Neonatal Hemochromatosis 

Updated: Oct 20, 2017
Author: Ann M Simonin, MD, FAAP; Chief Editor: Carmen Cuffari, MD 

Overview

Background

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.

Pathophysiology

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

Etiology

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.

Epidemiology

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]

 

Presentation

History

Clues that the patient has or does not have neonatal hemochromatosis may not be present. Clues during pregnancy may indicate the diagnosis of neonatal hemochromatosis, but they are nonspecific.

Oligohydramnios is frequently observed. Polyhydramnios is less commonly observed.

Suspect neonatal hemochromatosis if the infant develops liver disease and all other metabolic, infectious, and hemorrhagic causes are eliminated. Decreased fetal movement has been reported.

Forty percent of infants born with neonatal hemochromatosis are premature. Intrauterine growth restriction (IUGR) occurs in 25% of infants with neonatal hemochromatosis.

Physical Examination

The physical examination in the neonatal period is of little help but may reveal the following:

  • Placental edema

  • IUGR

  • Edema without ascites

  • Oliguria

  • Disseminated intravascular coagulation

  • Jaundice in the first few days after birth

  • Splenomegaly

Complications of the disease include liver failure, cardiac failure, respiratory failure, and disseminated intravascular coagulation.

Go to Dermatologic Manifestations of Hemochromatosis for complete information on this topic.

 

DDx

Diagnostic Considerations

When liver failure is diagnosed in the first 1-2 days of life, neonatal hemochromatosis is by far the most common diagnosis. Afterward, many other conditions can manifest and must be excluded. They include all other causes of hepatic failure, including infective, metabolic, and hemorrhagic causes.

The following are other causes of liver failure in the newborn:

  • Antenatal infection with adenovirus

  • Coxsackievirus

  • Alpha1-antitrypsin (A1At) deficiency

  • Hereditary fructose intolerance

  • Maternofetal blood group incompatibility

  • Hemoglobinopathy

  • Hemophagocytic syndrome

  • Inborn defects in erythrocyte membrane or enzymes

  • Sepsis

  • Ischemia or abnormal perfusion

  • Extrahepatic biliary atresia

  • Hepatic infarct

  • Congenital leukemia

All infants with a diagnosis of liver failure should undergo testing until a final diagnosis is reached.

Failure to diagnose neonatal hemochromatosis, resulting in the family having subsequent children with the same diagnosis, could result in legal actions against the physician.

Differential Diagnoses

 

Workup

Approach Considerations

Relevant laboratory tests and findings include the following:

  • CBC count with differential - To check for anemia and thrombocytopenia

  • Total and direct bilirubin levels - Elevated

  • Reticulocyte count - To check for any signs of hemolysis

  • Glucose level - Infants with neonatal hemochromatosis can present with hypoglycemia

  • Albumin level - May be low, which accounts for the infants' edema

  • Urinalysis - To check for causes of oliguria and any renal involvement

  • BUN and creatinine levels - To evaluate renal function

  • Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrin split products - To rule out any hemorrhagic causes

  • Transferrin level - Low but hypersaturated (one of the most common findings)

  • Serum ferritin levels - Elevated

  • Total iron-binding capacity - Low

  • Cytoferrin level - Markedly elevated

  • Lactic acid dehydrogenase (LDH) level - Markedly elevated

  • Aminotransferases level - Mildly elevated

  • Iron levels - Usually in the reference range

MRI and Ultrasound

Imaging studies include MRI and ultrasonography. MRI is the most helpful study in the diagnosis of neonatal hemochromatosis.[9]

Ultrasonography demonstrates patency of the ductus venosum; this is because of liver injury and, thus, portocaval shunting occurs.

MRI can be used to detect increased levels of iron in the liver compared with levels in normal tissues and can be used to document any areas of siderosis of the pancreas and myocardium. Absence of siderosis of the spleen may also be observed.

MRI of infants in utero has not demonstrated any siderosis or signs of neonatal hemochromatosis.

Biopsy

Liver biopsy is not easily performed in these infants because of the increased tendency of bleeding, but it is helpful in aiding in the diagnosis.

Another option is to perform a punch biopsy of the oral mucosa. This area is used because of the presence of the small salivary glands. Punch biopsy is performed by using 3-mm punch biopsy of the mucosa of the lower lip, and bleeding can be controlled. Salivary glands are siderotic if neonatal hemochromatosis is present.

Histologic Findings

Microscopic examination of the liver reveals that the hepatocytes have giant-cell transformation or pseudoacinar transformation with bile plugs, or no hepatocytes are present at all. Also, the hepatocytes may show siderosis, while Kupffer cells are spared. Scarring may be present from macrophages, which contain high levels of stainable iron. The bile duct is proliferated. The spleen, lymph nodes, and bone marrow contain a small amount of stainable iron. The placenta is not siderotic, and villitis has not been reported.

 

Treatment

Approach Considerations

If an infant with neonatal hemochromatosis is born outside of a tertiary care setting, transfer the patient to a level IV neonatal intensive care unit (NICU) or to a center that regularly performs neonatal liver transplantation.

At present, liver transplantation is the only known curative treatment. Studies have shown that iron does not redeposit after transplantation.

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

Maternal Treatment

In a study by Whitington and Hibbard, 15 women whose most recent pregnancy ended in documented neonatal hemochromatosis were treated with intravenous immunoglobulin 1 g/kg/wk from 18 weeks’ gestation until end of gestation; 12 infants had evidence of neonatal hemochromatosis, but all survived with or without medical treatment and were healthy at the time of the report.[10] However, this is a small study, and further trials are needed.

Supportive Care

Current care is basically supportive. No definitive or curative care has been identified as of this publication; however, experience with treatment is very limited.

Infants with neonatal hemochromatosis have been treated with a combination of antioxidants, cryoprotective agents, and chelation. The few infants who received this combination therapy had normalization of liver function, improved clotting factors, and decrease in serum ammonia levels.[11]

The first order of treatment in infants with neonatal hemochromatosis is attention to airway, breathing, and circulation (the ABCs) because the infants are usually born very ill or deteriorate shortly thereafter. Therefore, intubate infants with neonatal hemochromatosis shortly after birth to establish a patent airway. In addition, if any cardiovascular support is needed, such as volume replacement or inotropic therapy, add it accordingly.

Intubation is usually warranted because infants with neonatal hemochromatosis are born prematurely and possibly require surfactant to improve their lung function. These infants can also have pneumonia and, in severe cases, pleural effusions.

These infants usually require some sort of pressor support because of poor contractility and the deposition of iron in the myocardium. Also, these infants are born with heart failure and require much cardiac support.

General support care of nutrition and replacement of hematologic factors, such as fresh-frozen plasma (FFP), platelets, cryoprecipitate, and packed red blood cells (PRBCs), are necessary.[12]

Consultations

Consult a pediatric gastroenterologist and pediatric surgeon if transplantation may be needed.

Because of the rarity of this disease process, a pediatric gastroenterologist can provide recent updates in research and experimental therapy.

Consult a pediatric surgeon for possible transplantation and need for possible biopsy for accurate diagnosis.

Social services are offered mainly for family and financial support.

 

Medication

Medication Summary

Few drugs are available for treating neonatal hemochromatosis. Infants with neonatal hemochromatosis have been treated with a combination of antioxidants, cryoprotective agents, and chelation.

Three antioxidants are used throughout the course of therapy: N -acetylcysteine, alpha-tocopherol polyethylene glycol succinate (TPGS), and selenium. These are used in combination with prostaglandin E and deferoxamine, which have a cryoprotective effect and which chelate iron, respectively.

A suggested cocktail is the following: N -acetylcysteine 200 mg/kg/d PO divided tid for 17-21 doses, alpha-TPGS 25 IU/kg/d PO divided bid for 6 weeks, deferoxamine 30 mg/kg/d IV infused over 8 hours until the serum ferritin level is less than 500 mcg/L, selenium 3 mcg/kg/d IV continuous infusion for the length of hospitalization, and prostaglandin E1 0.4 mcg/kg/h IV increased to 0.6 mcg/kg/h over 3-4 hours. The infusion is maintained for 10 days.[13]

Chelating agents

Class Summary

These agents inhibit toxin by reacting with it to form less active or inactive complex. The complex is then excreted from the body.

Deferoxamine (Desferal)

Deferoxamine is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg. It is excreted in urine and bile and produces red discoloration of urine. This agent readily chelates iron from ferritin and hemosiderin but not transferrin. It is most effective with continuous infusion. It may be administered IM, SC, or slow IV infusion. Deferoxamine does not effectively chelate other trace metals of nutritional importance.

Vials contain 500 mg of lyophilized sterile drug; add 2 mL sterile water for injection to each vial, bringing concentration to 250 mg/mL. For IV use, may be diluted in 0.9% sterile saline, dextrose 5% in water (D5W), or Ringer solution. IM administration is preferred except in patients with hypotension and cardiovascular collapse, in whom IV should be considered.

The use of deferoxamine in treatment of neonatal hemochromatosis is controversial. Experience is limited; therefore, use with caution.

Antioxidants

Class Summary

These agents protect sensitive tissues throughout the body from oxidizing substances known as free radicals. Although antioxidants protect most cell membranes, vitamin E is particularly important in preventing damage to the linings of blood vessels and maintaining good circulation.

N-Acetylcysteine (Acetadote)

This agent is a derivative of amino acid cysteine and scavenger of oxygen free radicals. It is also a glutathione precursor and is used to replenish depleted intracellular glutathione. Therefore, it theoretically augments antioxidant defenses.

Alpha-tocopherol (Aquasol-E, E-Gems, Ester-E)

Vitamin E is particularly important in preventing damage to linings of blood vessels and maintaining good circulation. It acts as an antioxidant in cell membranes to prevent propagated oxidation of unsaturated fatty acids. It is also known to impair hematologic response to iron.

Selenium (Selenicaps, Selenimin)

Selenium is an essential trace element, part of the enzyme glutathione peroxidase. It protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Prostaglandins

Class Summary

These agents elicit cryoprotective effect.

Alprostadil (Prostin VR Pediatric)

Alprostadil (prostaglandin E1) is used primarily to keep patency of ductus arteriosus but also has a mild pulmonary vasodilatory effect. It is reported to inhibit macrophage activation, neutrophil chemotaxis, and release of oxygen radicals and lysosomal enzymes. It affects coagulation by inhibiting platelet aggregation and possibly by inhibiting activation of factor X. It may promote fibrinolysis by stimulating production of tissue plasminogen activator.

Surfactants

Class Summary

Exogenous surfactant can be helpful in treatment of airspace disease (eg, respiratory distress syndrome [RDS]). After inhaled administration, surface tension is reduced and alveoli are stabilized, decreasing the work of breathing and increasing lung compliance.

Beractant (Survanta)

This agent mimics the surface tension–lowering properties of natural lung surfactant. It contains colfosceril palmitate, cetyl alcohol, and tyloxapol. It is used for prophylaxis of RDS in premature infants with birthweight < 1350 g or RDS in premature infants with birthweight >1350 g who have evidence of pulmonary immaturity. It is also used for rescue treatment of infants who develop RDS.

Calfactant (Infasurf)

This is a natural bovine calf lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (260 mcg/mL) and C (390 mcg/mL). Surfactant is an endogenous complex of lipids and proteins that lines alveolar walls and promotes alveolar stability by reducing surface tension. Relative surfactant deficiency is variably present in many lung diseases.

Poractant alfa (Curosurf)

This agent lines alveolar walls and promotes alveolar stability against collapse by reducing surface tension at the air-liquid interface of the alveoli.

Inotropic agents

Class Summary

Positive inotropic agents increase the force of contraction of the myocardium and are used to treat acute and chronic congestive heart failure (CHF). Some may also increase or decrease the heart rate (ie, positive or negative chronotropic agents), provide vasodilatation, or improve myocardial relaxation. These additional properties influence the choice of drug for specific circumstances.

Dopamine

Dopamine is used to treat hypotension that is not secondary to hypovolemia. It has a preferential sparing effect on the renal circulation. It is often used with dobutamine.

Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect depends on dose. Low doses predominantly stimulate dopaminergic receptors that in turn produce renal and mesenteric vasodilation. High doses produce cardiac stimulation and renal vasodilation.

The mechanism of action of dopamine in neonates is controversial because of variations in endogenous norepinephrine stores, receptor function, and ability to increase stroke volume.

Low doses (< 2 mcg/kg/min) provide dopaminergic stimulation and increases urine output, fractional excretion of sodium, and creatinine clearance.

Intermediate doses (2-10 mcg/kg/min) increase cardiac contractility and blood pressure at low doses and increases heart rate at high doses. Inotropic response varies with gestational age and baseline stroke volume.

High doses (>20 mcg/kg/min) predominantly increase systemic and pulmonary vascular resistance. Use with caution in patients with persistent pulmonary hypertension of the newborn.

Dobutamine

Dobutamine provides inotropic support in patients with shock and hypotension. It is not a pressor. This agent is used for demonstrated or suspected decreased cardiac contractility. It is often used in concert with dopamine. Echocardiography is useful in evaluating need (eg, contractility, ventricular dilation, ejection fraction).

Dobutamine produces vasodilation and increases the inotropic state. At high dosages, it may increase heart rate. Onset of action is 1-2 min, peak effect in 10 min. Administer as continuous IV infusion because half-life is several minutes. It is metabolized in the liver.

Dobutamine acts as a synthetic catecholamine with primarily beta1-adrenergic activity. It increases myocardial contractility, cardiac index, oxygen delivery, and oxygen consumption. It decreases systemic and pulmonary vascular resistance in adults.