| 书目名称 | Journal of Inherited Metabolic Disease | | 编辑 | R. A. Harkness,R. J. Pollitt,G. M. Addison | | 视频video | http://file.papertrans.cn/502/501234/501234.mp4 | | 图书封面 |  | | 描述 | The articles in Issue 4 of .Journal of Inherited MetabolicDisease., Vol. 14 (1991) contain the main lectures presented at the28th Annual Symposium of the Society for the Study of Inborn Errors ofMetabolism, Birmingham, UK, 1990, which was dedicated to `The Liverand Inherited Metabolic Disease‘ with a half-day workshop on`Screening and Economics‘. .The subjects covered include metabolic functions of the liver, bileacids, alpha-1-antitrypsin deficiency, tyrosinaemia type I,Crigler-Najjar disease type I and Niemann-Pick disease type C,providing updates on a wide range of metabolic disorders andillustrating the importance of the complementary contributions fromprofessionals in different disciplines. Also covered in detail is theexciting potential of liver transplantation as treatment for severalinborn errors of metabolism. .This state-of-the-art review will be of interest to clinicians andresearch workers alike. . | | 出版日期 | Book 1991 | | 关键词 | enzymes; liver; liver disease; liver transplantation; metabolism; transplantation | | 版次 | 1 | | doi | https://doi.org/10.1007/978-94-011-9749-6 | | isbn_softcover | 978-0-7923-8982-8 | | isbn_ebook | 978-94-011-9749-6 | | copyright | Springer Science+Business Media Dordrecht 1991 |
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Front Matter |
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Abstract
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,The Role of the Liver in Metabolic Homeostasis: Implications for Inborn Errors of Metabolism, |
G. van den Berghe |
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Abstract
The 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 by .-oxidation of fatty acids to synthesize glucose. The mechanisms whereby a number of inborn errors of glycogen metabolism, of gluconeogenesis and of ketogenesis c
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| 3 |
,Detoxification Pathways in the Liver, |
D. M. Grant |
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Abstract
The 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 populat
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,Hereditary Variation of Liver Enzymes involved with Detoxification and Neurodegenerative Disease, |
A. C. Williams,G. B. Steventon,S. Sturman,R. H. Waring |
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Abstract
Enzymes involved with the metabolic transformation of xenobiotics have recently been studied in patients with the neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease and motor neurone disease. Defects were detected in sulphur pathways and also, in the case of Parkinson’s disease, in monoamine oxidase B. The possibility exists that the ability to cope safely with endogenous and exogenous substances which have neurotoxic properties is important in the pathogenesis of these diseases. Potentially such individuals could be identified preclinically and these diseases postponed by reduction in the load of toxin or modification of the relevant enzymic activity.
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,Interrelationships of Liver and Brain with Special Reference to Reye Syndrome, |
J. K. Brown,H. Imam |
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Abstract
Reye syndrome is an acute non-inflammatory encephalopathy that can be precipitated by toxic, infective, metabolic or hypoxic upsets. The biochemical changes point to mitochondrial dysfunction and this is substantiated by structural changes in mitochondria on electron microscopy. The toxic metabolites that accumulate are similar to those incriminated in hepatic encephalopathy and other metabolic diseases. These metabolites exert their deleterious effects by direct neuronal damage, neurotransmitter blockade, vascular damage, cerebral oedema, hypoxic ischaemic damage, demyelination, retardation of brain growth and neuronal storage. Brain capillary endothelial cells are very rich in mitochondria and mitochondrial disorders can effect the central nervous system primarily, and not just as a consequence of systemic metabolic upset.
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,Fetal and Neonatal Bile Acid Synthesis and Metabolism — Clinical Implications, |
W. F. Balistreri |
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Abstract
It has become apparent that with sophisticated technology we are now able to recognize defective bile acid metabolism in a wide variety of disease states. Recognition of specific aberrations, such as inborn errors in bile acid metabolism manifesting as neonatal cholestasis, offers new opportunities for therapeutic intervention. Future studies should determine the incidence of inborn errors in patients with enigmatic and unexplained liver diseases such as idiopathic neonatal hepatitis.
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,Inborn Errors of Bile Acid Metabolism, |
P. T. Clayton |
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Abstract
Cholesterol 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 — 3.-hydroxy-Δ5-C27-steroid dehydrogenase deficiency — leads to excretion of 3.-7.-dihydroxy-5-cholenoic acid and 3.,7.,12.-trihydroxy-5-cholenoic acid in the urine. The liver disease improves dramatically on treatment with chenodeoxycholic acid. Deficient activity of 3-oxo-Δ4-steroid 5.-reductase is thought to be the cause of familial liver disease in some infants who excrete 7.-hydroxy-3-oxo-4-cholenoic acid and 7.,12.-dihydroxy-3-oxo-4-cholenoic acid in the urine. However, diagnosis of this disorder is problematical; a similar pattern of metabolite excretion can occu
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,α1-Antitrypsin Deficiency and Liver Disease: Clinical Presentation, Diagnosis and Treatment, |
M. Hussain,G. Mieli-Vergani,A. P. Mowat |
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Abstract
The α.-antitrypsin deficient subject (protease inhibitor (PI) phenotype ZZ) has an increased susceptibility to liver disease. The condition is most commonly identified in early infancy as a conjugated hyperbilirubinaemia with hepatitis (11%) or a bleeding state due to vitamin K malabsorption (2%). 50% of cases have cirrhosis and 25% die in the first decade of life. A further 2% present with cirrhosis in later childhood. Adult males are at risk of hepatoma development with or without cirrhosis. Diagnosis is by isoelectric focussing or allele-specific oligonucleotide hybridization. The treatment is that of cholestasis and cirrhosis including transplantation. The pathobiology of the deficiency state, the mechanism of liver damage and the vulnerability of the newborn liver are discussed in this review. A plea is made for a trial of infusions of α.-antitrypsin in early infancy, as is used safely but without proven efficacy in the emphysematous PIZZ subject. Prospects of therapy by gene modification are also reviewed.
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,,,-Antitrypsin Deficiency and Liver Disease, |
P. Birrer,N. G. McElvaney,L. M. Chang-Stroman,R. G. Crystal |
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Abstract
..-Antitrypsin (..AT) deficiency, one of the most common lethal hereditary disorders among Caucasians, is associated with emphysema in adults, while in children it is associated with liver disease. Produced in the liver and released into the plasma, ..AT serves as the body’s major inhibitor of neutrophil elastase, a powerful proteolytic enzyme capable of degrading extracellular structural proteins. The pathogenesis of the liver disease associated with ..AT deficiency is not as well understood, but is clearly linked to specific mutations in coding exons of the ..AT gene, and the resulting accumulation of ..AT within hepatocytes. At present, therapy for the liver disease associated with ..AT deficiency is symptomatic, with liver transplantation as a last resort. New strategies are being developed to suppress the accumulation of ..AT by transferring the normal gene into the liver.
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,Clinical Presentation of Metabolic Liver Disease, |
M. Odievre |
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Abstract
Some clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories:.Appropriate investigations for recognizing all these entities are proposed.
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,Investigation of Paediatric Liver Disease, |
D. Kelly,A. Green |
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Abstract
The 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.
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,The Role of Histochemical Investigations in Metabolic Disorders Affecting the Liver, |
B. D. Lake |
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Abstract
The 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’ stai
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,Techniques for Studying Hepatic Metabolism ,, |
J. V. Leonard,G. N. Thompson |
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Abstract
Techniques for studying metabolic events . in patients with inborn errors are reviewed. Loading or provocation tests that have been used widely are insensitive and frequently non-specific. Compounds labelled with stable isotopes can be used to study enzyme kinetics and substrate turnover, providing more detailed and specific information. Intracellular events may be studied using nuclear magnetic resonance spectroscopy..The results using these techniques to study patients with selected inborn errors are discussed, namely phenylketonuria, glycogen storage disease type I and propionic acidaemia.
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,Tyrosinaemia Type I — an Update, |
E. A. Kvittingen |
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Abstract
Tyrosinaemia type I is a recessively inherited disorder caused by a deficiency of fumarylacetoacetase (FAH), the last enzyme in tyrosine degradation. The presumed toxic agents are fumaryl- and maleylacetoacetate which are converted to succinylacetone (SA), a metabolite found in increased amounts in urine and plasma of the patients. The major clinical features are progressive liver damage and renal tubular defects with hypophosphataemic rickets. Renal tubular dysfunctions with secondary rickets may be lacking altogether, even in chronic patients. Hepatocellular carcinoma is a major cause of death in the chronic form. Diagnosis of the disorder is made by assay of SA in urine and serum and by determination of FAH in lymphocytes or fibroblasts. Prenatal diagnosis is performed by SA assay in amniotic fluid supernatant and FAH analysis in cultured amniotic fluid cells or chorionic villus material. Presence of a ‘pseudodeficiency’ gene for FAH prevents prenatal diagnosis by enzyme analysis in some families, and this gene also precludes identification of heterozygotes outside tyrosinaemia families. Immunoblot analyses show that acute patients and some chronic patients lack immunoreactive F
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,Investigation of the Molecular Basis of the Genetic Deficiency of UDP-Glucuronosyl-transferase in C |
K. J. Robertson,D. Clarke,L. Sutherland,R. Wooster,M. W. H. Coughtrie,B. Burchell |
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Abstract
Liver biopsy samples were obtained from eight Crigler-Najjar patients. Bilirubin UDPGT activity, assayed by a microassay with HPLC analysis, was not detectable in type I livers, and low levels (9–26% of controls) of monoglucuronide conjugates only were observed in type II livers. 1-Naphthol UDPGT activity was normal in most patients, where membrane integrity was maintained by correct sample procurement and preparation. Our data on type II livers suggest that a defect in UDPGA transport is an unlikely cause of the hyperbilirubinaemia, but reduced affinity for UDPGA was observed in one sample. Analysis of four patient liver samples by immunoblot analysis revealed the heterogeneous nature of this inherited disease within the patient population, and one sample where 1-naphthol UDPGT activity was considerably reduced appeared to correlate with the non-detection of a phenol UDPGT protein. Progress towards a molecular genetic diagnosis of Crigler-Najjar syndromes is discussed.
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,Niemann-Pick Disease Type C: An Update, |
M. T. Vanier,P. Pentchev,C. Rodriguez-Lafrasse,R. Rousson |
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Abstract
The 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 dia
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,Paediatric Liver Transplantation: Review of Current Experience, |
J. A. C. Buckels |
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Abstract
During the 1980s the results of liver replacement in children improved dramatically, with 12-month survival rates rising from around 20% to over 85% at the most experienced centres. This improvement has been due to several factors, including better patient selection and timing of transplantation, advances in immunosuppressive therapy, and developments in liver preservation. Moreover, the learning curve effect has contributed with advances both in surgical technique and in the rapid diagnosis and treatment of complications, including the need to retransplant patients in whom the first graft has been irreversibly damaged. One major development is the refinement of the anatomically reduced grafts where a larger, usually adult, graft is cut down to fit a child. This has allowed a greater number of children to be grafted, including emergency cases such as fulminant hepatic failure in whom there is insufficient time to wait for a size-matched donor.
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,Treatment of Inherited Metabolic Disorders by Liver Transplantation, |
M. Burdelski,B. Rodeck,K. Latta,K. Latta,J. Brodehl,B. Ringe,R. Pichlmayr |
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Abstract
Among the worldwide accepted indications for liver transplantation, inherited metabolic disorders play an increasing role. In some paediatric centres this indication runs second after extrahepatic biliary atresia..The aim of liver transplantation in inherited metabolic disorders is twofold: the first is to save a patient’s life, the second is to accomplish phenotypic and functional cure of his disease. These aims may be achieved in disorders presenting with cirrhosis, hepatoma, life-threatening progression or failure of other organs with preserved liver function. The timing of liver transplantation has become easier with development of surgical techniques of reduced-size donor livers. These techniques enable the performance of liver transplantation with ABO blood group compatible organs of almost any size if indicated either by deterioration of liver function or impending complications such as hepatoma or life-threatening progression. In comparison with other indications such as extrahepatic biliary atresia, postnecrotic liver cirrhosis or acute liver failure, the results of transplantation in patients with inherited metabolic disorders seem to be better, reaching up to 78–95% actu
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,The Place of Fetal Liver Transplantation in the Treatment of Inborn Errors of Metabolism, |
J.-L. Touraine |
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Abstract
Over the last 16 years, 202 fetal tissue transplants have been performed in our department to treat 29 patients with severe inborn errors of metabolism without immunodeficiency, 26 patients with congenital and severe immunodeficiency diseases, and 2 patients with severe aplastic anaemia. The actuarial survival curve of patients with inborn errors of metabolism treated with fetal liver transplantation shows a 12-year survival of 77%. The condition of many of these patients has been improved by the treatment, but transplantation has had to be repeated in order to maintain clinical amelioration. Enzyme levels were not significantly and durably increased in peripheral blood but the quantities of substrates detected in sera and urines were significantly reduced and tissue deposits were stabilized.
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,Screening and Economics, |
J. A. Stilwell |
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Abstract
Screening for disease involves expenditure now in order to reap benefits in the future. It is important to understand why future benefits should be . 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.
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