As rates of obesity and diabetes increase in the U.S. and worldwide, so too does the prevalence of nonalcoholic fatty liver disease (NAFLD).
NAFLD, recently renamed as metabolic-dysfunction associated steatotic liver disease (MASLD), is the most common form of chronic liver disease in the U.S. “Reports suggest about 20-30% of adults in the U.S. have MASLD, and about 5-10% have the more severe form called metabolic-dysfunction associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH),” Hirsh Trivedi, MD, a liver specialist at Cedars-Sinai Health System in Los Angeles, told MedPage Today.
A 2021 study identified NASH in 14% of asymptomatic middle-age Americans who were undergoing colon cancer screening, among whom 6% had significant liver fibrosis. This represents a twofold increase in the prevalence of clinically significant fibrosis (>stage 2) over what was found in a 2011 prospective study of prevalence.
By 2040, over half of the adult population (55.7%) worldwide is expected to have MASLD, with the largest increases likely to occur in women, smokers, and people without metabolic syndrome, according to a forecast in Clinical and Molecular Hepatology. “Intensified efforts are needed to raise awareness of NAFLD and to determine long-term solutions addressing the driving factors of the disease,” the authors argued.
MASLD occurs in about 75% of people who have obesity and over 90% of people who have morbid obesity (BMI >40), said Jamile Wakim-Fleming, MD, director of the Center for Metabolic Steatosis of the Liver at the Cleveland Clinic. Importantly, MASLD also occurs in about 25% of people of normal weight who have metabolic dysfunction (lean MASLD), Wakim-Fleming added.
A recent review in the Journal of Clinical Medicine noted that major challenges in diagnosing MASLD and MASH include “limited awareness of the disease and its potential implications in patients, a lack of consensus on diagnostic tools, [and] difficulty for patients and physicians in identifying symptoms and establishing their underlying cause.”
MASH is typically asymptomatic and found incidentally during routine blood tests that show mildly elevated liver chemistries or on an ultrasound for evaluation of abdominal pain. Common symptoms, if present, are nonspecific and can include fatigue, insomnia, decreased energy levels, and foggy brain.
“MASLD is commonly caused by metabolic risk factors, but there are also genetic polymorphisms such as PNPLA3 that propagate risk,” Trivedi noted. “Typically, metabolic factors that increase risk of MASLD include insulin resistance or type 2 diabetes, hypercholesterolemia, and elevated body mass index. However, as noted, increasing recognition of ‘lean’ MASLD in those with normal or low BMI suggests etiologic factors outside of obesity play a role,” Trivedi said.
Several noninvasive markers, such as enhanced liver fibrosis, the NAFLD activity score (NAS), and fibrosis-4 index (FIB-4), are used to assess people suspected to be at risk of having MASH. The NAS provides an objective measure of MASH severity based on the components of steatosis (score of 0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2).
The most common imaging studies are shear wave elastography (SWE) or vibration-controlled elastography (VCTE), but others can include ultrasound, MRI, and magnetic resonance elastography (MRE) CT scan, said Wakim-Fleming.
MRI, specifically MRE or MRI-estimated proton density fat fraction, is more accurate to diagnose MASLD and related fibrosis compared with ultrasound, which may miss patients with less than 10% steatosis, said Trivedi. “Newer technologies, like vibration-controlled transient elastography or magnetic resonance elastography, however, are increasingly used given their reliability.”
Ultrasound may be less accurate, picking up only the presence of 30% or more of fat in the liver, noted Wakim-Fleming. “Liver biopsy is indicated when another diagnosis is suspected or when results of two of the non-invasive tests (such as FIB-4 and liver elastography, for example) are not consistent.”
Patients with MASLD are monitored for progression using serial evaluation of liver enzymes in conjunction with VCTE, MRE, or both to determine level of liver fibrosis, which is the true predictor of poor outcomes, said Bubu Banini, MD, PhD, an obesity medicine specialist at Yale School of Medicine in New Haven, Connecticut. “The non-invasive tests for MASH tend to have better performance at either ends of the disease spectrum (i.e., early or severe disease), and are typically not suited for disease evaluation at intermediate stages.” For advanced fibrosis detection, MRE has an area under the receiver operating characteristic curve of 0.89–0.96 compared with liver biopsy, she noted.
The most important risks associated with MASH as it progresses include cirrhosis, liver failure, and hepatocellular carcinoma. In addition to manifestations of end-stage liver disease, MASH progression is also associated with extra-hepatic conditions, including heart disease, kidney disease, and stroke, Banini noted.
With rising prevalence, “the incidence of hepatic decompensation, HCC [hepatocellular carcinoma], and death related to NASH cirrhosis are likewise expected to increase 2- to 3-fold by 2030,” noted the American Association for the Study of Liver Diseases practice guidance on the clinical assessment and management of NAFLD.
The degree of liver scarring or fibrosis is the major determinant of mortality among patients with MASH, with higher morality linked with higher fibrosis, said Banini. “Thus, in addition to routine labs once or twice yearly, patients with MASH typically have liver elastography or other imaging-based assessment of fibrosis every 1-2 years to monitor for disease progression.”
There’s work to be done to reduce the impact of MASLD, the Journal of Clinical Medicine review noted. “Raising awareness and improving understanding of MASLD remains crucial, as MASLD is under-diagnosed/recognized, and standardized and comprehensive models of care are lacking.”
Trivedi disclosed relationships with Novo Nordisk, Sermo, and Guidepoint.
Wakim-Fleming and Banini had no disclosures.