Small extracellular vesicles and liver diseases: From diagnosis to therapy

Table 1 Diagnostic small extracellular vesicles markers in relation to liver diseases

Diseases	Types of molecules	Markers	Refs.
HCC	Protein	Aminopeptidase N, Galectin-3-binding protein, SMAD, ANGPT2, 14-3-3 ζ, β-catenin, P120-catenin, EPCAM	[15–21]
	RNA	miR-21, miR-21, -96, miR-122, miR-18a, -221, -222, -224, miR-10b-5p, -215-5p, miR-101, -106b, 12, -195, miR-519d, -595, -939, miR-19b,-92, miR-125, miR-9-3, miR-122, 148a, -1246, miR-122, miR-93, miR 144-3p, -21-5p, miR210, miR-638, miR-665, miR-774, miR-1262, miR-320d, miR-23a/b, miR-45-1a, miR-224, miR-21, -10b, miR-122, -125b, -145, -192, -194, 29a, 17-5p, -106a, miR-26a, -29c, -21, lncRNA Jpx, lncRNA FAL1, lncRNA-RP11-513I15.6, mRNA RAB11A, miR-1262, lncRNA HEIH, lncRNA LINC00161, lnc RNA HULC, AFP mRNA	[22–50]
HBV	miRNA	miR-21-5p	[33]
HCV	RNA	HCV-RNA, miR-122-5p, -222-3p, -146-5p, -150-5p, -30c-5p, -378a-3p, -20a-5p,	[51–53]
NAFLD/NASH	Protein	ITGβ1, CD68	[54,55]
	RNA	miR-192-5p	[56]
	Lipid	ceramides and sphingosin 1-phosphate	[57]
ALD	Protein	ASGR2 and CYP2E1, CD163, 206, ASGPR, CD40L, CK18, Glutathione synthetase	[55,58–62]
	RNA	miR-122, -155, miR-Let-7f, 29a, -340, miR-122, let7f, -21, -29a, -146a, miR-192-5p, miR-192, -30a	[56,63–66]
	Lipid	Sphingosin 1-phosphate	[67]
Cirrhosis	Protein	CD163, 206, PDGFRβ, urinary maltase and glucoamylase (for AKI during cirrhosis)	[59,68–70]
	RNA	miR-19a, -19b, -92, 17a, -20a	[27]
ALI	Protein	Apolipoprotein A-1, Argininosuccinate synthase-1	[62]
	RNA	Gnb21 mRNA,	[71]

HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; ALD: Alcoholic liver disease; ALI: Acute liver injury; RNA: Ribonucleic acid; SMAD: Suppressor of Mothers against Decapentaplegic; ANGPT: Angiopoietin; EPCAM: Epithelial cell adhesion molecule; lnc: Long non-coding; FAL1: Focally amplified lncRNA on chromosome 1; HEIH: High expression in hepatocellular carcinoma; HULC: Highly up-regulated in liver cancer; LINC: Long intergenic noncoding; AFP: α-fetoprotein; ITG: Integrin; CD: Cluster of differentiation; ASGR: Asialoglycoprotein receptor; CYP: Cytochrome P450; ASGPR: Asialoglycoprotein receptor; CK: Cytokeratin; PDGFR: Platelet-derived growth factor; AKI: Acute kidney injury; Gnb: Guanine nucleotide binding protein.

Table 2 Small extracellular vesicles markers in relation to liver pathogenesis

Pathophysiology	Types of molecules	Markers	Refs.
NASH inflammation and fibrosis	miRNA	miR-122, -192	[75]
NASH fibrosis	miRNA	miR-122	[76]
ALD outcome	protein	ASGR2 and CYP2E1	[58]
HBV fibrosis	miRNA	miR-150, -192, -200b, -91a	[77]
HCV treatment response	miRNA	miR-122, -199a, miR-122, miR-122-5p, -222-3p, -146-5p, -150-5p, -30c-5p, -378a-3p, -20a-5p	[53,78,79]
HCV fibrosis	protein	CD81	[80]
	miRNA	Let-7s, miR-122, -150, -192, 200b, 92a, miR-19a	[77,81]
HCC recurrence	protein	SMAD3, CASC9	[16,82]
	RNA	miR-718, miR-125, miR-21, miR-103, miR1247-3p, miR-92b, miR-21 and lncRNA-ATB, miR-21, -10b, miR-215-5p, miR-155, mRNA RAB11A, miR-211-3p, -6826-3p, -1236-3p, 4448	[25,26,36,42,83–90]
HCC survival	RNA	miR-125, miR-21, miR-103, miR-22a-3p, miR-335, miR-25-5p, miR-320a-PBX3, miR-718, miR-210, miR-122, miR-93, miR-21, -96, -122, miR-1247-3p, miR-638, miR-665, miR-21 and lncRNA-ATB, miR-30d, -140, miR-106a, miR-224, miR-320d, long non-coding RNA (ENSG00000258332.1 and LINC00635), hnRNPH1, circPTGR1, circRNA-100, -338, circ DB	[18,23,31,32,34,36,38,41,43,82–86,88,91–99]

NASH: Nonalcoholic steatohepatitis; ALD: Alcoholic liver disease; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; RNA: Ribonucleic acid; ASGR: Asialoglycoprotein receptor; CYP: Cytochrome P450; CD: Cluster of differentiation; SMAD: Suppressor of Mothers against Decapentaplegic; CASC: Cancer Susceptibility; PBX: Pre-B cell leukemia homeobox; lnc: long non-coding; ATB: Activated By TGF-Beta; ENSG: Ensembl Gene ID; LINC: Long intergenic noncoding; RNPH: Ribonucleoprotein H; PTGR: Prostaglandin Reductase; DB: Deubiquitination.