Current status, problems, and perspectives of non-alcoholic fatty liver disease research

Table 1 Biomarkers predicting ≥ F3 fibrosis in Japanese non-alcoholic fatty liver disease patients

Biomarker	Fibrosis stage	Cut-off value	AUC	Ref.
Platelet count	F4	15.3 × 104/μL	0.92	[58]
	F4	16 × 104/μL	0.98	[59]
Hyaluronic acid	≥ F3	42 ng/mL	0.97	[59]
Type 4 collagen 7S	≥ F3	6.0 ng/mL	0.88	[60]
Mac2-binding protein	≥ F3	2.24 μg/mL	0.78	[61]
WFA+Mac2-binding protein	≥ F3	0.83 COI	0.82	[60]
	≥ F3	1.23 COI	0.83	[62]
Autotaxin	≥ F3	1.19 mg/L	0.75	[63]
	F4	1.20 mg/L	0.87

AUC: Area under the receiver operating characteristic curve.

Table 2 Representative indices predicting ≥ F3 fibrosis in non-alcoholic fatty liver disease patients

Score/Index	Formula	Ref.
NAFLD fibrosis score	1.675 + 0.037 × Age + 0.094 × BMI + 1.13 × IFG/DM (with = 1, without = 0) + 0.99 × AST/ALT - 0.013 × PLT - 0.66 × Alb	[64]
APRI	[(AST/upper limit of normal AST)/PLT] × 100	[65]
FIB-4 index	[Age × AST]/[PLT × ALT1/2]	[66]
BARD score	BMI ≥ 28 (1 point)	[67]
	AST/ALT ≥ 0.8 (2 points)
	The presence of DM (1 point)
CA index-fibrosis	1.5 × 4C7S + 0.0264 × AST	[68]
ELF score	2.494 + ln(hyaluronic acid) + ln(P-III-P) + ln(TIMP-1)	[69]

BMI: Body mass index; IFG: Impaired fasting glucose; DM: Diabetes mellitus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PLT: Platelet count; Alb: Albumin; 4C7S: Type 4 collagen 7S; P-III-P: Procollagen type III amino-terminal peptide; TIMP-1: Tissue inhibitor of metalloproteinase-1; NAFLD: Non-alcoholic fatty liver disease.

Table 3 Novel therapeutic agents for non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis under clinical trials

Target	Agent	Action	Clinical trial
Diabetes, insulin resistance	Semaglutide	DPP4 inhibitor	Phase II
	Gliflozin	SGLT2 inhibitor[89]	Pilot
	BMS-986036	Recombinant FGF21[90]	Phase II
Dyslipidemia	Aramchol	SCD inhibitor	Phase II
	GS-0976	ACC inhibitor	Phase II
Nuclear receptor	Obeticholic acid	FXR agonist[84]	Phase III
	Elafibranor	PPARα/δ agonist[85]	Phase III
	MGL-3196	TRβ agonist	Phase II
Apoptosis	Emricasan	Pan-caspase inhibitor[91]	Phase II
Inflammation, fibrosis	Selonsertib	ASK1 inhibitor[87]	Phase III
	Cenicriviroc	CCR2/5 antagonist[88]	Phase III
	JKB-121	TLR4 antagonist	Phase II
	GR-MD-02	Galectin 3 inhibitor[92]	Phase II
	ND-LO2-s0201	HSP47 siRNA[93]	Phase I

Table 4 Dysbiosis in human non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis

Ref.	Patients	Changes in microbiota	Related phenotypic changes
Boursier et al[94]	F0/1 NAFLD 30 (NASH 10), ≥ F2 NAFLD 27 (NASH 25)	Bacteroides↑ in NASH, Ruminococcus↑ in ≥ F2	Not assessed
Da Silva et al[95]	NAFLD 39 (NASH 24, NAFL 15); healthy control 28	Lactobacillus↑, Lactobacillaceae↑, Bacteroidetes↓, Firmicutes↓, Ruminococcus↓, Faecalibacterium prausnitzii↓, Coprococcus↓ in NAFLD compared to control; no differences between NASH and NAFL	Fecal propionate↑, isobutyric acid↑, Serum 2-hydroxy-butyrate↑, L-lactate↑ in NAFLD
Rau et al[96]	NAFLD 32 (NASH 18, NAFL 14); healthy control 27	Fusobacteria↑, Fusobacteriaceae↑ in NASH compared to NAFL and control	Fecal propionate↑, acetate↑, Treg↓ in NASH

NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis.