LOS ANGELES – The way , sees it, nonalcoholic steatohepatitis (NASH) is an epidemic of the 21st century that can trigger a cascade of reactions.
“If more than 5.8% of fat is in the liver, we call it nonalcoholic fatty liver disease [NAFLD],” Dr. Mantzoros, professor of medicine at Harvard Medical School, Boston, and Boston University, explained at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease. “If inflammation develops to remove the fat, we call it NASH. If this progresses to decompensated reaction and fibrosis and cirrhosis, then we call it nonalcoholic steatohepatitis with fibrosis. That can lead to liver cirrhosis, hepatocellular carcinoma, and liver failure.”
The underlying problem stems from the rise in obesity prevalence, according to Dr. Mantzoros, who is also chief of endocrinology at the Boston Veterans Affairs Healthcare System. For 75%-80% of individuals with metabolically unhealthy obesity, the storage space in their adipose tissue is exceeded. “Fat is deposited into muscle, causing insulin resistance, and into the liver,” he explained. “If it’s more than 5.8%, it causes NAFLD. Most of us don’t realize that most of the patients with diabetes we have in our clinics also have nonalcoholic fatty liver disease. That’s because we don’t have an easy diagnostic tool or an easy treatment. It’s an unmet clinical need.” (There are currently no drugs approved for the treatment of NASH or NAFLD. Current recommended first-line treatment is weight loss through diet and exercise and control of diabetes, if it is present.)
“Assuming the rate of increase in cost due to NAFLD parallels the growth in obesity, the 10-year projection for direct cost is $1.005 trillion,” said Dr. Mantzoros, who is also editor in chief of the journal Metabolism. “Obesity, NAFLD, and insulin resistance are each independently associated with a twofold risk for diabetes. If all three are present, there is a 14-fold risk for diabetes. Insulin resistance promotes an increase in free fatty acid traffic to the liver, which can trigger hepatic lipotoxicity. Hyperinsulinemia enhances free fatty acid uptake and activates de novo lipogenesis. Hyperglycemia can also activate de novo lipogenesis.”
About 85 million Americans have NAFLD, he continued. Most (80%) are cases of steatosis, but 20% have NASH. Of those, 20% develop advanced fibrosis, which leads to liver failure and transplantation or death. A study of data from the National Health and Nutrition Examination Survey found that(odds ratio, 18.20), followed by a body mass index of 30 kg/m2 or greater (OR, 9.10), hypertension (OR, 1.20), and age (OR, 1.08; ). “Most of the patients who come to our clinics with diabetes have nonalcoholic fatty liver disease – 75%-80% in our clinics, and about 10% have advanced fibrosis,” Dr. Mantzoros said. “Most of them go undiagnosed.”
Patients with type 2 diabetes and NAFLD progress faster to fibrosis and end-stage liver disease, compared with those who do not have diabetes. One study of 108 patients with biopsy-proven NALFD showed that 84% of those with fibrosis progression had type 2 diabetes (). Other findings have shown that patients with type 2 diabetes are at increased risk of chronic NAFLD and hepatocellular carcinoma ( ). “We are doing more liver transplantations because of NAFLD and NASH than because of hepatitis C,” Dr. Mantzoros said. “What we need to keep in mind is that, although liver morbidity and mortality is important, this is a component of the cardiometabolic syndrome. So, people have all the risk factors for cardiovascular disease. Because CVD is much more common, people with NAFLD suffer from and die from CVD. The more advanced the NAFLD, the higher the risk of death from cardiovascular disease.”
Multiple risk factors can help identify patients with advanced fibrosis because of NASH, he continued, including having features of the metabolic syndrome, being over 50 years of age, being Hispanic, having high levels of ALT/AST, low platelets, and having low albumin. “These are frequent tests that we can find in the EMR,” Dr. Mantzoros said. “The problem with ALT is that, in many stages of the disease, ALT goes up. But after a certain stage of the disease, when most of the liver is controlled by fibrosis and cirrhosis, most of the hepatocytes are dead and don’t secrete ALT, so ALT in end-stage renal disease goes up.”
Recent guidelines recognize the association between diabetes, NAFLD, and NASH, and call for increased vigilance and screening tests. According to guidelines from the American Association for the Study of Liver Diseases, the Fibrosis-4 Index or the NAFLD Fibrosis Score are clinically useful tools for identifying NAFLD in patients with higher likelihood of having bridging fibrosis or cirrhosis (). Vibration-controlled transient elastography or MRI are clinically useful tools for identifying advanced fibrosis in patients with NAFLD, whereas clinical decision aids, such as Fibrosis-4, NAFLD Fibrosis Score, or vibration-controlled transient elastography, can be used to identify patients at low or high risk for advanced fibrosis.
“If we have a patient with suspected NAFLD, we need to rule out alcohol use, we need to confirm NAFLD, and we need to risk stratify, and classify as low, intermediate, or high risk,” Dr. Mantzoros said. Most of his patients who meet criteria for high-risk NASH do not elect to undergo a liver biopsy. “I don’t blame them for that,” he said. “There is a 0.1 per 1,000 mortality risk, even in the best hands. If 80 million people who have fatty liver were to undergo a liver biopsy, we would have 16,000 deaths every year just because of that. We would not tolerate that.”
Recently, Dr. Mantzoros and colleagues published a proof-of-concept study that proposes novel models using lipids, hormones, and glycans that can diagnose the presence of NASH, NAFLD, or healthy status with high accuracy (). “We are now working with companies to validate it and expand it, not only as a diagnostic marker, but as a prognostic marker, and to try to commercialize it in the future,” he said.
Current pharmacotherapies are limited to patients with biopsy-confirmed NASH and fibrosis. Pioglitazone is a first-line, off-label pharmacologic treatment, while vitamin E may be used in patients with biopsy-confirmed NASH without diabetes. Metformin, glucagonlike peptide–1 receptor agonists, and sodium-glucose transporter 2 inhibitors are either not recommended or have insufficient evidence to recommend their use. More than 60 phase 2 trials are planned or ongoing, Dr. Mantzoros added, with phase trials underway for cenicriviroc, elafibranor, obeticholic acid, and selonsertib.
The role of lifestyle management is also important. “The Mediterranean diet has the best evidence, along with exercise, to improve early stages of NAFLD,” he said. “Weight loss is very important. If the patient loses 10% of their weight or more, there is NASH resolution 90% of the time. With less weight loss, we have less resolution. The problem is that only 10% of patients or less can sustain a more than 90% weight loss over a year.”
Dr. Mantzoros reported being a shareholder of Coherus BioSciences and Pangea Therapeutics, having served as an adviser to Coherus, Novo Nordisk, and Genfit and having received research grants through his institution from Coherus, Eisai, and Novo Nordisk.