NAFLD: An Emerging Epidemic with No Approved Treatment

Experts suggest that approximately 80 million Americans have some form of fatty liver disease. Non-alcoholic fatty liver disease is currently the most common type of liver disease in the Western world and is associated with obesity, insulin resistance, diabetes and other metabolic risk factors, and can progress to more severe diseases, including nonalcoholic steatohepatitis, fibrosis and hepatocellular carcinoma. Healio Gastroenterology spoke to several experts in the field to determine where this epidemic stems from, where it is going and if there will ever be a cure.

The Beginning

According to the AASLD and ACG practice guideline, NAFLD is categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. NAFL is defined as the presence of hepatic steatosis without evidence of hepatocellular injury, also known as ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with ballooning with or without fibrosis. It was in the 1980s that a pathologist at the Mayo Clinic first described NASH, according to Naim Alkhouri, MD, staff physician and medical director of the Metabolic Liver Disease Clinic, Digestive Disease Institute, Cleveland Clinic.

“People didn’t start thinking about NASH as a cause of liver cirrhosis and the need for liver transplant until the 1990s, but now it is the most common form of chronic liver disease in the United States,” Alkhouri told Healio Gastroenterology. “It is number two or three on the list of indications for liver transplant after HCV and alcoholic liver disease. It is a true epidemic.”

Dina Halegoua-De Marzio, MD, director of the Jefferson Fatty Liver Center at Thomas Jefferson University Hospital in Philadelphia, agreed it is a disease that many clinicians or people did not find concerning previously.

“Fatty liver disease was historically thought to be of little importance, but recent advances have shown that fatty liver disease can progress to NASH in up to 25% of patients. Of those who develop NASH, 15% to 25% will progress to end-stage liver disease over 10 to 20 years,” Halegoua-De Marzio told Healio Gastroenterology.

Douglas T. Dieterich, MD, professor of medicine in the division of liver diseases at Icahn School of Medicine at Mount Sinai in New York, also called NAFLD an epidemic and believes it is on the rise alongside obesity and diabetes.

“[NAFLD] is very prevalent, very common. About 70% of diabetics have NAFLD and about 30% have NASH, which is a much more serious version and progresses more rapidly to cirrhosis, liver cancer and liver failure,” Dieterich told Healio Gastroenterology. “It is increasing with the increasing amount of obesity and diabetes that we have in the U.S. population.”

Risk Factors

Recent research on the cause of NAFLD has shown that sugar-sweetened beverages and a diet filled with high amounts of carbohydrates and sugars are risk factors for the disease.

In an analysis of the Framingham Heart Study cohort published in the Journal of Hepatology, researchers examined the association between the intake of sugar-sweetened beverages or diet soda and fatty liver disease. Among more than 5,000 participants, the researchers found that regular consumption of sugar-sweetened beverages increased fatty liver disease risk, more exclusively in obese and overweight individuals.

“This study shows the impact of processed, sugary foods on the risk of developing fatty liver disease,” Halegoua-De Marzio said in reference to the study. “More education about impact of sugar and processed foods on liver health is needed. Eliminating soda from one’s diet is an important step in the prevention of fatty liver disease.”

Halegoua-De Marzio further stated that high fructose corn syrup found in processed foods is the “biggest cause of NAFLD.”

“An example of this is soda, which is the number one source of calories in the American diet and cause of NAFLD,” she said.

Dieterich also believes high fructose corn syrup to be a significant problem: “High fructose corn syrup has a direct proportion to obesity in the U.S. and to fatty liver. They are rising exponentially in parallel.”

In addition to soda, Dieterich stated that juice, which is a common beverage among children, poses a problem among the pediatric population. He said, “High amounts of high fructose corn syrup are found in juice, a frequent drink in children, and parents mistakenly think it is good to give to children.”

In addition to sugar consumption, Dieterich said diabetes and obesity are the biggest risk factors for fatty liver, especially among Hispanics.

“If you have a history of diabetes in the family, keep this in mind, because it is one of the highest risk factors. Hispanics have the highest prevalence of obesity and this is due to certain PNPLA genes that are more concentrated in this population compared with Caucasians and African Americans,” Dieterich said.

Diagnosing NAFLD and NASH

Lee F. Peng, MD, PhD, associate medical director of liver transplantation at Temple University Hospital, told Healio Gastroenterology that the current “gold standard” for diagnosing NAFLD is liver biopsy.

“Although fatty liver can be visualized radiologically by ultrasound, computed tomography or MRI, the gold standard for the diagnosis of NAFLD remains liver biopsy,” he said. “At the present time, liver biopsy remains the best and most reliable way to distinguish between bland steatosis and NASH.”

Variants of NAFLD

Halegoua-De Marzio echoed Peng’s sentiments about liver biopsy, and added that diagnosing NAFLD can be difficult.

“Patients are usually first identified when they are noted to have abnormal liver tests,” she said. “The actual diagnosis of NAFLD is often made by an imaging test. However, to truly diagnose NASH and give an overall prognosis, a liver biopsy is still often needed.”

Dieterich stated that liver biopsy is not performed by “real life” clinicians.

“NAFLD is currently mostly being diagnosed by liver enzyme tests. Another hint of NAFLD [in a patient] is if [aspartate aminotransferase] is greater than ALT and in the absence of cirrhosis, which is a good way to diagnose it. Liver biopsy is currently used in clinical trials for the diagnosis of NASH in patients with NAFLD, not in real life,” Dieterich said.

Current Treatment Options

There are currently no approved therapies for the treatment of NAFLD or NASH. The best way to prevent and treat NAFLD is to maintain a healthy diet and rigorous exercise regimen, according to the experts.

“The cornerstone of therapy for NAFLD is weight loss through exercise and healthy diet, control of serum lipids in dyslipidemia and control of serum glucose levels in diabetes mellitus,” Peng said.

Peng added that there have been patients with biopsy-proven NASH treated with vitamin E by their hepatologists, as well as pioglitazone (Actos, Takeda), according to recommendations from research performed in the PIVENS trial.

Kathleen E. Corey, MD, MPH, presented updated results of the PIVENS trial at The Liver Meeting 2014. In this trial, 222 individuals were randomized to daily pioglitazone, vitamin E or placebo to compare changes in lipid levels between those who experienced resolution of NASH with those whose NASH was unresolved.

“In the PIVENS study, treatment of NASH patients with vitamin E led to histological improvement in 43% of patients vs. 34% of patients treated with pioglitazone and 19% of patients with placebo,” Peng said.

Halegoua-De Marzio agreed there have been good data to support vitamin E and pioglitazone for NAFLD. However, neither is “terribly effective” and she only treats specific patients with these drugs.

“Clinical trials have looked at vitamin E as a possible treatment for NAFLD, which has been available on the market for therapy,” Alkhouri said. “It showed some benefit, for NASH, but did not improve liver fibrosis.”

Alkhouri stated his recommendations for patients with NAFLD and NASH are a Mediterranean diet with plenty of exercise.

“Diet and exercise are very important. I recommend a low-calorie Mediterranean diet under nutrition supervision. Both aerobic and resistance exercises are good in terms of decreasing liver fat. It has to be rigorous exercise, not just walking around the block, but rigorous exercise 45 minutes at a time, four to five times a week,” Alkhouri said.

Researchers in Australia, including Marno C. Ryan, MD, conducted a study showing that a Mediterranean diet improved steatosis and NAFLD. In the study, 12 patients without diabetes underwent a Mediterranean and control diet for 6 weeks and showed reduced liver steatosis and improved insulin sensitivity upon completion of the diet as compared with other dietary advice.

Dieterich stated that while a healthy diet and exercise are the best treatment options for NAFLD, it is also the hardest.

“The best treatment is the least likely to succeed and least favorite with the patients: diet and exercise. We typically advise low carb diets to reduce insulin secretion and insulin resistance. In major cases, we do use insulin sensitizer,” Dieterich said. “Diet and exercise should always come first and, though it depends on clinical factors, metformin is the first and most influential sensitizer.”

Drugs in the Pipeline

Despite a lack of approved regimens for the treatment of NAFLD or NASH, many drugs currently exist in the pipeline. Drugs, such as obeticholic acid (OCA; Intercept Pharmaceuticals), oltipraz (Sigma-Aldrich Co.), cenicriviroc (CVC; Tobira Therapeutics), and aramchol (Galmed Pharmaceuticals) are currently being evaluated in multiple clinical trials.

In the FLINT trial, presented at The Liver Meeting 2014, 283 adult patients with NASH were randomized to receive either a 25-mg dose of OCA or placebo for 72 weeks. More patients who received OCA showed significant improvement in the primary histological endpoint of NAFLD Activity Score, as well as steatosis, lobular inflammation and hepatocellular ballooning. Results also indicated a significant improvement in fibrosis.

“The largest study we have to date of obeticholic acid is the FLINT study and that showed the resolution of NASH, but in less than 25% of patients. Fibrosis improved in 35% of patients, which was impressive,” Alkhouri said. “You have something that seems like it is helping with the resolution of NASH, so I’m excited to see how it will do long-term, interested in looking at fibrosis and looking at improvement in fibrosis.”

The FDA granted breakthrough therapy designation to Intercept Pharmaceutical’s OCA in January.

In another study presented by Won Kim, MD, department of internal medicine and Liver Research Institute, Seoul National University Boramae Medical Center, at The Liver Meeting 2014, patients with NAFLD showed reduced liver fat and BMI after a 24-week regimen of oltipraz compared with placebo.

“The trial was small and only phase 2, but treatment of patients with NAFLD with oltipraz led to reductions in liver fat, BMI and fibrosis scores over placebo,” Peng said, in reference to the Kim study. “However, this study did not involve liver biopsy and did not look at NASH in particular.”

Recent research data on drugs for the treatment of other diseases, such as liraglutide (Victoza, Novo Nordisk) for the treatment of diabetes, have shown promise for NAFLD/NASH as well.

Data from the LEAN trial presented at the International Liver Congress 2015 by Matthew J. Armstrong, MSc, MBChB, MRCP, from the University of Birmingham, UK, showed positive results of obese patients with biopsy-proven NASH treated with liraglutide or placebo for 48 weeks. Of 45 patients who underwent liver biopsy, 39% of them treated with liraglutide (n = 9/23) had resolved NASH and no worsening of fibrosis compared with 9% of patients who received placebo (n = 2/22).

“This trial was small, but shows future promise for Victoza,” Peng said in reference to the Armstrong study. “Eighty-two percent of patients on liraglutide showed improvement in fat content of the liver.”

“At the end of the day, [Victoza is] a medication that is good for diabetes, insulin resistance and weight loss; it is very promising,” Alkhouri said.

Halegoua-De Marzio stated the Kim and Armstrong studies showed promise, but more data is needed.

“Phase 3 studies with larger, more diverse patient groups are needed to make final determinations,” Halegoua-De Marzio said.

“The new, potential treatments for NAFLD are not fixing the etiology, which is insulin resistance caused by obesity and a high carb and high sugar diet,” Dieterich said.

Other ongoing studies for the treatment of NAFLD/NASH include: the ARREST study to test the efficacy of aramchol for NASH and to look at efficacy rates in patients who are obese or experience insulin resistance; the ORION study, in which researchers will evaluate the treatment effects of CVC in 50 obese adults with prediabetes or diabetes and suspected NAFLD; and the REGENERATE study that will evaluate OCA therapy on approximately 2,500 patients with NASH and stage 2 or stage 3 advanced liver fibrosis.

Treatment Recommendations

The AASLD in collaboration with the ACG and the AGA developed NAFLD and NASH guidelines in 2012 that were published in Hepatology. They provided multiple recommendations on how to diagnose and treat NAFLD and NASH in adults and children.

Diagnosis recommendations include that NAFLD Fibrosis Score should be used to identify NAFLD patients with a higher likelihood of having fibrosis or cirrhosis. Liver biopsy, then, should be used in patients with NAFLD who are at increased risk for steatohepatitis and advanced fibrosis.

For treatments, metformin is not recommended as a specific treatment for liver disease in adults with NASH due to no significant effect on liver histology. The guidelines do support pioglitazone to treat steatohepatitis in patients with biopsy-proven NASH, but long-term safety and efficacy of the drug in these patients has not been established. Vitamin E at a dose of 800 IU per day could be used as a therapy for adults without diabetes with biopsy-proven NASH, though it is not recommended in patients with NASH who have diabetes.

Ursodeoxycholic acid is not recommended for the treatment of NAFLD or NASH due to data showing no significant “histological benefit” over placebo in clinical trials of patients with NASH and bariatric surgery is not considered an option to specifically treat NASH due to insufficient clinical data.

According to the published guidelines, NAFLD is found in children as young as age 2 years and with NASH-related cirrhosis by age 8 years. For children, the AASLD/ACG practice guidelines recommend “intensive lifestyle modification” as the first line of treatment. Metformin is not recommended in children with NAFLD because it offers no significant benefit. Vitamin E has some histological benefit in children with NASH, but more studies are needed to confirm this, so it is not currently recommended in clinical practice.

Search for a Cure

Even with a rigorous drug pipeline, some of the experts still believe a cure for NAFLD and NASH is difficult, if not impossible, to achieve.

“Control — good diabetic control, good obesity control and good control of insulin — are the main goals at the moment,” Dieterich said. “Unless we can cure diabetes and obesity, I don’t think we will be curing fatty liver any time soon.”

Alkhouri agreed. “NAFLD is a chronic disease. You just want to keep it under control,” he said. “I don’t think we will have a medication where you take it for 6 months and it will be cured; I think it will be medication you have to take long term. I am optimistic that within the next 5 years, we will have medications that will help patients with more severe forms of NAFLD and fibrosis and prevent them from turning into liver cirrhosis.”

Halegoua-De Marzio said: “The prevalence of NAFLD will continue to increase across the world and will become the leading cause of liver failure and HCC within the next 15 years, maybe sooner. Part of this is due to the rise of the disease in both children and adults. We need to continue focusing on effective treatment for this disease. Additionally, food companies need to work on providing us with better, less processed foods.”

Peng also emphasized his thoughts on an increasing wave of NAFLD.

“Given the close relationship of NAFLD to the metabolic syndrome and its multifactorial nature, NAFLD should not be considered a traditional disease process, such as an infection,” Peng said. “While we can cure a bacterial infection with the appropriate antibiotic medication, the treatment of NAFLD will likely require dietary and lifestyle modification and treatment of its underlying and predisposing factors.”

Peng stated that preventing the rise in NAFLD, obesity and metabolic syndrome will be a challenge for the future.

“With the growing epidemic of obesity and the metabolic syndrome in the U.S., NAFLD is most certainly on the rise. At the rate of increasing disease prevalence and growing awareness of NAFLD, as well as the advent of very effective medications for the treatment of hepatitis C, NASH will most likely be the leading cause of cirrhosis, HCC and liver transplantation in the U.S. in 15 years,” Peng said. – by Melinda Stevens

• References:
• Armstrong MJ. Abstract G01. Presented at: International Liver Congress; April 22-26, 2015; Vienna.
• Chalasani N, et al. Hepatology. 2012;doi:10.1002/hep.25762.
• Corey K. Abstract 56. Presented at: The Liver Meeting; Nov. 7-11, 2014; Boston, MA.
• Kim W. Abstract 55. Presented at: The Liver Meeting, Nov. 7-11, 2014; Boston, MA.
• Ma J, et al. J Hepatol. 2015;doi:10.1016/j.jhep.2015.05.021.
• Neuschwander-Tetri BA, et al. Lancet. 2014;doi:10.1016/S0140-6736(14)61933-4.
• Ryan MC, et al. J Hepatol. 2013;59:138-143.

• For more information:
• Naim Alkhouri, MD, can be reached at alkhoun@ccf.org.
• Douglas T. Dieterich, MD, can be reached at douglas.dieterich@mountsinai.org.
• Dina Halegoua-De Marzio, MD, can be reached at dlh004@jefferson.edu.
• Lee F. Peng, MD, PhD, can be reached at Lee.Peng@tuhs.temple.edu.

Disclosures: Alkhouri and Peng report no relevant financial disclosures. Dieterich reports associations with Achillion Pharmaceuticals, Boehringer Ingelheim, Gilead Sciences, Idenix Pharmaceuticals, Janssen, Merck and Vertex. Halegoua-De Marzio reports being a consultant for Intercept Pharma.