PEDIATRICS Vol. 118 No. 5 November 2006, pp. 2060-2065 (doi:10.1542/peds.2006-0908)
ARTICLE |
Neonatal Hemochromatosis: Long-term Experience With Favorable Outcome
a Departments of Pediatrics
b Hepatobiliary Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Neonatal hemochromatosis is a severe, often fatal multiorgan disorder of iron metabolism. Liver transplantation can be curative; the benefit of antioxidant treatment is discussed controversially. We summarize our experience with neonatal hemochromatosis over the past 13 years.
METHODS. A retrospective study was performed of 16 patients with acute liver failure attributable to neonatal hemochromatosis between 1992 and 2004.
RESULTS. Median age at the onset of neonatal hemochromatosis was 2 days (range: 0–21 days). Median weight at the time of diagnosis was 2900 g (range: 1520–4200 g). All patients had elevated ferritin levels (median: 4179 µg/L), and transferrin saturation (median: 99%). Fourteen patients (87.5%) showed significant hepatocyte siderosis in biopsies; 4 children had additional iron deposition in extrahepatic tissue. Four patients were diagnosed by MRI. Seven infants received liver transplants, 5 of them in combination with a preceding antioxidant treatment. Four children (25%) received antioxidants without the necessity of liver transplantation and were in good clinical condition at the time of this evaluation. Five patients (31.3%) died, 3 of them without any treatment because of initial fulminant multiorgan failure. In September 2005, 68.7% of the patients were still alive after a median follow-up of 5 years.
CONCLUSIONS. Neonatal hemochromatosis is a severe metabolic disease, but early antioxidant treatment and liver transplantation in addition to optimal medical care can improve the outcome dramatically. Children with moderate liver failure can survive without liver transplantation, but should be monitored closely for deterioration.
Key Words: neonatal hemochromatosis • liver transplantation • infants • outcome
Abbreviations: NH—neonatal hemochromatosis
Neonatal hemochromatosis (NH) is a neonatal iron-storage disease that phenotypically resembles the more common hereditary hemochromatosis of the adult. It was first described in 19571 and since then, a growing number of investigations focused on this rare multiorgan disorder.2–4 The etiology of this severe disease seems to vary, leading to a common end point of acute liver failure. The liver is the most severely affected organ by iron deposition, but pancreas, heart, and endocrine as well as exocrine glands also show an iron overload with possible functional deficits.3 The characteristic clinical feature is perinatal liver failure with hypoalbuminemia and consecutive edema, hypoglycemia, hyperbilirubinemia, and coagulopathy. If not stillborn, affected children are often premature or small for gestational age.2 Family analyses show a recurrence rate up to 80%; genetic as well as nongenetic factors are discussed.5–8 The diagnosis can be made by either histology or MRI, which show the excessive deposition of iron in nonreticuloendothelial tissue, especially in liver, pancreas, and salivary glands.3,9,10 Usually, ferritin is highly elevated, transferrin is low, and the iron saturation high.2,11 Frequently, the definite diagnosis could only be made by postmortem evaluation. The prognosis of NH is often fatal,12 but liver transplantation can be curative even in early infancy if patients survive until a suitable organ is available.4 Antioxidant and chelation therapy has shown a benefit in some studies but is very controversial in the literature.2,3,13 In this study we analyzed short- and long-term results of patients with suspected NH in our institution who were treated with antioxidants and liver transplantation between 1992 and 2004.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patient Characteristics and Diagnostic Approach
A retrospective study was performed of 16 patients with acute liver failure attributable to NH between 1992 and 2004. The diagnosis of NH based on the combination of acute severe liver failure, raised ferritin levels (reference value: up to 142 µg/L), and transferrin saturation as well as reduced transferrin. Moreover, the histology or MRI had to show an increased intrahepatic iron deposition with hepatocyte siderosis that spared the reticuloendothelial system (Fig 1), and, where possible, evidence of extrahepatic siderosis. Other reasons for acute liver failure such as viral hepatitis, tyrosinemia, galactosemia, mitochondriopathia, and
1-antitrypsin deficiency were excluded. The patients were followed until September 2005, with a median follow-up of 5 years (range: 1–13 years).
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Medication
Depending on the clinical status and parents' consent, the patients were treated with antioxidant and chelation therapy starting immediately after admission and were listed for high-urgency liver transplantation in case of severe deterioration. The antioxidant and chelation treatment consisted of deferoxamine (30–40 mg/kg per day), vitamin E (20 mg/kg per day), selenium (3 µg/kg per day), and N-acetylcysteine (3 x 50 mg/kg per day). In 3 infants, prostaglandin-E1 was administered as well. Treatment was continued until ferritin levels were below 500 µg/L or until liver transplantation was performed.
The primary immunosuppression after liver transplantation consisted of an intraoperative bolus of methylprednisolone (10 mg/kg) followed by daily methylprednisolone (starting dose: 60 mg/m2) and cyclosporine A (initial trough levels: 170–200 µg/L; trough levels for maintenance immunosuppression after 1 year: 100–120 µg/L). The steroids were reduced to 40 mg/m2 after 1 week followed by a weekly tapering to 5 mg/m2, and the steroids were withdrawn 12 months after liver transplantation. The anti-interleukin-2 receptor antibody basiliximab (Simulect, Novartis Pharma, Basel, Switzerland) was given from 1998 on in 4 patients (25%) in 2 single doses on day 0 and 4 posttransplant.
Graft Sources
Types of allografts used included 6 from deceased donors (reduced-size n = 4, split n = 1, full-size n = 1) and living-related in 1 case. The maximal cold ischemic time was 12 hours.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patient Data
In all patients, the disease started within the first 21 days after birth (range: 0–21 days; median: 2 days). Median weight of the patients was 2900 g (range: 1520–4200 g), median weight of patients who received a liver transplant was 2670 g (range: 2440–3890 g). Eight (50%) of 16 patients were small for gestational age, and 7 (43.8%) of 16 patients were premature infants. The study included 5 female and 11 male patients. The clinical condition was life-threatening in 10 of 16 patients; the remaining 6 infants were critically ill but stable in the ICU.
In all patients, the parents were nonconsanguineous. The family history was positive for recurrent NH in 4 of 16 and for recurrent abortion or stillbirth of unknown origin in 6 of 16 infants. In 5 cases it was the first pregnancy, and 3 infants had healthy siblings without additional medical history (Table 1). None of the mothers were examined for the presence of autoantibodies.
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Laboratory Tests and Diagnostic Tools
All patients had elevated ferritin levels (median: 4179 µg/L; range: 353–197041 µg/L), and transferrin saturation (median: 99%; range 67%–159%). Moreover, all patients had reduced transferrin levels (median: 1.2 g/L; range: 0.7–1.7 g/L). The patient with rather unusual slightly elevated ferritin levels showed extrahepatic siderosis (pancreas, heart) typical for NH in postmortem evaluation. Three patients had elevated C-reactive protein concentrations, but only 1 patient showed bacterial species in cultures taken from ascites, which was interpreted as secondary peritonitis. This patient had liver cirrhosis as well as siderosis of the liver and the pancreas in the postmortem histology apart from typical laboratory alterations and therefore met the criteria for NH. Ten patients had elevated levels of aspartate aminotransferase (median: 253 U/L; range: 82–560 U/L) and alanine aminotransferase (median: 215 U/L; range: 40–683 U/L), and 6 infants had normal parameters. The bilirubin levels were elevated in all patients with a median of 17.3 mg/dL (range: 8.9–37 mg/dL), and the albumin was decreased with a median of 26 mg/dL (14–33 mg/dL). The coagulation was extremely impaired in all patients (median prothrombin time: 4%; range: 0%–53%). In 14 children hyperammonemia was measured with clinical signs of hepatic encephalopathy (median: 126 mmol/L; range: 60–341 mmol/L); in 2 children the ammonium level could not be found because of incomplete files (Table 1).
Fourteen patients (87.5%) showed significant hepatocyte siderosis in biopsies; 4 had additional iron deposition in minor salivary glands, pancreas, and heart. Four patients were diagnosed by MRI showing signs of enhanced iron in liver, kidney, pancreas, and heart (Table 1).
Therapy and Patient Survival
Seven infants (43.8%) received liver transplantation, 5 of them in combination with preceding antioxidant treatment. Of these, all children survived the first 2 years after liver transplantation. Five children received antioxidant treatment, 4 of them without the necessity of liver transplantation, and those children remain well up at the time of this writing. One patient survived without any antioxidant or chelation therapy despite initial severe illness with massive bleeding and encephalopathy. Altogether, 5 patients (31.3%) died, 3 of them without any treatment because of initial fulminant multiorgan failure. In 1 case, the parents refused liver transplantation after partial response to treatment with antioxidants over 4 weeks, and the patient finally died from liver failure shortly after interruption of treatment. Two patients suffered from chronic graft failure after liver transplantation: 1 received a second successful transplant 2 years after the first, and 1 died 26 months after the initial liver transplantation.
In September 2005, 11 (68.7%) of 16 patients were still alive after a median follow-up of 5 years (range: 1–13 years). The patient survival rate was 75% after 1 year (12 of 16), and 69.2% (9 of 13) after 2 years (Fig 2).
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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NH is a severe, often lethal multiorgan disorder of iron metabolism. The diagnosis is not easy to establish because other hepatic disorders can show siderosis of the liver or high ferritin levels as well.6 The hallmark of this disease is the evidence of extrahepatic siderosis, but the problem is that it cannot always be easily demonstrated.2,4 It can either be shown by autopsy, MRI, or biopsy of the minor salivary glands in the living. Although the latter was reported to be a safe procedure,10 we had problems obtaining proper material and saw bleeding complications. Therefore, it is no longer part of our standard regimen. The MRI is a safe procedure, but in cases of acute deterioration with severe coagulopathy, transport is an additional risk. Moreover, 1 of our patients showed a massive siderosis of liver and salivary glands but had normal MRI results, raising the question of sensitivity. Extrahepatic siderosis could be demonstrated in 7 of our patients by either histology or MRI. Interestingly, 1 patient had exclusive liver siderosis without extrahepatic siderosis in postmortem evaluation but had 2 siblings with NH shown by extrahepatic siderosis. It is improbable that he suffered from a distinct disease, especially because he otherwise had a very typical course of disease. Similar cases were reported by other groups as well.4 Other centers were able to demonstrate extrahepatic siderosis in a greater proportion of patients, especially by means of autopsy. In a study by Rodrigues et al,13 10 of 19 patients were identified by postmortem evaluation; altogether, 12 of 19 patients showed extrahepatic siderosis. Fortunately, in our study there were more survivors; therefore, it was not possible to do those examinations. Of 5 patients who died, 3 were examined postmortem, and in 2 cases the parents refused consent for autopsy. In 9 patients for whom evidence of extrahepatic siderosis was not examined, 2 patients had family history of NH, 5 patients showed typical intrauterine growth retardation, 5 were premature, and in 2 cases there was history of recurrent stillbirth. All 9 patients had very low (median: 0.9 g/L) and high (median: 122%) transferrin saturation apart from high ferritin levels (median: 4613 µg/L) and significant siderosis of the liver. Transferrin and transferrin saturation were recently suggested to be more helpful for the diagnosis of NH in comparison with rather unspecific elevated ferritin levels.6 The ferritin levels showed a wide range from 353 to 197041 µg/L in our patients, giving rise to doubt whether the patient with only slightly elevated ferritin levels really suffered from NH. But, this patient especially showed typical extrahepatic siderosis of pancreas and heart in postmortem specimens and, therefore, met the criteria for NH. The wide range of ferritin levels was comparable to other studies and did not correlate with severity of disease.4
NH is a rare disease but the most common reason for liver failure and liver transplantation in the neonatal period. In studies from various centers, the prognosis of affected infants has been shown to be very poor, and there is no consensus about the optimal treatment so far. Flynn et al4 reported a mortality rate of >60% in 8 infants presented between 1990 and 1998 with NH. In their study, antioxidant therapy was given from 1994 on in 5 infants with suspected NH. Of these, 2 children survived with antioxidant therapy; an additional child survived long enough for liver transplantation but died as a result of graft failure afterward. Sigurdsson et al2 treated 8 patients with NH with antioxidant therapy from 1993 on; only 1 survived until a suitable organ was available for liver transplantation. In our study cohort of 16 patients, we could state a satisfying survival rate of 75% after 1 year. Ten patients received antioxidant treatment immediately after admission, and 5 received a successful transplantation afterward. Three patients had fulminant multiorgan failure and were not considered for any specific treatment other than supportive care. Altogether, 7 infants received a transplant with a survival rate of 100% after 1 year. On one hand, these promising data may be attributable to early referral to our center and optimal medical care in the ICU. On the other hand, the developments in reduced-size and living-donor liver transplantation14,15 as well as the split-liver technique16 led to a significant decrease of deaths on the waiting list for liver transplantation even for small infants, especially in case of acute deterioration. Therefore, it is possible to transplant infants before they are too ill for surgical interventions. All but 1 of our patients received reduced-sized or split-liver organs and were given their transplants within a maximum of 2 days after high-urgency listing. Nevertheless, many centers pointed out that especially younger children have an increased risk with respect to morbidity and mortality, especially in case of metabolic diseases and therefore do not achieve comparable results as older children.17–20 We have recently shown that liver transplantation performed for chronic or acute liver failure can have excellent results for short- and long-term outcome even in early infancy with a 1-year patient survival of 90.7%.21
The benefit of antioxidant therapy is discussed very controversially in the literature. Murray et al6 postulated that deferoxamine therapy is not efficacious and that a combination with an antioxidant therapy has not proven to be successful. Apart from that, it has even been suggested that its use may potentiate bacterial growth.2 In the patients studied by Sigurdsson et al, antioxidant therapy did not improve outcome, and they underlined the curative approach of liver transplantation.2 Most recently, Rodrigues et al13 compared the outcome of medical treatment versus liver transplantation in 19 infants with NH treated between 1990 and 2002. They concluded that antioxidant treatment does not seem to modify the prognosis of NH, at least in severe cases. In their opinion, liver transplantation remains the treatment of choice and should be promptly offered to those infants not improving with supportive medical treatment. Nevertheless, the long-term survival rate was only 
50% after liver transplantation.13 Our patients showed a 1-year survival rate of 100% after liver transplantation (7 of 7) and 80% after exclusive antioxidant treatment (4 of 5). The difference between the patients of Rodrigues et al and our patients was an earlier onset of disease. Whereas most of their patients presented at the first day of life or at the age of 5 days at the latest indicating a rapid progression of disease, our patients presented up to the age of 21 days. However, the age at presentation does not correlate with severity of disease in our patients. So, on one hand, one of the patients with a fatal course was already 3 weeks old before symptoms started; on the other hand, infants survived although they got severely ill immediately after birth. It was not possible to predict the course of disease by age at presentation. Another difference was the median weight of patients. Whereas the median weight of the Rodrigues patients was 2520 g, our patients had a median weight of 2900 g.13 A liver transplantation is always a difficult procedure in a neonate but especially risky in those who are very small. This might be of importance. Another striking difference is the great proportion of recurrent NH in the patients of Rodrigues et al. When comparing the antioxidant therapy, there were some differences regarding the dosage of selenium (3 mg/kg per day vs 3 µg/kg per day) and N-acetylcysteine (100 mg/kg per day vs 150 mg/kg per day). If this is of importance is not easy to decide. However, they saw no benefit of antioxidant treatment. In contrast, Flynn et al4 are convinced that early treatment with antioxidants is beneficial and may be curative in cases of milder clinical phenotype as well. They strongly recommended an early initiation of antioxidants while the diagnosis is being confirmed. Our patients were similar to the Birmingham cohort in respect to age at presentation and ferritin levels. However, there was no detailed information about the dosage of medication.4 In our study population, 10 patients received antioxidants, 4 improved without surgical intervention, and 5 required subsequent liver transplantation. All but 1 infant survived and remain well up to September 2005. Interestingly, another patient initially stabilized under chelation and antioxidant treatment. After initial severe liver failure, clotting and synthetic liver function improved. Nevertheless, the response was incomplete and, therefore, liver transplantation was recommended. Unfortunately, the parents refused liver transplantation, and the patient finally died after interruption of antioxidants. This seems to underline the benefit of antioxidants. With our experience, we support the efficacy of early antioxidant and chelation treatment. Children with moderate liver failure can survive without liver transplantation by antioxidant treatment but should be monitored closely for deterioration and the necessity for high-urgency transplantation.
In our study population, 1 patient survived without any antioxidant or chelation therapy despite initial severe illness with massive intestinal as well as pulmonal bleeding and encephalopathy. There have already been single reports of spontaneous recovery from NH without any treatment other than supportive intensive care. Colletti et al22 reported on 2 siblings with NH, 1 survived despite initial severe illness without any specific treatment. Muller-Berghaus et al23 described a child with progressive failure attributable to suspected NH, who unexpectedly improved and finally showed normal liver function. The iron overload in this case was reversible and not progressive without antioxidant treatment. Our patient showed massive fibrosis and necrosis apart from extensive siderosis in the initial liver histology but finally fully recovered and was doing fine 1 year after. Nevertheless, this spontaneous recovery is a rare event, and we are currently not able to distinguish these patients from those with a fatal course of illness.
The etiology and pathogenesis of NH has still not been clearly determined yet. Recently, Whitington et al8 proposed the possibility of a gestational alloimmune disease that lead to fetal liver injury. Therefore, they treated 18 women in consecutive pregnancies after cases of NH by weekly high-dose intravenous immunoglobulin administration from the 18th week until birth. There were no deaths and no need for liver transplantation in 22 children. Nevertheless, 6 infants showed clinically significant signs of liver disease and were partly treated with antioxidants.24 Unfortunately, no parameter exists to distinguish between which pregnancies will be affected again or not. In our study group, there were only 4 cases of recurrent NH within 13 years of experience with NH. Therefore, there were only a few patients who would have benefited from this therapy in our study population so far. Nevertheless, the therapy has shown an improvement in outcome and the question arises of whether one can refuse this option to an affected family. Studies must be undertaken in the future to identify this fetal antigen target for a possible alloimmune process to support this approach and to be able to distinguish between infants who will benefit from this expansive therapy.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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NH is a severe metabolic disease, but early antioxidant treatment and liver transplantation can result in a favorable outcome. To achieve optimal results, an early referral to an experienced transplant center is mandatory. Immunomodulation during pregnancy might be useful in cases of recurrent NH.
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FOOTNOTES |
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Accepted Jun 29, 2006.
Address correspondence to Enke Grabhorn, MD, Department of Pediatrics, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: e.grabhorn{at}uke.uni-hamburg.de
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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