Tackling the liver disease linked to T2D

Ron S. Newfield, MD

A new study reveals that nonalcoholic steatohepatitis (NASH)-a more complex type of nonalcoholic fatty liver disease that includes inflammation and liver cell damage-is common in children with type 2 diabetes, but that lifestyle changes and improved diabetes management may help.

The study, published in Pediatric Diabetes, analyzed data from 38 children with a mean age of 13 years who had been diagnosed with type 2 diabetes mellitus.¹ The children were patients seen at Rady Children’s Hospital, San Diego, California, and had undergone liver biopsies for chronically elevated alanine transaminase (ALT) levels. The research team found that 26% of these biopsies showed advanced fibrosis in patients with NASH, according to the report.

Lead author Ron S. Newfield, MD, a pediatric endocrinologist at the University of California, San Diego, and Rady Children’s Hospital-San Diego, says the report highlights how common NASH is in children with type 2 diabetes and fatty liver.

“NAFLD incidence is rising as part of the rise in the number of overweight and obese children and adults. Insulin resistance is an integral part of the metabolic syndrome and it increases with obesity and has a central role in the pathogenesis of both type 2 diabetes and NAFLD,” Newfield says. “Diabetes is typically a more advanced form of the metabolic syndrome, with metabolic derangements including both hyperglycemia and dyslipidemia. It has been shown by other investigators that those patients with type 2 diabetes have much higher liver fat content. There are other factors that may predispose to NASH, such as the polymorphism in the PNPLA3 gene that was shown to correlate with higher liver fat content and a higher risk of developing liver fibrosis.”

Study results

For the children in the study, the research team was able to demonstrate some factors leading to NASH, but more research is needed.

“Pediatric patients with type 2 diabetes mellitus and fatty liver are more likely to have the more advanced form of NAFLD called NASH that was observed in about 60% of our subjects based on liver biopsy, as compared to about 20% that has been reported in nondiabetic obese children and adolescents with NAFLD,” Newfield says. “NASH was observed even in those with mild elevations of transaminase levels. When we compared diabetic subjects with NASH versus those without NASH, those with NASH had more steatosis, and 26% had a higher stage of fibrosis (stage 3) that was only observed in those with NASH. This is of concern as those may be more likely to progress to cirrhosis (stage 4).”

The goal of the study was to determine the histologic characteristics in children with type 2 diabetes, and to determine what factors contribute to the development of NASH, including phenotypes, ethnicity, lipid profiles, and diabetes management and control. Although the study group was mostly Hispanic (63.2%) with more females than males, the research team did not find any association in NASH prevalence across age, gender, or ethnicity.

In the cases studied, the research team found that 78.9% of the children had had their diabetes treated with metformin, and 50% were treated with insulin therapy. Liver function was evaluated using the NASH Clinical Research Network scoring system (NAFLD activity score), and patients were also assessed using lab results, lipid panels, biopsies, and HbA1C levels near to the time of biopsy. At the time of NAFLD diagnosis, the researchers found that 61% of the patients in the study group had NASH, 13% had borderline NASH, and 26% had NAFLD without NASH. The children who received a NASH diagnosis had higher steatosis grades than those without, and 26% of the children with NASH had advanced-stage 3-fibrosis compared with no stage 3 fibrosis in children with borderline or no NASH diagnosis.

The report also revealed higher ALT levels in children with NASH, and that 88% of children diagnosed with NASH had a NAFLD activity score of at least 4 with higher stage fibrosis than children with a NAFLD activity score of 4 or less.

“A higher NAFLD activity score (NAS) of 4 or higher correlated well with the presence of NASH, and NAS was higher in those with higher mean triglyceride levels, higher A1C and lower HDL,” Newfield notes. “These can be modified with lifestyle changes and good glycemic control. We were encouraged to find that in 8 subjects with a repeat biopsy (1.7 to 5.6 years after the initial biopsy) there was no worsening, and in almost two-thirds the NAS improved.”

Important takeaways

The research team concludes that this data warrants a review of the current cutoff of a NAFLD score of 5 for considering a NASH diagnosis, as well as further research into when biopsies should be performed, investigation of a larger cohort to assess ethnic associations, and whether therapies such as metformin may help improve NAFLD or slow progression.

“Our study reinforces the notion that lifestyle changes, including healthy diet and increased physical activity, together with keeping good glycemic control may help improve the diabetic dyslipidemia, and reduce weight and the chances of developing NASH,” Newfield says. “Those interventions may also help halt the progression in the degree of steatosis and fibrosis in those with NASH and ultimately the progression towards cirrhosis.”

Newfield says he hopes the study will motivate clinicians to take a closer look at diabetic patients with abnormal liver enzymes, perhaps allowing for earlier evaluation.

“We hope this study will raise awareness of the high likelihood of NAFLD and NASH in patients with type 2 diabetes, even with mild transaminase elevations, and will spur more providers to have diabetes patients undergo a complete evaluation to exclude other treatable causes of elevated transaminases, which may require a liver biopsy in addition to other ancillary testing,” Newfield says. “Taking a history about alcohol consumption and educating youth with type 2 diabetes about avoiding alcohol and certain medications that affect the liver is important. Until effective medications to treat NAFLD are available, lifestyle modifications and achieving good glycemic control appear to offer the best and safest way to help address NASH.”

References:

1. Newfield RS, Graves CL, Newbury RO, et al. Non-alcoholic fatty liver disease in pediatric type 2 diabetes: metabolic and histologic characteristics in 38 subjects. Pediatr Diabetes. 2019;20(1):41-47.