Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A method is described for the rapid determination of urinary bile salt profiles by fast atom bombardment--mass spectrometry (FAB-MS). Urine was passed through a reverse-phase octadecylsilane bonded silica cartridge and the bile salts eluted with methanol. Negative ion FAB spectra could be obtained from the equivalent of 10 microliter of urine loaded onto the target probe with glycerol as matrix. In samples from normal infants and children bile salt peaks were rarely detectable above the background whereas peaks produced by steroid sulphates and glucuronides and bile alcohol glucuronides could usually be identified. In samples from infants and children with cholestasis the major peaks were produced by the taurine and glycine conjugates of di-, tri- and tetrahydroxycholanoic acids (and their monosulphates). In samples from patients with Zellweger syndrome and infantile Refsum's disease, a unique ion at m/z 572 indicated the presence of taurine-conjugated tetrahydroxy-cholestanoic acid(s). The amide linkage to taurine was cleaved by alkaline hydrolysis but not by cholylglycine hydrolase. Capillary gas chromatography--mass spectrometry (GC-MS) of the bile acids liberated by alkaline hydrolysis indicated the presence of at least two nuclear-tetrahydroxylated cholestanoic acids, probably the 6 alpha- and 1 beta-hydroxylated derivatives of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid.
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PMID:Rapid diagnosis of Zellweger syndrome and infantile Refsum's disease by fast atom bombardment--mass spectrometry of urine bile salts. 243 77

We examined serum bile acids in patients with different peroxisomal disorders. Patients with Zellweger syndrome (n = 23), infantile form of Refsum disease (n = 6) and neonatal adrenoleukodystrophy (n = 4) consistently had increased levels of bile acid precursors. Patients with X-linked adrenoleukodystrophy, (n = 5) classical Refsum disease (n = 3), hyperpipecolic acidaemia (n = 4) and rhizomelic chondrodysplasia punctata (n = 9) did not have increased bile acid precursor levels. Total serum bile acids (41 micrograms ml-1) and the percentage of bile acid precursors (80%) were highest in typical Zellweger patients who died young. Long-living Zellweger patients, neonatal adrenoleukodystrophy patients and infantile Refsum disease patients had, on average, less cholestasis and a lower percentage of bile acid precursors. We also observed that total serum bile acids and the percentage of bile acid precursors decreased with age in long-living Zellweger patients. Screening for bile acid precursors, combined with very long chain fatty acids analysis is, in our experience, an easy and reliable first-line approach to the detection of peroxisomal disorders.
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PMID:Bile acids in peroxisomal disorders. 244 76

This discussion has illustrated the enormous variety found within the category of familial intrahepatic cholestasis. It has also demonstrated how much more there is to learn about these fascinating disorders, which may be examples of experiments in nature on bile formation. This analysis should be recognized to be the author's own, and there is much debate about this classification. For example, some workers in this field contend that North American Indian cholestasis is in reality Byler's syndrome. Such an identity seems unlikely, given the differences between the two syndromes (Table 2). This is a field that is changing rapidly. Recently, a new cholestatic syndrome, bearing some similarities to benign recurrent intrahepatic cholestasis, but dissimilar in several ways, has been reported. There is evidence that cholestasis of pregnancy may be inherited as an autosomal dominant, sex-limited trait. If further studies confirm a genetic etiology, this syndrome would be the most common form of familial intrahepatic cholestasis. The assessment of any individual case remains difficult, particularly early in the course. Table 2 can serve as a guide to the differential diagnosis of these conditions. When faced with a neonate with jaundice, all of the usual causes must be ruled out first. The pattern of bile acids in serum is useful for ruling out Zellweger's syndrome. A good family history and physical examination, particularly of the heart, are important. An ophthalmologic examination by a specialist, often under anesthesia, and a spine radiograph can be useful in confirming a diagnosis of Alagille's syndrome. A liver biopsy, carefully interpreted with input from the clinician, is useful in pointing toward one direction or another. Often a firm conclusion cannot be reached, or is reached prematurely, so the clinician would be advised to inform the parents of all diagnostic possibilities in order to avoid false hopes or unwarranted depression. The diagnostic pitfalls to be avoided in this evaluation are many. No histologic findings are clearly pathognomonic for one syndrome or another. Giant cell transformation and paucity of intrahepatic bile ducts may be found in several syndromes. Biliary atresia, or at least failure to demonstrate a patent biliary tree from the liver to the cystic duct, may be present in patients with Alagille's syndrome. In that syndrome, the eye findings, particularly the posterior embryotoxon, may not be appreciated except on extensive ophthalmologic testing, including gonioscopy. Butterfly vertebrae may not be visible at birth and may be no longer evident in adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Familial intrahepatic cholestatic syndromes. 330 44

A male born to first cousins presented at 12 months with hypocalcemic convulsions, rickets, epistaxis due to vitamin K deficiency, and extremely low serum levels of beta-carotene and vitamin A. Liver function was altered moderately (glutamic-oxaloacetic transaminase, 55 U/L; glutamic-pyruvic transaminase, 37 U/L; lactate dehydrogenase, 255 U/L; alkaline phosphatase, 437 U/L). To correct the deficiencies, 8,000 IU vitamin D/day, 10,000 IU vitamin A/day, and intramuscular administration of vitamin K1 were required. At 9 years, he presented signs of neuromuscular affection, and the serum vitamin E level (measured for the first time) was extremely low. Classic lipid malabsorption syndromes (abetalipoproteinemia, chronic cholestasis, mucoviscidosis, coeliac disease, Whipple's disease) were excluded by appropriate examinations. Composition of duodenal bile acids was characterized by undetectable levels of cholic acid metabolites, and only chenodeoxycholic acid metabolites were present. Serum total bile acid concentration was normal, with an atypical low cholic acid/chenodeoxycholic acid ratio and abnormal presence of 3 beta-OH-delta 5-cholenic acid and 6-OH-bile acids. Urinary bile acid composition was also characterized by elevated 6-OH-bile acids. Known enzymopathies of the bile acid synthetic pathway were excluded (cerebrotendinous xanthomatosis, cerebro-hepato-renal syndrome of Zellweger, coprostanic acidemia). Bile acid pool sizes were determined by using stable isotopes: cholic acid pool size [2.90 (N, 32 +/- 16) microM/kg] and chenodeoxycholic acid pool size [10.8 (N, 32.6 +/- 9.9) microM/kg] were extremely low; fractional turnover rates of both bile acids were in a normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Malabsorption of liposoluble vitamins in a child with bile acid deficiency. 379 31

The Zellweger or cerebro-hepato-renal syndrome (CHRS) is a congenital disorder characterized by cerebral dysfunction, craniofacial dysmorphic features, transient cholestasis and renal cysts. Patients fail to thrive, and usually die in their first year of life. In some cases, a definite diagnosis on purely clinical signs might not be possible. Several biochemical abnormalities have been observed in these patients and some of them have been tested as diagnostic markers. The aim of this study is to evaluate bile acid metabolites as biochemical markers of the CHRS. From a study of 20 CHRS patients, we conclude that screening for the presence of coprostanic acids and the C-29 dicarboxylic bile acid in serum or urine is for detection of CHRS and confirmation of the diagnosis.
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PMID:Bile acid abnormalities and the diagnosis of cerebro-hepato-renal syndrome (Zellweger syndrome). 402 24

A newborn female, the second child of consanguineous parents, exhibited general muscle hypotonia, apathy, hepatomegaly and failure to thrive from birth and signs of craniofacial dysmorphia were present. Pipecolic and trihydroxicoprostanoic acid were excreted in the urine and serum transferrin, ferritin and iron were markedly elevated. At the age of 7 weeks the baby died of respiratory insufficiency. Besides malformations of the brain, renal cysts, liver damage with hypoplastic intrahepatic bile ducts and cholestasis, increased storage of iron and cytochemically proven deficiency of peroxisomes in liver and kidney, morphological studied provided evidence of a mitochondrial myopathy in striated muscle with the accumulation of enlarged bizarre mitochondria, showing only minor structural abnormalities. No defects of NADH-reductase, succinate-dehydrogenase or cytochrome-c-oxidase were demonstrated histochemically. Cytochemical-ultrastructural investigation of mitochondrial ATPase revealed activation of the ATP-synthesising enzyme even before the addition of an uncoupler, this indicating loosely coupled oxidative phosphorylation. In addition a high rate of subcellular autophagy with segregation of mitochondria and focal loss of fibrils was present. Muscle damage in Zellweger syndrome appears to be the consequence of complex, interacting metabolic processes. The mitochondrial myopathy thereby induced allows a better understanding of general muscle hypotonia, one of the leading symptoms of this disorder.
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PMID:Mitochondrial myopathy with loosely coupled oxidative phosphorylation in a case of Zellweger syndrome. A cytochemical-ultrastructural study. 614 41

Two infants with the cerebro-hepato-renal syndrome (Zellweger's disease) exhibited cholestasis and progressive liver damage. Because abnormalities of mitochondrial structure and function have been reported in this condition, we examined the bile acids for evidence of defects in the mitochondrial phase of bile acid synthesis, namely, oxidation of the cholesterol side chain to form C-24 bile acids. The presence of increased amounts of the C-27 bile acid intermediates (trihydroxycoprostanic acid, varanic acid, and dihydroxycoprostanic acid) were noted and identified by gas-liquid chromatography-mass spectrosocopy confirming that a defect in the mitochondrial pathways for bile acid side chain cleavage is involved in this entity. The clinical course, liver histopathology, and hepatocyte ultrastructural abnormalities suggest that these bile acids may reflect an underlying mitochondrial dysfunction in this disease and possibly may contribute to the progressive hepatic lobular fibrosis observed in these patients.
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PMID:Liver in the cerebro-hepato-renal syndrome: defective bile acid synthesis and abnormal mitochondria. 743 36

Peroxisomes or microbodies are peculiar subcellular organelles with an important role in the metabolism of a variety of different organic compounds. Particularly they are an important site of bile acids synthesis. Some hepatic diseases, mainly cholestatic, can to be reconnected at disorders of bile acids synthesis by these organelles. From the biochemical point some diseases present alterations of the cholesterol side chain (Zellweger syndrome, pseudo-Zellweger syndrome, infantile Refsum's disease, neonatal adrenoleukodystrophy), other diseases present errors involving the steroid nucleus (familial giant cell hepatitis). Zellweger disease or cerebro-hepato-renal syndrome is characterized clinically by skeletal changes, muscle hypotonia, renal cysts, psychosomatic retardation and persistent cholestasis and from the ultrastructural standpoint by the virtual absence of liver cell peroxisomes. Pseudo-Zellweger disease shows many of the clinical features of Zellweger disease but differs from this condition on account of the presence of abundant peroxisomes in the liver cells. Infantile Refsum's disease and neonatal adrenoleukodystrophy show typical clinical disorders and liver damage leading to cirrhosis. "Familial giant cell hepatitis" is characterized by jaundice from the first days of life, hepatosplenomegaly, cholestasis, lack of physical malformations. The disorder is due to defective biosynthesis of the bile acids with formation of allo-bile acids.
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PMID:[Liver pathologies due to peroxisome disorders]. 818 91

We treated a girl with Zellweger syndrome using a special infant formula supplemented with middle chain triglyceride (MCT) milk, docosahexaenoic acid (DHA), Lorenzo's oil, and Lunaria oil, which is rich in nervonic acid (C24:1). We examined the fatty acid contents of the plasma and red blood cell (RBC) membrane. Neurological development was evaluated using Denver developmental screening test and auditory brainstem response (ABR). Her delayed neurological development, liver dysfunction, and cholestasis were all improved 2 weeks after starting the dietary treatment. DHA level in RBC membranes was increased and very long chain fatty acid (VLCFA,C26:0) levels were decreased. Our findings suggest that the dietary treatment with combination of MCT milk, DHA, Lorenzo's oil, and Lunaria oil in the patients with Zellweger syndrome bring some benefits for neurological development.
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PMID:Early dietary treatments with Lorenzo's oil and docosahexaenoic acid for neurological development in a case with Zellweger syndrome. 1741 16

Mutations in 12 different PEX genes can cause a generalized peroxisomal biogenesis disorder with clinical phenotypes ranging from Zellweger syndrome to infantile Refsum disease. To identify the specific PEX gene to be sequenced, complementation analysis is first performed in fibroblasts using catalase immunofluorescence. A patient with a relatively mild phenotype of infantile cholestasis, hypotonia and motor delay had elevated plasma very long-chain fatty acids and bile acid precursors, but fibroblast studies revealed normal or only mildly abnormal peroxisomal parameters and mosaic catalase immunofluorescence. This mosaicism persisted even when the incubation temperature was increased from 37 degrees C to 40 degrees C, a maneuver previously shown to abolish mosaicism by exacerbating peroxisomal dysfunction. As mosaicism precludes complementation analysis, a candidate gene approach was employed. After PEX1 sequencing was unrewarding, PEX12 sequencing revealed homozygosity for a novel c.102A>T (p.R34S) missense mutation affecting a partially conserved residue in the N-terminal region important for localization to peroxisomes. Transfection of patient fibroblasts with wild-type PEX12 cDNA confirmed that a PEX12 defect was the basis for the PBD. Homozygosity for c.102A>T was identified in a second patient of similar ethnic origin also presenting with a mild phenotype. PEX12 is a highly probable candidate gene for direct sequencing in the context of a mild clinical phenotype with mosaicism and minimally abnormal peroxisomal parameters in fibroblasts.
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PMID:A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C. 1753 73


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