It starts with excess ectopic fat:

Once the liver accumulates small amounts of liver fat, the liver is functionally impaired and insulin resistant. Once more than 5% fat has accumulated, steatosis or fatty liver is present and, in the presence of at least one cardiometabolic risk factor like type 2 diabetes or abdominal obesity, the diagnosis of MASLD is official.

"The excess fat in hepatocytes puts stress on them," says Wajahat Mehal, MD, PhD, DPhil, Director of the Yale Fatty Liver Disease Program. While triglycerides per se are not believed to damage hepatocytes, other lipid intermediates, such as ceramides or diacylglycerol, likely result in the death of liver cells. Cell death results in more inflammation and scarring.

With enough fibrosis, the liver becomes cirrhotic. Hepatocellular carcinoma (HCC) can develop. For most, it's a slow, chronic disease, and it can take up to 35 years to advance from stage F1 to F4. But nearly 20 percent of people with MASH progress rapidly and can reach cirrhosis in just 5 years.

Next Steps to Diagnosis

When evaluating patients for MASLD, liver enzymes alone may not fully reflect underlying disease burden. Many individuals with MASLD have aminotransferase levels within the normal range, and even when elevated, these markers may not capture the presence or progression of fibrosis.

Fibrosis develops gradually and may persist despite improvements in biochemical markers. Increasingly, noninvasive tests (NITs)—including serum-based scores and imaging—are being used to support earlier identification and risk stratification in a more patient-friendly manner.

Step 1: Initial risk assessment

In addition to a comprehensive medical history and physical exam, current guidelines recommend calculating a FIB-4 score as an initial assessment tool in appropriate patients.

"FIB-4 has been shown to help estimate risk not only for liver-related outcomes, but also for cardiovascular disease in patients with metabolic risk factors," says Kenneth Cusi, MD, Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida, in Gainesville, and lead author of the 2025 ADA consensus report on MASLD in type 2 diabetes.

FIB-4 incorporates routinely available laboratory values—including AST, ALT, platelet count, and age—to provide a practical estimate of fibrosis risk. Platelet count, in particular, may reflect changes associated with portal hypertension and evolving liver disease.

While not intended as a standalone diagnostic tool, FIB-4 can be helpful in identifying patients at low risk for advanced fibrosis and guiding next steps in evaluation.

Step 2: Follow-up assessment

For patients with indeterminate or elevated FIB-4 results, additional noninvasive assessment may be considered.

Transient elastography and other imaging modalities can provide further insight into liver stiffness and fibrosis risk. "FIB-4 is a useful initial tool, while elastography offers greater diagnostic precision when available," explains Mehal.

In settings where advanced imaging is not readily accessible, FIB-4 remains a practical and informative first step.

Referral Considerations

If advanced fibrosis or cirrhosis is suspected, referral to a hepatology specialist is appropriate. Collaboration across primary care, endocrinology, gastroenterology, and hepatology can help support optimal patient management.

Patients with cirrhosis or complex presentations may benefit from specialist evaluation, particularly when interpretation of noninvasive tests is uncertain, explains Zobair Younossi, MD, MPH, a gastroenterologist and hepatologist and Chairman of the Global NASH/MASH Council and Professor for Liver Outcomes & Policy Research at Georgetown University School of Medicine, in Washington, DC.

Clinical Guidance

The American Diabetes Association 2025 consensus report and the American Gastroenterological Association 2026 Clinical Care Pathway provide detailed, evidence-based recommendations and algorithms to support screening, risk stratification, and management decisions.