Considerations and clinical utility of referral pathways for early detection of liver disease in at-risk populations

Table 1 Wilson and Jungner criteria for assessing screening eligibility

Wilson and Jungner criteria
Disease	The condition sought should be an important health problem
	The natural history of the condition, including development from latent to declared disease, should be adequately understood
	There should be a recognizable latent or early symptomatic stage
Diagnosis	There should be a suitable test or examination
	The test should be acceptable to the population
	Case-finding should be a continuing process and not a “once and for all” project
Treatment	There should be an agreed policy on whom to treat as patients
	There should be an accepted treatment for patients with recognized disease
Setting	Facilities for diagnosis and treatment should be available
Cost-effectiveness	The cost of case-finding should be economically balanced in relation to possible expenditure on medical care as a whole

Table 2 Summary of guideline recommendations on target population for screening

	Metabolic dysfunction			Elevated ALT	Steatosis
	T2DM	Obesity + ≥ 1 other criteria	≥ 2 criteria
2021 EASL NIT clinical practice guideline	+	+1	+1	+1	-
2021 AGA clinical care pathway	+	+	+	+	+
2023 AASLD practice guidance	+	+1	+1	+2	+
2024 EASL-EASD-EASO clinical practice guideline	+	+	-	+3	+
2025 APASL clinical practice guideline	+	+4	+	+	+

¹Scored yes based on the overarching term “individuals with clinical suspicion of metabolic dysfunction-associated steatotic liver disease such as those with metabolic risk factors” or “at-risk for chronic liver disease (metabolic or alcohol)”.

²Only an indication when it is unexplained.

³Only an indication when it is persistently elevated.

⁴Overweight is also included.

T2DM: Type 2 diabetes mellitus; ALT: Alanine aminotransferase; EASL: European Association for the Study of the Liver; NIT: Non-invasive test; AGA: American Gastroenterological Association; EASD: European Association for the Study of Diabetes; EASO: European Association for the Study of Obesity; APASL: Asian Pacific Association for the Study of Liver; AASLD: American Association for the Study of Liver Diseases.

Table 3 Recommended primary non-invasive tests for screening for liver disease in at-risk populations

	Rule out	Rule in
2021 EASL NIT clinical practice guideline	FIB-4: < 1.3	FIB-4: ≥ 2.67
2021 AGA clinical care pathway	FIB-4: < 1.3 (2.0 aged ≥ 65 years)	FIB-4: ≥ 2.67
2023 AASLD practice guidance	FIB-4: < 1.3 (< 2.0 aged ≥ 65 years)	FIB-4: ≥ 2.67
2024 EASL-EASD-EASO clinical practice guideline	FIB-4: < 1.3 (2.0 aged ≥ 65 years)	FIB-4: ≥ 2.67
2025 APASL clinical practice guideline	FIB-4: 1.3 NFS1	FIB-4: ≥ 2.67 NFS1

¹No cut-offs have been provided in the guideline.

FIB-4: Fibrosis-4; NFS: Nonalcoholic fatty liver disease fibrosis score; EASL: European Association for the Study of the Liver; NIT: Non-invasive test; AGA: American Gastroenterological Association; EASD: European Association for the Study of Diabetes; EASO: European Association for the Study of Obesity; APASL: Asian Pacific Association for the Study of Liver; AASLD: American Association for the Study of Liver Diseases.

Table 4 Recently presented non-invasive tests for liver disease detection

	Components	Target	Derivation population
SAFE	Age, BMI, diabetes, AST, ALT, globulin, platelets	≥ F2 fibrosis	MASLD patients
LRS	Age, sex, fasting glucose, cholesterol, AST, ALT, GGT and platelets	LSM (score correlates with expected LSM)	General population/primary care population
MAF-5	BMI, waist circumference, diabetes AST and platelets	≥ LSM 8 kPa	General population
FIB-9	AST, ALT, GGT, ALP, bilirubin, albumin, platelets, prothrombin index and urea	≥ F2 fibrosis	MASLD patients
LiverPRO	Age, AST, GGT, alkaline phosphatase, total cholesterol, sodium, INR, bilirubin, albumin, platelets	≥ F2 fibrosis	At-risk metALD population
acMASH	AST, creatine	MASH	MASLD patients
CORE	Age, sex, GGT, AST, ALT	Liver related events	General population
CLivD	Age, sex, alcohol use, waist-hip ratio, diabetes, smoking, with or without GGT values	Fatal and non-fatal advanced liver disease	General population

SAFE: Steatosis-associated fibrosis estimator; LRS: Liver risk score; MAF-5: Metabolic dysfunction-associated fibrosis 5; FIB-9: Fibrosis-9; acMASH: Aspartate aminotransferase creatinine metabolic dysfunction-associated steatohepatitis index; CORE: A new risk score measuring gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase; ClivD: Chronic liver disease; BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; ALP: Alkaline phosphatase; INR: International normalized ratio; LSM: Liver stiffness measurement; MASH: Metabolic dysfunction-associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease; metALD: Metabolic and alcohol-associated liver disease.

Table 5 Test characteristics to obtain 80% sensitivity in a general population setting

	Cut-off	Specificity (%)	NPV	PPV
FIB-4	0.73	24	0.93	0.08
SAFE	-7.04	52	0.97	0.12
LRS	4.98	46	0.97	0.11
MAF-5	-0.37	62	0.97	0.15
CORE	0.0018	37	0.96	0.10

FIB-4: Fibrosis-4; SAFE: Steatosis-associated fibrosis estimator; LRS: Liver risk score; MAF-5: Metabolic dysfunction-associated fibrosis 5; CORE: A new risk score measuring gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase; NPV: Negative predictive value; PPV: Positive predictive value. Data was extracted from Van Kleef et al[72]. Citation: Van Kleef LA, Pustjens J, Schattenberg JM, Holleboom AG, Castro Cabezas M, Tushuizen ME, de Knegt RJ, Ikram MA, Janssen HLA, Francque SM, Brouwer WP. Comparison of diagnostic accuracy and utility of non-invasive tests for clinically significant liver disease in a general population with metabolic dysfunction. Hepatology 2025. Copyright ©The Author(s) 2025. Published by American Association for the Study of Liver Diseases, Wolters Kluwer Health.

Table 6 Confirmatory non-invasive tests to diagnose advanced liver disease when the primary non-invasive test is inconclusive

	Rule out	Rule in
2021 EASL NIT clinical practice guideline	LSM: < 8 kPa	LSM: ≥ 8 kPa
	Alternatives: ELF, FibroMeter, Fibrotest	Alternatives: ELF, FibroMeter, Fibrotest
2021 AGA clinical care pathway	LSM: < 8 kPa	LSM: ≥ 12 kPa
	Alternatives: SWE, ultrasound	Alternatives: SWE, ultrasound
2023 AASLD practice guidance	LSM: < 8 kPa	LSM: ≥ 8 kPa
		Alternatives: ELF
2024 EASL-EASD-EASO clinical practice guideline	LSM: < 8 kPa	LSM: ≥ 8 kPa
		Alternatives: MRE, SWE or ELF with adjusted thresholds
2025 APASL clinical practice guideline	Not mentioned	LSM: ≥ 12 kPa, SWE ≥ 8 kPa, MRE ≥ 3.6 kPa, ELF ≥ 9.8, ADAPT ≥ 6.328

EASL: European Association for the Study of the Liver; NIT: Non-invasive test; AGA: American Gastroenterological Association; EASD: European Association for the Study of Diabetes; EASO: European Association for the Study of Obesity; APASL: Asian Pacific Association for the Study of Liver; AASLD: American Association for the Study of Liver Diseases; ELF: Enhanced liver fibrosis; SWE: Shear wave elastography; MRE: Magnetic resonance elastography; ADAPT: Age, diabetes, N-terminal propeptide of type III collagen and platelets panel; LSM: Liver stiffness measurement.

Table 7 Recommended re-evaluation strategies

	Interval	Early re-evaluation	Screening test
2021 EASL NIT clinical practice guideline	1-3 years		FIB-4
2021 AGA clinical care pathway	2-3 years		FIB-4
2023 AASLD practice guidance	2-3 years	After 1-2 years in individuals with T2DM or ≥ 2 metabolic risk factors	FIB-4
2024 EASL-EASD-EASO clinical practice guideline	1-3 years	Within 1 year when FIB-4 was indeterminate and management of comorbidities was intensified, whilst VCTE was not performed	FIB-4
2025 APASL clinical practice guideline	2-3 years		FIB-4, NFS

EASL: European Association for the Study of the Liver; NIT: Non-invasive test; AGA: American Gastroenterological Association; EASD: European Association for the Study of Diabetes; EASO: European Association for the Study of Obesity; APASL: Asian Pacific Association for the Study of Liver; AASLD: American Association for the Study of Liver Diseases; VCTE: Vibration controlled transient elastography; FIB-4: Fibrosis-4; T2DM: Type 2 diabetes mellitus; NFS: Nonalcoholic fatty liver disease fibrosis score.