaine treatment does not positively influence second hit mechanisms in NASH: The 59th Annual Meetinf of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.

194.

Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr. 1988;48:612–619.PubMed

195.

Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.PubMed

196.

Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745–750.PubMed

197.

Georgescu EF, Ionescu R, Georgescu M, Florescu G, Dobrinescu A, Vancica L, Niculescu M. Are angiotensin-receptor blockers candidates for the first choice treatment in non-alcoholic steatohepatitis with mild-to moderate hypertension: 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.

198.

Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225.PubMed

199.

Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ. 2005;172:899–905.PubMed

200.

Molloy R, Komorowski R, Varma R. Recurrent nonalcoholic steatohepatitis and cirrhosis after liver transplantation. Liver Transplant. 2003;3:177–178.

201.

Clinicaltrials.Gov, 2008, 2008.

202.

Trophos: BioPortfolio, 2008, 2008.

203.

Bordet T, Buisson B, Michaud M, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007;322:709–720.PubMed

204.

Phase 1 pharmacokinetic study of cp-945598 in patients with NASH, 2008.

205.

Recombinant leptin therapy for treatment of nonalcoholic steatohepatitis (NASH). 2008.

Title: Nonalcoholic Fatty Liver Disease: A Review and Update
Authors: Jeffrey R. Lewis
Smruti R. Mohanty
Publication date: 01-03-2010
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 3/2010
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-009-1081-0

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2010

Pneumonitis as A Consequence of (Peg)Interferon-Ribavirin Combination Therapy for Hepatitis C: a Review of the Literature

Clinical Outcomes of Self-Expandable Metal Stent and Prognostic Factors for Stent Patency in Gastric Outlet Obstruction Caused by Gastric Cancer

Cytomegalovirus Infection in Patients Who Required Colectomy for Toxic Megacolon or Severe Steroid-Refractory Ulcerative Colitis

Alterations of Bone Marrow Sinusoidal Endothelium in Rat and Patients with Liver Cirrhosis

Acknowledgment of 2009 Reviewers

Here’s My Phone Number, Don’t Call Me: Physician Accessibility in the Cell Phone and E-mail Era

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials