bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of the liver in metabolic homeostasis: Implications for inborn errors of metabolism
Authors: van den Berghe G. 
Published: June 2005

SummaryThe mechanisms by which the liver maintains a constant supply of oxidizable substrates, which provide energy to the body as a whole, are reviewed. During feeding, the liver builds up energy stores in the form of glycogen and triglyceride, the latter being exported to adipose tissue. During fasting, it releases glucose and ketone bodies. Glucose is formed by degradation of glycogen and by gluconeogenesis from gluconeogenic amino acids provided by muscle. Ketone bodies are produced from fatty acids, released by adipose tissue, and from ketogenic amino acids. The major signals which control the transition between the fed and the fasted state are glucose, insulin and glucagon. These influence directly or indirectly the enzymes which regulate liver carbohydrate and fatty acid metabolism and thereby orient metabolic fluxes towards either energy storage or substrate release. In the fed state, the liver utilizes the energy generated by glucose oxidation to synthesize triglycerides. In the fasted state it utilizes that produced byβ‐oxidation of fatty acids to synthesize glucose. The mechanisms whereby a number of inborn errors of glycogen metabolism, of gluconeogenesis and of ketogenesis cause hypoglycaemia are also briefly overviewed.
Detoxification pathways in the liver
Authors: Grant D. M. 
Published: June 2005

SummaryThe liver plays an important rôle in protecting the organism from potentially toxic chemical insults through its capacity to convert lipophiles into more water‐soluble metabolites which can be efficiently eliminated from the body via the urine. This protective ability of the liver stems from the expression of a wide variety of xenobiotic biotransforming enzymes whose common underlying feature is their ability to catalyse the oxidation, reduction and hydrolysis (Phase I) and/or conjugation (Phase II) of functional groups on drug and chemical molecules. The broad substrate specificity, isoenzyme multiplicity and inducibility of many of these enzyme systems make them particularly well adapted to handling the vast array of different chemical structures in the environment to which we are exposed daily. However, some chemicals may also be converted to more toxic metabolites by certain of these enzymes, implying that variations in the latter may be important predisposing factors for toxicity. Pharmacogenetic defects of xenobiotic biotransformation enzymes, a subclass of inborn errors of metabolism which are manifested only upon drug challenge, introduce marked variation into human populations for the pharmacokinetics and pharmacodynamics of therapeutic and toxic agents, and thus may have important clinical consequences for drug efficacy and toxicity.
Inborn errors of bile acid metabolism
Authors: Clayton P. T. 
Published: June 2005

SummaryCholesterol is converted to cholic acid and chenodeoxycholic acid by a series of reactions involving modifications to the steroid nucleus and oxidation of the side chain. These reactions can be affected by a number of inborn errors of metabolism. When this happens unusual bile acids or bile alcohols are synthesized; these can be identified using gas chromatography‐mass spectrometry and fast atom bombardment mass spectrometry techniques. Two defects affecting the modifications to the steroid nucleus have been described; both present with cholestatic liver disease of neonatal onset. The better characterized of the two — 3β‐hydroxy‐Δ5‐C27‐steroid dehydrogenase deficiency — leads to excretion of 3β‐7α‐dihydroxy‐5‐cholenoic acid and 3β,7α,12α‐trihydroxy‐5‐cholenoic acid in the urine. The liver disease improves dramatically on treatment with chenodeoxycholic acid. Deficient activity of 3‐oxo‐Δ4‐steroid 5β‐reductase is thought to be the cause of familial liver disease in some infants who excrete 7α‐hydroxy‐3‐oxo‐4‐cholenoic acid and 7α,12α‐dihydroxy‐3‐oxo‐4‐cholenoic acid in the urine. However, diagnosis of this disorder is problematical; a similar pattern of metabolite excretion can occur as a result of liver damage caused by viruses or inborn errors of pathways unrelated to bile acid synthesis. Defective side chain oxidation in patients with cerebrotendinous xanthomatosis (CTX) leads to synthesis of bile alcohols such as 5β‐cholestane‐3α,7α,12α,25‐tetrol and 5β‐cholestane‐3α,7α,12α,23,25‐pentol. Patients with CTX do not have cholestatic liver disease. Their major problems (neurological disease, atherosclerosis and xanthomata) are caused by accumulation of cholestanol and cholesterol in the tissues. Bile acid precursors are probably diverted into synthesis of cholestanol. Chenodeoxycholic acid suppresses the production of abnormal metabolites from cholesterol (by inhibition of cholesterol 7α‐hydroxylase) and leads to improvement in the neurological disease. Defective side chain oxidation also occurs in peroxisomal disorders but this time it leads to accumulation of C27 bile acids such as 3α,7α,12α‐trihydroxy‐5β‐cholestanoic acid (trihydroxycoprostanic acid, THCA). This compound is readily detected in the bile and plasma of patients with defects of peroxisome biogenesis. In patients with defects of a single peroxisomalβ‐oxidation enzyme (the 3‐hydroxyacyl‐CoA component of the bifunctional protein or the thiolase), the major C27 bile acid in bile may be 3α,7α,12α,24‐tetrahydroxy‐5β‐cholestanoic acid (varanic acid). In addition to the above inborn errors, others which are less well characterized undoubtedly exist, as do defects of bile acid transport across membranes.
Clinical presentation of metabolic liver disease
Authors: Odievre M. 
Published: June 2005

SummarySome clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories:

Manifestations due to hepatocellular necrosis, acute or subacute, which can reveal galactosaemia, hereditary fructose intolerance, tyrosinaemia type I, Wilson disease andα1‐antitrypsin deficiency. Symptoms and signs suggestive of Reye syndrome should lead to a study of fatty acid oxidation and urea cycle enzymes. All these manifestations may necessitate a rapid diagnosis and treatment when liver dysfunction is severe.

Cholestatic jaundice can revealα1‐antitrypsin deficiency, Byler's disease, cystic fibrosis, Niemann‐Pick disease and some disorders of peroxisome biogenesis.

Hepatomegaly can reveal disorders with liver damage but also storage diseases such as glycogen storage diseases, cholesteryl ester storage disease and, when associated with splenomegaly, lysosomal storage diseases.
Appropriate investigations for recognizing all these entities are proposed.
Investigation of paediatric liver disease
Authors: Kelly D. , Green A. 
Published: June 2005

SummaryThe investigation of children with liver disease falls into two categories: the investigation of the cholestatic baby and the investigation of the older child (over 2 years) with hepatomegaly. The approach to investigation is directed by the clinical features and employs many different investigational methods including biochemistry, haematology, radiology, electrophysiology and histology. As the clinical presentation of many diseases is similar, it is appropriate to perform a variety of first‐line tests, proceeding to more complex investigations only as indicated.
The role of histochemical investigations in metabolic disorders affecting the liver
Authors: Lake B. D. 
Published: June 2005

SummaryThe application of histochemical techniques to the study of metabolic disorders affecting the liver can yield considerable information, provided the methods used are sound and the interpretation is not over‐enthusiastic. The appropriate methods can give insight into liver function and can identify and localize a wide variety of carbohydrates, lipids, proteins and enzyme activities. It is often thought that tissue taken for histochemical analysis cannot be used for morphology, but properly prepared tissue will provide the architectural and cytological detail necessary for histological assessment. There are several advantages to the histochemical approach, the main ones being economy of use of the valuable tissue sample (in theory about 100 sections and tests can be done on a 1 mm depth of tissue) and that the results of the tests can be assessed in relation to the structure of the liver.There are two areas in which histochemical investigations are used: firstly, to detect cellular constituents, structures and cells not otherwise visible by routine methods. In this mode, histochemistry is an extension of the histological approach and constitutes a ‘super haematoxylin and eosin’ stain. Secondly, it is possible to assess enzyme activities and their localization, and in some well‐defined instances to offer reliable indications of whether there is deficient activity, normal activity or enhanced activity.Although there is a body of opinion which believes that quantitative enzyme histochemistry is possible and reliable, the author has not found the data, in particular on lysosomal enzymes, to be reliable and remains unconvinced that this technique has a place in the study of pathological tissue.This review outlines a simple approach to the study of metabolic liver disease and illustrates the findings in a range of disorders of glycogen and lipid metabolism.
Niemann‐Pick disease type C: An update
Authors: Vanier M. T. , Pentchev P. , Rodriguez‐Lafrasse C. , Rousson R. 
Published: June 2005

SummaryThe concept of Niemann‐Pick disease type C as a secondary sphingomyelin storage disorder (in contrast to the sphingomyelinase‐deficient types A and B) has become more and more prevalent, in view of the complex lipid storage pattern and variable sphingomyelinase activities. Although the primary lesion is still unknown, studies conducted over the past six years have led to a breakthrough by showing that this disorder is characterized by unique abnormalities of intracellular translocation of exogenous cholesterol. In cultured fibroblasts of patients, this block leads to a delayed induction of the homeostatic responses to exogenous cholesterol, in particular cholesteryl ester formation, and to the accumulation of unesterified cholesterol in a vesicular, essentially lysosomal, compartment. The transport of endogenous cholesterol is apparently unaffected. The spectrum of phenotypic heterogeneity in relation to abnormal LDL‐processing has been defined in a large patient population. Clinical presentation of the disease is also reviewed and biochemical correlations are discussed. This discovery has had immediate medical applications, by providing the first strategy for reliable prenatal diagnosis of the disorder and easy diagnosis of patients. To date, the exact implication of the cholesterol transport defect in the pathogenesis of Niemann‐Pick type C is not known; recent observations have opened up new possible approaches for the understanding of this lesion. Although final classification of Niemann‐Pick disease type C must await elucidation of the primary defect(s), present knowledge already establishes that the disease is a nosological entity distinct from Niemann‐Pick disease type A and B, and suggests that it might be the model for a new molecular concept of neurolipidosis — and even of inherited metabolic disease.
Screening and economics
Authors: Stilwell J. A. 
Published: June 2005

SummaryScreening for disease involves expenditure now in order to reap benefits in the future. It is important to understand why future benefits should bediscounted in the cost‐benefit calculation. The reasons are derived from a societal preference for consumption now over consumption tomorrow, combined with the productivity of capital, which enables goods today to be transformed into more goods tomorrow.It is also necessary to put costs and values on human lives. This is simplified at present in the UK because a highly restrictive immigration policy implies that the net value of the average additional citizen is zero (or even negative).The cost‐benefit calculations that are presented must be carried out highly systematically in order to avoid double counting or omission. A computerized spreadsheet is ideal for this purpose.
Economic evaluation of cost‐benefit ratio of neonatal screening procedure for phenylketonuria and hypothyroidism
Authors: Dhondt J. ‐L. , Farriaux J. ‐P. , Sailly J. ‐C. , Lebrun T. 
Published: June 2005

SummaryA comparison between the cost of identification and care of patients with phenylketonuria (PKU) and congenital hypothyroidism (CH) and the expenditure for the care of untreated retarded patients has been established on the basis of the activity of the Nord‐Pas‐de‐Calais regional screening centre and of interviews with patients' families. The analysis yields a benefit‐cost ratio of 6.6 for PKU and 13.8 for CH prophylaxis. However, cost‐benefit varies depending on the economic partner, i.e. the patient's family, Social Security or Administration.
Studies on pyruvate carboxylase from cultured human fibroblasts and amniotic fluid cells
Authors: Hansen Torben L. , Christensen Ernst 
Published: June 2005

AbstractThe properties of pyruvate carboxylase in cultured human fibroblasts were investigated. A pH optimum around pH 7.6 was found in Tris buffer at 37°C. The apparentKm for pyruvate and bicarbonate were 0.22 mmol/l and 2.1 mmol/l respectively. The activity of the crude homogenate was most stable at room temperature. The major end product was identified as citric acid during the assay conditions used. During growth the specific activity increased from 0.5 to 2 nmol/min per mg protein.The activity of pyruvate carboxylase in the crude homogenate from cultured human fibroblasts was 0.76±0.12 nmol/min per mg protein, while the activity in cultured amniotic fluid cells was 0.66±0.17 nmol/min per mg protein, suggesting the possibility of prenatal diagnosis of pyruvate carboxylase deficiency.
Biochemical studies in the cerebro‐hepato‐renal syndrome of Zellweger: A disturbance in the metabolism of pipecolic acid
Authors: Trijbels J. M. F. , Monnens L. A. H. , Bakkeren J. A. J. M. , Van Raay‐Selten A. H. J. , Corstiaensen J. M. B. 
Published: June 2005

AbstractThe metabolism of pipecolic acid has been studied in three patients suffering from the cerebro‐hepato‐renal syndrome of Zellweger. A marked pipecolic aciduria was observed in these patients and serum levels of pipecolic acid were also elevated. Fromin vivo studies evidence was obtained that a disturbance in the catabolic pathway of pipecolic acid was present in all patients. This conclusion was based on the delayed return of the serum pipecolic acid concentration to the fasting concentration after oral loading of the patients withdl‐pipecolic acid. Moreover, no increase in the excretion of α‐amino adipic acid was observed in the patients after loading, in contrast with the control subjects, who showed a marked increase in the excretion of this metabolite of pipecolic acid. Further evidence for the presence of a metabolic defect in the catabolism of pipecolic acid was obtained from the observation that patients excreted significantly higher amounts of pipecolic acid during the loading experiment.
Review: Preimplantation diagnosis of inherited disease
Authors: Lissens W. , Sermon K. , Staessen C. , Van Assche E. , Janssenswillen C. , Joris H. , Van Steirteghem A. , Liebaers I. 
Published: June 2005

SummaryPreimplantation diagnosis of inherited diseases has become possible with the techniques ofin vitro fertilization, blastomere biopsy of the 6‐ to 10‐cell embryo and DNA analysis of the single blastomeres. Disease‐free embryos are selected for transfer to the uterus, thereby avoiding the need for termination of a fetus diagnosed as affected in prenatal diagnosis in the first or early‐second trimester of pregnancy. The genetic indications for preimplantation diagnosis are theoretically the same as for prenatal diagnosis, but the defects must be detectable by the polymerase chain reaction. For X‐linked recessive diseases, fluorescencein situ hybridization can be used as an alternative for the selection of female embryos. So far almost 40 healthy children have been born worldwide after preimplantation diagnosis for genetic disease. The possibilities and limitations of preimplantation diagnosis, especially in prevention of inherited disease, are discussed in this review.
Plasma total odd‐chain fatty acids in the monitoring of disorders of propionate, methylmalonate and biotin metabolism
Authors: Çoker M. , de Klerk J. B. C. , Poll‐The B. T. , Huijmans J. G. M. , Duran M. 
Published: June 2005

SummaryTotal plasma odd‐numbered long‐chain fatty acids were analysed in patients with methylmalonic acidaemia (vitamin B12‐responsive and unresponsive), combined methylmalonic acidaemia/homocystinuria (CblC), propionic acidaemia (both neonatal‐onset and late‐onset), biotinidase deficiency and holocarboxylase synthase deficiency, as well as in hospital controls. Total odd‐numbered long‐chain fatty acids (C15:0, C17:1 and C17:0) were expressed as a percentage of total C12–C20 fatty acids. Control values were 0.72%±0.31% (n=12). Normalization of the percentage of odd‐chain fatty acids occurred in all vitamin‐responsive patients, following the institution of vitamin treatment. In general the neonatal‐onset propionic acidaemia and B12‐unresponsive methylmalonic acidaemia patients had the highest plasma odd‐chain fatty acid concentrations, which correlated with the clinical condition but not with the urinary excretion of methylcitrate or methylmalonate. Plasma odd‐chain fatty acid concentrations and methylmalonate excretions in CblC patients reacted very well to vitamin B12 treatment, but with no clinical response. Measurement of plasma odd‐chain fatty acids is of no value for the monitoring of defects of biotin metabolism.
Ataxia associated with increased plasma concentrations of pristanic acid, phytanic acid and C27 bile acids but normal fibroblast branched‐chain fatty acid oxidation
Authors: Clayton P. T. , Johnson A. W. , Mills K. A. , Lynes G. W. , Wilson J. , Casteels M. , Mannaerts G. 
Published: June 2005

SummaryInvestigations of peroxisomal function were undertaken in an 8‐year‐old girl who developed motor difficulties at the age of 3.5 years and went on to develop a progressive ataxia and dysarthria. There were no other neurological abnormalities and she was of normal intelligence. Analysis of plasma very long‐chain fatty acids revealed a normal C26 concentration and normal C24/C22 and C26/C22 ratios. Analysis of branched‐chain fatty acids showed an elevated plasma phytanic acid concentration of 60 µmol/L (normal<15) and a considerably elevated pristanic acid concentration of 50 µmol/L (normal<2). Plasma concentrations of the C27 bile acids 3α,7α‐dihydroxycholestanoic acid (DHCA) and 3α,7α,12α‐trihydroxycholestanoic acid (THCA) and of the C29‐dicarboxylic acid were also increased. We postulated that these results might be due to deficiency of the peroxisomal branched‐chain acyl‐CoA oxidase, but when oxidation of branched‐chain fatty acids was studied in cultured skin fibroblasts it was found to be normal. Alternative explanations for the accumulation of branched‐chain substrates for peroxisomalβ‐oxidation are discussed. Treatment with a low‐phytanic acid diet arrested the progression of the ataxia and led to a slight improvement.
Co‐cultivation of Niemann‐Pick disease type C fibroblasts belonging to complementation groupsα andβ stimulates LDL‐derived cholesterol esterification
Authors: Steinberg S. J. , Mondal D. , Fensom A. H. 
Published: June 2005

SummaryNiemann‐Pick disease type C (NPC) is a neurovisceral storage disorder with an unknown primary deficiency. Somatic cell hybridization experiments using human cultured fibroblasts have shown that two complementation groups (NPC‐α and NPC‐β) are associated with the biochemical and clinical phenotypes comprising NPC. We identified the rarer complementation group NPC‐β originally using the technique of filipin staining as a marker for complementation. In this study we show that the esterification of cholesterol derived from the LDL pathway can be used as an isotopic assay. However, multinuclear hybrids exhibit a delayed induction in this pathway. Furthermore, we discovered that, in the presence of an LDL source, co‐cultivation of fibroblasts belonging to NPC‐α and NPC‐β stimulated cholesterol esterification.
Cytochrome c oxidase deficiency in subacute necrotizing encephalopathy (Leigh syndrome)
Authors: Hayasaka K. , Brown G. K. , Danks D. M. , Droste M. , Kadenbach B. 
Published: June 2005

SummaryTissues and cultured fibroblasts from two patients with Leigh syndrome (subacute necrotizing encephalopathy) were examined. A systemic defect in cytochrome oxidase was identified by enzyme assay and estimation of cytochrome concentrations. Immunochemical analysis showed a reduction of most subunits of the cytochrome oxidase complex.The rate of synthesis of cytochrome oxidase subunits, determined by labelling experiments in cultured fibroblasts, was the same in the patients and normal controls. The reduced cytochrome oxidase content of the patients' tissues must therefore result from abnormal turnover of the protein subunits.
Deficit of uridine diphosphate galactose in galactosaemia
Authors: Ng W. G. , Xu Y. K. , Kaufman F. R. , Donnell G. N. 
Published: June 2005

SummaryThe levels of uridine diphosphate galactose (UDPGal) and uridine diphosphate glucose (UDPGlc) have been determined in liver autopsy samples, erythrocytes and cultured skin fibroblasts from galactosaemic patients and compared to non‐galactosaemic controls. In patients with undetectable erythrocyte galactose‐1‐phosphate uridyltransferase (transferase) activity, the levels of UDPGal were substantially lower than in controls. In patients with detectable transferase activity, even though in less than 1% of normal values, both UDPGal and UDPGlc levels were in the normal range. Incubation of erythrocytes from both galactosaemic patients and normal individuals with 10 mmol/L uridine increased UDPGal and UDPGlc levels several‐fold, both in the presence or absence of galactose in the incubation medium. We hypothesize that a deficit of UDPGal is responsible for the late onset clinical manifestations in galactosaemia which include ovarian failure, speech defect and neurological abnormalities. We suggest that uridine administration may be of therapeutic value in raising the intracellular concentrations of UDPGal. We conclude that the transferase reaction, however small in activity, is essential for optimal UDPGal formation.
A fluorimetric assay of steroid sulphatase in leukocytes: Evidence for two genetically different enzymes with arylsulphatase C activity
Authors: van Diggelen O. P. , Konstantinidou A. E. , Bousema M. T. , Boer M. , Bakx Th. , Jöbsis A. C. 
Published: June 2005

SummaryArylsulphatase C (ASC) activity in leukocytes and fibroblasts measured with 4‐methylumbelliferylsulphate, is caused by at least two genetically different sulphatases. One of these is steroid sulphatase (STS). Depending on the substrate concentration, about 10–50% of the ASC activity in leukocytes can be attributed to sulphatases other than STS. Steroid sulphatase can be measured specifically with 4‐methylumbelliferylsulphate as the fraction of total ASC activity which is inhibitable by dehydroepiandrosterone sulphate. Using this assay, the adjusted ASC activity in leukocytes from patients with X‐linked ichthyosis was 2% of normal. Obligate heterozygotes showed reduced activity.