Semin Liver Dis 2012; 32(01): 022-029
DOI: 10.1055/s-0032-1306423
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Dyslipidemia in Patients with Nonalcoholic Fatty Liver Disease

Hemant Chatrath
1   Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
,
Raj Vuppalanchi
1   Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
,
Naga Chalasani
1   Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
› Author Affiliations
Further Information

Publication History

Publication Date:
13 March 2012 (online)

Abstract

Patients with nonalcoholic fatty liver disease (NAFLD) often have dyslipidemia along with other features of metabolic syndrome such as obesity, diabetes mellitus, and hypertension. The dyslipidemia in NAFLD is characterized by increased serum triglycerides, increased small, dense low-density lipoprotein (LDL nontype A) particles, and low high-density lipoprotein (HDL) cholesterol. The pathogenesis of dyslipidemia in NAFLD is not well understood, but it is likely related to hepatic overproduction of the very low-density lipoprotein particles and dysregulated clearance of lipoproteins from the circulation. There is unequivocal evidence that cardiovascular disease is the most common cause of mortality in patients with NAFLD. Aggressive treatment of dyslipidemia plays a critical role in the overall management of patients with NAFLD. Statins are the first-line agents to treat high cholesterol and their dosage should be adjusted based on achieving therapeutic targets and tolerability. Although all statins appear to be effective in improving cholesterol levels in patients with NAFLD, there is more experience with atorvastatin in patients with NAFLD; furthermore, it is the only statin to date to show a reduced cardiovascular morbidity in patients with NAFLD. The risk for serious liver injury from statins is quite rare and patients with NAFLD are not at increased risk for statin hepatotoxicity. Omega-3 fatty acids are perhaps the first choice to treat hypertriglyceridemia because of their safety, tolerability, and efficacy in improving serum triglycerides, as well as their potential to improve liver disease.

 
  • References

  • 1 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 (6) 1387-1395
  • 2 Williams CD, Stengel J, Asike MI , et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140 (1) 124-131
  • 3 Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141 (4) 1249-1253
  • 4 Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 2009; 49 (1) 306-317
  • 5 Neuschwander-Tetri BA, Clark JM, Bass NM , et al; NASH Clinical Research Network. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010; 52 (3) 913-924
  • 6 Ruhl CE, Everhart JE. Epidemiology of nonalcoholic fatty liver. Clin Liver Dis 2004; 8 (3) 501-519, vii
  • 7 Marchesini G, Bugianesi E, Forlani G , et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37 (4) 917-923
  • 8 Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005; 42 (1) 44-52
  • 9 Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99 (8) 1497-1502
  • 10 Liangpunsakul S, Chalasani N. Unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III). Am J Med Sci 2005; 329 (3) 111-116
  • 11 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363 (14) 1341-1350
  • 12 Speliotes EK, Massaro JM, Hoffmann U , et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 2010; 51 (6) 1979-1987
  • 13 Nseir W, Shalata A, Marmor A, Assy N. Mechanisms linking nonalcoholic Fatty liver disease with coronary artery disease. Dig Dis Sci 2011; 56 (12) 3439-3449
  • 14 Norris AL, Steinberger J, Steffen LM, Metzig AM, Schwarzenberg SJ, Kelly AS. Circulating oxidized LDL and inflammation in extreme pediatric obesity. Obesity (Silver Spring) 2011; 19 (7) 1415-1419
  • 15 Vos MB, Weber MB, Welsh J , et al. Fructose and oxidized low-density lipoprotein in pediatric nonalcoholic fatty liver disease: a pilot study. Arch Pediatr Adolesc Med 2009; 163 (7) 674-675
  • 16 Kantartzis K, Rittig K, Cegan A , et al. Fatty liver is independently associated with alterations in circulating HDL2 and HDL3 subfractions. Diabetes Care 2008; 31 (2) 366-368
  • 17 Taskinen MR, Adiels M, Westerbacka J , et al. Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects. Arterioscler Thromb Vasc Biol 2011; 31 (9) 2144-2150
  • 18 Misra VL, Khashab M, Chalasani N. Nonalcoholic fatty liver disease and cardiovascular risk. Curr Gastroenterol Rep 2009; 11 (1) 50-55
  • 19 Söderberg C, Stål P, Askling J , et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2) 595-602
  • 20 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
  • 21 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 (1) 113-121
  • 22 Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol 2009; 44 (10) 1236-1243
  • 23 Rafiq N, Bai C, Fang Y , et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7 (2) 234-238
  • 24 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 (6) 1413-1419
  • 25 Rzouq FS, Volk ML, Hatoum HH, Talluri SK, Mummadi RR, Sood GK. Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians. Am J Med Sci 2010; 340 (2) 89-93
  • 26 National Heart, Lung, and Blood Institute, National Institutes of Health. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. ATP III Final Report (NIH Publication No. 02-5215). Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2002
  • 27 Genest J, McPherson R, Frohlich J , et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol 2009; 25 (10) 567-579
  • 28 Athyros VG, Tziomalos K, Gossios TD , et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756) 1916-1922
  • 29 Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R ; Pravastatin in Chronic Liver Disease Study Investigators. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46 (5) 1453-1463
  • 30 Kiyici M, Gulten M, Gurel S , et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 2003; 17 (12) 713-718
  • 31 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 2006; 23 (11) 1643-1647
  • 32 Hyogo H, Tazuma S, Arihiro K , et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008; 57 (12) 1711-1718
  • 33 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 (4) 131-134
  • 34 Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis 2007; 16 (1) 39-46
  • 35 Athyros VG, Mikhailidis DP, Didangelos TP , et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 2006; 22 (5) 873-883
  • 36 Abel T, Fehér J, Dinya E, Eldin MG, Kovács A. Safety and efficacy of combined ezetimibe/simvastatin treatment and simvastatin monotherapy in patients with non-alcoholic fatty liver disease. Med Sci Monit 2009; 15 (12) MS6-MS11
  • 37 Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial. J Clin Gastroenterol 2009; 43 (10) 990-994
  • 38 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 (1) 233-234
  • 39 Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004; 174 (1) 193-196
  • 40 Harano Y, Yasui K, Toyama T , et al. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver. Liver Int 2006; 26 (5) 613-620
  • 41 Kondo K, Sugioka T, Tsukada K , et al. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, improves hepatic microcirculatory patency and oxygen availability in a high-fat-diet-induced fatty liver in mice. Adv Exp Med Biol 2010; 662: 77-82
  • 42 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 (6) 1464-1467
  • 43 Report of the Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984; 2 (8403) 600-604
  • 44 Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999; 31 (2) 384
  • 45 Fernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2008; 40 (3) 200-205
  • 46 van Heek M, Farley C, Compton DS, Hoos L, Davis HR. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol 2001; 134 (2) 409-417
  • 47 Sweeney ME, Johnson RR. Ezetimibe: an update on the mechanism of action, pharmacokinetics and recent clinical trials. Expert Opin Drug Metab Toxicol 2007; 3 (3) 441-450
  • 48 Yoneda M, Fujita K, Nozaki Y , et al. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: an open-label, pilot study. Hepatol Res 2010; 40 (6) 613-621
  • 49 Park H, Shima T, Yamaguchi K , et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011; 46 (1) 101-107
  • 50 Chan DC, Watts GF, Gan SK, Ooi EM, Barrett PH. Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care 2010; 33 (5) 1134-1139
  • 51 Shiwa T, Kawanami Y, Yokoyama T, Moritani A, Hashimoto M, Gotoh T. The efficacy of ezetimibe on nonalcoholic fatty liver disease (NAFLD). Nihon Shokakibyo Gakkai Zasshi. 2011; 108: 1383-1392
  • 52 Takeshita Y, Takamura T, Yamada K , et al. Ezetimibe improves histology of nonalcoholic fatty liver disease independently from the insulin resistance: A randomized, controlled trial. Hepatology 2011; 54: 1117A
  • 53 Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2010; 31 (7) 679-692
  • 54 Capanni M, Calella F, Biagini MR , et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23 (8) 1143-1151
  • 55 Spadaro L, Magliocco O, Spampinato D , et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 2008; 40 (3) 194-199
  • 56 Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42 (4) 413-418
  • 57 Vega GL, Chandalia M, Szczepaniak LS, Grundy SM. Effects of N-3 fatty acids on hepatic triglyceride content in humans. J Investig Med 2008; 56 (5) 780-785
  • 58 Itoh M, Suganami T, Satoh N , et al. Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects. Arterioscler Thromb Vasc Biol 2007; 27 (9) 1918-1925
  • 59 Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 2008; 14 (41) 6395-6400
  • 60 Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011; 106 (1) 71-77
  • 61 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005; 41 (4) 690-695
  • 62 Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004; 126 (5) 1287-1292
  • 63 Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci 2005; 329 (2) 62-65
  • 64 Pfeffer MA, Keech A, Sacks FM , et al. Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project. Circulation 2002; 105 (20) 2341-2346
  • 65 Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006; 44 (2) 466-471