5 Questions on NAFLD, Type 2 Diabetes, and Obesity

A team of researchers, led by Wanqing Liu, PhD—who is an associate professor of pharmaceutical sciences at the Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences in Detroit, Michigan—set out to determine the association among nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and obesity. Dr Liu answered some questions for us about this research and its implications.

Gastroenterology Consultant: Your team discovered that NAFLD has 2 subtypes, which you attribute to either “nature”—where genetics is the prime mover—or “nurture,” caused by other factors such as metabolic syndrome. Can you explain more about the type of NAFLD that is related to genetics?

Wanqing Liu: The NAFLD subtype related to genetic factors is observed as a unique disease subgroup primarily initiated by these genetic variants. Patients with this type of NAFLD carry one or, more likely, multiple genetic risk alleles, which are so far identified in 6 to 7 genes in our genome.

Our study indicated that this subgroup characterized by NAFLD may also be at increased risk for central obesity as opposed to an overall obesity. These patients are also likely to develop hyperglycemia but not necessarily insulin resistance, which is a hallmark of T2D. We think that this may resemble a late-onset, type 1-like diabetes.

Also, patients with NAFLD and these genetic factors are more likely to have low or normal cholesterol levels. According to other studies, this would lead to a protective effect against cardiovascular disease. Therefore, a patient with the type of NAFLD strongly driven by genetic factors often tends to appear “healthy,” given that they might not have obvious obesity, insulin resistance, or high blood lipids. However, this does not mean that they do not have a liver issue. Actually, some studies suggest that this type of NAFLD may have similar or even more severe liver histology changes compared with NAFLD typically observed in obese and/or T2D populations. Therefore, this type of NAFLD subtype may be underdiagnosed in a regular medical examination until it develops into late stages.

GASTRO CON: How does the “nurture” type of NAFLD differ from that caused primarily by genetics?

WL: In our study, we found that that obesity and/or diabetes promote the development of NAFLD. When genetic risk factors for NAFLD as noted above are also present, obesity and diabetes may accelerate this process. These individuals, while they may already develop general obesity and/or T2D, are also more likely to have increased blood lipid levels and be at higher risk for cardiovascular disease. Our study suggests that these two types of NAFLD should be treated differently given the differences in their cause. For example, for the “nurture”-driven NAFLD subtype, perhaps reducing weight would be the priority to improve the liver function as well as improve overall health.

GASTRO CON: You mentioned that patients with genetically induced NAFLD may actually develop late-onset type 1-like diabetes rather than the typical type 2 diabetes. Is this an important distinction in terms of the type of treatment these patients should receive?

WL: Yes. This is an interesting observation in our study. As I mentioned, we observed in a large human population that patients with NAFLD driven by genetic factors may develop hyperglycemia but not necessarily develop insulin resistance.

This is further demonstrated in our mouse model—that the animals carrying the genetic variant for NAFLD gradually produce less insulin from the pancreas. Obviously, this abnormal glucose metabolism is not developed from a young age, as typically observed in type 1 diabetes. We, therefore, thought this looks more like a late-onset type 1-like diabetes. We are now further validating this observation in clinical populations with diabetes. If confirmed, this means these adults who develop diabetes do not show insulin resistance. These patients may benefit from earlier insulin treatment.

GASTRO CON: How can a practicing gastroenterologist or hepatologist identify these patients who are genetically predisposed to develop NAFLD? Is it possible for patients to be tested for this genetic mutation?

WL: Yes, these patients can be readily identified by genotyping several well-established genetic variants. Even though not all individuals carrying these genetic risk alleles would develop NAFLD, individuals carrying multiple risk alleles are likely at a much higher risk for NAFLD.

Although the chance of carrying multiple risk alleles in one person is relatively low, given the large NAFLD population (~30%-35% of the entire US population), this would be still a considerable number. While the benefit-cost balance is debatable and certainly needs a detailed investigation at the current stage, we should keep in mind that the incidence of NAFLD keeps increasing, while the cost of genotyping is dropping. Identifying these patients at an early stage may lead to better prevention or management of the disease, which is especially important because no drug treatment for NAFLD is available now.

GASTRO CON: Are there clinical signs that physicians should look for when trying to determine the most likely cause for NALFD and, therefore, the best course of treatment?

WL: Unfortunately, there is no convenient biomarker or sign for NAFLD. Clinically, diagnosis of NAFLD still largely relies on imaging (eg, ultrasound), liver function test, and, when necessary, a histologic examination for liver biopsy. Our study indicated that, while people with obesity or T2D should receive regular follow-ups to monitor their liver health, those with central obesity (eg, increased waist-to-hip ratio) and/or high glucose levels should also be monitored, even when they have normal or low lipid levels.

Reference:

Liu Z, Zhang Y, Sarah Graham S, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol. 2020;73(2):263-276. doi: 10.1016/j.jhep.2020.03.006.