NAFLD

Sedentary lifestyles, nutrient-poor diets, chemical exposure, and an excess of sugar and refined foods are wreaking havoc on and in our bodies more than ever before. And the effects aren’t just cosmetic – beyond bulging waistlines, the incidence of high blood pressure, high blood sugar, and high cholesterol associated with metabolic syndrome are all on the rise, along with the rate of nonalcoholic fatty liver disease (NAFLD).

As the name implies, NAFLD (casually pronounced “naffled”) is a condition in which the liver stores excess fat occurring in those who drink little to no alcohol. Over time NAFLD can not only increase the risk of cardiovascular disease, but can also lead to further ailments of the liver like cirrhosis and liver cancer – conditions also seen in heavy alcohol consumers, but now more commonly seen in non-drinkers. In fact, NAFLD is the leading cause of liver disease in the West, often concurrent with other metabolic conditions: approximately 40 to 80% of people with the disease also have type 2 diabetes, and 30 to 90% are obese. As with metabolic syndrome, the incidence of NAFLD is also on the rise among children, affecting an estimated 3 to 12% of children with normal body mass and an alarming 40 to 80% of obese children.

The umbrella term NAFLD encompasses two sub-categories: nonalcoholic fatty liver (NAFL), which is characterized by fatty liver with little to no inflammation; and nonalcoholic steatohepatitis (NASH), which is the more harmful of the two and is defined as fatty liver with inflammation. It’s estimated that 30 to 40% of American adults have NAFL and about 3 to 12% have NASH.

Wisdom Wednesday: Metformin for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Clinical Question
How effective is metformin in the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis?

Evidence-based Answer
Metformin does not seem to be an effective treatment for nonalcoholic steatohepatitis. There are no studies evaluating whether metformin improves long-term patient-oriented outcomes such as progression from NAFLD to nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, or death from liver failure. Metformin does not improve anatomic outcomes (histologic or ultrasound features of the liver) or biochemical outcomes (alanine transaminase [ALT] and aspartate transaminase [AST] levels, or insulin resistance) in adults. Metformin does not improve liver histologic or biochemical outcomes, or body mass index (BMI) in adults with nonalcoholic steatohepatitis. (Strength of Recommendation: C, based on a meta-analysis of randomized, controlled trials [RCTs] evaluating laboratory parameters.) Similarly, metformin does not improve histologic or biochemical outcomes, or BMI in children and adolescents with NAFLD. (Strength of Recommendation: C, based on RCTs evaluating laboratory parameters.)

Evidence Summary
Adults With NAFLD
No studies have evaluated patient-oriented outcomes of metformin therapy for NAFLD or nonalcoholic steatohepatitis. An RCT found no improvement in liver histology on biopsy.[1,2] Two placebo-controlled RCTs (N = 113) evaluating the effect of metformin (850 to 1,700 mg per day) on ALT and AST levels, insulin resistance, and BMI found no differences. One RCT (n = 48) found a small decrease in BMI. Another RCT (n = 2,153) found no improvement in ALT levels after treatment with metformin (850 mg twice per day) vs. placebo.[2]

Adults With Nonalcoholic Steatohepatitis
Two RCTs (N = 52) evaluating metformin (500 to 1,000 mg per day) in patients with nonalcoholic steatohepatitis found that it did not improve liver histology, ALT and AST levels, BMI, or insulin resistance.[1,3]

Children With NAFLD
Two RCTs (N = 172) evaluating metformin (1,000 to 1,500 mg per day) vs. placebo in children with obesity and NAFLD found no improvement in liver histology on biopsy, ALT and AST levels, BMI, or insulin resistance.[4,5] A smaller RCT (n = 50; mean age: 15 years) found that metformin (850 mg twice per day) improved ultrasound scores for fatty liver but did not improve ALT and AST levels.[6]

Recommendations From Others
An evidence-based guideline from the American Association for the Study of Liver Diseases, the American College of Gastroenterology, and the American Gastroenterological Association states that metformin has no significant effect on liver histology and is not recommended as a treatment for liver disease in adults with nonalcoholic steatohepatitis.[7]