Bile acids as drivers and biomarkers of hepatocellular carcinoma

Table 1 Summary data of clinical studies examining the utility of bile acid profiling in the diagnosis and screening for hepatocellular carcinoma

	Ref.	Type of study	Clinical cohort (No.)	Control cohort	Underlying chronic liver disease	No. of subjects (Male)	Samples	Outcome vs control	Outcome vs cirrhosis
1	Wang et al[17], 2016	Retrospective	Cirrhosis without HCC (1082)	NA	HBV	2262 (1710)	Serum	Increased TBA	Increased TBA-> risk factor for HCC
2	Thomas et al[22], 2021	Case-Control	HCC (100)	Healthy Match (age, gender, dialect group)	MAFLD/ Cryptogenetic	200 (150)	Serum	Increased TBA and CPBA	Increased TBA and CPBA -> risk factor for HCC
3	Stepien et al[23], 2020	Case-Control	Cirrhosis without HCC (129)	Healthy Match (age, sex, centre etc.)	Any	258 (176)	Serum	Increased TBA and CPBA -> risk factor vs healthy control	Increased TBA and CPBA
4	Han et al[25], 2019	Cross-Sectional	HCC (30)	Healthy (30) Cirrhosis (30)	HBV	90 (58)	Serum	Serum GCDCA reduced in HCC	Serum GCDCA reduced. GCDCA, CDCA, GCA in HCC tissue are reduced.
5	Sun et al[26], 2020	Cross-Sectional	HCC (16) HCC-T2DM (10)	Healthy (27) T2DM (27)	NAFLD/ Cryptogenetic	80 (50)	Serum	Increased TBA in HCC +/- T2DM vs T2DM and healthy
6	Hsu et al[27], 2017	Case Control	HCC (121)	HBV positive non-cirrhotic	HBV	242 (242)	Serum	Increased TDCA, CA, TC, GC
7	Li et al[28], 2017	Case Control	HCC (14)	Healthy	NA	28	Plasma/ Urine	Urine and Plasma GCA 3-24 times increased in HCC
8	Luo et al[29], 2018	Cross-Sectional	HCC (516)	Cirrhosis Healthy	NA	1448 (1076)	Serum	GCA and Phe-Trp validated for HCC prevention and detection	GCA (increased) and Phe-Trp validated for HCC prevention and detection
9	Ikegami et al[30], 2016	Case Control	HCC (11)	Healthy	NASH	79	Serum	Increased PBA in NASH-HCC vs NASH
10	Ressom et al[35], 2012	Prospective	HCC (78)	Cirrhosis	HCV	262 (165)	Serum		Metabolites of PBA are downregulated in HCC (GCDCA, GCA)
11	Xiao et al[34], 2012	Cross-Sectional	HCC (40)	Cirrhosis	HCV	89 (64)	Serum	GCA, GDCA increased	GCA, GDCA reduced
12	Banales et al[31], 2019	Cross-sectional	PSC (20), CCA (20), HCC (20)	Healthy	NA	80 (55)	Serum	GCA elevated in HCC vs control
13	Patterson et al[38], 2011	Case Control	HCC (30)	Healthy (6), Cirrhosis (7), AML (22)	NA	53 (35)	Plasma	Fetal BAs increased in HCC vs AML
14	El-Mir et al[39], 2001	Cross-sectional	HCC (27)	Cirrhosis (49), Viral Hepatitis (11), Liver Metastasis (19), Healthy (26)	NA	132 (91)	Urine		Increased Delta(4)- and/or allo-bile acids in urine
15	Changbumrung et al[30], 1990	Cross-sectional	CCA (25), HCC (75)	Healthy (21)	NA	121 (121)	Serum	Glyco-BA:Tauro-BA increased in CCA and HCC vs control
16	Stepien et al[33], 2021	Case Control	HCC (233)	Healthy (233)	Any	466 (306)	Plasma	Increased total BAs and TC in HCC vs control

TBA: Total bile acids; CPBA: Conjugated primary bile acids; GCDCA: Glycochenodeoxycholic acid; CDCA: Chenodeoxycholic acid; GCA: Glycocholic acid; TDCA: Taurodeoxycholic acid; CA: Cholic acid; TC: Taurin-conjugated bile acids; GC: Glycin-conjugated bile acids; PBA: Primary bile acids; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; T2DM: Type 2 diabetes mellitus; NASH: Non-alcoholic fatty liver disease; PSC: Primary sclerosing cholangitis; AML: Acute myeloid leukemia: MAFLD: Metabolic associated fatty liver disease; Phe: Phenylalanine; Trp: Tryptophane.