Heterogeneity of non-alcoholic fatty liver disease: Implications for clinical practice and research activity

Table 1 Non-invasive tests of hepatic fibrosis and potential confounding factors

Biomarker panel	Parameters	Validation	Prognostic ability	Confounding factors/limitations
APRI	AST, platelet	Good	Fair	Large number of individuals fall in the indeterminate range
Fibrosis-4 index	Age, AST, ALT, platelet	Very good	Very good	Poor performance in patients aged ≤ 35 yr
				Low specificity in patients aged ≥ 65 yr
				Less sensitive in South Asian Population
NAFLD fibrosis score	Age, BMI, IFG or diabetes, AST, ALT, platelet, albumin	Very good	Good	Different cutoff values needed for younger or older participants
				Albumin may decrease in chronic illnesses, malnutrition, nephrotic syndrome and protein-losing enteropathy
				Less sensitive in South Asian Population
Enhanced liver fibrosis panel	PIIINP, HA, TIMP1	Good	Very good	PIIINP is increased in other fibrotic diseases or bone fracture
				TIMP1 is increased in cancer and inflammation
				Not as widely available as non-patented scores and more expensive
FibroMeter NAFLD	Age, weight, prothrombin index, ALT, AST, ferritin, fasting glucose	Fair	NA	Prothrombin index affected by anti-coagulants
				Ferritin is an acute phase protein
				Glucose is affected by anti-diabetic treatment
				More validation needed
NIS4	miR-34a-5p, α2-M, YKL-40, and glycated hemoglobin	Fair	NA	Not as widely available as non-patented scores and more expensive
				More validation is needed

ALT: Alanine aminotransferase; APRI: AST-to platelet ratio index; AST: Aspartate aminotransferase; BMI: Body mass index; HA: Hyaluronic acid; IFG: Impaired fasting glucose; α2-M: α2 macroglobulin; NA: Not applicable; NAFLD: Non-alcoholic fatty liver disease; PIIINP: Procollagen type III N-terminal peptide; PTI: Prothrombin index; TIMP-1: Tissue inhibitor of matrix metalloproteinase 1.

Table 2 Liver-targeted therapies in development for the treatment of nonalcoholic fatty liver disease

Treatment targets	Mechanism of action	Agent (oral/injectable)	Current status
Metabolism	FXR agonism	Obeticholic acid	Interim analysis of a phase 3 RCT (REGENERATE) showed significant histological improvement[141]
		Tropifexor (LJN452)	A phase 2 study recently completed (NCT02855164)
		Cilofexor	A phase 2 study in patients with NASH showed a decrease in hepatic fat[142]
	PPAR agonism	Elafibranor	Interim analysis a phase 3 trial (RESOLVE-IT) failed to show any treatment effect
		Lanifibranor (IVA337)	A phase 2 study in patients with T2DM and NAFLD is actively recruiting (NCT03459079)
		Saroglitazar	A phase 2 RCT (EVIDENCES IV) in participants with NAFLD/NASH has shown significant improvement in ALT, LFC, and IR[143]
	Acetyl-CoA Carboxylase inhibition	PF-05221304	Improved liver chemistry and liver fat in an RCT[144]
	GLP-1 agonism	Liraglutide	Only data from small studies have been published and the relative contribution of weight loss and improvement in glycemic control to the observed benefits in NASH are yet to be determined[145-147]
		Semaglutide	In a phase 2 trial, the primary endpoint (resolution of NASH with no worsening in fibrosis), was met[148]
	FGF21 agonism	Pegbelfermin (BMS-986036)	A series of phase 2b trials of pegbelfermin are underway
	MCP2 antagonism	MSDC-0602 K	The EMMINENCE phase 2b trial didn’t meet the primary end point[149]
	THRβ agonism	Resmetirom (MGL-3196)	A phase 3 study is actively recruiting (NCT03900429)
Cell stress and apoptosis	Antioxidant	Vitamin E	Resolution of NASH in some studies, but not all; no impact on fibrosis[150]
	Pan-caspase inhibition	Emricasan	Phase 2b clinical trials for NASH failed to meet their primary efficacy end points[151]
	ASK1 inhibition	Selonsertib	Phase 3 STELLAR trials discontinued due to lack of efficacy
Inflammation	CCR2/CCR5 inhibition	Cenicriviroc	Phase 3 trial AURORA terminated due to lack of efficacy
	Inflammasome inhibition	SGM-1019	A phase 2 study is terminated due to a safety event (NCT03676231)
Fibrosis	LOXL2 inhibition	Simtuzumab	No benefit on histological analysis or on clinical outcomes[152]
Gut–liver signaling axis	FGF19 agonism	Aldafermin (NGM282)	In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement[153]

ACC: Acetyl-CoA carboxylase; ALT: Alanine aminotransferase; ASK1: Apoptosis signal-regulating kinase; CCR: C–C motif chemokine receptor; FGF: Fibroblast growth factor; FXR: Farnesoid X receptor; GLP1: Glucagon-like peptide 1; IR: Insulin resistance; LFC: Liver fat content; LOXL2: Lysyl oxidase homolog 2; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; PPAR: Peroxisome proliferator-activated receptor; THRβ: Thyroid hormone receptor β.