NORD gratefully acknowledges Peter F. Whitington, MD, the Sally Burnett Searle Professor of Pediatrics and Transplantation, Northwestern University Feinberg Medical School, and Director of the Siragusa Transplantation Center, Chicago, for assistance in the preparation of this report.
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.
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.
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.
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.
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. Therapy with a combination of certain drugs and antioxidants has proven ineffective. 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 immunosuppressant 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.
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.
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