New Guidelines Emphasize Liver Care in T2D, Obesity

MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.

“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.

“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.

Gastaldelli moderated a session focused on the guidelines at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting. In an interview with Medscape Medical News after the session, Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.

“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.

Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoproteins, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.

The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, the Journal of Hepatology, and Obesity Facts.

A Metabolic Condition

In the EASD meeting session, Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.

“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,'” she said.

According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.

MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.

In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).

The change in the nomenclature has been incremental and regional, Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD,” she said.

Case-Finding and Diagnosis

Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Gastaldelli.

The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.

Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.

Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.

“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia," she said.

“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.” 

The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.

Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Gastaldelli. A Fib-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.

“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Gastadelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.” 

“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.

“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.

Management of MASLD — Lifestyle and Treatment

“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Gastaldelli said.

“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”

She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced. 

If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Gastaldelli.

Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, stated the guidelines.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”

There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.

Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

After the session, Medscape Medical News spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, she added that, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”

These individuals are exactly those amenable to primary care prevention strategies, said Kailayanathan. Due to the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care, she said.

“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs, SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said

“Case-finding and detection of early stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”

Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly and Company, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly and Company, Novo Nordisk, and Pfizer. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.