Olmesartan for non-alcoholic steatohepatitis complicated with hypertension: An open-label study

Hisashi Hidaka, Makoto Ohbu, Yasuhiro Matsumoto, Tsutomu Minamino, Juichi Takada, Yoshiaki Tanaka, Yusuke Okuwaki, Masaaki Watanabe, Takahide Nakazawa, Akitaka Shibuya, Wasaburo Koizumi

Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Department of Pathology, Kitasato University School of Allied Health Science, Sagamihara, Kanagawa, Japan.

DOI: 10.4236/ojgas.2013.32021                

Abstract

Aim: We evaluated the long-term effects of olmesartan, an angiotensin type 1 receptor blocker, in patients with non-alcoholic steatohepatitis (NASH) complicated with hypertension. Methods: All patients were given a standard calorie diet and exercise counseling more than 3 months before the treatment. Seven patients with NASH received olmesartan treatment for 1 year. Liver biopsy, clinical parameters and blood markers of hepatic fibrosis, including serum hyaluronic acid, type IV collagen, and procollagen III N-terminal propeptide levels, were also examined at the beginning and the end of the study. Results: The median dose of the final administration was 20 mg (range, 10 - 40 mg). Olmesartan reduced MAP by –11.3 ± 13.0% (P = 0.046) after 1 year. In the laboratory data, serum AST, ALT, and ferritin significantly decreased after a year of administration (AST, 62 ± 24 vs. 39 ± 20 IU/L, P = 0.018; ALT, 106 ± 79 vs. 55 ± 35 IU/L, P = 0.043; ferritin, 323.8 ± 252.8 vs. 202.3 ± 194.1 ng/ml, P = 0.028). Furthermore, fasting glucose significantly decreased. However, transforming growth factor-beta1, the serum concentration of the fibrosis markers, and all histological features were unchanged at the end of the study. No side effects of the treatment were noted at any time during the study. Conclusion: Olmesartan significantly reduced blood pressure, fasting glucose, aminotransferase, and serum ferritin but could not suppress the hepatic fibrosis markers or histological features after 1 year. Therefore, olmesartan is advisable only for its anti-inflammatory effect in patients with NASH-complicated hypertension.

Keywords

Angiotensin Type 1 Receptor Blocker; Hepatic Fibrosis; TGF-Beta1

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Chalasani, N., Younossi, Z., Lavine, J.E., et al. (2012) The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastro-enterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Hepatology, 55, 2005-2023. doi:10.1002/hep.25762
[2]	Ekstedt, M., Franzén, L.E., Mathiesen, U.L., et al. (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology, 44, 865-873. doi:10.1002/hep.21327
[3]	Yoshiji, H., Kuriyama, S., Yoshii, J., et al. (2001) Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology, 34, 745-750. doi:10.1053/jhep.2001.28231
[4]	Gaedeke, J., Peters, H., Noble, N.A. and Border, W.A. (2001) Angiotensin II, TGF-beta and renal fibrosis. Contributions to Nephrology, 135, 153-160. doi:10.1159/000060162
[5]	Nagy, P., Scaff, Z. and Lapis K. (1991) Immunohistochemical detection of transforming growth factor-beta 1 in fibrotic liver diseases. Hepatology, 14, 269-273. doi:10.1002/hep.1840140211
[6]	Matsuoka, M. and Tsukamoto, H. (1990) Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: Implication for a pathogenetic role in alcoholic liver fibrogenesis. Hepatology, 11, 599-605. doi:10.1002/hep.1840110412
[7]	Nagy, P., Scaff, Z. and Lapis, K. (1991) Immunohistochemical detection of transforming growth factor-beta 1 in fibrotic liver diseases. Hepatology, 14, 269-273. doi:10.1002/hep.1840140211
[8]	Yokohama, S., Yoneda, M., Haneda, M., et al. (2004) Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology, 40, 1222-1225. doi:10.1002/hep.20420
[9]	Mizuno, M., Sada, T., Ikeda, M., et al. (1995) Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist. European Journal of Pharmacology, 285, 181-188. doi:10.1016/0014-2999(95)00401-6
[10]	Oparil, S., Williams, D., Chrysant, S.G., Marbury, T.C. and Neutel, J. (2001) Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. Journal of Clinical Hypertension (Greenwich), 3, 283-291. doi:10.1111/j.1524-6175.2001.01136.x
[11]	Hirose, A., Ono, M., Saibara, T., et al. (2007) Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology, 45, 1375-1381. doi:10.1002/hep.21638
[12]	Kleiner, D.E., Brunt, E.M., Van Natta, M., et al. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 41, 13131321. doi:10.1002/hep.20701
[13]	Brunt, E.M., Janney, C.G., Di Bisceglie, A.M., Neuschwander-Tetri, B.A. and Bacon, B.R. (1999) Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. American Journal of Gastroenterology, 94, 2467-2474. doi:10.1111/j.1572-0241.1999.01377.x
[14]	Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F. and Turner, R.C. (1985) Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412-419. doi:10.1007/BF00280883
[15]	Hamaguchi, M., Kojima, T., Takeda, N., et al. (2005) The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Annals of Internal Medicine, 143, 722-728. doi:10.7326/0003-4819-143-10-200511150-00009
[16]	Torres, D.M., Jones, F.J., Shaw, J.C., Williams, C.D., Ward, J.A. and Harrison, S.A. (2011) Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: A 12-month randomized, prospective, open-label trial. Hepatology, 54, 1631-1639. doi:10.1002/hep.24558
[17]	Sanyal, A.J., Chalasini, N., Kowdley, K.V., et al. (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New England Journal of Medicine, 362, 16751685. doi:10.1056/NEJMoa0907929
[18]	Aithal, G.P., Thomas, J.A. and Kaye, P.V. (2008) Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology, 135, 1176-1184. doi:10.1053/j.gastro.2008.06.047
[19]	Belfort, R., Harrison, S.A., Brown, K., et al. (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. New England Journal of Medicine; 355, 2297-2307. doi:10.1056/NEJMoa060326
[20]	Ratziu, V., Giral, P., Jacqueminet, S., et al. (2008) Rosiglitazone for nonalcoholic steatohepatitis: One-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology, 135, 100-110. doi:10.1053/j.gastro.2008.03.078
[21]	Hidaka, H., Nakazawa, T., Shibuya, A., et al. (2011) Effects of 1-year administration of olmesartan on portal pressure and TGF-beta1 in selected patients with cirrhosis: A randomized controlled trial. Journal of Gastroenterology, 46, 1316-1323. doi:10.1007/s00535-011-0449-z
[22]	Jin, H., Yamamoto, N., Uchida, K., Terai, S. and Sakaida, I. (2007) Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet. Biochemical and Biophysical Research Communications, 364, 801807. doi:10.1016/j.bbrc.2007.10.083
[23]	Fujita, K., Yoneda, M., Wada, K., et al. (2007) Telmisartan, angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Digestive Diseases Sciences, 52, 3455-3464. doi:10.1007/s10620-007-9741-4
[24]	Yoshida, T., Yamagishi, S., Matsui, T., et al. (2008) Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-elicited hepatic insulin resistance via peroxisome proliferator-activated receptor-gamma activation. Journal of International Medical Research, 36, 237-243. doi:10.1177/147323000803600204