Biochemical screen correction possibilities in patients with non-alcoholic fatty liver disease with diabetes mellitus

Keywords: type 2 diabetes mellitus; dyslipidemia; hepatoprotectors; essential phospholipids; omega-3 polyunsaturated fatty acids; alpha-lipoic acid


The rationale for this study is the controversial data regarding the efficacy of hepatoprotectors and antioxidants for lipid profile correction in non-alcoholic fatty liver disease, the prevalence of which is increasing especially in association with diabetes mellitus. We examined 100 non-alcoholic fatty liver disease patients (40–75 years old) with concomitant type 2 diabetes mellitus (n = 73) or without it (n = 27), the groups were standardized by age and gender. In patients with non-alcoholic fatty liver disease with diabetes mellitus we revealed significantly higher rates of total cholesterol, triglycerides and atherogenic factor in association with a significantly lower high-density lipoproteins level versus the group of patients without concomitant diabetes. We recommended the modification of lifestyle as basic management of their condition to all patients, hypoglycemic therapy with metformin to persons with concomitant diabetes mellitus and rosuvastatin to patients with non-alcoholic fatty liver disease without diabetes. In addition, 25 patients received essential phospholipids (2 caps. 3 times a day) and omega-3 polyunsaturated fatty acids (1000 mg per day) for 3 months; 26 patients – α-lipoic acid (600 mg daily) for 3 months, 22 patients received rosuvastatin (10 mg daily), 27 patients with non-alcoholic fatty liver disease without diabetes mellitus received rosuvastatin (10 mg daily). We evaluated the treatment efficiency after 3 months treatment, and the remote consequences – 12 months after the start of combined treatment. After 3 months, the alanine-aminotransferase rate had decreased by 15.1% in the group taking combined essential phospholipids and ω3-polyunsaturated fatty acids and by 12.9% in the group taking alpha-lipoic acid, which was significantly larger than in the rosuvastatin group (7.5%); gamma-glutamate transpeptidase level decreased by 16.7%, 18.7% and 9.4% respectively indicating anticholestatic and hepatoprotective effect of both proposed treatment combinations. The same tendency of cytolysis and cholestasis processes inhibition was observed after 12 months as well. In conclusion, the combination of standard treatment with antioxidant and hepatoprotective agents (omega-3 polyunsaturated fatty acids with essential phospholipids or only alpha-lipoic acid) promotes both cytolysis and cholestasis syndromes inhibition in non-alcoholic fatty liver disease patients with concomitant type 2 diabetes mellitus.


Anavi, S., Madar, Z., & Tirosh, O. (2017). Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers. Redox Biology, 13, 386–392.

Argo, C. K., Loria, P., Caldwell, S. H., & Lonardo, A. (2008). Statins in liver disease: A molehill, an iceberg, or neither? Hepatology, 48(2), 662–669.

Armstrong, M. J., Hazlehurst, J. M., Hull, D., Guo, K., Borrows, S., Yu, J., Gough, S. C., Newsome, P. N., & Tomlinson, J. W. (2014). Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis. Diabetes, Obesity and Metabolism, 16, 651–660.

Babio, N., Toledo, E., Estruch, R., Ros, E., Martínez-González, M. A., & Castañer, O. (2014). Mediterranean diets and metabolic syndrome status in the Predimed randomized trial. Canadian Medical Association Journal, 186(17), 649–657.

Ballestri, S. (2016). Nonalcoholic fatty liver disease is associated with an almost two-fold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. Journal of Gastroenterology and Hepatology, 31(5), 936–944.

Basu, P. P., Shah, N. J., Aloysius, M. M., & Brown Jr., R. S. (2014). Effect of vitamin E and alpha lipoic acid in nonalcoholic fatty liver disease: A randomized, placebo-controlled, open-label, prospective clinical trial (vain trial). Open Journal of Gastroenterology, 4, 199–207.

Bedogni, G., Kahn, H. S., Bellentani, S., & Tiribelli, C. (2010). A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterology, 10, 98.

Berlanga, A., Guiu-Jurado, E., Porras, J. A., & Auguet, T. (2014). Molecular pathways in non-alcoholic fatty liver disease. Clinical and Experimental Gastroenterology, 7, 221–239.

Berzigotti, A., Ferraioli, G., Bota, S., Gilja, O. H., & Dietrich, C. F. (2018). Novel ultrasound-based methods to assess liver disease: The game has just begun. Digestive and Liver Disease, 50(2), 107–112.

Brunt, E. M., & Tiniakos, D. G. (2010). Histopathology of nonalcoholic fatty liver disease. World Journal of Hepatology, 16(42), 5286–5296.

Buzzetti, E., Pinzani, M., & Tsochatzis, E. A. (2016). The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism, 65(8), 1038–1048.

Dai, H., Wang, W., Chen, R., Chen, Z., Lu, Y., & Yuan, H. (2017). Lipid accumulation product is a powerful tool to predict non-alcoholic fatty liver disease in Chinese adults. Nutrition and Metabolism, 1, 14–49.

Dajani, A., & Abu Hammour, A. (2016). Treatment of nonalcoholic fatty liver disease: Where do we stand? An overview. Saudi Journal of Gastroenterology, 22(2), 91–105.

Dajani, A. I., Abu Hammour, A. M., Zakaria, M. A., Al Jaberi, M. R., Nounou, M. A., & Semrin, A. I. (2015). Essential phospholipids as a supportive adjunct in the management of patients with NAFLD. Arab Journal of Gastroenterology, 16(3–4), 99–104.

de Oliveira, A. M., Rondo, P. H., Luzia, L. A., D’Abronzo, F. H., & Illison, V. K. (2011). The effects of lipoic acid and alpha-tocopherol supplementation on the lipid profile and insulin sensitivity of patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Diabetes Research and Clinical Practice, 92, 253–260.

Di Minno, M. N., Russolillo, A., Lupoli, R., Ambrosino, P., Di Minno, A., & Tarantino, G. (2012). Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease. World Journal of Gastroenterology, 18, 5839–5847.

EASL–EASD–EASO (2016). Clinical practice guidelines for the management of non-alcoholic fatty liver disease. Journal of Hepatology, 64(6), 1388–1402.

Federico, A., Dallio, M., Caprio, G. G., Gravina, A. G., Picascia, D., Masarone, M., Persico, M., & Loguercio, C. (2017). Qualitative and quantitative evaluation of dietary intake in patients with non-alcoholic steatohepatitis. Nutrients, 9(10), e1074.

Firneisz, G. (2014). Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age? World Journal of Gastroenterology, 20(27), 9072–9089.

Gaggini, M., Morelli, M., Buzzigoli, E., DeFronzo, R. A., Bugianesi, E., & Gastaldelli, A. (2013). Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients, 5, 1544–1560.

Ganesh, S., & Rustgi, V. K. (2016). Current pharmacologic therapy for nonalcoholic fatty liver disease. Clinics in Liver Disease, 20(2), 351–364.

Gastaldelli, A., Cusi, K., Pettiti, M., Hardies, J., Miyazaki, Y., Berria, R., Buzzigoli, E., Sironi, A. M., Cersosimo, E., & Ferrannini, E. (2007). Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology, 133, 496–506.

Gonciarz, Z., Besser, P., Lelek, E., Gundermann, K. J., & Johannes, K. J. (1988). Randomised placebo-controlled double blind trial on “essential” phospholipids in the treatment of fatty liver associated with diabetes. Medecine et Chirurgie Digestives, 17(1), 61–65.

Gundermann, K.-J., Gundermann, S., Drozdzik, M., & Mohan Prasad, V. G. (2016). Essential phospholipids in fatty liver: A scientific update. Clinical and Experimental Gastroenterology, 9, 105–117.

Hansen, H. H., Feigh, M., Veidal, S. S., Rigbolt, K. T., Vrang, N., & Fosgerau, K. (2017). Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discovery Today, 22(11), 1707–1718.

Hazlehurst, J. M., Woods, C., Marjot, T., Cobbold, J. F., & Tomlinson, J. W. (2016). Non-alcoholic fatty liver disease and diabetes. Metabolism, 65(8), 1096–1108.

Kajikawa, S., Imada, K., Takeuchi, T., Shimizu, Y., Kawashima, A., & Harada, T. (2011). Eicosapentaenoic acid attenuates progression of hepatic fibrosis with inhibition of reactive oxygen species production in rats fed methionine- and choline-deficient diet. Digestive Diseases and Sciences, 56, 1065–1074.

Kim, W. (2017). [Treatment options in non-alcoholic fatty liver disease]. Korean Journal of Gastroenterology, 69(6), 353–358 (in Korean).

Lazo, M., Hernaez, R., Eberhardt, M. S., Bonekamp, S., Kamel, I., Guallar, E., Koteish, A., Brancati, F. L., & Clark, J. M. (2013). Prevalence of nonalcoholic fatty liver disease in the United States: The Third National Health and Nutrition Examination Survey, 1988–1994. American Journal of Epidemiology, 178, 38–45.

Lee, D. H. (2017). Imaging evaluation of non-alcoholic fatty liver disease: Focused on quantification. Clinical and Molecular Hepatology, 23, 290–301.

Lee, H. W., Kim, B. K., Kim, S. U., Park, J. Y., Kim, D. Y., Ahn, S. H., Kim, K. J., & Han, K. H. (2017). Prevalence and predictors of significant fibrosis among subjects with transient elastography-defined nonalcoholic fatty liver disease. Digestive Diseases and Sciences, 62(8), 2150–2158.

Li, J. H., Chen, X. Y., Zhong, C. F., & Min, J. (2000). A randomized controlled study of essential phospholipids (Essentiale capsules) in the treatment of fatty liver. Infectious Diseases Info, 13(4), 180–181.

Lombardi, R., Onali, S., Thorburn, D., Davidson, B. R., Gurusamy, K. S., & Tsochatzis, E. (2017). Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): An attempted network meta-analysis. Cochrane Database of Systematic Reviews, 3, CD011640pub2.

Loomba, R., & Sanyal, A. J. (2013). The global NAFLD epidemic. Nature Reviews Gastroenterology and Hepatology, 10, 686–690.

Lou, D. J., Zhu, Q. Q., Si, X. W., Guan, L. L., You, Q. Y., Yu, Z. M., & Zhang, A. Z. (2014). Serum phospholipid omega-3 polyunsaturated fatty acids and insulin resistance in type 2 diabetes mellitus and non-alcoholic fatty liver disease. Journal of Diabetes Complications, 28(5), 711–714.

Machado, M. V., & Cortez-Pinto, H. (2014). Non-alcoholic fatty liver disease: What the clinician needs to know. World Journal of Gastroenterology, 20(36), 12956–12980.

Magee, N., Zou, A., & Zhang, Y. (2016). Pathogenesis of nonalcoholic steatohepatitis: Interactions between liver parenchymal and nonparenchymal cells. BioMed Research International, 2016, 1–11.

Martínez-Rodríguez, L. A., Rojas, S. J., & Aldo, T. (2014). Siliphos selenium methionine alpha lipoic acid for non alcoholic fatty liver disease: Results of a pilot study. Journal of Clinical and Experimental Pharmacology, 4, 167.

Martin-Rodriguez, J. L., Gonzalez-Cantero, J., Gonzalez-Cantero, A., Arrebola, J. P., & Gonzalez-Calvin, J. L. (2017). Diagnostic accuracy of serum alanine aminotransferase as biomarker for nonalcoholic fatty liver disease and insulin resistance in healthy subjects, using 3T MR spectroscopy. Medicine (Baltimore), 96(17), e6770.

Maximos, M., Bril, F., Portillo Sanchez, P., Lomonaco, R., Orsak, B., Biernacki, D., Suman, A., Weber, M., & Cusi, K. (2015). The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology, 61(1), 153–160.

Michelotti, G. A., Machado, M. V., & Diehl, A. M. (2013). NAFLD, NASH and liver cancer. Nature Reviews of Gastroenterology and Hepatology, 10(11), 656–665.

Musso, G., Gambino, R., Cassader, M., & Pagano, G. (2011). Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Annals of Medicine, 43, 617–649.

Newsome, P. N., Cramb, R., Davison, S. M., Dillon, J. F., Foulerton, M., Godfrey, E. M., Hall, R., Harrower, U., Hudson, M., Langford, A., Mackie, A., Mitchell-Thain, R., Sennett, K., Sheron, N. C., Verne, J., Walmsley, M., & Yeoman, A. (2018). Guidelines on the management of abnormal liver blood tests. Gut, 67, 6–19.

Nseir, W., & Mahamid, M. (2013). Statins in nonalcoholic fatty liver disease and steatohepatitis: Updated review. Current Atherosclerosis Reports, 15, 305.

Ohbayashi, H. (2004). Twelve-month chronic administration of polyenephos-phatidylcholine (EPL®) for improving hepatic function of fatty liver patients. Progress of Medicine, 24(7), 1751–1756.

Padma, L., Mukaddam, Q., & Trailokya, A. (2013). An observational study of Essentiale-L in the treatment of patients with fatty liver disease. Indian Journal of Clinical Practice, 23, 735–739.

Patel, P. J., Hayward, K. L., Rudra, R., Horsfall, L. U., Hossain, F., Williams, S., Johnson, T., Brown, N. N., Saad, N., Clouston, A. D., Stuart, K. A., Valery, P. C., Irvine, K. M., Russell, A. W., & Powell, E. E. (2017). Multimorbidity and polypharmacy in diabetic patients with NAFLD: Implications for disease severity and management. Medicine (Baltimore), 96(26), e6761.

Perazzo, H., & Dufour, J. F. (2017). The therapeutic landscape of non-alcoholic steatohepatitis. Liver International, 37(5), 634–647.

Pivtorak, K. V. (2017). Features of nonalcoholic fatty liver disease pharmacotherapy in patients with overweight and obesity. Zaporozhye Medical Journal, 19(4), 520–524.

Poongothai, S., Karkuzhali, K., & Siva Prakash, G. (2005). Effect of essentiale in diabetic subjects with non-alcoholic fatty liver. International Journal of Diabetes in Developing Countries, 25(1), 12–19.

Riche, D. M., Fleming, J. W., Malinowski, S. S., Black, C. A., Miller, K. H., & Wofford, M. R. (2014). Resistant nonalcoholic fatty liver disease amelioration with rosuvastatin and pioglitazone combination therapy in a patient with metabolic syndrome. Annals of Pharmacotherapy, 48, 137–141.

Sanyal, A. J., Abdelmalek, M. F., Suzuki, A., Cummings, O. W., & Chojkier, M. (2014). EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology, 147, 377–384.

Sas, E., Grinevich, V., Efimov, O., & Shcherbina, N. (2013). Beneficial influence of polyunsaturated phosphatidylcholine enhances functional liver condition and liver structure in patients with nonalcoholic steatohepatitis accompanied by diabetes type 2. Results of prolonged randomized blinded prospective clinical study [abstract]. Journal of Hepatology, 58, S549.

Schleicher, J., Guthke, R., Dahmen, U., Dirsch, O., Holzhuetter, H. G., Schuster, S. (2014). A theoretical study of lipid accumulation in the liver-implications for nonalcoholic fatty liver disease. Biochimica et Biophysica Acta, 1841(1), 62–69.

Sharma, M., Mitnala, S., Vishnubhotla, R. K., Mukherjee, R., Reddy, D. N., & Rao, P. N. (2015). The riddle of nonalcoholic fatty liver disease: Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis. Journal of Clinical and Experimental Hepatology, 5(2), 147–158.

Stankovic, M. N., Mladenovic, D., Ninkovic, M., Ðuricic, I., Sobajic, S., Jorgacevic, B., de Luka, S., Vukicevic, R. J., & Radosavljevic, T. S. (2014). The effects of a-lipoic acid on liver oxidative stress and free fatty acid composition in methionine-choline deficient diet-induced NAFLD. Journal of Medicinal Food, 17(2), 254–261.

Stepanov, Y., Nedzvetskaya, N., Yagmur, V., & Kononenko, I. (2018). The significance of hepatic transaminases and ultrasound in the diagnosis of non-alcoholic fatty liver disease. Regulatory Mechanisms in Biosystems, 9(1), 105–111.

Stepanov, Y. M. (2016). The ese of essential phospholipids for the treatment of fatty liver disease. Gastroenterology, 62, 58–64.

Sumida, Y., Nakajima, A., & Itoh, Y. (2014). Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease / nonalcoholic steatohepatitis. World Journal of Gastroenterology, 20(2), 475–485.

Takahashi, Y., & Fukusato, T. (2014). Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World Journal of Gastroenterology, 20(42), 15539–15548.

Verbeek, J., Cassiman, D., Lannoo, M., Laleman, W., van der Merwe, S., Verslype, C., Van Steenbergen, W., & Nevens, F. (2013). Treatment of non-alcoholic fatty liver disease: Can we already face the epidemic? Acta Gastro-Enterologica Belgica, 76(2), 200–209.

Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L., & Harrison, S. A. (2011). Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology, 140, 124–131.

Wu, Y. (2009). Effective analysis of type 2 diabetic united adiposis hepatica with polyene phosphatidylcholine. Journal of Traditional Chinese Medicine, 29, 41–42.

How to Cite
Feisa, S. V., Rostoka-Reznikova, M. V., Tovt-Korshynska, M. I., & Siksai, L. T. (2018). Biochemical screen correction possibilities in patients with non-alcoholic fatty liver disease with diabetes mellitus. Regulatory Mechanisms in Biosystems, 9(3), 384-390.