Neonatal Hemochromatosis

Neonatal Hemochromatosis

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Neonatal hemochromatosis is a syndrome in which severe liver disease of fetal or perinatal onset is associated with deposition of stainable iron in extrahepatic sites. [1] The distribution of extrahepatic iron mimics that observed in hepatic iron (HFE) disease, the most common form of hemochromatosis known in Europe and the Americas, and liver disease is common in late-stage HFE disease. Nonetheless, neonatal hemochromatosis is not a manifestation of HFE disease.

Neonatal hemochromatosis is not a single disorder but is a syndrome with an unclear etiology. Neonatal hemochromatosis represents disordered iron handling due to injury to the perinatal liver [2] and can be thought of as a form of fulminant hepatic failure.

Treatment after birth requires supportive care with or without administration of an iron-chelating cocktail and several antioxidants. Survival rates in babies who undergo liver transplantation is reportedly 50%. [3]  Exchange transfusions and intravenous immunoglobulins have emerged as possible new treatments. [4, 5] Liver disease ascribed to hemosiderosis has not recurred in survivors to date.

The prognosis is extremely poor. Some infants recover with supportive care, but this rarely occurs.

Suggest genetic counseling if the parents of a child with neonatal hemochromatosis desire to have another child. However, genetic patterns are unclear.

Go to Hemochromatosis and Dermatologic Manifestations of Hemochromatosis for complete information on these topics.

In hemochromatosis, hepatocytes are the first site of iron deposition. Liver tissue of affected infants displays severe injury with marked loss of hepatocytes.  Involvement then extends to the hepatic lobule and the pancreatic parenchyma. The myocardial and endocrine systems may also be involved, which can lead to failure of both. The effects can be observed antenatally with involvement of the placenta, causing placental edema and oligohydramnios. These infants may be stillborn, premature, or have intrauterine growth restriction (IUGR).

Postmortem examination reveals the following:

The liver is small and bile stained; contours may be irregular, and the stroma may be collapsed

Microscopic examination of the liver reveals that the hepatocytes have giant cell transformation with bile plugs or that the hepatocytes may not be present at all; also, the hepatocytes may show siderosis. Scarring from macrophages, which contain high levels of stainable iron, may be present.  Cirrhosis may be present

Bile ducts are proliferated

The spleen, lymph nodes, and bone marrow contain minimal levels of stainable iron

Splenomegaly, pancreatic islet cell hyperplasia, and absence of proximal renal tubules is noted

The exact cause of neonatal hemochromatosis is unknown. There are two schools of thought: one hypothesizes that injury to the liver causes abnormal handling of iron by the liver; the other hypothesizes that the abnormal handling of iron by the liver leads to liver injury and failure.

Four pieces of evidence suggest that neonatal hemochromatosis may be due to an acquired and persistent maternal factor. First, neonatal hemochromatosis recurs within sibships at a rate higher than expected for disorders transmitted in an autosomal recessive manner. Second, several kindreds are known in which mothers have given birth to children with neonatal hemochromatosis who were fathered by different men.

Third, several kindreds are known in which parents of children with neonatal hemochromatosis had histories of exposure to blood with or without clinical hepatitis. Fourth, anecdotal evidence suggests that administering intravenous immunoglobulin during pregnancy in a woman who has already had an infant with neonatal hemochromatosis leads to a relatively favorable outcome.

These data suggest mitochondrial disease, transplacental transmission of an infective (possibly viral) agent, or transplacental transmission of an antibody as a cause of at least some instances of neonatal hemochromatosis. Because neonatal hemochromatosis is a syndrome, any of these possibilities may be correct in a given family, and all of them must be considered.

Neonatal hemochromatosis is rare. [6] To date, no rates of this disease are reported. Studies suggest a genetic prevalence of 0.03-0.038 or a heterozygosity prevalence of 6-7%. It has been described variously as a dominant and a recessive disorder. [7]

Neonatal hemochromatosis has been documented in Filipino, African American, Hong Kong Chinese, and white infants. No reported increase rates in any race are noted to date. No sex predilection is known. Neonatal hemochromatosis is thought to occur with damage to the liver at 16-30 weeks’ gestation. [8]

Adams PC, Searle J. Neonatal hemochromatosis: a case and review of the literature. Am J Gastroenterol. 1988 Apr. 83(4):422-5. [Medline].

Muller-Berghaus J, Knisely AS, Zaum R, et al. Neonatal haemochromatosis: report of a patient with favourable outcome. Eur J Pediatr. 1997 Apr. 156(4):296-8. [Medline].

Rodrigues F, Kallas M, Nash R, et al. Neonatal hemochromatosis–medical treatment vs. transplantation: the king’s experience. Liver Transpl. 2005 Nov. 11 (11):1417-24. [Medline].

Machtei A, Klinger G, Shapiro R, Konen O, Sirota L. Clinical and Imaging Resolution of Neonatal Hemochromatosis following Treatment. Case Rep Crit Care. 2014. 2014:650916. [Medline].

Babor F, Hadzik B, Stannigel H, Mayatepek E, Hoehn T. Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: a case report. J Perinatol. 2013 Jan. 33 (1):83-5. [Medline].

Colletti RB, Clemmons JJ. Familial neonatal hemochromatosis with survival. J Pediatr Gastroenterol Nutr. 1988 Jan-Feb. 7(1):39-45. [Medline].

McKusick VA. Mendelian Inheritance in Man. 5th ed. Baltimore, Md: Johns Hopkins University Press; 1978.

Whitington PF. Gestational alloimmune liver disease and neonatal hemochromatosis. Semin Liver Dis. 2012 Nov. 32(4):325-32. [Medline].

Liet JM, Urtin-Hostein C, Joubert M, et al. Neonatal hemochromatosis [in French]. Arch Pediatr. 2000 Jan. 7(1):40-4. [Medline].

Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet. 2004 Nov 6-12. 364(9446):1690-8. [Medline].

Sigurdsson L, Reyes J, Kocoshis SA, et al. Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J Pediatr Gastroenterol Nutr. 1998 Jan. 26(1):85-9. [Medline].

Babor F, Hadzik B, Stannigel H, Mayatepek E, Hoehn T. Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: a case report. J Perinatol. 2013 Jan. 33(1):83-5. [Medline].

Whitington PF, Kelly S, Ekong UD. Neonatal hemochromatosis: fetal liver disease leading to liver failure in the fetus and newborn. Pediatr Transplant. 2005 Oct. 9(5):640-5. [Medline].

Ann M Simonin, MD, FAAP Fellow in Neonatology, Children’s Hospital of Georgia

Ann M Simonin, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Jatinder Bhatia, MBBS, FAAP Professor of Pediatrics, Medical College of Georgia, Georgia Regents University; Chief, Division of Neonatology, Director, Fellowship Program in Neonatal-Perinatal Medicine, Director, Transport/ECMO/Nutrition, Vice Chair, Clinical Research, Department of Pediatrics, Children’s Hospital of Georgia

Jatinder Bhatia, MBBS, FAAP is a member of the following medical societies: Academy of Nutrition and Dietetics, American Academy of Pediatrics, American Association for the Advancement of Science, American Pediatric Society, American Society for Nutrition, American Society for Parenteral and Enteral Nutrition, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Nestle<br/>Serve(d) as a speaker or a member of a speakers bureau for: Nestle<br/>Received income in an amount equal to or greater than $250 from: Nestle.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David A Piccoli, MD Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine

David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Royal College of Physicians and Surgeons of Canada

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers’ bureau.

Hisham Nazer, MBBCh, FRCP, DTM&H Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, University of Jordan Faculty of Medicine, Jordan

Hisham Nazer, MBBCh, FRCP, DTM&H is a member of the following medical societies: American Association for Physician Leadership, Royal College of Paediatrics and Child Health, Royal College of Surgeons in Ireland, Royal Society of Tropical Medicine and Hygiene, Royal College of Physicians and Surgeons of the United Kingdom

Disclosure: Nothing to disclose.

Roland L Boyd, DO Neonatologist, Section of Neonatology, Neonatal Services, Ltd

Roland L Boyd, DO is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians

Disclosure: Nothing to disclose.

Neonatal Hemochromatosis

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