Patients with T2D Should be Assessed for NAFLD

A growing complication of type 2 diabetes—non-alcoholic fatty liver disease—is found in more than half of all patients, and the risk appears to rise with obesity, necessitating routine assessment.

by Paola Portillo-Sanchez, MD, and Giovanni Targher, MD

Nonalcoholic fatty liver disease (NAFLD) was found in 50% of patients with type 2 diabetes who had normal aminotransferase levels in a recent study reported in the Journal of Clinical Endocrinology & Metabolism.


“We found that in patients with type 2 diabetes (T2D) who were screened by the non-invasive gold-standard diagnostic process of liver magnetic resonance spectroscopy (H-MRS), there was a surprisingly high prevalence of NAFLD (36% and 56% in overweight and obese, respectively), even in the absence of plasma AST/ALT elevations,” said lead author Paola Portillo-Sanchez, MD, a post-doctoral fellow in the Division of Endocrinology, Diabetes, and Metabolism at the University of Florida in Gainesville. 

“Moreover, more than half of these patients (56%) had developed the more severe form of liver disease called nonalcoholic steatohepatitis (NASH),” Dr. Portillo-Sanchez said. “From these findings, the most important clinical implication for practitioners is that NAFLD and NASH occur frequently in patients with T2DM, regardless of aminotransferase levels, and therefore, AST and ALT should be interpreted with caution when screening or following these patients,” Dr. Portillo-Sanchez said.

The study involved 103 patients with type 2 diabetes and normal plasma aminotransferase levels, and without a prior diagnosis of NAFLD. The majority of patients (70%) were obese (BMI ≥30 kg/m2).

The prevalence of NAFLD was 56% in patients with obesity and 36% in patients without obesity. Increasing body mass index was significantly associated with a greater prevalence of NAFLD (P=0.001). In addition, a higher plasma hemoglobin A1C was significantly associated with a higher prevalence of NAFLD (P=0.01) and an increased liver triglyceride accumulation (P=0.005).

Poor Glycemic Control Linked to Nonalcoholic Fatty Liver Disease

“Regarding the role of hyperglycemia in the pathogenesis of NAFLD, we found that the prevalence of NAFLD among these patients increased with worsening diabetes control,” Dr. Portillo-Sanchez said. “This suggests uncontrolled diabetes as a risk factor that promotes NAFLD, and that adequate diabetes control may contribute to prevent, or ameliorate, the development of NAFLD. However, this hypothesis requests future testing,” Dr. Portillo-Sanchez said.

In addition, a higher degree of insulin resistance was found among patients with NAFLD than among those without this condition, both systemically (HOMA-IR, 2.2 vs 3.8; P<0.001) and at the level of the adipose tissue (Adipo-IRindex, 5.8 vs 2.5 mmol/Lº; mU/mL; all P<0.01).

“We hope that these results will generate awareness among health care providers about the increased risk of NAFLD in patients with obesity and T2DM, and the need to consider early screening and control of hyperglycemia in these patients,” Dr. Portillo-Sanchez concluded.

Commentary by Giovanni Targher, MD

"Existing guidelines do not advocate screening for liver-related complications among persons with type 2 diabetes (T2D), making the liver a potentially neglected target organ for undetected chronic disease progression to cirrhosis," said Giovanni Targher, MD, assistant professor of endocrinology and diabetology at the University of Verona Medical School, Verona, Italy, "However, the perception of NAFLD as an uncommon and benign condition is rapidly changing."

Dr. Portillo-Sanchez and colleagues have examined for the first time the prevalence of NAFLD and NASH in a relatively large sample of predominantly obese patients with type 2 diabetes and normal serum aminotransferase levels. As recognized by the same authors, this study is unique by screening such patients with the gold-standard technique of proton magnetic resonance spectroscopy and performing a liver biopsy when possible to assess for NASH. Notably, this study shows that approximately half (56%) of these patients with T2D and normal aminotransferase levels have NASH, the more advanced form of NAFLD. NASH has the potential to progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC).

In clinical practice, it is well known that most patients with T2D and NAFLD (approximately 80%) have normal serum aminotransferase levels. The finding of this study is consistent with earlier studies showing that the full histological spectrum of NAFLD may be present among patients with fairly normal serum aminotransferases. This suggests that serum aminotransferase levels are insensitive markers for the detection of NAFLD and that the “normal” reference values for these serum liver enzymes currently used to exclude NAFLD need to be challenged and revised.

If confirmed in further larger studies, the results of this study strongly suggest that diabetologists/endocrinologists and clinical physicians need to be aware that NASH is a highly prevalent condition in people with T2DM, and also that NAFLD is associated with poor glycemic control and increased risk of developing both cardiovascular disease and chronic kidney disease—as recently shown by other investigators—in this patient population.

From the results of this and other recently published studies, I believe that the possibility of NAFLD should be entertained as a part of the routine evaluation of patients with T2D, in the same way, we search for microvascular and macrovascular complications. Additionally, a multidisciplinary approach to the treatment of patients with NAFLD, based on a careful evaluation of related cardiometabolic risk factors and monitoring for cardiovascular, kidney, and liver complications, is warranted.

Because of the link between T2D, NAFLD, and adverse vascular and hepatic outcomes, more careful surveillance of these at-risk patients is needed with the combined use of serum liver enzymes, liver imaging (mainly ultrasonography and Fibroscan, I think, given that proton magnetic resonance spectroscopy, as used in the study by Portillo-Sanchez et al, is too expensive to be used routinely for the screening of NAFLD in diabetes patients), and clinical risk score systems for advanced liver fibrosis.


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