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Semin Liver Dis 2007; 27(3): 243-250
DOI: 10.1055/s-2007-985069
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Neonatal Hemochromatosis: A Congenital Alloimmune Hepatitis

Peter F. Whitington1
  • 1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Children's Memorial Hospital, Chicago, Illinois
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Publikationsverlauf

Publikationsdatum:
08. August 2007 (online)

   Lizenzen und Reprints

ABSTRACT

Neonatal hemochromatosis (NH) is a rare and enigmatic disease that has been clinically defined as severe neonatal liver disease in association with extrahepatic siderosis. It recurs at an alarming rate in the offspring of certain women; the rate and pattern of recurrence led us to hypothesize that maternal alloimmunity is the likely cause at least of recurrent cases. This hypothesis led to a trial of gestational treatment to prevent the recurrence of severe NH, which has been highly successful adding strength to the alloimmune hypothesis. Laboratory proof of an alloimmune mechanism has been gained by reproducing the disease in a mouse model. NH should be suspected in any very sick newborn with evidence of liver disease and in cases of late intrauterine fetal demise. Given the pathology of the liver and the mechanism of liver injury, NH could best be classified as congenital alloimmune hepatitis.

KEYWORDS

Neonatal hemochromatosis - acute liver failure - alloimmune disease - cirrhosis - hepatitis

REFERENCES

  • 1 Knisely A S, Mieli-Vergani G, Whitington P F. Neonatal hemochromatosis.  Gastroenterol Clin North Am. 2003;  32 877-889
    CrossrefPubMedGoogle Scholar
  • 2 Knisely A S. Neonatal hemochromatosis.  Adv Pediatr. 1992;  39 383-403
    PubMedGoogle Scholar
  • 3 Goldfischer S, Grotsky H W, Chang C H et al.. Idiopathic neonatal iron storage involving the liver, pancreas, heart, and endocrine and exocrine glands.  Hepatology. 1981;  1 58-64
    CrossrefPubMedGoogle Scholar
  • 4 Murray K F, Kowdley K V. Neonatal hemochromatosis.  Pediatrics. 2001;  108 960-964
    CrossrefPubMedGoogle Scholar
  • 5 van Dijk J P. Regulatory aspects of placental iron transfer: a comparative study.  Placenta. 1988;  9 215-226
    PubMedGoogle Scholar
  • 6 Fleming R E, Bacon B R. Orchestration of iron homeostasis.  N Engl J Med. 2005;  352 1741-1744
    CrossrefPubMedGoogle Scholar
  • 7 Georgieff M K, Wobken J K, Welle J, Burdo J R, Connor J R. Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta.  Placenta. 2000;  21 799-804
    CrossrefPubMedGoogle Scholar
  • 8 Bradley J, Leibold E A, Harris Z L et al.. Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta.  Am J Physiol Regul Integr Comp Physiol. 2004;  287 R894-R901
    PubMedGoogle Scholar
  • 9 Gruper Y, Bar J, Bacharach E, Ehrlich R. Transferrin receptor co-localizes and interacts with the hemochromatosis factor (HFE) and the divalent metal transporter-1 (DMT1) in trophoblast cells.  J Cell Physiol. 2005;  204 901-912
    CrossrefPubMedGoogle Scholar
  • 10 Nicolas G, Bennoun M, Devaux I et al.. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.  Proc Natl Acad Sci U S A. 2001;  98 8780-8785
    CrossrefPubMedGoogle Scholar
  • 11 Nicolas G, Bennoun M, Porteu A et al.. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.  Proc Natl Acad Sci U S A. 2002;  99 4596-4601
    CrossrefPubMedGoogle Scholar
  • 12 Hoogstraten J, de Sa D J, Knisely A S. Fetal liver disease may precede extrahepatic siderosis in neonatal hemochromatosis.  Gastroenterology. 1990;  98 1699-1701
    PubMedGoogle Scholar
  • 13 Kershisnik M M, Knisely A S, Sun C C, Andrews J M, Wittwer C T. Cytomegalovirus infection, fetal liver disease, and neonatal hemochromatosis.  Hum Pathol. 1992;  23 1075-1080
    CrossrefPubMedGoogle Scholar
  • 14 Witzleben C L, Uri A. Perinatal hemochromatosis: entity or end result?.  Hum Pathol. 1989;  20 335-340
    CrossrefPubMedGoogle Scholar
  • 15 Camaschella C, Roetto A, De Gobbi M. Juvenile hemochromatosis.  Semin Hematol. 2002;  39 242-248
    CrossrefPubMedGoogle Scholar
  • 16 De Gobbi M, Roetto A, Piperno A et al.. Natural history of juvenile haemochromatosis.  Br J Haematol. 2002;  117 973-979
    CrossrefPubMedGoogle Scholar
  • 17 Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload.  J Clin Invest. 2005;  115 2180-2186
    CrossrefPubMedGoogle Scholar
  • 18 Whitington P F, Malladi P. Neonatal hemochromatosis: is it an alloimmune disease?.  J Pediatr Gastroenterol Nutr. 2005;  40 544-549
    CrossrefPubMedGoogle Scholar
  • 19 Kelly A L, Lunt P W, Rodrigues F et al.. Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism.  J Med Genet. 2001;  38 599-610
    CrossrefPubMedGoogle Scholar
  • 20 Shneider B L. Genetic counseling in neonatal hemochromatosis.  J Pediatr Gastroenterol Nutr. 2002;  34 328
    CrossrefPubMedGoogle Scholar
  • 21 Whitington P F, Hibbard J U. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis.  Lancet. 2004;  364 1690-1698
    CrossrefPubMedGoogle Scholar
  • 22 Allen K J, Hart J, Whitington P F. Spectrum of outcomes in family of male siblings with neonatal hemochromatosis [abstract].  J Pediatr Gastroenterol Nutr. 1996;  23 352
    PubMedGoogle Scholar
  • 23 Malladi P, Wang H, Pan X, Kohli R, Whitington P F. The pathogenesis of neonatal hemochromatosis involves maternal IGG alloantibody mediated complement-dependent hepatocytolysis and necrosis.  Hepatology. 2006;  44 56A
    PubMedGoogle Scholar
  • 24 Shneider B L, Setchell K D, Whitington P F, Neilson K A, Suchy F J. Delta 4-3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis.  J Pediatr. 1994;  124 234-238
    PubMedGoogle Scholar
  • 25 Visapaa I, Fellman V, Vesa J et al.. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L.  Am J Hum Genet. 2002;  71 863-876
    CrossrefPubMedGoogle Scholar
  • 26 Cox T M, Halsall D J. Hemochromatosis: neonatal and young subjects.  Blood Cells Mol Dis. 2002;  29 411-417
    CrossrefPubMedGoogle Scholar
  • 27 Silver M M, Valberg L S, Cutz E, Lines L D, Phillips M J. Hepatic morphology and iron quantitation in perinatal hemochromatosis: comparison with a large perinatal control population, including cases with chronic liver disease.  Am J Pathol. 1993;  143 1312-1325
    PubMedGoogle Scholar
  • 28 Knisely A S, O'Shea P A, Stocks J F, Dimmick J E. Oropharyngeal and upper respiratory tract mucosal-gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis.  J Pediatr. 1988;  113 871-874
    PubMedGoogle Scholar
  • 29 Silver M M, Beverley D W, Valberg L S, Cutz E, Phillips M J, Shaheed W A. Perinatal hemochromatosis: clinical, morphologic, and quantitative iron studies.  Am J Pathol. 1987;  128 538-554
    PubMedGoogle Scholar
  • 30 Johal J S, Thorp J W, Oyer C E. Neonatal hemochromatosis, renal tubular dysgenesis, and hypocalvaria in a neonate.  Pediatr Dev Pathol. 1998;  1 433-437
    CrossrefPubMedGoogle Scholar
  • 31 Morris S, Akima S, Dahlstrom J E, Ellwood D, Kent A, Falk M C. Renal tubular dysgenesis and neonatal hemochromatosis without pulmonary hypoplasia.  Pediatr Nephrol. 2004;  19 341-344
    CrossrefPubMedGoogle Scholar
  • 32 Rodrigues F, Kallas M, Nash R et al.. Neonatal hemochromatosis: medical treatment vs. transplantation: the King's experience.  Liver Transpl. 2005;  11 1417-1424
    CrossrefPubMedGoogle Scholar
  • 33 Durand P, Debray D, Mandel R et al.. Acute liver failure in infancy: a 14-year experience of a pediatric liver transplantation center.  J Pediatr. 2001;  139 871-876
    CrossrefPubMedGoogle Scholar
  • 34 Shneider B L. Neonatal liver failure.  Curr Opin Pediatr. 1996;  8 495-501
    CrossrefPubMedGoogle Scholar
  • 35 Ku S W, Luk I S, Yuen M K, Wong C P. Subacute hepatic failure after the perinatal period with haemochromatotic siderosis at the age of 11 months: an unusual perspective on neonatal haemochromatosis.  Acta Paediatr. 2002;  91 856-858
    CrossrefPubMedGoogle Scholar
  • 36 Inui A, Fujisawa T, Kubo T, Sogo T, Komatsu H, Kagata Y. A case of neonatal hemochromatosis-like liver failure with spontaneous remission.  J Pediatr Gastroenterol Nutr. 2005;  40 374-377
    CrossrefPubMedGoogle Scholar
  • 37 Bellini C, Mazzella M, Scopesi F, Serra G. Spontaneous recovery in neonatal hemochromatosis.  J Hepatol. 2004;  41 882-883
    CrossrefPubMedGoogle Scholar
  • 38 Ekong U D, Kelly S, Whitington P F. Disparate clinical presentation of neonatal hemochromatosis in twins.  Pediatrics. 2005;  116 e880-e884
    CrossrefPubMedGoogle Scholar
  • 39 Lee W S, McKiernan P J, Kelly D A. Serum ferritin level in neonatal fulminant liver failure.  Arch Dis Child Fetal Neonatal Ed. 2001;  85 F226
    CrossrefPubMedGoogle Scholar
  • 40 Smith S R, Shneider B L, Magid M, Martin G, Rothschild M. Minor salivary gland biopsy in neonatal hemochromatosis.  Arch Otolaryngol Head Neck Surg. 2004;  130 760-763
    CrossrefPubMedGoogle Scholar
  • 41 Hayes A M, Jaramillo D, Levy H L, Knisely A S. Neonatal hemochromatosis: diagnosis with MR imaging.  AJR Am J Roentgenol. 1992;  159 623-625
    CrossrefPubMedGoogle Scholar
  • 42 Udell I W, Barshes N R, Voloyiannis T et al.. Neonatal hemochromatosis: radiographical and histological signs.  Liver Transpl. 2005;  11 998-1000
    CrossrefPubMedGoogle Scholar
  • 43 Flynn D M, Mohan N, McKiernan P et al.. Progress in treatment and outcome for children with neonatal haemochromatosis.  Arch Dis Child Fetal Neonatal Ed. 2003;  88 F124-F127
    CrossrefPubMedGoogle Scholar
  • 44 Vohra P, Haller C, Emre S et al.. Neonatal hemochromatosis: the importance of early recognition of liver failure.  J Pediatr. 2000;  136 537-541
    CrossrefPubMedGoogle Scholar
  • 45 Sundaram S S, Alonso E M, Whitington P F. Liver transplantation in neonates.  Liver Transpl. 2003;  9 783-788
    CrossrefPubMedGoogle Scholar
  • 46 Woodle E S, Millis J M, So S K et al.. Liver transplantation in the first three months of life.  Transplantation. 1998;  66 606-609
    CrossrefPubMedGoogle Scholar
  • 47 Rand E B, McClenathan D T, Whitington P F. Neonatal hemochromatosis: report of successful orthotopic liver transplantation.  J Pediatr Gastroenterol Nutr. 1992;  15 325-329
    PubMedGoogle Scholar
  • 48 Sigurdsson L, Reyes J, Kocoshis S A, Hansen T W, Rosh J, Knisely A S. Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies.  J Pediatr Gastroenterol Nutr. 1998;  26 85-89
    CrossrefPubMedGoogle Scholar
  • 49 Rand E B, Karpen S J, Zweiner J et al.. Treatment of neonatal hemochromatosis based on alloimmune causation.  Hepatology. 2006;  44 435A
    PubMedGoogle Scholar
  • 50 Ekong U, Melin-Aldana H, Whitington P F. Reversal of cirrhosis in two children with neonatal hemochromatosis.  J Pediatr Gastroenterol Nutr. 2007;  , In press
    PubMedGoogle Scholar
  • 51 Whitington P F. Fetal and infantile hemochromatosis.  Hepatology. 2006;  43 654-660
    CrossrefPubMedGoogle Scholar

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