Nonalcoholic Fatty Liver Disease and Diabetes: So Dangerous Together

Nonalcoholic fatty liver disease (NAFLD) is closely linked to the twin epidemics of diabetes and obesity. Like diabetes and obesity, NAFLD is on the rise. Approximately 20% to 30% of adults in developed countries have NAFLD, and its prevalence has markedly increased in children and adolescents.¹ The prevalence of NAFLD among adolescents has doubled over the past 3 decades, with the proportion affected reaching almost 11% by 2008. The disease affects approximately one-half of obese male adolescents.² Mexican American youths are disproportionately affected, with increased risk linked to the PNPL3 genetic mutation that causes overproduction and excess storage of triglycerides. The marked rise in NAFLD among the pediatric population is alarming because it heralds chronic ill health beginning at an earlier age for our nation’s youths.

A tangled web  

Accumulation of fat in the liver interferes with glucose metabolism, putting individuals with NAFLD at high risk for developing T2DM. In fact, some researchers have suggested that elevations in ALT liver enzyme levels could be a predictor for development of T2DM.¹ In addition, having NAFLD is closely linked to dyslipidemia and increased risk for cardiovascular disease, thus those with NAFLD should be screened and closely monitored for standard cardiovascular risk factors.¹

Although NAFLD is usually benign, a minority of patients develop nonalcoholic steatohepatitis (NASH), which can progress to liver fibrosis, cirrhosis, and occasionally hepatocellular carcinoma.³ Persons with T2DM, in particular, may be at higher risk for mortality from chronic liver disease, primarily as a result of NAFLD.⁴

Treatment options

When it comes to therapy, physicians have few choices. Current treatment options include:

  • Lifestyle: Weight loss through diet and exercise remains the cornerstone of treatment, although many patients may find it difficult to adapt and maintain sufficient behavior modifications.

  • Bariatric surgery: Research suggests that bariatric surgery could decrease hepatic inflammation associated with NAFLD, but should not replace weight loss through lifestyle modification.⁵

  • Oral antihyperglycemics: Metformin and glitazones are used; glitazones are generally thought to redistribute fat from the liver to subcutaneous areas, but at the risk of increased overall weight; increased cardiovascular risk may also be a consideration for certain glitazones.¹

  • High-dose vitamin E: Some studies suggest improvement in NAFLD symptoms with high-dose vitamin E therapy in adults, although its efficacy in pediatric patients has been debated.⁶

  • Statins: Could improve liver histology¹ and decrease hepatic steatosis when combined with vitamins E and C.⁷

  • Liver transplant: NASH is now the third most common indication for liver transplant nationwide; in the US, the percentage of transplants performed for NASH rose from 1% in 2001 to 10% in 2009.⁸

In the pipeline

Currently no drugs are approved specifically for the treatment of NAFLD or NASH. Drugs in the pipeline include:

  • Obeticholic acid: A bile acid analogue currently in development by Intercept Pharmaceuticals. In January 2014, the company announced interim results from the NIH-sponsored FLINT clinical trial looking at obeticholic acid in the treatment of NASH. It was announced that the trial would be stopped early for “efficacy based on highly statistically significant improvement in liver histology.” On May 28, 2014, Intercept was also granted fast-track status by the FDA to study obeticholic acid in the treatment of primary biliary cirrhosis in patients with treatment nonresponse, or intolerance, to ursodiol.⁹

  • GR-MD-02: A galectin inhibitor in development by Galectin Therapeutics. In August 2013, the FDA granted the company fast-track status to develop GR-MD-02, which targets NASH-associated hepatic fibrosis. The hope is that the agent could reverse more advanced symptoms of NASH.¹⁰ 

Take-Home Points

  • NAFLD has increased dramatically among developed nations, particularly among youths.

  • NASH is now the third leading cause of liver transplant in the US.

  • Weight loss remains the cornerstone of treatment for NAFLD, although bariatric surgery, oral hypoglycemics, statins, and vitamin E may also have roles.

  • New drugs in the pipeline for the treatment of NASH include obeticholic acid and GR-MD-02 .

References:

• Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci. 2008;115:141–150. doi:10.1042/CS20070402
• Welsh JA1, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr. 2013;162:496-500. doi:10.1016/j.jpeds.2012.08.043. Epub 2012 Oct 17.
• Kopec KL, Burns D. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract. 2011;26:565–76.
• Zoppini G, Fedeli U, Gennaro N, et al. Mortality from chronic liver diseases in diabetes. Am J Gastroenterol. 2014;109:1020-1055. doi:10.1038/ajg.2014.132.
• Dixon JB. Surgical management of obesity in patients with morbid obesity and nonalcoholic fatty liver disease. Clin Liver Dis. 2014;18:129-146. doi:10.1016/j.cld.2013.09.011. Epub 2013 Oct 24.
• Lavine JE1, Schwimmer JB, Van Natta ML, et al; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659-1668. doi:10.1001/jama.2011.520.
• Foster T, Budoff MJ, Saab S, et al. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol. 2011;106:71-77. doi:10.1038/ajg.2010.299. Epub 2010 Sep 14.
• Charlton M. Evolving aspects of liver transplantation for nonalcoholic steatohepatitis. CurrOpin Organ Transplant. 2013;18:251-258. doi:10.1097/MOT.0b013e3283615d30.
• Intercept Pharmacetucials. Press Releases. http://ir.interceptpharma.com/releases.cfm?view=all. Accessed July 9, 2014.
• Galectin Therapeutics. Development Programs. http://galectintherapeutics.com/what-we-do/develop-proprietary-compounds-for-disease/development-program. Accessed July 9, 2014.