A 54-year-old woman with type 2 diabetes mellitus (hemoglobin A1c 8.1%), body mass index 34 kg/m2, and hypertension presents for routine follow-up of her cardiometabolic diseases. Should she be screened for advanced liver fibrosis due to metabolic dysfunction–associated steatohepatitis (MASH), and what is the recommended approach to risk stratification?
Patients with type 2 diabetes or obesity with additional cardiometabolic risk factors have a higher risk of developing “at-risk” MASH (liver fibrosis stages F2 or F3), a severe form of metabolic dysfunction–associated steatotic liver disease (MASLD). Identifying these high-risk patients is critical for risk stratification and guiding management strategies that prevent disease progression to liver cirrhosis and other liver-related complications. Screening should follow a stepwise, sequential approach, beginning with calculation of the fibrosis-4 index. This score will determine whether a patient requires continued management of cardiometabolic risk factors in primary care, with periodic fibrosis-4 recalculation, or needs second-step evaluation with vibration-controlled transient elastography to assess fibrosis and a possible referral to hepatology.
DEFINING MASLD AND MASH
MASLD is a chronic liver disease defined as hepatic steatosis in 5% or more of hepatocytes in individuals with at least 1 cardiometabolic risk factor such as type 2 diabetes or obesity with additional cardiometabolic risk factors, minimal alcohol intake (≤ 20 g/day for women and ≤ 30 g/day for men), and no alternate cause of liver disease.1,2 MASLD ranges from metabolic dysfunction–associated steatotic liver, characterized by hepatic steatosis without significant inflammation or fibrosis, to MASH, defined by hepatocellular injury, inflammation, and fibrosis, which can lead to cirrhosis.1
Liver fibrosis is staged on a scale from F0 (none) to F4 (cirrhosis), and the stage is the principal determinant of liver-related outcomes (Figure 1).3–6 When histology or validated noninvasive tests identify patients with fibrosis stages F2 or F3, they are considered to have “at-risk” MASH, which means they are at higher risk of adverse outcomes, including progression to cirrhosis, the most advanced fibrosis stage. Cirrhosis is characterized by architectural distortion and is associated with portal hypertension, hepatic decompensation (eg, ascites, variceal hemorrhage, hepatic encephalopathy), hepatocellular carcinoma, and liver-related mortality.1
Natural progression of metabolic dysfunction–associated steatotic liver disease and clinical outcomes. Fibrosis stages F2 and F3 are considered “at-risk” metabolic dysfunction–associated steatohepatitis (MASH). Patients with metabolic dysfunction–associated steatotic liver (MASL) progress by 1 fibrosis stage approximately every 7 years, but 22% of patients can progress quickly to cirrhosis in 2 years.3,4 Early intervention can prevent fibrosis progression and induce regression.
BURDEN OF MASLD AND RATIONALE FOR EARLY DIAGNOSIS AND MANAGEMENT
MASLD affects nearly a quarter of adults worldwide and is the leading cause of chronic liver disease.2 Among patients with MASLD, up to 14% progress to MASH, and an estimated 20% of patients with MASH develop cirrhosis.2 MASH is now a leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation in the United States.7
MASLD is bidirectionally linked with cardiometabolic disease, mutually accelerating both hepatic and metabolic injury. Diabetes accelerates fibrosis, while MASLD worsens glycemic control and cardiovascular risk through insulin resistance, proinflammatory signaling, and dyslipidemia.8 More than 75% of individuals with obesity and 65% of those with type 2 diabetes have MASLD.9,10 Advanced fibrosis is also common, and often unrecognized, in these patients.
The economic burden is substantial. In the United States, annual MASH-related medical costs may exceed $79 billion by 2040,11 with additional societal costs related to disability, lost productivity, and premature death.12 Despite this, less than 5% of patients with MASLD are aware of their disease,2 while less than 15% with MASH receive a formal diagnosis.13
As MASLD is often clinically silent, systematic screening in primary care can identify patients with at-risk MASH before cirrhosis develops, when intervention is most effective at slowing or halting disease progression and potentially regressing fibrosis. Patient care is based on risk stratification: those with advanced fibrosis require referral to hepatology, while lower-risk patients can be treated in primary care or endocrinology with focused cardiometabolic disease management.
SCREENING FOR ADVANCED LIVER FIBROSIS
The approach to screening for advanced liver fibrosis starts with identifying patients with any one of the following risk factors (Figure 2)1,14:
Stepwise screening approach to identify patients at risk of metabolic dysfunction–associated steatohepatitis (MASH) with advanced liver fibrosis. This algorithm may also be used in cases of incidentally detected steatosis.
aFibrosis-4 calculator is embedded in some electronic medical record systems and is also available online (www.mdcalc.com/calc/2200/fibrosis-4-fib-4-index-liver-fibrosis).
bA higher cutoff (> 2.0) should be used for adults older than 65.
cIf vibration-controlled transient elastography is unavailable, alternate tests include magnetic resonance elastography and the Enhanced Liver Fibrosis test.
Type 2 diabetes (fasting glucose ≥ 126 mg/dL) or prediabetes (fasting glucose 100–125 mg/dL).
Obesity (body mass index ≥ 30 kg/m2 in Western populations or ≥ 25 kg/m2 in Asian populations) with 1 or more of the following additional cardiometabolic risk factors:
Increased waist circumference (≥ 94 cm [37 in] in men and ≥ 80 cm [31.4 in] in women for Western populations, ≥ 90 cm [35.4 in] in men and ≥ 85 cm [33.5 in] in women for Asian individuals)
Dyslipidemia (triglyceride level ≥ 150 mg/dL, high-density lipoprotein cholesterol < 40 mg/dL in men, < 50 mg/dL in women) or on lipid-lowering therapy
Hypertension (blood pressure ≥ 130/85 mm Hg) or on antihypertensive therapy.
Persistently elevated alanine transaminase or aspartate transaminase for 6 months or more (≥ 2 tests done ≥ 4 weeks apart), or incidentally noted hepatic steatosis on imaging, after excluding alternative causes.
Stepwise risk stratification
Once an at-risk patient is identified, stratify the patient’s fibrosis risk with sequential noninvasive tests.
Calculating the fibrosis-4 index is the first step.15 This tool is used to identify patients at risk for advanced liver fibrosis, but does not diagnose hepatic steatosis or advanced fibrosis. It is calculated as fibrosis-4 score = [age (years) × aspartate transaminase (U/L)] ÷ [platelet count (109/L) × √alanine transaminase (U/L)].
A fibrosis-4 score below 1.3 indicates a low risk of advanced fibrosis; these patients may continue cardiometabolic disease management in primary care with repeat fibrosis-4 assessment every 1 to 3 years.15 A score of 1.3 or higher suggests an increased fibrosis risk, and these patients should proceed to secondary evaluation with elastography (see below). For adults older than 65, guidelines recommend using a higher cutoff (> 2.0) to improve specificity.1,14 Patients with a fibrosis-4 score higher than 2.67 are at highest risk of advanced fibrosis and should be referred directly to hepatology.
It is important to note that fibrosis-4 is less reliable in adults younger than 35 and in patients with diabetes.15 For these individuals, vibration-controlled transient elastography may be considered even when the fibrosis-4 score is below 1.3 if clinical suspicion remains high.
Secondary evaluation is warranted for patients with a fibrosis-4 score of 1.3 or higher, and vibration-controlled transient elastography is the preferred modality.14,15 It estimates liver stiffness and can also be used along with the controlled attenuation parameter to quantify hepatic steatosis, though accuracy may be limited in patients with severe obesity (particularly central obesity), inflammation, or ascites.
A liver stiffness measurement less than 8 kPa suggests a low likelihood of advanced fibrosis, and the patient can continue cardiometabolic disease management in primary care.14,15 Patients with a liver stiffness measurement of 8 kPa or greater should be referred to hepatology, while a measurement of 20 kPa or greater highly suggests cirrhosis and requires urgent hepatology evaluation.
If vibration-controlled transient elastography is unavailable or technically limited, another modality may be used based on availability.
Magnetic resonance elastography is as accurate as liver biopsy for fibrosis staging and less operator-dependent than vibration-controlled transient elastography, making it particularly useful for patients with severe obesity or when results from vibration-controlled transient elastography are indeterminate or staging is uncertain. A liver stiffness measurement of 3.63 kPa or greater indicates advanced fibrosis and supports referral to hepatology.15 Magnetic resonance elastography may also be combined with magnetic resonance imaging to assess hepatic fat by using proton density fat fraction, though cost and access limit its use.
Another option is the Enhanced Liver Fibrosis test, a serum biomarker panel that reflects fibrogenesis by measuring markers of matrix turnover: hyaluronic acid, aminoterminal propeptide of type III procollagen, and tissue inhibitor of metalloproteinase 1.2 An Enhanced Liver Fibrosis score below 9.8 indicates a low fibrosis risk, and these patients can continue cardiometabolic disease management in primary care with repeat fibrosis-4 assessment in 1 to 3 years. A score of 9.8 or higher suggests clinically significant fibrosis (≥ F2), and these patients should be referred to hepatology. A score of 11.3 or higher strongly suggests cirrhosis, and these patients should be urgently evaluated by hepatology.15
Clinicians should be aware that liver biopsy is no longer routine, as fibrosis is the key determinant of prognosis and management and can be assessed using the noninvasive tests discussed above. Biopsy should be reserved for discordant or inconclusive results or suspected mixed or alternative liver disease (eg, alcohol-associated liver disease or autoimmune hepatitis overlap), or when histologic confirmation may be needed to guide treatment decisions.
THE BOTTOM LINE
At-risk MASH is common and underrecognized in patients with cardiometabolic disease. A sequential non-invasive screening approach using the fibrosis-4 score followed by vibration-controlled transient elastography, or another available test, enables cost-effective risk stratification, timely referral, and intervention before patients progress to cirrhosis.
DISCLOSURES
Dr. Mauer has disclosed ownership interest (stock in a publicly traded company) in Lilly. Dr. Laique has disclosed consulting for Madrigal and serving as an advisor or review panel participant for Novo Nordisk, Inc. Dr. Naseem reports no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2026 The Cleveland Clinic Foundation. All Rights Reserved.
REFERENCES
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.