EASD/EASL Symposium: is NAFLD a risk for health in the context of diabetes?
Michael Roden, MD
German Diabetes Center, Leibniz Institute at Heinrich Heine University Düsseldorf, Düsseldorf, Germany Stefano Romeo, MD
Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden Elisabetta Bugianesi, MD, PhD
Division of Gastroenterology and Hepatology, University of Turin, Italy
NAFLD and diabetes are common metabolic disorders that are often comorbid. Proper dietary and pharmacological treatment is essential for preventing NAFLD progression. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone, and pharmacological treatments are helpful in this regard. Attention should be paid to the management of NAFLD and diabetes: efforts should be made to intervene early and individualise treatment of NAFLD in patients with diabetes.
NAFLD comprises a spectrum of liver disease spanning non-alcoholic fatty liver (NAFL)/fatty liver steatosis and non-alcoholic steatohepatitis (NASH), which are a cause of cirrhosis and hepatocellular carcinoma.
NAFLD and NASH are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase.
NAFLD is also associated with metabolic risk factors, including increased waist circumference, arterial blood pressure, fasting glucose, serum triacylglycerols and HDL cholesterol.
Patients with type 2 diabetes have increased risk for NAFLD that is more than 5 times higher than that of the general population: more than half of patients with type 2 diabetes have NAFLD, over a third have NASH and almost 20% have advanced fibrosis.
As expected, mortality is increased in patients with both diabetes and NAFLD.
Recently, several clusters of diabetes phenotypes have been identified and, of note, those in the insulin-resistant clusters are at higher risk for NAFLD.
This highlights that the liver is a key organ in systemic metabolism, contributing substantially to the development of insulin resistance and type 2 diabetes.
The mechanisms underlying these processes are not entirely understood, but involve hepatic fat accumulation, alterations of energy metabolism and inflammatory signals derived from various cell types including immune cells.
Lipotoxins, mitochondrial function, cytokines and adipocytokines have also been proposed to play a major part in both NAFLD and type 2 diabetes.
Moreover, saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism and insulin resistance, which is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD.
In terms of treatment of NAFLD, lifestyle intervention can be effective: weight reductions of ≥10% can induce a near universal NASH resolution and fibrosis improvement by at least one stage.
Following a Mediterranean diet can reduce liver fat even without weight loss and is the most recommended dietary pattern for NAFLD.
Treatment of NAFLD includes aggressive management of diabetes and cardiovascular risk factors, although the role of controlling hyperglycaemia per se in patients with type 2 diabetes in improving NAFLD has not been confirmed; there is some evidence that thiazolidinediones may be of benefit, but there are no drugs approved to treat NAFLD.
NAFLD is known to have a strong genetic component.
Despite the tight association between NAFLD and insulin resistance, genome-wide association studies have identified genetic variants associated with NAFLD severity that do not correlate with insulin resistance.
Among these, the most widely studied gene is patatin-like phospholipase domain-containing protein 3 (PNPLA3).
Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD, and variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution.
These genetic studies are thus offering new tools for targeted screening of high-risk individuals, and may aid in patient stratification, as well as prognostication.
Some of these newly identified genes, such as PNPLA3, may also represent viable therapeutic targets for NAFLD.
Considering the impact of NAFLD, screening has been advocated by some management guidelines in selected patients, but there is still some debate on the need for screening due to the high direct and indirect costs of testing, low predictive value of non-invasive tests, risks of liver biopsy and lack of effective treatments.
However, there appears to be general consensus that routine screening should not be employed in all patients.