Indian Childhood Cirrhosis

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform

M. S. Tanner - One of the best experts on this subject based on the ideXlab platform.

  • Liver disease in India
    2016
    Co-Authors: S.a Bhave, A N Pandit, A M Pradhan, D G Sidhaye, A Kantarjian, A Williams, I C Talbot, M. S. Tanner
    Abstract:

    SUMMARY One hundred and twenty-five children with chronic liver disease were seen in Pune in 13 months. Fifty-nine of them, aged 8-39 months, had Indian Childhood Cirrhosis histologically diagnosed. Their characteristics included an insidious onset of symptoms, a geographical clustering of cases in rural areas north-east of Pune, a high rate of parental consanguinity and affected siblings, and a very high hepatic copper concentration (790-6654,ug/g dry weight). Only 8 survived for 6 months, adverse prognostic features being jaundice, ascites, enlargement of the gall bladder, and severe anaemia at presentation. Clinical differentiation from other liver disorders in the same age group was clear in advanced cases but unreliable in earlier cases. Four asymptomatic siblings with hepatomegaly had a benign course. The need for non-invasive methods to diagnose early cases in the community is demonstrated. The other major diagnostic categories were: unresolved hepatitis (12); chronic active hepatitis (7); cryptogenic Cirrhosis (6); neonatal hepatitis and biliary atresia (8). Indian Childhood Cirrhosis (ICC) and other hepatic disorders are common causes of hospital admission of children in India.1-3 Descriptions of ICC from different centres in India however, show differences with respect to its definition, incidence, clinical features, prognosis, and response to treatment with steroids.4-7 The recent finding of high concentrations of copper in the liver in ICC has raised hopes of its treatment or prevention.8-15 It also increases the need for accurate and early diagnosis of ICC. A prospective study of chronic liver disease in children was therefore started at the King Edward Memorial Hospital, Pune, with four objectives: (1) To study the pattern of chronic liver disease in Childhood in this area. (2) To define the clinical features of a group of children with ICC in whom the diagnosis was made upon histological criteria. (3) To measure hepatic copper concentration in a larger group of children than in the previous studies. (4) To provide an epidemiological basis for future studies

  • Indian Childhood Cirrhosis and Tyrolean Childhood Cirrhosis
    Advances in Experimental Medicine and Biology, 1999
    Co-Authors: M. S. Tanner
    Abstract:

    Indian Childhood Cirrhosis (ICC) (Tanner 1997) and Tyrolean Childhood Cirrhosis (TCC) (Muller et al 1996) have both now virtually disappeared. In ICC, and putatively in TCC, greatly increased levels of ingested dietary copper in infancy were associated with greatly increased hepatic copper concentrations and, hence, Cirrhosis. Cessation of this feeding habit has been associated with disappearance of the disease in each case.

  • role of copper in Indian Childhood Cirrhosis
    The American Journal of Clinical Nutrition, 1998
    Co-Authors: M. S. Tanner
    Abstract:

    Of the cirrhoses that affect Indian children, Indian Childhood Cirrhosis (ICC) is a discrete clinical and histologic entity in which large amounts of copper are deposited in the liver. The evidence linking copper deposition to increased dietary copper intake in infancy was reviewed. Prevention of this feeding pattern prevents ICC, and the disease has now largely disappeared from many parts of India. Penicillamine, if given before the terminal clinical stage of ICC, reduces mortality from 92% to 53%. Long-term survivors show a sequence of histologic resolution, resulting either in inactive micronodular Cirrhosis or in virtually normal histologic appearance. Twenty-nine treated ICC patients reexamined at 8.8 y of age (range: 6.3-13 y), 5-12 y after diagnosis, were well and had normal results from liver function tests. Clinical and epidemiologic evidence show that there must be excessive copper ingestion for ICC to develop, but the lack of an animal model, the inconstant relation between liver copper concentrations and liver damage, and the rarity of liver disease in adults suggests that other etiologic factors contribute. Two mechanisms are discussed: 1) that copper may be acting in synergy with a hepatotoxin, or 2) that there may be a genetic predisposition to copper-associated liver damage, as suggested recently for Tyrollean Childhood Cirrhosis. Although ICC is now rare, sporadic cases of an ICC-like disorder in infants continue to occur. There should be a greater awareness among pediatricians of this disease to enable early diagnosis. Penicillamine should be used early and adverse prognostic factors recognized as indications for early transplantation and unregulated water supplies should not be used to prepare infant feeds.

  • long term survival in Indian Childhood Cirrhosis treated with d penicillamine
    Archives of Disease in Childhood, 1996
    Co-Authors: Ashish Bavdekar, Anand Pandit, Sheila Bhave, A M Pradhan, M. S. Tanner
    Abstract:

    Indian Childhood Cirrhosis (ICC) is an almost uniformly fatal disease whose outcome may be modified with penicillamine if given at a sufficiently early stage. Twenty nine children with ICC seen in Pune, India, in 1980-7, who had survived at least five years from onset of penicillamine treatment, were reviewed aged 6.3 to 13 years. They were assessed clinically, biochemically, histologically, and by duplex Doppler ultrasound examination. None had symptoms suggestive of liver disease. There were no toxic effects of penicillamine other than asymptomatic proteinuria. Hepatosplenomegaly reduced significantly and liver function tests returned to normal in all. In four children, significant hepatosplenomegaly was associated with an abnormal duplex Doppler hepatic vein flow pattern and micronodular Cirrhosis on biopsy. Clinical findings, growth and development, and ultrasound examination were normal in the remainder. Review of serial liver biopsy specimens showed a sequence of recovery from ICC through inactive micronodular Cirrhosis to virtually normal histological appearances. The four children who still have micronodular Cirrhosis beyond four years from onset remain on penicillamine treatment. In the others penicillamine was stopped after 1-7 (mean 3.5) years without relapse, strong evidence that ICC is not due to an inborn error of copper metabolism.

  • normal metallothionein synthesis in fibroblasts obtained from children with Indian Childhood Cirrhosis or copper associated Childhood Cirrhosis
    Biochemical and Molecular Medicine, 1995
    Co-Authors: S H Hahn, M. S. Tanner, D M Danke, W A Gahl
    Abstract:

    We previously demonstrated decreased metallothionein (MT) synthesis in cultured fibroblasts obtained from an American boy with findings typical of Indian Childhood Cirrhosis (ICC). We now report normal basal, copper-induced, and zinc-induced MT synthesis in the fibroblasts of two Indian boys and one Irish boy with typical ICC and one Indian boy with copper-associated Childhood Cirrhosis. This suggests that etiologies other than impaired MT production should be sought as the primary defect in these disorders.

Susan J. Baserga - One of the best experts on this subject based on the ideXlab platform.

  • NOL11, Implicated in the Pathogenesis of North American Indian Childhood Cirrhosis, Is Required for Pre- rRNA Transcription and Processing
    2016
    Co-Authors: Emily F. Freed, Kathleen L. Mccann, Brian Mcstay, Susan J. Baserga
    Abstract:

    The fundamental process of ribosome biogenesis requires hundreds of factors and takes place in the nucleolus. This process has been most thoroughly characterized in baker’s yeast and is generally well conserved from yeast to humans. However, some of the required proteins in yeast are not found in humans, raising the possibility that they have been replaced by functional analogs. Our objective was to identify non-conserved interaction partners for the human ribosome biogenesis factor, hUTP4/Cirhin, since the R565W mutation in the C-terminus of hUTP4/Cirhin was reported to cause North American Indian Childhood Cirrhosis (NAIC). By screening a yeast two-hybrid cDNA library derived from human liver, and through affinity purification followed by mass spectrometry, we identified an uncharacterized nucleolar protein, NOL11, as an interaction partner for hUTP4/Cirhin. Bioinformatic analysis revealed that NOL11 is conserved throughout metazoans and their immediate ancestors but is not found in any other phylogenetic groups. Co-immunoprecipitation experiments show that NOL11 is a component of the human ribosomal small subunit (SSU) processome. siRNA knockdown of NOL11 revealed that it is involved in the cleavage steps required to generate the mature 18S rRNA and is required for optimal rDNA transcription. Furthermore, abnormal nucleolar morphology results from the absence of NOL11. Finally, yeast two-hybrid analysis shows that NOL11 interacts with the C-terminus of hUTP4/Cirhin and that the R565W mutation partially disrupts this interaction. We have therefore identified NOL11 as a novel protein required for the early stages of ribosome biogenesi

  • nol11 implicated in the pathogenesis of north american Indian Childhood Cirrhosis is required for pre rrna transcription and processing
    PLOS Genetics, 2012
    Co-Authors: Emily F. Freed, Kathleen L. Mccann, Brian Mcstay, Joseluis Prieto, Susan J. Baserga
    Abstract:

    The fundamental process of ribosome biogenesis requires hundreds of factors and takes place in the nucleolus. This process has been most thoroughly characterized in baker's yeast and is generally well conserved from yeast to humans. However, some of the required proteins in yeast are not found in humans, raising the possibility that they have been replaced by functional analogs. Our objective was to identify non-conserved interaction partners for the human ribosome biogenesis factor, hUTP4/Cirhin, since the R565W mutation in the C-terminus of hUTP4/Cirhin was reported to cause North American Indian Childhood Cirrhosis (NAIC). By screening a yeast two-hybrid cDNA library derived from human liver, and through affinity purification followed by mass spectrometry, we identified an uncharacterized nucleolar protein, NOL11, as an interaction partner for hUTP4/Cirhin. Bioinformatic analysis revealed that NOL11 is conserved throughout metazoans and their immediate ancestors but is not found in any other phylogenetic groups. Co-immunoprecipitation experiments show that NOL11 is a component of the human ribosomal small subunit (SSU) processome. siRNA knockdown of NOL11 revealed that it is involved in the cleavage steps required to generate the mature 18S rRNA and is required for optimal rDNA transcription. Furthermore, abnormal nucleolar morphology results from the absence of NOL11. Finally, yeast two-hybrid analysis shows that NOL11 interacts with the C-terminus of hUTP4/Cirhin and that the R565W mutation partially disrupts this interaction. We have therefore identified NOL11 as a novel protein required for the early stages of ribosome biogenesis in humans. Our results further implicate a role for NOL11 in the pathogenesis of NAIC.

Pierre Chagnon - One of the best experts on this subject based on the ideXlab platform.

  • a missense mutation r565w in cirhin flj14728 in north american Indian Childhood Cirrhosis
    American Journal of Human Genetics, 2002
    Co-Authors: Pierre Chagnon, Grant A. Mitchell, Jacques L Michaud, Jocelyne Mercier, Jeanfrancois Marion, Eric Drouin, Andree Rasquinweber, Thomas J Hudson, Andrea Richter
    Abstract:

    North American Indian Childhood Cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology. It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary Cirrhosis and portal hypertension. Clinical and physiological investigations have not revealed the underlying cause of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease. We previously identified the NAIC locus by homozygosity mapping to chromosome 16q22. Here we report that an exon 15 mutation in gene FLJ14728 (alias Cirhin ) causes NAIC: c.1741C→T in GenBank cDNA sequence NM_032830, found in all NAIC chromosomes, changes the conserved arginine 565 codon to a tryptophan, altering the predicted secondary structure of the protein. Cirhin is preferentially expressed in embryonic liver, is predicted to localize to mitochondria, and contains WD repeats, which are structural motifs frequently associated with molecular scaffolds.

  • localization of a recessive gene for north american Indian Childhood Cirrhosis to chromosome region 16q22 and identification of a shared haplotype
    American Journal of Human Genetics, 2000
    Co-Authors: Christine Betard, Jocelyne Mercier, Eric Drouin, Andree Rasquinweber, Carl Brewer, Suzanne Clark, Andrei Verner, Corinne Darmondzwaig, Julie Fortin, Pierre Chagnon
    Abstract:

    North American Indian Childhood Cirrhosis (NAIC, or CIRH1A) is an isolated nonsyndromic form of familial cholestasis reported in Ojibway-Cree children and young adults in northwestern Quebec. The pattern of transmission is consistent with an autosomal recessive mode of inheritance. To map the NAIC locus, we performed a genomewide scan on three DNA pools of samples from 13 patients, 16 unaffected siblings, and 22 parents from five families. Analysis of 333 highly polymorphic markers revealed 3 markers with apparent excess allele sharing among affected individuals. Additional mapping identified a chromosome 16q segment shared by all affected individuals. When the program FASTLINK/LINKAGE was used and a completely penetrant autosomal recessive mode of inheritance was assumed, a maximum LOD score of 4.44 was observed for a recombination fraction of 0, with marker D16S3067. A five-marker haplotype (D16S3067, D16S752, D16S2624, D16S3025, and D16S3106) spanning 4.9 cM was shared by all patients. These results provide significant evidence of linkage for a candidate gene on chromosome 16q22.

Emily F. Freed - One of the best experts on this subject based on the ideXlab platform.

  • NOL11, Implicated in the Pathogenesis of North American Indian Childhood Cirrhosis, Is Required for Pre- rRNA Transcription and Processing
    2016
    Co-Authors: Emily F. Freed, Kathleen L. Mccann, Brian Mcstay, Susan J. Baserga
    Abstract:

    The fundamental process of ribosome biogenesis requires hundreds of factors and takes place in the nucleolus. This process has been most thoroughly characterized in baker’s yeast and is generally well conserved from yeast to humans. However, some of the required proteins in yeast are not found in humans, raising the possibility that they have been replaced by functional analogs. Our objective was to identify non-conserved interaction partners for the human ribosome biogenesis factor, hUTP4/Cirhin, since the R565W mutation in the C-terminus of hUTP4/Cirhin was reported to cause North American Indian Childhood Cirrhosis (NAIC). By screening a yeast two-hybrid cDNA library derived from human liver, and through affinity purification followed by mass spectrometry, we identified an uncharacterized nucleolar protein, NOL11, as an interaction partner for hUTP4/Cirhin. Bioinformatic analysis revealed that NOL11 is conserved throughout metazoans and their immediate ancestors but is not found in any other phylogenetic groups. Co-immunoprecipitation experiments show that NOL11 is a component of the human ribosomal small subunit (SSU) processome. siRNA knockdown of NOL11 revealed that it is involved in the cleavage steps required to generate the mature 18S rRNA and is required for optimal rDNA transcription. Furthermore, abnormal nucleolar morphology results from the absence of NOL11. Finally, yeast two-hybrid analysis shows that NOL11 interacts with the C-terminus of hUTP4/Cirhin and that the R565W mutation partially disrupts this interaction. We have therefore identified NOL11 as a novel protein required for the early stages of ribosome biogenesi

  • nol11 implicated in the pathogenesis of north american Indian Childhood Cirrhosis is required for pre rrna transcription and processing
    PLOS Genetics, 2012
    Co-Authors: Emily F. Freed, Kathleen L. Mccann, Brian Mcstay, Joseluis Prieto, Susan J. Baserga
    Abstract:

    The fundamental process of ribosome biogenesis requires hundreds of factors and takes place in the nucleolus. This process has been most thoroughly characterized in baker's yeast and is generally well conserved from yeast to humans. However, some of the required proteins in yeast are not found in humans, raising the possibility that they have been replaced by functional analogs. Our objective was to identify non-conserved interaction partners for the human ribosome biogenesis factor, hUTP4/Cirhin, since the R565W mutation in the C-terminus of hUTP4/Cirhin was reported to cause North American Indian Childhood Cirrhosis (NAIC). By screening a yeast two-hybrid cDNA library derived from human liver, and through affinity purification followed by mass spectrometry, we identified an uncharacterized nucleolar protein, NOL11, as an interaction partner for hUTP4/Cirhin. Bioinformatic analysis revealed that NOL11 is conserved throughout metazoans and their immediate ancestors but is not found in any other phylogenetic groups. Co-immunoprecipitation experiments show that NOL11 is a component of the human ribosomal small subunit (SSU) processome. siRNA knockdown of NOL11 revealed that it is involved in the cleavage steps required to generate the mature 18S rRNA and is required for optimal rDNA transcription. Furthermore, abnormal nucleolar morphology results from the absence of NOL11. Finally, yeast two-hybrid analysis shows that NOL11 interacts with the C-terminus of hUTP4/Cirhin and that the R565W mutation partially disrupts this interaction. We have therefore identified NOL11 as a novel protein required for the early stages of ribosome biogenesis in humans. Our results further implicate a role for NOL11 in the pathogenesis of NAIC.

A M Pradhan - One of the best experts on this subject based on the ideXlab platform.

  • Liver disease in India
    2016
    Co-Authors: S.a Bhave, A N Pandit, A M Pradhan, D G Sidhaye, A Kantarjian, A Williams, I C Talbot, M. S. Tanner
    Abstract:

    SUMMARY One hundred and twenty-five children with chronic liver disease were seen in Pune in 13 months. Fifty-nine of them, aged 8-39 months, had Indian Childhood Cirrhosis histologically diagnosed. Their characteristics included an insidious onset of symptoms, a geographical clustering of cases in rural areas north-east of Pune, a high rate of parental consanguinity and affected siblings, and a very high hepatic copper concentration (790-6654,ug/g dry weight). Only 8 survived for 6 months, adverse prognostic features being jaundice, ascites, enlargement of the gall bladder, and severe anaemia at presentation. Clinical differentiation from other liver disorders in the same age group was clear in advanced cases but unreliable in earlier cases. Four asymptomatic siblings with hepatomegaly had a benign course. The need for non-invasive methods to diagnose early cases in the community is demonstrated. The other major diagnostic categories were: unresolved hepatitis (12); chronic active hepatitis (7); cryptogenic Cirrhosis (6); neonatal hepatitis and biliary atresia (8). Indian Childhood Cirrhosis (ICC) and other hepatic disorders are common causes of hospital admission of children in India.1-3 Descriptions of ICC from different centres in India however, show differences with respect to its definition, incidence, clinical features, prognosis, and response to treatment with steroids.4-7 The recent finding of high concentrations of copper in the liver in ICC has raised hopes of its treatment or prevention.8-15 It also increases the need for accurate and early diagnosis of ICC. A prospective study of chronic liver disease in children was therefore started at the King Edward Memorial Hospital, Pune, with four objectives: (1) To study the pattern of chronic liver disease in Childhood in this area. (2) To define the clinical features of a group of children with ICC in whom the diagnosis was made upon histological criteria. (3) To measure hepatic copper concentration in a larger group of children than in the previous studies. (4) To provide an epidemiological basis for future studies

  • long term survival in Indian Childhood Cirrhosis treated with d penicillamine
    Archives of Disease in Childhood, 1996
    Co-Authors: Ashish Bavdekar, Anand Pandit, Sheila Bhave, A M Pradhan, M. S. Tanner
    Abstract:

    Indian Childhood Cirrhosis (ICC) is an almost uniformly fatal disease whose outcome may be modified with penicillamine if given at a sufficiently early stage. Twenty nine children with ICC seen in Pune, India, in 1980-7, who had survived at least five years from onset of penicillamine treatment, were reviewed aged 6.3 to 13 years. They were assessed clinically, biochemically, histologically, and by duplex Doppler ultrasound examination. None had symptoms suggestive of liver disease. There were no toxic effects of penicillamine other than asymptomatic proteinuria. Hepatosplenomegaly reduced significantly and liver function tests returned to normal in all. In four children, significant hepatosplenomegaly was associated with an abnormal duplex Doppler hepatic vein flow pattern and micronodular Cirrhosis on biopsy. Clinical findings, growth and development, and ultrasound examination were normal in the remainder. Review of serial liver biopsy specimens showed a sequence of recovery from ICC through inactive micronodular Cirrhosis to virtually normal histological appearances. The four children who still have micronodular Cirrhosis beyond four years from onset remain on penicillamine treatment. In the others penicillamine was stopped after 1-7 (mean 3.5) years without relapse, strong evidence that ICC is not due to an inborn error of copper metabolism.

  • reversal of Indian Childhood Cirrhosis by d penicillamine therapy
    Journal of Pediatric Gastroenterology and Nutrition, 1995
    Co-Authors: A M Pradhan, Sheila Bhave, Anand Pandit, Ashish Bavdekar, V V Joshi, M. S. Tanner
    Abstract:

    Serial liver biopsy changes have been reviewed in 30 patients with Indian Childhood Cirrhosis (ICC) who were randomly allocated to receive treatment with penicillamine in a dose of 20 mg/kg/day, 10 of whom also received prednisolone, and five receiving placebo. The latter died within 185 (mean, 149) days of starting treatment. Nine receiving penicillamine died within 540 (mean, 338) days, but the remainder are well 5.1-9.3 years after commencing treatment. Initial biopsies showed severe hepatocellular injury, pericellular fibrosis, inflammatory infiltration, and orcein-staining granules. Second biopsies taken within 6 months of starting penicillamine usually showed persistence of inflammation and an increase in nodularity with thick and thin active septae. Subsequently the appearances were of an inactive micronodular Cirrhosis, with reduction in septal inflammatory infiltrate, hepatocellular injury, and intensity of orcein staining. This further improved to a stage of incomplete fibrous septae. The last liver biopsies at 6-60 months (in 21 survivors) showed almost normal histology in four, incomplete fibrous septae in five, and inactive micronodular Cirrhosis with thin septae in 12. Mean liver copper concentrations decreased from 1,407 (SEM, 121) micrograms/g at presentation to 925 (183), 317 (100), and 127 (35) at 6, 6-18, and > 18 months after starting treatment. By contrast, a second biopsy taken in the 6 months after diagnosis in placebo-treated children showed persistence of ICC with increase in inflammation, fibrosis, and orcein staining.