Plasma bile acids in patients with peroxisomal dysfunction syndromes: analysis by capillary gas chromatography — mass spectrometry

Abstract

Six patients with disorders of peroxisomal function have been studied. Two presented in the neonatal period with the classical features of the Zellweger syndrome, two had incomplete Zellweger phenotypes, one infantile Refsum's disease and one rhizomelic chondrodysplasia punctata. Plasma bile acid profiles were determined using capillary gas chromatography-mass spectrometry. In all patients, except the case of chondrodysplasia punctata, 27-carbon and 29-carbon bile acids were present. The compounds identified included trihydroxycoprostanic acid (THCA), dihydroxycoprostanic acid (DHCA), C24-, C25- and C26-hydroxylated derivatives of THCA, a 27-carbon acid with four nuclear hydroxy groups and 3 alpha,7 alpha,12 alpha-trihydroxy-27a,27b-dihomo-5 beta-cholestan-26, 27b-dioic acid (C29-dicarboxylic acid). THCA was present at a low concentration in the patient with infantile Refsum's disease; the concentration of DHCA and the C29 dicarboxylic acid were considerably higher. The presence of abnormal bile acids in patients with Zellweger syndrome and infantile Refsum's disease could be explained by the absence of peroxisomes from their hepatocytes. In chondrodysplasia punctata the cause of peroxisomal dysfunction must be different, since normal bile acid synthesis is preserved.

Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor

“…However, much higher levels of these C 27 bile acids are present in the plasma of patients with inherited peroxisome disorders, such as Zellweger syndrome, than the levels of CA and CDCA in normal subjects (37,38), and the concentration of 25-OH-THC [10] in the hepatic microsomes of CTX patients is 20-to 100-fold higher than in control subjects (39). Our findings indicate that these precursors modulate FXR target gene expression more potently or TABLE 1.…”

Familial Giant Cell Hepatitis with Low Bile Acid Concentrations and Increased Urinary Excretion of Specific Bile Alcohols: A New Inborn Error of Bile Acid Synthesis?

“…Materials used for analysis of plasma bile acids by GC-MS (11)(12)(13)(14) and for analysis of urinary cholanoids by FAB-MS (3,14,15) have been described previously. For analysis of urinary bile alcohols by GC-MS, P-glucuronidase/sulfatase from Helix pomatia was obtained from Sigma Chemical Co. Ltd. (Poole, Dorset, UK).…”

“…The dried eluate was reconstituted in toluene/hexane (1:1, vol/vol) and subjected to chromatography on neutral alumina (as used in the purification of bile acid methyl esters). The TMS ethers of the bile alcohols were prepared and analyzed by GC-MS using the same gas chromatography and mass spectrometry settings as used for bile acids (13,14). Urinary bile alcohol profiles from the patient described below were compared with profiles from normal infants, from infants with cholcstatic liver disease of known cause and from three adults with CTX (samples supplied by Dr. B. J. Koopman).…”

Peroxisomal disorders in neurology

“…In 8 of the 10 peroxisomal disorders in which there is neurological involvement, there is an accumulation of VLCFAs which suggests that VLCFA analysis should be used as a primary test rather than analysis of pipecolic acid or phytanic acid, or bile acid intermediates (Clayton et al 1987;Gustafsson et al 1987;Van Elderen et al 1987).…”