A combination of noninvasive tests can identify patients with metabolic dysfunction–associated steatohepatitis who have stage F2 or F3 pre-cirrhotic fibrosis, potentially easing the need for liver biopsies, according to a new study.
“We just don’t have enough providers to perform liver biopsies on the more 6 million people in this country with [MASH],” Manal Abdelmalek, MD, the director of NAFLD Clinical Research at Mayo Clinic in Rochester, Minn., told GEN Priority Report. “We’re going to need a sequential or combination testing [approach] with at least two or more noninvasive biomarkers along with additional serum markers to accurately identify the at-risk patient with [MASH] and pre-cirrhotic fibrosis and minimize the misclassification of patients for clinical trials or therapies,” said Dr. Abdelmalek, who was not involved with the study.
Previous work has suggested that noninvasive tests (NITs) could be useful, but the new study is the first to examine them in the context of a clinical trial, according to Rohit Loomba, MD, MHSc, who presented the results at EASL Congress 2023. “It is critical that individual NITs be tested in diverse cohorts, populations and settings to ensure that a clear picture of their performance and limitations is developed,” said Dr. Loomba, a professor of medicine, the chief of the Division of Gastroenterology and Hepatology and the director of the NAFLD Research Center at the University of California, San Diego.
Dr. Loomba and his co-investigators analyzed data from 6,060 patients who were screened for eligibility for the REGENERATE and REVERSE trials, which evaluated obeticholic acid for the treatment of pre-cirrhotic fibrosis in MASH patients. In the new research, they assessed whether the Enhanced Liver Fibrosis (ELF) score, the fibrosis-4 (FIB-4) score and FibroScan (Echosens) results could be combined with laboratory test results—such as direct bilirubin, albumin and platelet count—to identify patients with MASH. They compared findings from the NITs with biopsy-confirmed fibrosis stage.
The combination of FIB-4 with either ELF or FibroScan, in addition to serum markers to rule out cirrhosis, revealed pre-cirrhotic fibrosis in MASH patients with high specificity and high positive predictive value (PPV), although the sensitivity remained low. Nevertheless, the approach identified about one-third of patients who later had biopsy-confirmed F2/F3 fibrosis, and 38% of patients with F3 fibrosis.
Upper bound values of FIB-4 (2.7), FibroScan (18 kPa) and ELF (11.0) excluded up to 56.9% of F4 cases, and missed just 16.6% of F2/F3 cases. When both lower and upper bounds were considered, FIB-4 (1.3-2.7), FibroScan (9.5-18 kPa) and ELF-4 (9.6-11.0) identified approximately half of F3/F4 patients but on their own did not adequately discriminate F2/F3 from F0, F1 and F4. To exclude F4 patients, the researchers identified low platelet levels (<150,000/mcL), high conjugated bilirubin (>0.5 mg/dL) and low albumin (<3.8 g/dL) as the best performers to distinguish F2/F3 from F4.
Ultimately, the best performance at distinguishing F2/F3 and excluding other stages was achieved by combining FIB-4 (1.3-2.7) and either ELF (9.6-11.0) or FibroScan (9.6-18.0 kPa), along with exclusion of low platelets, high conjugated bilirubin or low albumin. This led to a 91% specificity and 89% PPV, with the highest area under the receiver operating characteristic curve (0.75; 95% CI, 0.73-0.76).
Other NIT combinations performed nearly as well, and the researchers called for all of them to be tested against multiple independent data sets to determine the best combination.
Although the performance of the approach wasn’t perfect, Dr. Loomba said positive results could trigger intermediate or indeterminate cases to undergo more accurate and expensive diagnostic workups. “This approach eliminates unnecessary testing for low-risk cases, reduces risks that serious cases might be missed, reduces the healthcare burden and can be cost-effective,” he said.
The new research is the first to examine NITs in the context of a clinical trial. “Previous studies have suggested individual NITs can be extremely useful with high accuracy when used in concert with more accurate but more expensive tests,” Dr. Loomba said. “However,” he stressed that “it is critical that individual NITs be tested in diverse cohorts, populations and settings to ensure that a clear picture of their performance and limitations is developed.”
—Jim Kling
Dr. Abdelmalek reported a financial relationship with Intercept and was an investigator for the REGENERATE and REVERSE trials. Dr. Loomba reported financial relationships with 89bio, Aardvark, Altimmune, Alnylam/Regeneron, Amgen, Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CohBar, Galectin, Galmed, Gilead, Glympse Bio, Hanmi, HighTide, Inipharm, Intercept, Inventiva, Ionis, Janssen, Lilly, LipoNexus, Madrigal, Merck, Metacrine, NGM Bio, Novartis, Novo Nordisk, Pfizer, Sagimet, Sonic Incytes, Terns, Theratechnologies and Viking.
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