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Sulphated and Unsulphated Bile Acids in Serum, Bile, and Urine of Patients with Cholestasis1

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Sulphated and Unsulphated Bile Acids in Serum, Bile, and Urine of Patients with Cholestasis1 Gut: first published as 10.1136/gut.17.11.861 on 1 November 1976. Downloaded from Gut, 1976, 17, 861-869 Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis1 G. P. VAN BERGE HENEGOUWEN2, K-H. BRANDT, H. EYSSEN, AND G. PARMENTIER From the Department of Internal Medicine, Municipal Hospital, Arnhem, The Netherlands; Rega Institute, Louvain, Belgium SUMMARY Samples of serum, bile, and urine were collected simultaneously from patients with cholestasis of varying aetiology and from patients with cirrhosis; their bile acid composition was determined by gas/liquid chromatography and mass spectrometry In cholestasis, the patterns in all three body fluids differed consistently and strikingly. In serum, cholic acid was the major bile acid and most bile acids (> 93 %) were unsulphated, whereas, in urine, chenodeoxycholic was the major bile acid, and the majority of bile acids (> 60 %) were sulphated. Secondary bile acids were virtually absent in bile, serum, and urine. The total amount ofbile acids excreted for 24 hours correlated highly with the concentration of serum bile acids; in patients with complete obstruction, urinary excretion averaged 71 6 mg/24 h. In cirrhotic patients, serum bile acids were less raised, and chenodeoxy- cholic acid was the predominant acid. In healthy controls, serum bile acids were consistently richer in chenodeoxycholic acid than biliary bile acids, and no bile acids were present in urine. No unusual monohydroxy bile acids were present in patients with primary biliary cirrhosis, but, in several patients, there was a considerable amount of hyocholic acid present in the urinary bile acids. The analyses of individual bile acids in serum and urine did not appear to provide helpful information in http://gut.bmj.com/ the differential diagnosis of cholestasis. Thus, in cholestasis, conjugation of chenodeoxycholic acid with sulphate becomes a major biochemical pathway, urine becomes a major route of bile acid excretion, and abnormal bile acids are formed. In cholestasis the enterohepatic circulation of bile 1972; Stiehl, 1974). Older studies using methods of acids is interrupted and retention of bile acids in the low precision and sensitivity suggested that cholic on September 26, 2021 by guest. Protected copyright. liver occurs with a rise in serum bile acid levels. acid became the major bile acid in biliary obstruc- Renal excretion of bile acids becomes a significant tion (Rudman and Kendall, 1957; Carey, 1958), a route of elimination (Gregg, 1967) and sulphation of finding generally confirmed by more recent studies bile acids seems to play an important role in the rate (Makino et al., 1969; Murphy et al., 1972; Greim et of renal excretion (Palmer, 1967; Admirand et al., al., 1972). More recently, unsaturated monohydroxy bile acids have been detected in urine and serum of cholestatic patients (Makino et al., 1971; Back, 'Part of this work was presented at the Third Bile Acid Meeting, 13-15 June 1974, Freiburg, West Germany, and at 1973). the 76th Annual Meeting of the American Gastroentero- The aim of our study was to define the bile acid logical Association, 17-22 May 1975, San Antonio, Texas, pattern of simultaneously obtained serum, bile, and USA, and published in abstract form (Gastroenterology, 68: urine samples in patients with cholestasis in order to 1005, 1975). gain insight into the changes occurring in bile acid 2Present addresss and for reprints: Nijmegen University metabolism in this condition. We report here such School of Medicine, Department of Internal Medicine, analyses in a well-defined group of patients, as well as Division of Gastroenterology, St. Radboud Hospital, similar analyses in samples from patients with cir- Nijmegen, Netherlands. rhosis and healthy control subjects. After this work Received for publication 28 June 1976 had been completed, analysis of serum and urine bile 861 Gut: first published as 10.1136/gut.17.11.861 on 1 November 1976. Downloaded from 862 G. P. van Berge Henegouwen, K-H. Brandt, H. Eyssen, and G. Parmentier acids in patients with cirrhosis was reported by obtained in the fasting state on the same day that the Stiehl et al. (1975). Makino etal. (1975) alsoreported 24-hour urine collection was done. All patients had a results of bile acid analyses in samples of serum, normal renal function, as assessed by serum crea- urine, and bile of patients with cirrhosis. tinine. During collection urine was stored at 4°C and thereafter at - 20°C. Methods Bile acid analyses PATIENTS Major steps in isolation and preparation of bile acids Thirty-two patients with cholestasis of varying from serum and urine are summarised in Fig. 1. aetiology were studied as well as 18 patients with Bile acids are referred to by their trivial names only; cirrhosis (Table 1) and healthy control subjects. for systematic nomenclature, see Hofmann and Diagnosis was established by liver biopsy. The Mosbach (1964). Since hydrolysis and solvolysis diagnosis of total obstruction of the biliary tract steps were included in the analyses, the data pro- was made before laparotomy and cholangiography vide no information on the degree or mode of con- onthebasisof negative urinary and faecal urobilin ex- jugation. cretion and confirmed at laparotomy. All patients with complete obstructions were in a steady-state Serum and bile Unsulphated bile acids were condition when samples were collected, as repeated analysed as described (van Berge Henegouwen et al., liver function tests-for example, bilirubin, SGOT, SGPT, alkaline phosphatase, 5'-nucleotidase, cholesterol, and protein electrophoresis-revealed Unsulphated Sulphated no significant changes over a two week period. Serum Urine Serum Urine Pruritus was graded on a scale from 1 to 4 by pre- deconjugation extraction extraction extraction defined criteria. (enzyme) (XAD) (ethanol) (XAD) i i Collection ofsamples Extraction Deconjugation Solvolysis Serum samples were collected during the fasting (ethanol) (enzyme) Deconjugation state. In 26 (13 cirrhosis and 13 primary biliary (enzyme) cirrhosis) patients and in 15 control subjects, serum and bile samples were collected simultaneously. Bile /7 http://gut.bmj.com/ rich duodenal fluid was obtained, under standardised Derivatization conditions, five to 15 minutes after cholecystokinin (TFA - Methyl esters) (Cecekin, Vitrum, Stockholm) stimulation using a double lumen Dreiling tube. Samples were stored at GLC on OV 210 200C. Mass spectrometry Urine analyses were carried out on 24-hour collec- on September 26, 2021 by guest. Protected copyright. tions from 23 patients with cholestasis and six Fig. 1 Procedure for analyses of unsulphated (left) normal controls; serum of these patients was or sulphated (right) bile acids. Table 1 Clinical data ofsubjects studied Number Diagnosis Aetiology and pathology Reference for diagnostic criteria 18 Cirrhosis (needle biopsy) Cryptogenic (5) Scheuer (1973) Alcoholic (5) Chronic aggressive hepatitis (3) Post hepatitic (4) Haemochromatosis (1) 19 Primary biliary cirrhosis Stage (needle or wedge biopsy) I (4) Popper and Schaffner (1970) It (5) III (7) IV (3) 13 Complete extrahepatic Carcinoma obstruction (laparotomy) Bile duct (6) Pancreatic (6) Gastric, with invasive growth (1) 15 Healthy controls Gut: first published as 10.1136/gut.17.11.861 on 1 November 1976. Downloaded from Sulphated and unsulphated bile acids in serum, bile, and urine ofpatients with cholestasis 863 1974). In preliminary studies of 10 serum and 10 able (less than 0-2 mg/l) and solvolysis did not in- bile samples, solvolysis (Palmer and Bolt, 1971) was crease the amount of bile acids. added to the isolation procedure in order to detect sulphated bile acids. As these studies indicated that Mass spectrometry As several urine samples of the proportion of bile acids present as sulphates in patients with cholestasis showed unusual peaks, serum and bile was quite low, the solvolysis step was combined gas/liquid chromatography-mass spectro- not included routinely in the analysis of bile acids metric studies were carried out. The identity of litho- in serum or bile. Recovery for conjugated reference cholic acid, 3p-hydroxy-5-cholen-24-oic acid, urso- bile acids was satisfactory (84 5 to 96-3 %), and good deoxycholic acid, and hyocholic acid was confirmed separation between the individual bile acids-cholic using combined gas/liquid chromatography-mass acid, chenodeoxycholic acid, deoxycholic acid, and spectrometry (standards of bile acids tested were lithocholic acid-and the internal standard 7- obtained from Steroloids Inc. (Pawling, NY). For ketodeoxycholic acid was achieved by gas/liquid the identification studies not only bile acid methyl chromatography (GLC) (van Berge Henegouwen et ester acetates, but also trimethylsilyl ether deriva- al., 1974). Determinations ofconjugated serum cholic tives were prepared. They were separated on columns and chenodeoxycholic acid were also performed by packed with 3% OV-1, 3% OV-17,; or 3% Hi-Eff radioimmunoassay (Simmonds et al., 1973; and 8BP. Mass spectrometry was carried out using a Schalm et al., 1975), and the values correlated well combined Pye (Series 104) chromatography-AEI-MS with our GLC method. The correlation coefficient mass spectrometer. Helium was used as carrier gas. of serum cholic acid was 0 99 with a slope of 0-84 As the presence of hyocholic acid in human urine (concentration range 7 0 to 456 0 Mmol/l) and for was unexpected, supplementary work to prove the serum chenodeoxycholic acid 100 with a slope of structure was
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