Endocrine Targets: Treating Steatotic Liver Disease

Endocrine dysfunction plays a prominent role in the development of steatotic liver disease and was featured prominently with a multi-session program at ENDO 2023. Endocrinologists will be on the front lines to help patients stave off this disorder that will no longer be known as “fatty liver disease,” which is projected to become the leading cause of liver transplants.

Because endocrine dysfunction plays a prominent role in the development of steatotic liver disease, endocrinologists could play a larger role in its prevention and treatment, several specialists tell Endocrine News.

To raise awareness of endocrinologists’ importance for this condition, ENDO 2023 included a session on endocrine targets in steatotic liver disease — and as a reflection of attendees’ interest, the room had to be enlarged to accommodate all those who wished to attend.

In the time since that session was organized, the American Association for the Study of Liver Diseases published in the journal Hepatology an international, multi-society consensus statement delineating new nomenclature for fatty liver disease that aims to be more precise and avoid stigmatizing language.

The statement says “steatotic liver disease was chosen as the overarching term to encompass the various etiologies of steatosis.” The term metabolic dysfunction-associated steatotic liver disease (MASLD) will replace nonalcoholic fatty liver disease, and metabolic dysfunction-associated steatohepatitis (MASH) will replace nonalcoholic steatohepatitis. (See the sidebar for more details on the new nomenclature. To avoid confusion, this article will conform to the new nomenclature.)

Endocrinologists Take the Lead

The impact of MASLD has grown so much with the increase in obesity and diabetes that MASLD is expected to become the leading cause of liver transplants.

“Endocrinologists should take a lead in treating MASLD because the increase in incidence of this disorder is in large part driven by metabolic factors,” says Karen Klahr Miller, MD, the moderator of the ENDO session. Miller is a professor of medicine at Harvard Medical School and chief of the neuroendocrine unit at the Massachusetts General Hospital. “In treating the root causes of MASLD, endocrinologists can have a significant impact on the incidence, prevalence, and morbidity of the disorder. For similar reasons, we should also take a lead in research in this area. We can and should identify metabolic and endocrine therapeutic targets and test potential new treatments for MASLD.”

“In addition to the obvious link with obesity, diabetes, and insulin resistance, many other conditions that we treat as endocrinologists impact MASLD and MASH,” says Laura E. Dichtel, MD, MHS, one of the speakers at the session, who is an assistant professor at Harvard Medical School and the director of Steatotic Liver Disease Research in the Neuroendocrine Unit at Massachusetts General Hospital. “Many of the hormones that we manage as endocrinologists have been implicated in the pathophysiology of MASLD or MASH — including thyroid hormone, cortisol, sex steroid, and growth hormone. Patients with polycystic ovary syndrome and post-menopausal women have been shown to be at higher risk of MASLD and MASH. Endocrine conditions are inherently intertwined in the pathophysiology of the disease and have the potential to impact the early-stage disease development and progression.”

“Too much growth hormone is not a good thing, and it is a hard hormone to manage in a therapeutic range without the negative consequences. But perhaps over the next few years, we will find ways to raise endogenous growth hormone levels or develop drugs that directly target mechanisms downstream of GH receptor signaling to directly treat MASLD.”

Rhonda D. Kineman, PhD, professor, Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago; research career scientist, Jesse Brown VA Medical Center, Chicago, Ill.

Intrigued by the role of these hormones, Dichtel has researched growth hormone’s effects. Some clues to the hormone’s importance are that patients with acromegaly have very high growth hormone levels and low levels of liver fat, whereas, in contrast, patients with hypopituitarism and severe growth hormone deficiency have higher levels of liver fat. Growth hormone levels of patients with obesity can be 25% lower than those of lean individuals.

To explore the role of growth hormone, Dichtel led a team that conducted a six-month, randomized, double-blind, placebo-controlled trial among 53 adults with BMIs greater than 25 and MASLD without diabetes that was published this year in The Journal of Clinical Endocrinology & Metabolism. The test group received daily subcutaneous injections of growth hormone targeted to raise their IGF-1 levels to the upper-quartile of the normal range. The researchers assessed liver fat using proton magnetic resonance spectroscopy before and after the trial and found that the treatment group showed a significant reduction in liver fat. The mean treatment effect between the two groups was a 9% reduction in liver fat with growth hormone, and the treatment group’s relative reduction was 20%. The two groups maintained their weight, so the improvement was not related to weight loss.

“We were able to show that growth hormone administration in this population improved the MASLD phenotype and associated metabolic risk factors. Growth hormone administration reduced liver fat, improved the liver enzyme ALT, reduced visceral adipose tissue, and reduced high-sensitivity C-reactive protein levels. There were no safety issues identified,” Dichtel says.

Mouse Models

Another speaker at the session also related her studies of growth hormone in MASLD. Rhonda D. Kineman, PhD, professor in the Division of Endocrinology, Diabetes, and Metabolism at the University of Illinois at Chicago and research career scientist at the Jesse Brown VA Medical Center, has used mouse models that allow for adult-onset, hepatocyte-specific knockdown of the GH receptor and manipulation of its downstream targets. “These studies show that GH acts directly on the hepatocytes of the liver to control excess fat accumulation, as well as protecting against liver injury due to excess caloric intake. Investigations are ongoing to dissect the mechanisms by which GH has these effects in hopes of unveiling novel targets to treat MASH,” Kineman says.

“Another important aspect of MASLD is that it can often go undiagnosed. Endocrinologists have the ability to screen and identify patients at higher risk for progression who are developing inflammation fibrosis and need to be monitored by our hepatology colleagues. We are truly on the frontlines of recognizing MASLD and treating the co-morbidities that can lead to its progression.”

Laura E. Dichtel, MD, MHS, director, Steatotic Liver Disease Research in the Neuroendocrine Unit, Harvard Medical School; Massachusetts General Hospital, Boston, Mass.

Because GH treatment requires daily injections, frequent monitoring, and is expensive, Kineman doubts that using growth hormone to treat MASLD and MASH is a viable option at this point. “Too much growth hormone is not a good thing, and it is a hard hormone to manage in a therapeutic range without the negative consequences,” she says. “But perhaps over the next few years, we will find ways to raise endogenous growth hormone levels or develop drugs that directly target mechanisms downstream of GH receptor signaling to directly treat MASLD.”

Drugs and Prevention

Such an option would be welcome because there are no Food and Drug Administration-approved drugs to treat MASLD, per se. But there are options among drugs currently in use, primarily for weight loss and diabetes treatment, according to speaker Diana Barb, MD, a clinical associate professor in the Division of Endocrinology, Diabetes, and Metabolism at the University of Florida.

For example, the GLP-1 receptor agonist semaglutide, approved for use in weight loss and type 2 diabetes, has been shown to improve hepatic parameters in patients with MASH. The thiazolinedione pioglitazone improves liver histology in patients with and without type 2 diabetes. Barb notes that currently a leading approach seems to be a combination of drugs that endocrinologists are already using to treat type 2 diabetes and obesity.

“In treating the root causes of MASLD, endocrinologists can have a significant impact on the incidence, prevalence, and morbidity of the disorder. For similar reasons, we should also take a lead in research in this area. We can and should identify metabolic and endocrine therapeutic targets and test potential new treatments for MASLD.”

Karen Klahr Miller, MD, professor of medicine, Harvard Medical School; chief, Neuroendocrine Unit, Massachusetts General Hospital, Boston, Mass.

In addition, bariatric surgery, with its associated weight loss and other benefits, is effective for long-term MASH resolution and fibrosis regression. These approaches are in the armamentarium that endocrinologists are accustomed to using in related conditions.

“It is definitely in endocrinologists’ wheelhouse to address lifestyle modification, diet, exercise, hyperlipidemia, type 2 diabetes, and overweight/obesity,” says Dichtel. “Another important aspect of MASLD is that it can often go undiagnosed. Endocrinologists have the ability to screen and identify patients at higher risk for progression who are developing inflammation fibrosis and need to be monitored by our hepatology colleagues. We are truly on the frontlines of recognizing MASLD and treating the co-morbidities that can lead to its progression.”

Seaborg is a freelance writer based in Charlottesville, Va. In the May issue, he wrote about the ENDO 2023 symposium “Addressing Racial and Ethnic Disparities in Osteoporosis Care.”