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The use of microbiome biomarkers to predict the stage of NASH has not yet been broadly validated. However, there is early evidence that the severity of NAFLD is associated with gut dysbiosis and a shift in the metabolic function of the gut microbiota.
Not outside a research study at this time. But, the future of liver disease management could well include microbiota modulation based on high-quality bench-to-bedside research carried out in the coming years.
This is always a personalized decision. And it is important to weigh carefully the risk-to-benefit ratio of the indication for the DMARDS with the severity of NAFLD/NASH.
In general, seeking the least hepatotoxic agents is recommended, as NAFLD may sensitize the liver to hepatotoxic agents. If/when there is an indication of DMARDS in patients with NASH, modification of the metabolic risk factors associated with fibrosis progression is important together with the need for monitoring liver injury.
The incidence of HCC in non-cirrhotic NASH is very low, so clinically, this is why we do not routinely check for HCC in this patient population. We need to study those patients who develop HCC outside of cirrhosis to learn what predictive factors may be at play.
SGLT-2 inhibitors have received attention due to their unique mechanism of inhibiting glucose reabsorption in the proximal renal tubules and increasing urinary glucose excretion. This type of antihyperglycemic method does not depend on insulin and reduces body weight. Early phase clinical studies have demonstrated an improvement in liver enzymes and liver fat content in patients with NAFLD; however, evidence that SGLT-2 inhibitors improve the histologic features of steatohepatitis and fibrosis is still lacking and there is a need for more data to guide decision-making before advice can be given.
Evidence suggests that GLP-1 secretion is impaired in patients with NAFLD and NASH, highlighting the role of GLP-1 agonists as potential therapeutic candidates. Some early phase studies suggest that GLP-1 agonists may be beneficial (although no drugs are licensed for NAFLD).
In the context of a patient with T2DM, using a GLP-1 to treat diabetes may provide some additional liver benefits. Trials are ongoing and more data is needed before firm advice can be given.
Although NAFLD in nonobese individuals may be caused, on rare occasions, by entities such as medications, infections, celiac disease, hyperlipidemia, obstructive, and genetic disorders, the most common cause is metabolic. After exclusion of other factors which can lead to NAFLD, the biggest risk factors for the development of NAFLD remain generally related to insulin resistance with or without clinical features of impaired fasting glucose, abnormal lipids, increased waist circumference, and abnormal blood pressure.
Patients with NAFLD and NASH and normal BMI may still demonstrate features of metabolic syndrome, but much less frequently than their overweight and obese counterparts. Although patients with NAFLD and NASH and normal BMI are often regarded as metabolically obese, they seem to have some insulin resistance, particularly at the adipose tissue level. It should also be noted that lean individuals are likely to have impaired fat storage mechanisms, lower muscle mass, and increased visceral adiposity. Other risk factors include genetic predispositions such as higher prevalence of PNPLA3, high fructose and cholesterol dietary intake, and alterations in the gut microbiome.
Exercise, independent of weight loss, may improve NAFLD/NASH. Further, dietary modification with avoidance of sugar-sweetened beverages, limiting red-meat intake to once weekly, and decreasing dietary carbohydrates and hydrogenated fat intake may be beneficial. Changing a patient’s diet alone may also help in the treatment of NASH, even in lean patients. Therefore, at the current time, the treatment of lean NASH is essentially no different from the treatment of nonlean NASH. Research is needed to identify specific environmental or genetic triggers that may be the focus of therapeutics in the future.
BMI, body mass index; DMARDS, disease-modifying antirheumatic drugs; GLP-1, Glucagon-like peptide 1; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis, PNPLA3, patatin-like phospholipase domain-containing protein 3; SGLT-2, sodium-glucose co-transporter 2; T2DM, type 2 diabetes mellitus
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