Noninvasive biomarkers in non-alcoholic fatty liver disease: Current status and a glimpse of the future

Table 1 Biomarkers for the diagnosis of nonalcoholic steatohepatitis (vs simple steatosis)

Biomarkers	Study description	Results	Ref.
Simple markers	Adults: 97 obese patients undergoing bariatric surgery, 35 had NASH	Algorithm using AST and presence of T2DM, AUC of 0.82 for prediction of NASH	[55]
	Adults: 80 NAFLD; 39 SS, 41 NASH	Score using age, gender, AST, BMI, Hyaluronic acid, AST: ALT ratio. AUROC for NASH of 0.76	[56]
	Adults: 200 patients undergoing bariatric surgery. 64 had NASH	AUROC for NASH: 0.8 using a score composed of Hypertension, Diabetes, AST > 27, ALT > 27, Sleep apnoea, non-black race	[53]
	Adults: 80 NAFLD; 39 SS, 41 NASH	Score using age, gender, AST, BMI, Hyaluronic acid, AST: ALT ratio. AUROC for NASH of 0.76	[56]
Inflammation	Adults: 57 NASH, 17 SS, 10 controls	AUROC NASH with HOMA-IR and Adiponectin/Leptin ratio: 0.82	[32]
	Adults: 26 NASH, 19 SS; 38 obese, 12 controls	TNF-α, IL8, Age, ALT higher in NAFLD; TNF-α predictor	[27]
	Adults: 20 NAFLD, 30 obese	Insulin resistance, ferritin, glutathione peroxidase, higher in NAFLD than obese	[23]
	Adults: 80 NASH, 29 simple steatosis	Lower Adiponectin, higher TNF-α, higher IR in NASH vs controls	[30]
		Lower Adiponectin, higher HOMA-IR in NASH vs SS
	Paediatric: 36 training and 36 validation NAFLD	AUROC for Adiponectin/HOMA-IR as predictors of NASH: 0.79 AUROC for NASH using TNF-α was 0.91, Leptin: 0.8 combined: 0.96	[29]
	Adults: 23 NASH, 21 SS, 18 controls	IL6 and TNF-α, TNFR1 higher in those with NASH vs rest TNF-α, CCL2/MCP-1 higher and Adiponectin lower in NASH	[35]
	Adults: 22 SS, 25 NASH, 30 controls		[28]
	Adults: 28 NAFLD, 33 controls, 30 obese	Resistin linked to NAFLD severity, but not adiponectin, leptin or IR	[33]
	Paediatric: 59 NAFLD	RBP-4 levels inverse relationship with NASH	[57]
Algorithms
NASH test	257 patients (17% NASH) and 383 controls	AUROC 0.79 for NASH. 13 variables: Age, Sex, Weight Height, TG, cholesterol, α2-macroglobulin, ApoA1, Haptoglobin, AST, ALT, γGT, bilirubin	[58]
NASH Diagnostics	Adults: 101 NAFLD, 69 test, (32% NASH) 32 validation	AUROC 0.91 for prediction of NASH. Sensitivity 96%, specificity70% with combination of CK18-M65, CK18-M30, resistin and adiponectin	[44]
NAFIC score	Adult Japanese patients with NAFLD	AUROC for NASH in test group 0.85. AUROC for NASH in validation group 0.78. Variables: Ferritin, fasting insulin, type IV collagen S	[59]
	177 test group (95 NASH), 442 validation group
Nice model	Adults: 454 obese, 310 test, 154 validation	Model: AUROC for prediction of NASH 0.88 in test and 0.83 in validation set Algorithm: CK18-M30, ALT, presence of MS Combination of Insulin resistance, Hypertension and ALT gives sensitivity of 80% and specificity of 89% in prediction of NASH	[60]
HAIR	Adults: 105 obese patients undergoing bariatric surgery, including 26 with NASH		[50]

BMI: Body mass index; AUROC: Area under the curve; NASH: Nonalcoholic steatohepatitis NAFLD: Nonalcoholic fatty liver disease; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; TNF-α: Tumor necrosis factor-α; CK: Cytokeratin; IL: Interleukin; HOMA-IR: Homeostasis model assessment-insulin resistance; TG: Triglycerides.

Table 2 Summarises previous studies investigating serum biomarkers of fibrosis in nonalcoholic fatty liver disease

Biomarkers	Cohort	Results	Ref.
FibroTest®: α2macroglobulin, Apolipoprotein A1, Haptoglobin, γGT, Bilirubin	267 patients	AUROC ≥ F2 0.8, ≥ F3 0.88	[81]
NAFLD Fibrosis score: Age, BMI, Hyperglycaemia, Platelets, Albumin, AST/ALT	733 patients	AUROC ≥ F3 0.88	[16]
	331 patients	AUROC ≥ F3 0.82	[71]
	162 patients	AUROC ≥ F3 0.64	[70]
	91 patients	AUROC ≥ F3 0.89	[80]
	92 patients	AUROC ≥ F3 0.74	[18]
	235 patients	AUROC ≥ F2 0.88	[67]
	138 patients	AUROC ≥ F3 0.68	[69]
	246 patients	AUROC ≥ F2 0.62, ≥ F3 0.75	[82]
	588 patients	AUROC ≥ F3 0.85	[59]
	541 patients	AUROC ≥ F3 0.77	[65]
	145 patients	AUROC ≥ F3 0.81	[66]
BARD:	827 patients	AUROC ≥ F3 0.81	[18]
BMI, AST:ALT ratio, DM	246 patients	AUROC ≥ F2 0.59, ≥ F3 0.64	[82]
	138 patients	AUROC ≥ F3 0.67	[69]
	541 patients	AUROC ≥ F3 0.7	[65]
	145 patients	AUROC ≥ F3 0.77	[66]
ELFTM	192 patients	AUROC ≥ F1 0.76, ≥ F2 0.82, ≥ F3 0.9	[80]
Hyaluronic acid, P3NP, TIMP1	91 patients (plus simple markers)	AUROC ≥ F1 0.84, ≥ F2 0.93, ≥ F3 0.98	[80]
	121 paediatric patients	AUROC ≥ F1 0.92, ≥ F2 0.98, ≥ F3 0.99	[83]
FibroMeterTM:	235 patients	AUROC ≥ F2 0.94, ≥ F3 0.94	[67]
APRI	111 patients	AUROC advanced fibrosis 0.85	[84]
	541 patients	AUROC ≥ F3 0.73	[65]
	145 patients	AUROC ≥ F3 0.67	[66]
	235 patients	AUROC ≥ F3 0.87	[67]
AST:ALT ratio	541 patients	AUROC ≥ F3 0.74	[65]
	145 patients	AUROC ≥ F3 0.83	[66]
BAAT:	93 patients	AUROC ≥ F1 0.86, ≥ F2 0.9	[68]
BMI Age ALT Triglycerides
FIB-4:	541 patients	AUROC ≥ F3 0.8	[65]
Age, AST, platelets, ALT	145 patients	AUROC ≥ F3 0.86	[66]

ELF^TM: European liver fibrosis score; HA: Hyaluronic acid; PIIINP: Procollagen III amino peptide; TIMP: Tissue inhibitor of MMP; BMI: Body mass index; HOMA-IR: Homeostasis model assessment- insulin resistance; PT: Prothrombin time; AUC/AUROC: Area under the curve; F1-F4: Fibrosis score; TE: Transient elastography; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.