Research published in The Journal of Clinical Endocrinology & Metabolism further shows the unique opportunity endocrinologists are in to manage nonalcoholic liver disease and its various comorbidities. However, without approved pharmaceutical solutions, endocrinologists will have much to offer in treating these ever-increasing conditions.  

In an October 2022 paper published in The Journal of Clinical Endocrinology & Metabolism, Kenneth Cusi, MD, chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Florida in Gainesville, and his co-authors write that endocrinologists are in a unique position to prevent cirrhosis in patients with fatty liver disease, since endocrinologists already follow patients with higher risk factors for liver disease’s progression – pre-diabetes, type 2 diabetes, and obesity.

The paper, “Approach to the Patient With Nonalcoholic Fatty Liver Disease,” details three clinical cases of patients with nonalcoholic fatty liver disease (NAFLD) and offers an approach for the appropriate management of these patients, including treatment recommendations, from lifestyle modification to pharmacological intervention to bariatric surgery.

The paper appeared in JCEM a couple of months after a commentary Cusi wrote for the journal, in which he describes a test for identifying nonalcoholic steatohepatitis (NASH) and cirrhosis and patients with obesity or diabetes and calls for more patient and clinician awareness. “The central message for the endocrinologist is that this study confirms that the time for screening is now,” Cusi writes.

“We have data that’s unpublished, that shows that people who attend endocrine clinics have twice the rate of people with advanced liver fibrosis and cirrhosis than in primary care,” Cusi says. “Because of that, we have a greater responsibility of identifying them, so they can be co-managed with hepatology and given a formal diagnosis, and some interventions that can be implemented today.”

The First Step in the Right Direction

Let’s start with the test. In his editorial, Cusi points to a study by Qadri, et al, that compared different tests and found that the simple panel FIB-4 covers most of what’s needed as a starting point to identify patients at risk. Cusi notes that the test isn’t perfect – it won’t catch everyone with liver disease; this test is more designed for people with stage F3 and F4, pre-cirrhosis and cirrhosis. Cusi says that many in the general population have F2, so the test would miss those patients. “We want to get people with advanced fibrosis F3s, so they don’t develop cirrhosis,” he says.

Cusi goes on to say that this test is already in electronic medical records and can almost be calculated automatically, so it would behoove an endocrinologist already treating a patient with pre-diabetes or diabetes to calculate that patient’s FIB-4. “I am sure there’ll be a better test developed in the future,” he says. “But at least it’s a first step in the right direction at no cost. The liver doctor will use imaging, will use other commercial tests, to sort out the urgency of care. But remember that, if you do this first step, I guarantee that you’ll find a couple of patients with cirrhosis in your next 10 patients, and that you’ll have had a unique impact in the life of some people with diabetes or obesity.”

“We have data that’s unpublished, that shows that people who attend endocrine clinics have twice the rate of people with advanced liver fibrosis and cirrhosis than in primary care. Because of that, we have a greater responsibility of identifying them, so they can be co-managed with hepatology and given a formal diagnosis, and some interventions that can be implemented today.”

Kenneth Cusi, MD, chief, Division of Endocrinology, Diabetes and Metabolism at the University of Florida, Gainesville, Florida

Rates of liver disease are passing rates of obesity, so the chances of endocrinologists will have more and more chances to have that impact on a patient’s life. Cusi says most might be surprised to hear that about half of overweight people with diabetes have NAFLD, and that maybe 5 or 10% already are having advanced fibrosis. Indeed, more and more experts are implicating diabetes in this spike in liver disease cases. “I like to say [diabetes and liver disease are] like a couple that get the worst out of each other,” Cusi says. “They hate each other. Diabetes is affecting your liver more. And the liver is angrier and more inflamed and makes your diabetes more difficult to control. They feed off each other in the most negative way unfortunately.”

And of course, that “couple’s” fights tend to spill out into other neighborhoods, namely the cardiovascular system. Now we might find the route they take to get there.

Linking Fibrosis and Cardiovascular Mortality

In January, Fernando Bril, MD, an assistant professor in the Division of Endocrinology at University of Alabama at Birmingham, and his co-authors published a paper in JCEM titled, “Differences in HDL-Bound Apolipoproteins in Patients With Advanced Liver Fibrosis Due to Nonalcoholic Fatty Liver Disease,” describing how the researchers assessed HDL-bound proteins in patients with NAFLD with or without advanced fibrosis.

The authors point out that while liver disease is associated with cardiovascular disease, the reason for that association remains unclear. Bril and Cusi studied mainly LDL particles and published a paper in 2016, showing that there were changes in patients with a fatty liver, but these were independent of histology; it was mainly the insulin resistance and the fat accumulation that were driving the changes in the LDL size.

“With that in mind, and because the liver is the one synthesizing many of the proteins in the HDL particle, we thought, ‘Well, if we are looking at proteins in the HDL, we should be looking at whenever the liver synthetic function is already impaired, so that’s advanced fibrosis and cirrhosis’” Bril says. “The recent paper was looking at that: what happens with proteins bound to HDL in patients with or without advanced fibrosis due to NAFLD.”

“Whether there is a causal relationship between liver fibrosis and cardiovascular mortality remains unclear,” Bril continues. “It may be that both are just the consequence of increased insulin resistance and metabolic dysfunction. But if they are indeed related, how do we go from liver fibrosis to cardiovascular mortality? With this question in mind, we thought that as the liver produces many of the proteins in lipoproteins, changes in HDL-bound proteins could be a mechanism that puts those two together.”

For this study, the researchers analyzed data from 185 patients who underwent liver proton magnetic resonance spectroscopy to measure intrahepatic triglyceride accumulation. Those with NAFLD underwent a percutaneous liver biopsy. They found that in cases of advanced fibrosis, there may be differences in the composition of proteins in the HDL, and they hypothesized this may play a role in HDL function.

“When we order a lipid panel, we are measuring HDL cholesterol levels, but we don’t really know exactly how those particles are working,” Bril says. “If the protein composition of the molecules is different, this can affect the function of the HDL particle without affecting the cholesterol levels. We didn’t measure cholesterol efflux in our study (a measure of HDL function), but one could hypothesize that because proteins were found to be different, maybe HDL function was also affected.”

Bril is careful to say that this was only an exploratory study and is nowhere close to being used in a clinical setting. Fatty liver carries an increased risk of cardiovascular mortality, but the exact reason remains elusive. “It may be just the background of metabolic dysfunction that these patients have,” Bril says. “Regardless of causality, that association exists, so healthcare providers need to pay close attention to it, and we need to be aggressive at treating dyslipidemia and all other cardio-metabolic risk factors in these patients. I think that those are the most important messages, because results from our study are far from being applicable in the clinic.”

Beyond Stereotypes

As rates of fatty liver rise, so does the number of treatment options. For Cusi, the name of the game is weight loss by any means, in addition to pharmacological therapy with drugs like thiazolidine and GLP-1s. The GLP-1 receptor agonist semaglutide has been in the news lately as celebrities use it to shed pounds, but more evidence is pointing to the drug’s benefits for the heart and liver. “As the guidelines by the ADA and the Liver Society are coming out, they will make doctors aware that they have a compelling reason, not a cosmetic reason, a compelling reason to prevent cirrhosis,” he says.

“Whether there is a causal relationship between liver fibrosis and cardiovascular mortality remains unclear. It may be that both are just the consequence of increased insulin resistance and metabolic dysfunction. But if they are indeed related, how do we go from liver fibrosis to cardiovascular mortality? With this question in mind, we thought that as the liver produces many of the proteins in lipoproteins, changes in HDL-bound proteins could be a mechanism that puts those two together.”

Fernando Bril, MD, clinical fellow, Division of Endocrinology, University of Alabama at Birmingham, Birmingham, Alabama

Cusi understands there are some patients who may not be as motivated as others to lose weight, but he also has patients who have sincerely tried and find it difficult to lose weight and even more difficult to keep it off. “When you put them on these medications, they drop many, 5, 10, 15%, 20% of their body weight” he says. “There’s clearly something beyond the stereotype that we have of just this kind of negative view of people who have excess weight. We have these tools: structured weight loss programs work, increased physical activity works. Anything that gets you to get into a negative calorie balance will help your liver get healthier, and your cardiovascular disease, and your diabetes, and everything else.”

And again, endocrinologists are primed to help these patients from progressing to cirrhosis and worse, starting with a simple, inexpensive test. Cusi says he hears, “There are no FDA-approved medications, so let’s just wait.” “In the meantime, your family member is drifting into cirrhosis, just because the doctors have not taken the time to do a simple test,” he says. “Preventing cirrhosis, you also prevent liver cancer. What many doctors and patients don’t know is that people with type 2 diabetes have a threefold chance of getting liver adenocarcinomas, what we call hepatocellular carcinomas. So, you are preventing cancer with a screening.”

Bagley is the senior editor of Endocrine News. In the August issue, he wrote about the debut of Endocrinology Mentor Day at ENDO 2023 in Chicago.