The Interplay of Metabolic Dysfunction and the Liver
It is expected that obesity, diabetes, and metabolic syndrome associated liver disease will soon be the leading cause of liver failure and liver transplants, no longer dominated by excessive alcohol intake nor hepatitis C. In my practice, I screen all patients with diabetes, insulin resistance, and obesity for liver disease through labs, risk assessment scores, and ultimately a fibroscan if I believe a patient may have moderate to advanced liver disease. We are entering an era of advanced understanding of the mechanisms that lead to steatosis, or fatty infiltration of the liver, and steatohepatitis, or steatosis with associated inflammation, as well as increased options for treatment.
An Overview
In recent months, the American Association for the Study of Liver Disease published a study encouraging a change in the nomenclature (name) of liver disease. The changes include
NAFLD (Non-alcoholic fatty liver disease) to be replaced by MASLD, or metabolic-dysfunction associated steatotic liver disease. This is to encompass patients with fatty liver and one of five metabolic risk factors (including diabetes and obesity)
NASH (non-alcoholic steatohepatitis) is to be replaced by MASH, or metabolic dysfunction-associated steatohepatitis
Using the terms MASLD and MASH demonstrates how closely metabolic syndrome, diabetes, and obesity are related to the presence of liver disease. MASLD and MASH start with metabolic dysregulation leading to fatty infiltration of the liver, often associated with weight gain and obesity. This fatty infiltration leads to worsening insulin resistance in the liver, contributing to the pathophysiology of diabetes. To treat MASLD and MASH, we must undue the metabolic dysregulation causing the disease.
Should I Be Screened?
It is estimated that up to 35-45% of American adults have MASLD or MASH, that is more than one in every three! If we consider patients with type 2 diabetes, MASLD may be present in 70% and MASH (meaning inflammation of the liver) in 20%! In my clinic, I currently use a score called FIB-4 Index to screen any patient with obesity, insulin resistance, diabetes, or metabolic syndrome. This score utilizes liver enzyme levels (AST/ALT), platelet count, and age. I sometimes also use the NAFLD score. If the either index suggests an intermediate risk or higher of advanced fibrosis, I send that patient for a fibroscan to better assess the degree of fat deposition in the liver and inflammation.
Are Hormones Involved?
This is an excellent question, as endocrinologists manage disease caused by hormone dysregulation; so for an endocrinologist to lead the charge on screening and management of liver disease, hormones should be central. More evidence is suggesting that altered function or amounts of growth hormone, thyroid hormone, cortisol, and sex steroids (estrogen, testosterone) may play a key role in the development of MASLD/MASH. Additionally, we absolutely know that insulin resistance and fatty liver are intimately related. This is a growing area of study, with multiple studies ongoing. Some of these clinical trials (not yet FDA approved for use in patients) include the treatment of fatty liver with growth hormone and the use of a TSH-receptor beta agonist. Understanding the relationship between the pathogenesis of MASLD/MASH and hormone dysfunction may be the key to unlocking new treatments in the future and is part of the reason this Endocrinologist cares so much about the presence of MASLD/MASH in my patients.
Current Treatments
First and foremost is lifestyle. One of the most effective therapies for fatty liver is at least 7% reduction in body weight, more is better, if the BMI is >=25. Eliminating alcohol and reducing red meat also help with liver health. I recommend a Mediterranean diet for most of my patients. Adding in exercise helps improve insulin resistance and with weight loss as well. These lifestyle measures have been shown to reduce inflammation in biopsy studies (the gold standard) for assessing improvement in liver health.
Multiple medications have shown significant improvement in liver health, though some are only approved currently for the treatment of obesity or diabetes.
Vitamin E 800 IU daily: This has been shown to improve liver health, but can slightly worsen diabetes and should not be used in men with personal or family history of prostate cancer.
Pioglitazone: Primarily used in patients who have diabetes, this has excellent data to support improvement in liver health on biopsy studies, including improvement in inflammation and fibrosis.
GLP-1 Receptor agonists: There is good data for Semaglutide (brand name Ozempic for diabetes, Wegovy for obesity); however, the studies utilized different doses than what is typical used for diabetes or obesity. I believe that these medications improve liver health, we just don’t know if that is through weight loss or independent of weight loss.
SGLT2i: This is an ongoing area of study, though a number of clinical trials have seen improvement in liver enzymes and steatosis markers by imaging (MRI, US). This remains unclear, but I am hopeful data will show this is a great treatment option for patients with MASLD/MASH.
Finally, metabolic or bariatric surgery to achieve significant weight reduction for patients with BMI >30 with comorbidities (such as MASLD/MASH) or BMI >35 is an excellent treatment for liver disease.I always discuss this options with patients who are candidates for surgery.
Future Treatments
The most promising therapy at this time is Resmetirom, a selective TSH-receptor beta agonist; this means it activates the thyroid hormone receptor found in the liver selectively. Four phase 3 clinical studies of Resmetirom have been completed and submitted to the FDA for review as a medication specifically intended to treat MASH/MASLD. It is too soon to tell if this will get approved or when it would be clinical available to patients, but I am watching this closely. There are some other treatments in the pipeline, including treatment through growth hormone receptor or fibroblast growth factor 21 (a drug known as Pegozafermin), but it is too soon to know if these will ever be clinically available. I believe the next decade will bring multiple new, targeted therapy for MASLD/MASH and be in the hands of endocrinologists to prescribe to our patients.
