Steven Grinspoon, MD, on Targeting Endocrine Pathways in NAFLD


In this podcast, Steven Grinspoon, MD, discusses his session on endocrine pathways and therapeutic options for patients with nonalcoholic fatty liver disease, which he presented at Harvard University’s 21st Annual Symposium on NAFLD.

For more coverage of the symposium, visit our resource center.


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Steven Grinspoon, MD, is a professor of medicine, chief of the Metabolism Unit, and director of the Nutrition Obesity Research Center at Harvard Medical School in Cambridge, Massachusetts. 



Amanda Balbi: Hello everyone, and welcome to another installment of Podcasts360. I’m your moderator, Amanda Balbi with Consultant360 Specialty Network.


On June 30, Harvard University’s Nutrition Obesity Research Center hosted its 21st Annual Symposium on nonalcoholic fatty liver disease (NAFLD): Mechanisms & Therapeutics. Internationally renowned researchers spoke about topics addressing the genetics behind NAFLD, the global and clinical burden of disease, and mechanisms and novel therapeutics.


With us today to discuss his session on “Endocrine Pathways for Treating NAFLD” is Dr Steven Grinspoon, who is a professor of medicine, chief of the Metabolism Unit, and director of the Nutrition Obesity Research Center at Harvard Medical School in Cambridge, Massachusetts.


Thank you so much for speaking with me today, Dr Grinspoon.


To start, can you give us an overview of the endocrine targets for treating NAFLD?


Steven Grinspoon: The most important target, I think, is insulin resistance. NAFLD has been associated with type 2 diabetes. Over 50% of patients with diabetes can have NAFLD, and it's thought that insulin resistance, which is selective such that it's not occurring in the pathway that produces fat—lipogenesis pathway—but it is occurring in the pathways that suppress gluconeogenesis.


That insulin resistance is occurring, and high insulin levels drive lipogenesis in the liver at this regulated situation, so targeting insulin resistance is important. And in that regard, I think the leading candidates are the GLP-1 agonists, liraglutide and others, which can reduce insulin resistance, reduce appetite actually centrally, reduce substrate flux to the liver, at the same time reduce inflammation.


So those are very attractive targets that really go to the core of the primary problem metabolically, which is insulin resistance that comes from overweight and other conditions.


Amanda Balbi: So why and how are these pathways targeted?


Steven Grinspoon: They're targeted to reduce lipogenesis, and that's an important concept. It's a good question.


It starts with the fat in the liver can initiate inflammatory pathways and other processes, which ultimately potentially can lead to fibrosis. So, it's ectopic adipose in the liver, which is thought to be toxic in a way so targeting lipogenesis, or the creation of fat, is very important in that regard.


There are other agents, which target insulin sensitivity, for example metformin, which has not been as successful as the GLP-1 agonists. In diabetics, the GLP-1 agonists are effective to reduce liver fat, to reduce ectopic fat in general, to reduce weight. They're not FDA approved in that regard. But when you treat, type 2 diabetics with those agents, you can get significant benefits on liver fat.


There's also other strategies, which are used, which are not necessarily targeting insulin resistance, but maybe targeting liver fat per se.


Amanda Balbi: Great. Let’s talk more about the treatment options. What are the current options available to treat NAFLD via endocrine pathways, and what therapeutics are on the horizon?


Steven Grinspoon: Great. Well, probably the most important treatment is weight loss per se and lifestyle, even before one considers a GLP-1 agonist. And that's really the cornerstone of treatment of diabetes, as well as in nondiabetics weight loss can improve insulin resistance.


Weight loss is a cornerstone. Of course, it's not easily achieved in all people, but it is important. There could be significant reductions in liver fat over time with consistent weight loss.


Beyond weight loss and insulin sensitizers, there are a few options that are on the horizon, which have been tested. One very interesting option is a thyroid hormone β analog. And this is an interesting option because the β receptors for the thyroid action are primarily in the liver and not on the heart and other organs, which can lead to sympathomimetic effects of thyroid hormones.


So when thyroid hormone is given, it acts on the thyroid hormone β receptor in the liver. It can actually reduce lipid production or lipogenesis and lipid levels in general. We know from medical school that hyperthyroid patients have high lipid levels and when you treat they come down. Indeed there's a whole series of studies now looking at the thyroid hormone β agonist to improve lipid levels and to improve lipid levels circulating and also lipid levels in the liver and lipogenesis.


There was a very interesting trial recently in this regard, which showed very significant changes in liver fat, as well as significant effects on inflammation in the liver and some potential effects on fibrosis. So that's a very interesting set of agents that's on the horizon. And there's now a phase 3 trial in that regard.


Another interesting potential treatment strategy is to activate the growth hormone axis. It's well known that in overweight patients, there's a relative reduction of growth hormone secretion. That's also true in patients who have abdominal capacity, which is very common.


Our group has shown that when you activate the growth hormone axis using a hypothalamic peptide, a GH analog, you physiologically activated, causing the positive growth hormone secretion, which is missing in obesity. The peak height of the pulses is off in obesity, and when you activate that axis, you can make a significant reductions in liver fat.


Growth hormone is known to reduce lipogenesis. It's well known. So when you augment it, you reduce lipogenesis, and that's probably the reason why giving growth hormone leads to reduced lower fat.


Another possibility is that the growth hormone increases hepatic oxidation or literally burns fat in the liver. These growth hormones are very potent in that regard. So by those 2 effects, it may work. We've shown—in a recent study in a lipodystrophic model—significant reductions in liver fat; 37% relative reduction in liver fat, which is quite significant. And importantly, a prevention of fibrosis progression in patients receiving that therapeutic.


So, that I think is a very interesting potential treatment strategy on the horizon targeting the low growth hormone and in obese patients to reduce liver fat.


Amanda Balbi: So this really sounds like a multidisciplinary approach to managing NAFLD.


Steven Grinspoon: Yeah, it really is. It's a great question. These patients are obviously seen by gastroenterologists, but the fascinating thing here is that a number of the strategies come into the realm of nutrition nutritionists, internists, endocrinologists, etc.


And there are even cardiovascular complications of NAFLD, which we haven't talked about. In fact, the leading complication of NAFLD in its early stages is cardiovascular disease. Now as it progresses through increased stages of fibrosis, hepatocellular cancer among other things, cirrhosis can occur, but in the early stages, its associated with a number of metabolic problems, which can be associated with cardiovascular disease.


So, not only do you need some lifestyle intervention, you may need an endocrinologist if you have type 2 diabetes. You may need a cardiologist if you have associated cardiovascular disease. And, of course, you need the gastroenterologist to quarterback the team. So, it is a multifaceted approach to these patients.


There are other approaches as well, which are not in the realm of endocrine but they’re experimental approaches now, in which link the microbiome to NAFLD. That was a topic of one of our talks in our symposium. There are certain bacterial species, which are higher prevalence among patients with NAFLD.


There are experimental models in mice that by manipulating those levels of bacteria to specific phage viruses, you can actually improve NAFLD. Very, very exciting set of experiments. It's in the future; it hasn't been really done in humans yet, but it's potentially quite interesting.


Amanda Balbi: Yeah, definitely. A lot of things have come to light that are connected with the microbiome, so definitely interested in seeing the results of that study in NAFLD patients, too. So what would you say are the overall key take-home points from the symposium as a whole and for your session specifically?


Steven Grinspoon: The larger take home points from this symposium were that the global burden of NAFLD and NASH is increasing significantly. As hepatitis C is decreasing, NAFLD is becoming the primary reason for liver transplants and that global burden is increasing.


It’s associated with the global burden of obesity and type 2 diabetes, and they all travel together. So one major point is that this is a disease that’s occurring in probably a quarter of all people around the world, even higher among type 2 diabetics. So number one take home message, it's a major problem.


Number two: We need to recognize and understand its long-term complications. And I think if we do that, we can try to treat it early through lifestyle and other disease modulations.


Number three is that work should continue on experimental therapeutics. In the case that lifestyle and diet are not working, we're going to need drugs and pharmacotherapeutics to improve this.


I think the major message that was from the symposium in my talk, and others, was that it's best to target a physiological pathway that's gone awry, rather than introduce something that's not really related to the underlying pathology. In that case, because insulin resistance is so common, its continued targeting is reasonable. Growth hormone levels are low, it makes sense to increase them. Thyroid hormone can decrease lipogenesis and make sense to give it, etc etc.


So I think the message is look at the pathways that are perturbed and try to create therapeutics around those pathways, which are specific and effective and safe. That's really, really important. The FDA has a very high bar for ultimately approving such strategies. They have to be effective, to reduce not only the fat but the inflammation, and they have to be safe.


All the participants in the symposium really took that message away from the symposium, and I think it's really important.


Amanda Balbi: Absolutely. Thank you again for speaking with me today about your session.


Steven Grinspoon: Thanks, Amanda. It's been a pleasure.

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