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Peter F Whitington - One of the best experts on this subject based on the ideXlab platform.
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Neonatal Hemochromatosis management outcome and prevention
Prenatal Diagnosis, 2013Co-Authors: Enrico Lopriore, Luisa M Mearin, Dick Oepkes, Roland Devlieger, Peter F WhitingtonAbstract:Neonatal Hemochromatosis (NH) is a rare disorder but the most common cause of acute liver failure in neonates. NH is characterized by severe hepatic injury and iron overload and is associated with high perinatal mortality and morbidity rates. NH is often preceded by oligohydramnios and intrauterine growth restriction, suggesting an important impact of NH during fetal life. Stillbirth and prematurity are not uncommon. During the last decade, major discoveries on the etiology of NH have radically changed the management and outcome of this disease. NH is now regarded as an alloimmune disease and is, as such, often referred to as gestational alloimmune liver disease. Antenatal treatment with intravenous immunoglobulins starting at 14 weeks' gestation has been shown to prevent the development of NH in subsequent pregnancies. Postnatal treatment, previously based on the use of anti-oxidants and chelation therapy, has now successfully been replaced by exchange transfusions and intravenous immunoglobulins substitution. This review summarizes the latest discoveries on the etiology of NH and the new recommendations concerning its management and prevention. © 2013 John Wiley & Sons, Ltd.
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gestational alloimmune liver disease and Neonatal Hemochromatosis
Seminars in Liver Disease, 2013Co-Authors: Peter F WhitingtonAbstract:Neonatal Hemochromatosis (NH) is a clinical syndrome consisting of liver disease and pathologic siderosis of various extrahepatic tissues. NH is a form of secondary Hemochromatosis in which severe fetal liver injury causes iron overload due to poor regulation of maternofetal iron flux. Gestational alloimmune liver disease (GALD) has been established as the cause of fetal liver injury resulting in nearly all cases of NH. In GALD, sensitization of some women to a fetal liver antigen results in development of specific antifetal liver IgG antibodies. When delivered to the fetal circulation these antibodies bind to the antigen and activate the terminal complement cascade resulting in hepatocyte injury and death. GALD may produce subacute and chronic fetal liver injury (congenital cirrhosis) typical of NH. It may also produce acute injury and acute liver failure of the fetus and newborn, often with no iron overload or siderosis.
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Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease
Journal of Hepatology, 2012Co-Authors: Silvana Bonilla, Joshua Prozialeck, Padmini Malladi, Xiaomin Pan, Hector Melinaldana, Peter F WhitingtonAbstract:Background & Aims Gestational alloimmune liver disease is the main cause of the Neonatal Hemochromatosis phenotype, wherein severe Neonatal liver disease is associated with iron overload and extrahepatic tissue siderosis. How fetal liver disease produces extrahepatic siderosis is not known. We hypothesized that fetal liver injury causes deficient hepcidin production and poor regulation of placental iron flux. Under the resulting conditions of iron overload, the tissue pattern of extrahepatic siderosis is determined by the normal expression of proteins involved in the import of non-transferrin-bound iron and the export of cellular iron. Methods Liver and extrahepatic tissues from infants with gestational alloimmune liver disease were examined and compared to normal age-appropriate tissues. Results Serum iron indices indicate iron overload and excess non-transferrin bound iron in gestational alloimmune liver disease. The diseased liver showed significantly reduced hepcidin, hemojuvulin, and transferrin gene expression compared to the normal fetal and Neonatal liver. Those extrahepatic tissues that are typically involved in pathological siderosis in Neonatal Hemochromatosis, whether from normal or diseased newborns, consistently expressed solute carrier family 39 (zinc transporter), member 14 (ZIP14) for non-transferrin-bound iron uptake and expressed little ferroportin for iron export. Conclusions Excess non-transferrin-bound iron in gestational alloimmune liver disease may result from fetal liver injury that causes reduced synthesis of key iron regulatory and transport proteins. Whereas, the pattern of extrahepatic siderosis appears to be determined by the normal capacity of various tissues to import non-transferrin-bound iron and not export cellular iron.
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gestational alloimmune liver disease in cases of fetal death
The Journal of Pediatrics, 2011Co-Authors: Peter F Whitington, Susan Kelly, Hector Melinaldana, Padmini MalladiAbstract:Objective To determine whether alloimmune liver disease can be identified as a cause of fetal death. Study design This is a retrospective examination of the autopsy tissue of 6 stillborn fetuses and 2 extreme preterm infants (gestational age, 20 to 34 weeks) drawn from families referred for suspected Neonatal Hemochromatosis. Thirteen appropriate nondisease controls and 8 cases of Neonatal acute liver failure with known etiology were also examined. Liver sections were immunostained using anti-human C5b-9 complex. Results All of the study cases had died with no preceding evidence of fetal distress. Histopathology showed findings of acute liver injury, including global hepatocyte necrosis with minimal reticulum collapse and no fibrosis. Hepatocytes in cases stained strongly positively for C5b-9 complex, suggesting premortem lgG complement–mediated liver injury. Hepatocytes in acute liver failure case controls did not demonstrate a similar mechanism of liver injury. Conclusions Alloimmune liver disease is sometimes associated with fetal death.
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treatment of Neonatal Hemochromatosis with exchange transfusion and intravenous immunoglobulin
The Journal of Pediatrics, 2009Co-Authors: Elizabeth B Rand, Susan Kelly, Saul J Karpen, Cara L Mack, Jeffrey J Malatack, Ronald J Sokol, Peter F WhitingtonAbstract:Objective To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favorably affect survival in neontatal Hemochromatosis (NH) diagnosed postnatally because it can effectively prevent occurrence of NH when applied during gestations at risk. Study design We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with exchangetransfusionin13(ET/IVIG),andcomparedtheoutcomewith131historicalcontrolstreatedconventionally. Results The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/ IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy. Twelve subjects (75%) had good outcome, defined as survival without liver transplantation, whereas good outcome was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after liver transplant. Survivors were discharged 6to 90 days after receivingET/IVIGtherapy, and those followed formore than 1 year are within normal measures for growth, development, and liver function. Conclusions Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver transplantation in patients with NH. (J Pediatr 2009;155:566-71).
Olivier Goulet - One of the best experts on this subject based on the ideXlab platform.
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Syndromic diarrhea/Tricho-hepato-enteric syndrome
Orphanet Journal of Rare Diseases, 2013Co-Authors: Alexandre Fabre, Olivier Goulet, Christine Martinez-vinson, Catherine BadensAbstract:Syndromic diarrhea/Tricho-hepato-enteric syndrome (SD/THE) is a rare and severe bowel disorder caused by mutation in SKIV2L or in TTC37 , 2 genes encoding subunits of the putative human SKI complex. The estimated prevalence is 1/1,000,000 births and the transmission is autosomal recessive. The classical form is characterized by 5 clinical signs: intractable diarrhea of infancy beginning in the first month of life, usually leading to failure to thrive and requiring parenteral nutrition; facial dysmorphism characterised by prominent forehead and cheeks, broad nasal root and hypertelorism; hair abnormalities described as woolly and easily removable; immune disorders resulting from defective antibody production; intrauterine growth restriction. The aetiology is a defect in TTC37 , a TPR containing protein, or in the RNA helicase SKIV2L , both constituting the putative human ski complex. The ski complex is a heterotetrameric cofactor of the cytoplasmic RNA exosome which ensures aberrants mRNAs decay. The diagnosis SD/THE is initially based on clinical findings and confirmed by direct sequencing of TTC37 and SKIV2L . Differential diagnosis with the other causes of intractable diarrhea is easily performed by pathologic investigations. During their clinical course, most of the children require parenteral nutrition and often immunoglobulin supplementation. With time, some of them can be weaned off parenteral nutrition and immunoglobulin supplementation. The prognosis depends on the management and is largely related to the occurrence of parenteral nutrition complications or infections. Even with optimal management, most of the children seem to experience failure to thrive and final short stature. Mild mental retardation is observed in half of the cases. Abstract in French Les diarrhées syndromiques ou syndrome tricho-hepato-enterique (SD/THE) sont un syndrome rare et sévère dont l’incidence est estimée à 1 cas pour 1 million de naissances et la transmission autosomique récessive. La forme typique associe 5 signes cliniques: une diarrhée grave rebelle nécessitant dans la majorité des cas une nutrition parentérale du fait de la malnutrition, une dysmorphie avec un front large et bombé, une racine du nez large et un hypertélorisme, des anomalies des cheveux qui sont fragiles, cassants, incoiffables et qualifiés de « laineux », un retard de croissance intra utérine et des anomalies de l’immunité à type de déficit en immunoglobuline ou d’absence de réponse aux antigènes vaccinaux. Des anomalies de deux protéines peuvent être à l’origine du syndrome SD/THE: TTC37 , une protéine à motif TPR et SKIV2L , une hélicase à ARN, toutes 2 étant des constituants du complexe SKI humain. Le complexe SKI est un co-facteur de l’exosome cytoplasmique qui assure la dégradation des ARN aberrants ou exogènes. Le diagnostic est d’abord clinique puis confirmé par le séquençage des gènes TTC37 et SKIV2L . Le diagnostic différentiel avec les autres formes de diarrhées intraitables est fait grâce aux analyses anatomopathologiques qui montrent dans les autres formes, des lésions spécifiques. La prise en charge clinique repose sur la nutrition parentérale et la supplémentation en immunoglobuline si nécessaire. Un certain nombre d’enfants peuvent être sevrés de la nutrition parentérale et des supplémentations en immunoglobulines. En cas d’atteinte hépatique, celle-ci peut être sévère et conduire au décès. Même avec une prise en charge optimale, les enfants présentent une petite taille et, dans la moitié des cas, un retard mental modéré. Disease name/synonyms – Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal Hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency- Syndromatic diarrhea. [ORPHA84064 MIM 222470 and MIM614602]. Possibly chronic diarrhea and skin hyperpigmentation.
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Syndromic (phenotypic) diarrhea in early infancy
Orphanet Journal of Rare Diseases, 2008Co-Authors: Olivier Goulet, Christine Vinson, Bertrand Roquelaure, Nicole Brousse, Christine Bodemer, Jean-pierre CézardAbstract:: Syndromic diarrhea (SD), also known as phenotypic diarrhea (PD) or tricho-hepato-enteric syndrome (THE), is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN). To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000–400,000 live births in Western Europe. Ethnic origin does not appear to be associated with SD. Infants are born small for gestational age and present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hairs are woolly, easily removed and poorly pigmented. Severe and persistent diarrhea starts within the first 6 months of life (≤ 1 month in most cases) and is accompanied by severe malabsorption leading to early and relentless protein energy malnutrition with failure to thrive. Liver disease affects about half of patients with extensive fibrosis or cirrhosis. There is currently no specific biochemical profile, though a functional T-cell immune deficiency with defective antibody production was reported. Microscopic analysis of the hair show twisted hair (pili torti), aniso- and poilkilotrichosis, and trichorrhexis nodosa. Histopathological analysis of small intestine biopsy shows non-specific villous atrophy with low or no mononuclear cell infiltration of the lamina propria, and no specific histological abnormalities involving the epithelium. The etiology remains unknown. The frequent association of the disorder with parental consanguinity and/or affected siblings suggests a genetic origin with an autosomal recessive mode of transmission. Early management consists of total PN. Some infants have a rather milder phenotype with partial PN dependency or require only enteral feeding. Prognosis of this syndrome is poor, but most patients now survive, and about half of the patients may be weaned from PN at adolescence, but experience failure to thrive and final short stature. Disease name and synonyms Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal Hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency.
Jean-pierre Cézard - One of the best experts on this subject based on the ideXlab platform.
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Syndromic (phenotypic) diarrhea in early infancy
Orphanet Journal of Rare Diseases, 2008Co-Authors: Olivier Goulet, Christine Vinson, Bertrand Roquelaure, Nicole Brousse, Christine Bodemer, Jean-pierre CézardAbstract:: Syndromic diarrhea (SD), also known as phenotypic diarrhea (PD) or tricho-hepato-enteric syndrome (THE), is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN). To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000–400,000 live births in Western Europe. Ethnic origin does not appear to be associated with SD. Infants are born small for gestational age and present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hairs are woolly, easily removed and poorly pigmented. Severe and persistent diarrhea starts within the first 6 months of life (≤ 1 month in most cases) and is accompanied by severe malabsorption leading to early and relentless protein energy malnutrition with failure to thrive. Liver disease affects about half of patients with extensive fibrosis or cirrhosis. There is currently no specific biochemical profile, though a functional T-cell immune deficiency with defective antibody production was reported. Microscopic analysis of the hair show twisted hair (pili torti), aniso- and poilkilotrichosis, and trichorrhexis nodosa. Histopathological analysis of small intestine biopsy shows non-specific villous atrophy with low or no mononuclear cell infiltration of the lamina propria, and no specific histological abnormalities involving the epithelium. The etiology remains unknown. The frequent association of the disorder with parental consanguinity and/or affected siblings suggests a genetic origin with an autosomal recessive mode of transmission. Early management consists of total PN. Some infants have a rather milder phenotype with partial PN dependency or require only enteral feeding. Prognosis of this syndrome is poor, but most patients now survive, and about half of the patients may be weaned from PN at adolescence, but experience failure to thrive and final short stature. Disease name and synonyms Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal Hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency.
Catherine Badens - One of the best experts on this subject based on the ideXlab platform.
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Syndromic diarrhea/Tricho-hepato-enteric syndrome
Orphanet Journal of Rare Diseases, 2013Co-Authors: Alexandre Fabre, Olivier Goulet, Christine Martinez-vinson, Catherine BadensAbstract:Syndromic diarrhea/Tricho-hepato-enteric syndrome (SD/THE) is a rare and severe bowel disorder caused by mutation in SKIV2L or in TTC37 , 2 genes encoding subunits of the putative human SKI complex. The estimated prevalence is 1/1,000,000 births and the transmission is autosomal recessive. The classical form is characterized by 5 clinical signs: intractable diarrhea of infancy beginning in the first month of life, usually leading to failure to thrive and requiring parenteral nutrition; facial dysmorphism characterised by prominent forehead and cheeks, broad nasal root and hypertelorism; hair abnormalities described as woolly and easily removable; immune disorders resulting from defective antibody production; intrauterine growth restriction. The aetiology is a defect in TTC37 , a TPR containing protein, or in the RNA helicase SKIV2L , both constituting the putative human ski complex. The ski complex is a heterotetrameric cofactor of the cytoplasmic RNA exosome which ensures aberrants mRNAs decay. The diagnosis SD/THE is initially based on clinical findings and confirmed by direct sequencing of TTC37 and SKIV2L . Differential diagnosis with the other causes of intractable diarrhea is easily performed by pathologic investigations. During their clinical course, most of the children require parenteral nutrition and often immunoglobulin supplementation. With time, some of them can be weaned off parenteral nutrition and immunoglobulin supplementation. The prognosis depends on the management and is largely related to the occurrence of parenteral nutrition complications or infections. Even with optimal management, most of the children seem to experience failure to thrive and final short stature. Mild mental retardation is observed in half of the cases. Abstract in French Les diarrhées syndromiques ou syndrome tricho-hepato-enterique (SD/THE) sont un syndrome rare et sévère dont l’incidence est estimée à 1 cas pour 1 million de naissances et la transmission autosomique récessive. La forme typique associe 5 signes cliniques: une diarrhée grave rebelle nécessitant dans la majorité des cas une nutrition parentérale du fait de la malnutrition, une dysmorphie avec un front large et bombé, une racine du nez large et un hypertélorisme, des anomalies des cheveux qui sont fragiles, cassants, incoiffables et qualifiés de « laineux », un retard de croissance intra utérine et des anomalies de l’immunité à type de déficit en immunoglobuline ou d’absence de réponse aux antigènes vaccinaux. Des anomalies de deux protéines peuvent être à l’origine du syndrome SD/THE: TTC37 , une protéine à motif TPR et SKIV2L , une hélicase à ARN, toutes 2 étant des constituants du complexe SKI humain. Le complexe SKI est un co-facteur de l’exosome cytoplasmique qui assure la dégradation des ARN aberrants ou exogènes. Le diagnostic est d’abord clinique puis confirmé par le séquençage des gènes TTC37 et SKIV2L . Le diagnostic différentiel avec les autres formes de diarrhées intraitables est fait grâce aux analyses anatomopathologiques qui montrent dans les autres formes, des lésions spécifiques. La prise en charge clinique repose sur la nutrition parentérale et la supplémentation en immunoglobuline si nécessaire. Un certain nombre d’enfants peuvent être sevrés de la nutrition parentérale et des supplémentations en immunoglobulines. En cas d’atteinte hépatique, celle-ci peut être sévère et conduire au décès. Même avec une prise en charge optimale, les enfants présentent une petite taille et, dans la moitié des cas, un retard mental modéré. Disease name/synonyms – Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal Hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency- Syndromatic diarrhea. [ORPHA84064 MIM 222470 and MIM614602]. Possibly chronic diarrhea and skin hyperpigmentation.
Susan Kelly - One of the best experts on this subject based on the ideXlab platform.
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gestational alloimmune liver disease in cases of fetal death
The Journal of Pediatrics, 2011Co-Authors: Peter F Whitington, Susan Kelly, Hector Melinaldana, Padmini MalladiAbstract:Objective To determine whether alloimmune liver disease can be identified as a cause of fetal death. Study design This is a retrospective examination of the autopsy tissue of 6 stillborn fetuses and 2 extreme preterm infants (gestational age, 20 to 34 weeks) drawn from families referred for suspected Neonatal Hemochromatosis. Thirteen appropriate nondisease controls and 8 cases of Neonatal acute liver failure with known etiology were also examined. Liver sections were immunostained using anti-human C5b-9 complex. Results All of the study cases had died with no preceding evidence of fetal distress. Histopathology showed findings of acute liver injury, including global hepatocyte necrosis with minimal reticulum collapse and no fibrosis. Hepatocytes in cases stained strongly positively for C5b-9 complex, suggesting premortem lgG complement–mediated liver injury. Hepatocytes in acute liver failure case controls did not demonstrate a similar mechanism of liver injury. Conclusions Alloimmune liver disease is sometimes associated with fetal death.
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treatment of Neonatal Hemochromatosis with exchange transfusion and intravenous immunoglobulin
The Journal of Pediatrics, 2009Co-Authors: Elizabeth B Rand, Susan Kelly, Saul J Karpen, Cara L Mack, Jeffrey J Malatack, Ronald J Sokol, Peter F WhitingtonAbstract:Objective To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favorably affect survival in neontatal Hemochromatosis (NH) diagnosed postnatally because it can effectively prevent occurrence of NH when applied during gestations at risk. Study design We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with exchangetransfusionin13(ET/IVIG),andcomparedtheoutcomewith131historicalcontrolstreatedconventionally. Results The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/ IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy. Twelve subjects (75%) had good outcome, defined as survival without liver transplantation, whereas good outcome was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after liver transplant. Survivors were discharged 6to 90 days after receivingET/IVIGtherapy, and those followed formore than 1 year are within normal measures for growth, development, and liver function. Conclusions Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver transplantation in patients with NH. (J Pediatr 2009;155:566-71).
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outcome of pregnancies at risk for Neonatal Hemochromatosis is improved by treatment with high dose intravenous immunoglobulin
Pediatrics, 2008Co-Authors: Peter F Whitington, Susan KellyAbstract:Objectives Neonatal Hemochromatosis is the result of severe fetal liver injury that seems to result from maternal-fetal alloimmunity. Women who have had an infant affected with Neonatal Hemochromatosis are at high risk in subsequent pregnancies for having another affected infant. This study was designed to determine whether therapy directed at limiting the severity of gestational alloimmunity can reduce the occurrence of severe Neonatal Hemochromatosis in infants of women at risk. A secondary objective was to use a prospectively collected data set to examine questions of vital interest about Neonatal Hemochromatosis. Methods Women with a history of pregnancy ending in documented Neonatal Hemochromatosis were treated with intravenous immunoglobulin at 1 g/kg of body weight weekly from week 18 until the end of gestation. Extensive data were prospectively collected regarding the gestational histories of the subjects. The outcomes of treated pregnancies were compared with those of previous affected pregnancies, which were used as historical controls. Results Forty-eight women were enrolled to be treated during 53 pregnancies. The gestational histories of these women demonstrated the high risk of occurrence of Neonatal Hemochromatosis: 92% of pregnancies at risk resulted in intrauterine fetal demise, Neonatal death, or liver failure necessitating transplant. In contrast, with gestational therapy, the 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone. When compared on a per-woman or per-infant basis, the outcome of gestation at risk for Neonatal Hemochromatosis was improved by gestational therapy. Conclusions Neonatal Hemochromatosis seems to be the result of a gestational alloimmune disease, and occurrence of severe Neonatal Hemochromatosis in at-risk pregnancies can be significantly reduced by treatment with high-dose intravenous immunoglobulin during gestation.
