Neonatal Hemochromatosis

Neonatal Hemochromatosis

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Neonatal Hemochromatosis is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • congenital hemochromatosis
  • neonatal iron storage disease

Disorder Subdivisions

  • None

General Discussion

Neonatal hemochromatosis is a disorder affecting fetuses and newborns. It is characterized by liver disease associated with the accumulation of excess iron in the liver and other areas of the body. Neonatal hemochromatosis is caused by severe fetal liver disease (see below). Some severe cases result in stillbirth, while live born infants with neonatal hemochromatosis typically show signs within 48 hours of birth. Neonatal hemochromatosis often produces life-threatening complications such as liver failure. However, some infants are less severely affected than others. There is a high risk of recurrence in subsequent pregnancies of women who have had a child with neonatal hemochromatosis. Although the exact cause of the disorder is not fully understood, researchers believe most cases of neonatal hemochromatosis result from maternal fetal alloimmunity, a condition in which antibodies from the mother travel over the placenta and mistakenly attack the fetus.

Symptoms

Neonatal hemochromatosis is characterized by liver disease that is present in the fetus or at birth (congenital). Damage to the liver occurs during pregnancy, ultimately leading to the abnormal accumulation of iron within tissue. Iron accumulation occurs while the fetus is developing in the womb and fetal loss late in pregnancy is common in families with a history of neonatal hemochromatosis. Growth delays within the womb (intrauterine growth deficiencies) are also common and many newborns are born prematurely.



Liver disease is usually apparent shortly after birth, although in rare cases it may not become apparent until days or weeks later. Symptoms of liver disease include low blood sugar (hypoglycemia), abnormalities in blood clotting (coagulopathy), yellowing of the skin and whites of the eyes (jaundice), decreased or absent urine production (oligouria) and swelling or puffiness due to fluid accumulation (edema), which may or may not occur in the abdomen (ascites). In many cases, scarring (cirrhosis), end stage liver disease and liver failure occur, sometimes within hours of birth. Iron accumulation may also occur in other organs including the pancreas, heart, thyroid, and salivary glands.



Neonatal hemochromatosis is considered a spectrum of disease with both severely affected and less severely affected infants. Some researchers speculate that some infants with neonatal hemochromatosis have no symptoms and the disorder may go undetected in such cases. In the medical literature, twins have developed neonatal hemochromatosis and one twin is severely affected while the other is only mildly affected.

Causes

The cause of neonatal hemochromatosis is not fully understood. A woman who has a child with neonatal hemochromatosis has approximately an 80 percent chance of having another child with the disorder. This pattern of recurrence cannot be explained by normal inheritance patterns. Thus, neonatal hemochromatosis appears to be congenital and familial, but not inherited.



Significant evidence indicates that most cases of neonatal hemochromatosis result from fetal liver disease due to maternal fetal alloimmunity, a condition termed gestational alloimmune liver disease. A developing fetus is protected from foreign material (e.g., bacteria) by antibodies from its mother, which travel from the mother to the fetus through the placenta. Antibodies are specialized proteins that react against foreign material in the body bringing about their destruction. However, in materno-fetal alloimmune diseases, certain maternal antibodies mistakenly recognize some fetal cells or proteins, causing fetal injury. In gestational alloimmune liver disease, the fetal liver is targeted. Liver cells (hepatocytes) are damaged or killed by the antibody, and damage to the liver ultimately results in the abnormal accumulation of excess iron in the body and the symptoms of neonatal hemochromatosis.



Maternal fetal alloimmunity would explain the high recurrence rate of neonatal hemochromatosis in children of women who have already had a child with the disorder. Also, some women have had multiple children with neonatal hemochromatosis despite the children having different fathers, which would also be explained by maternal fetal alloimmunity.



Although maternal fetal alloimmunity would explain the majority of cases of neonatal hemochromatosis, rare cases may have a different cause. Neonatal hemochromatosis has been seen in association with genetic diseases including mitochondrial disease (DGUOK gene mutations), metabolic disease (bile acid synthetic defect) and chromosomal abnormalities (trisomy 21). More research is necessary to determine all of the causes and internal mechanisms that result in the development of neonatal hemochromatosis.

Affected Populations

Neonatal hemochromatosis is a disorder that affects males and females in equal numbers. The exact incidence of the disorder is unknown. Neonatal hemochromatosis is the most common cause of liver failure in newborns and the most common reason for a liver transplant in newborns. Neonatal hemochromatosis was first reported in the medical literature in 1957.

Standard Therapies

Diagnosis

A diagnosis of neonatal hemochromatosis should be suspected in any infants demonstrating liver disease before birth (antenatally) or shortly after birth. Blood tests may reveal elevated levels of ferritin in the blood serum, which may be indicative of liver disease and iron accumulation. Ferritin is an iron compound that is used as an indicator of the body's iron stores.



A diagnosis of neonatal hemochromatosis may be confirmed based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests that can demonstrate the presence of excess iron in tissue outside the liver (extrahepatic siderosis). Surgical removal and microscopic evaluation of tissue (biopsy) can reveal excess iron. Magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, can also be used to detect excess iron in tissue.



Treatment

The treatment of neonatal hemochromatosis is controversial. Recent evidence suggests that interfering with the alloimmune liver injury by treating affected babies with double-volume blood exchange transfusion and high-dose intravenous immunoglobulin can significantly improve survival. Other treatment options include liver transplantation and therapy with a combination of certain drugs and antioxidants. The results of these treatments have varied. Regardless of the treatment option, early diagnosis and prompt treatment are essential for achieving a positive outcome.



Neonatal hemochromatosis is the most common cause of liver transplantation in newborns and the procedure has achieved long-term survival in some cases. However, there are numerous risks involved with liver transplant (e.g., cancer risk due to immunosuppresnt medications) and additional complications in infants with neonatal hemochromatosis (prematurity, small size for gestational age, potential damage to other organs).



In rare cases, some infants with neonatal hemochromatosis have improved without any treatment outside of standard supportive intensive care (spontaneous resolution).

Therapy aimed at preventing neonatal hemochromatosis before it occurs has proven very effective. Researchers treated pregnant women (all of whom previously have had a child with neonatal hemochromatosis) with high-dose IVIG during pregnancy, with greater than 95% successful outcome. IVIG therapy modifies the activity of the immune system (immunomodulation). IVIG is a solution containing antibodies donated from healthy individuals and administered directly to a vein. Any woman who has had a baby affected with NH should consider this therapy in subsequent pregnancies.

Investigational Therapies

The identification of neonatal hemochromatosis as a disorder caused by maternal fetal alloimmunity has opened new avenues of research and treatment for the disorder and undoubtedly will dramatically change how the disorder is treated in the future.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Toll-free: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Whitington PF, Fleming RE. Hemochromatosis. In: Kleinman RE, Goulet O-J, Sherman PM, Sanderson IR, Shneider BL, Walker WA, eds, Walker's Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 5th ed. Hamilton, Ontario: BC Decker; 2008:1049-56.



Knisely AS, Narkewicz MR. Iron Storage Disorders. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 3rd ed. New York: Cambridge University Press; 2007:661-76.



JOURNAL ARTICLES

Whitington PF, Pan X, Kelly S, Melin-Aldana H, Malladi P. Gestational alloimmune liver disease in cases of fetal death. J Pediatr. 2011;159:612-6



Pan X, Kelly S, Melin-Aldana H, Malladi P, Whitington PF. Novel mechanism of fetal hepatocyte injury in congenital alloimmune hepatitis involves the terminal complement cascade. Hepatology. 2010;51:2061-8.



Bonilla SF, Melin-Aldana H, Whitington PF. Relationship of proximal renal tubular dysgenesis and fetal liver injury in neonatal hemochromatosis. Pediatr Res. 2010;67:188-93.



Rand EB, Karpen SJ, Kelly S, et al. Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. J Pediatr. 2009;155:566-71.



Whitington PF, Kelly S. Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics. 2008;121:e1615-e1621.



Whitington PF. Neonatal hemochromatosis: a congenital alloimmune hepatitis. Semin Liver Dis. 2007;27:243-50.



Grabhorn E, Richter A, Burdelski M, Rogiers X, Ganschow R. Neonatal hemochromatosis: long-term experience with favorable outcome. Pediatrics. 2006;118:2060-2065.



Ekong UD, Kelly S, Whitington PF. Disparate clinical presentation of neonatal hemochromatosis in twins. Pediatrics. 2005;116:e880-e884.



Rodrigues F, Kallas M, Nash R, et al. Neonatal hemochromatosis - medical treatment vs. transplantation: the king's experience. Liver Transpl. 2005;11:1417-1424.



Whitington P, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet. 2004;364;1690-1698.



Knisely AS, Mieli-Vergani G, Whitington P. Neonatal hemochromatosis. Gastroenterol Clin North Am. 2003;32:877-879.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



Iron Overload Diseases Association, Inc.

525 Mayflower Road

West Palm Beach, Fl 33405

Tel: (561)586-8246

Fax: (561)842-9881

Tel: (866)768-8629

Email: iod@ironoverload.org

Internet: http://ironoverload.org



American Liver Foundation

39 Broadway, Suite 2700

New York, NY 10006

USA

Fax: (212)483-8179

Tel: (800)465-4837

Email: http://www.liverfoundation.org/contact/

Internet: http://www.liverfoundation.org



Children's Liver Disease Foundation

36 Great Charles Street

Birmingham, B3 3JY

United Kingdom

Tel: 01212123839

Fax: 01212124300

Email: info@childliverdisease.org

Internet: http://www.childliverdisease.org



British Liver Trust

2 Southampton Road

Ringwood, BH24 1HY

United Kingdom

Tel: 01425481320

Fax: 01425481335

Tel: 08006527330

Email: info@britishlivertrust.org.uk

Internet: http://www.britishlivertrust.org.uk



American Hemochromatosis Society

4044 W. Lake Mary Blvd.

Suite 104 PMB 416

Lake Mary, FL 32746-2012

USA

Tel: (407)829-4488

Fax: (407)333-1284

Tel: (888)655-4766

Email: mail@americanhs.org

Internet: http://www.americanhs.org



Iron Disorders Institute

PO Box 675

Taylors, SC 29687

USA

Tel: (864)292-1175

Fax: (864)292-1878

Tel: (888)565-4766

Email: info@irondisorders.org

Internet: http://www.irondisorders.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

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