Table 4.

Summarizes research questions, methods used in bile acid assays, and institute, country of first authors.

Study (year)Reference	Study goal/Research question	Method used in bile salt assay	Bile acid sensitivity/Specificity	Institute/University (Country)
Janssen et al (2001)[26]	Investigate the use of serum bile acids in the diagnosis of acute rejection after liver transplantation.	Bile acids were determined using an enzymatic photometrical method.	Serum bile acids had a sensitivity of 86% and specificity of 100%	Universitätsklinikum Essen, Hufelandstr. Essen, (Germany).
El Hady et al (2014)[27]	Assess the impact of occupational exposure to mixture of organic solvents on liver function tests.	Serum bile acids were measured using enzymatic colorimetric determination	The optimal sensitivity of SBA was 83.3% and specificity was 60.2%	Banha Faculty of Medicine, Banha (Egypt)
Lalisang (2012)[28]	Assess SBA as a marker for liver function test as compared to the conventional liver function tests	Automated clinical chemistry analyzer (ACA) TRX 7010 was used to measure serum bile acids.	Not available.	University of Indonesia-Cipto Mangunkusumo Hospital, Jakarta (Indonesia).
Elsendle et al (2011)[29]	Investigate the role of elevated TSBA levels in patients with pruritus of unknown origin (PUO).	Total serum bile acid concentrations were determined using quantitative enzymatic spectralphotometric test according to the manufacturer's instructions (Trinity Biotech, Bray, Ireland).	Not available.	Medical University Innsbruck, Innsbruck (Austria).
Nunes de Paiva and Pereira Bastos de Siqueira, (2005)[30]	Evaluate total SBA in car painters exposed to organic solvents and to compare the levels with classic liver function tests.	An enzymatic method using the Sigma Diagnostic Kit used.	Bile acid showed the highest sensitivity in detecting liver injury (X2, P = .0024).	Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil).
Sombattheera et al (2015)[31]	Determine the feasibility of using the total serum bile acid level as an aid for the diagnosis of cholangiocarcinoma in patients without jaundice.	Total serum bile acids was determined using the Total Bile Acids Assay kit (Diazyme Laboratories, Poway, CA) based on the enzyme cycling method.	The cut-off value of total SBA was determined for the low total bilirubin group of cholangiocarcinoma patients was 6.05 μmol/L with the sensitivity and specificity of 46.7% and 84.4%, respectively.When the total SBA and alkaline phosphatase were combined, the specificity increased to 72.9% compared with total SBA alone (67.4%) or alkaline phosphatase alone (43.5%).	Faculty of Associated Medical Sciences, Faculty of Medicine, Khon Kaen University, Khon Kaen, (Thailand).
Shomai et al (2013)[32]	Assess whether SBA levels are elevated in non-cholestatic chronic liver diseases, and whether they correlate with disease severity	Total SBAs were quantified using the Total Bile Acids Assay Kit (Diazyme Laboratories, CA 92064, USA).	The specificity of the SBA-based model (65%) was only moderately higher thanthe SBAs alone (63%). The SBA-based model had a sensitivity of 93%.	Tel Aviv University, Tel Aviv (Israel)
Woolbright et al (2014)[34]	Determine whether individual bile acid levels could determine outcome in patients with Acetaminophen-induced acute liver failure.	Bile acids were measured using Acquity ultra- performance liquid chromatograph (UPLC) equipped with a Waters Acquity BEH C18.	Not measured.	Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (USA)Department of Medicine, and Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, Arizona (USA)
Chen et al (2013)[35]	Identify possible biomarkers for the clinical grading of intrahepatic cholestasis of pregnancy (ICP) through serum bile acid profiling in women with ICP.	Bile acids were measured using highperformance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS)	Not measured	Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing Medical University, Chongqing, (China).
Collazos (1993)[36]	Determine whether GCA can identify the severity of various noncirrhotic liver diseases.	GCA was measured by radioimmunotherapy assay using a commercially available kit (Abbott Laboratories, North Chicago, Illinois).	The specificity of glycocholic acid was high in the detection of chronic active hepatitis patients at different cut-off levels.	Servicio de Medicina Interna, Hospital de Galdakao, Vizcaya (Spain).
Neghab et al (1997)[37]	Examine the hepatic effects of occupational exposure to 1,1,2-trichloro-1,2,2-trifluoroethane (FC 113) using conventional liver function tests and serum bile acids.). Also gather further data to support or refute the contention that serum bile acid levels could provide a sensitive biological marker of exposure to these solvents.	Bile salts were measured using high performance liquid chromatography.	Not measured	Toxicology Unit, National Institute of Occupational Health and Safety Worksafe Australia, Sydney, NSW, (Australia).
Collazos et al (1993)[38]	Determine the clinical value of measuring the glycocholic acid in patients with benign diffuse liver diseases.	GCA was measured by radioimmunotherapy assay using a commercially available kit (Abbott Laboratories, North Chicago, Illinois).	Not measured	Servicio de Medicina Interna, Hospital de Galdakao, Vizcaya (Spain).
Azer et al (1994)[39]	Determine whether changes in individual SBA levels after engraftment are sensitive, specific and reliable indicators of graft function and whether these changes can antedate other biochemical indicators of hepatic allograft rejection.	Bile acids were measured using high performance liquid chromatography.	The sensitivity and specificity of bile acids were in the range of 95–100%.	University of Sydney, National Institute of Occupational Health & Safety, NSW, Sydney (Australia).
Changbumrung (1990)[40]	Determine the changes in bile acids in patients with cholangiocarcinoma and hepatocellular carcinoma.	Bile acids were measured using high performance liquid chromatography.	Not measured	Faculty of Tropical Medicine, Mahidol University, Bangkok, (Thailand).
Azer et al (1996)[41]	Determine the value of serum bile acids in predicting the course of chronic cholestatic liver diseases (primary biliary cirrhosis, and primary sclerosing cholangitis).	Bile acids were measured using high performance liquid chromatography.	Not measured	University of Sydney, National Institute of Occupational Health & Safety, NSW, Sydney (Australia).
Jurate et al (2017)[42]	Assess the sensitivity and specificity of laboratory tests used for diagnosis of intrahepatic cholestasis of pregnancy including serum bile acids.	Bile acids were determined using gas-liquid chromatography.	Total serum bile acids has a sensitivity of 94% and specificity of 63%; Cholic acid has a sensitivity of 96%, and specificity of 63%; Chenodeoxycholic acid has a sensitivity of 88%, and specificity of 59%.	Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, (Lithuania).
Baumgartner et al (1995)[43]	Determine the usefulness of monitoring serum bile acids and biliary lipids after OLT with respect to early recognition of graft dysfunction.	Bile acids were measured using high performance liquid chromatography.	Bile acids were more sensitive and specific than standard liver function tests.	Department of Surgery, University of Freiburg, (Germany).
Huang et al (2009)[44]	Determine if the bile acid ratio of cholic acid to chenodeoxycholic acid (CA:CDCA) is an important component for diagnosis of intrahepatic cholestasis of pregnancy (ICP).	Bile acids were measured using one commercial laboratory (Quest Diagnostics Nichols Institute, San Juan Capistrano, CA).	The authors used test-positive and test-negative instead of sensitivity and specificity because there is no generally accepted criteria to diagnosis ICP.	Department of Obstetrics and Gynecology, New York University, New York, (The United States).
Trinchet et al (1994)[45]	Assay serum bile acids in patients with alcoholic hepatitis and to assess the relationship between these parameters, the usual liver tests and the histological features of alcoholic hepatitis.	Serum bile acids were measured using high performance liquid chromatography (HPLC).	Not measured	INSERM Unit-21, Villejuif, (France).
Trottier et al (2011)[46]	Compares serum bile acid levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis.	Bile acids were measured using a LC–MS/MS system with an electrospray interface.	Not measured	Laboratory of Molecular Pharmacology, CHUQ Research Center and the Faculty of Pharmacy, Laval University, Québec, (Canada).
Trottier et al. (2011)[47]	Investigates how biliary obstruction and restoration of bile flow interferes with urinary and circulating levels of 17 common bile acids.	Bile acids were measured using a HPLC-MS/MS system with an electrospray interface,	Not measured.	Centre Hospitalier Universitaire de Québec Research Center and the Faculty of Pharmacy, Laval University, Québec, (Canada).
Dasarathy et al (2011)[48]	Determine the changes in serum bile acids in patients with nonalcoholic steatohepatitis (NASH) and possible causes for increased hepatic fatty acid oxidation	Plasma bile acids were quantified in NASH and in controls using liquid chromatography mass spectrometry/mass spectrometry	Not measured	Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio, (The United States).
Tribe et al (2010)[49]	Determine the temporal changes in bile acids in normal pregnancy and in pregnancies complicated with intrahepatic cholestasis of pregnancy and pruritus gravidarum.	Bile acids were determined using an HPLC-MS system with electrospray interface using a novel method that allowed the evaluation of 15 bile acids.	Not determined	Division of Reproduction and Endocrinology, King's College London, London, (The United Kingdom).
Martinefski et al (2012)[50]	Determine better markers, including serum bile acids, in ICP for a precise diagnosis and parameters associated with severity of symptoms.	Bile acids were determined by capillary electrophoresis and were separated using cyclodextrin-modified micellar electrokinetic chromatography.	The highest sensitivity (84%) was achieved by determining LCA level, and the highest specificity (100%) from calculating UDCA/LCA ratio, and the highest accuracy (91.5%) if both LCA and UDCA/LCA were both considered.	Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, (Argentina).
Bathena et al (2015)[52]	Compare the urinary BA profiles between healthy subjects and patients with hepatobiliary diseases.	Urinary bile acids were quantified by LC-MS/MS	Depending on the cutoff value of BA concentration, the % amidation UDCA had a sensitivity in the range of 90%–93%, and specificity in the range of 70%–88%. The total CDCA had a sensitivity in the range of 70%–77% and specificity in the range of 70%–84%. The CA had a sensitivity in the range of 70–77% and specificity in the range of 70%–82%.The % sulfated DCA: sulfated BA had a sensitivity in the range of 70–81% and specificity in the range of 70–83%.	College of Pharmacy, Department of Internal Medicine, College of Medicine University of Nebraska Medical Center, Omaha, Nebraska (The United States)
Nanashima et al (2009)[53]	Clarify the clinical significances of urinary bile acid concentrations in liver diseases in adults.	Urinary bile acids were measured by a commercially available kit “UBASTEC by Marukin Bio, Inc, Kyoto, Japan,” utilizing direct enzymatic assay.	Not determined	Department of Translational Medical Sciences Nagasaki University Graduate School of Biomedical Sciences, 1 Sakamoto, Nagasaki, (Japan)