Neonatal hemochromatosis (NH) is a rare medical condition presenting as severe liver disease in the newborn period. The main feature of this syndrome, that is, hepatic and extrahepatic iron accumulation, is probably the result of a hepatic inflammatory process of incompletely understood etiology. Its severity is variable, ranging from cases of stillborns or fulminant liver failure to cases of spontaneous recovery (1). The prognosis of this condition is generally poor, and NH is a frequent indication for liver transplantation in the newborn. A positive family history, high serum ferritin levels, and siderosis demonstrated with histology or with magnetic resonance are the criteria usually considered to make a diagnosis of NH. The current medical treatment for NH, based on antioxidants and iron chelator, is often ineffective and associated with severe adverse effects.
Since treatment with antioxidant and chelator was proposed, a few series of patients with NH have been described. The overall outcome of this condition appears to be grim and scarcely influenced by the medical treatment. In the experience of Sigurdsson et al (2), the antioxidant-chelation cocktail did not improve the recovery rate after medical treatment, which was 12.5%. In a small series reported by Flynn et al (3), the recovery rate with antioxidant-chelation treatment alone was 2 of 5 patients, and the authors observed that the 2 responders started the treatment earlier and had lower peak ferritin levels (3). In the largest series of patients with NH, 10 who received the chelation-antioxidant cocktail were compared with 9 patients who did not: the survival rate was not better with medical treatment, being <10% (4). Grabhorn et al (5) described 14 children affected by NH, in whom 25% were successfully treated with the antioxidant-chelation cocktail, and did not need liver transplantation (5). Of 8 patients recently reported by Heffron et al (6), 3 survived with medical treatment alone, 2 died of multiorgan failure and sepsis, and 3 underwent liver transplantation. The overall survival rate appears to be strictly related to the availability of liver transplantation (2–7).
The use of antioxidants is based on the theory that the iron overload–related oxidant burden plays a significant role in determining the liver impairment. However, recent data suggest that the iron overload is only an epiphenomenon of the liver disease. In fact, accumulating evidence indicates that at least some of the cases have an alloimmune origin: NH would be caused by the transplacental passage of antifetal liver antigen immunoglobulin G to the fetus in NH-sensitized mothers, leading to liver damage and iron mishandling (8,9). This would also explain the 80% of recurrence in the subsequent gestations after the index case. The prevention trial by Whitington and Hibbard (9) with high-dose immunoglobulin during gestation, based on the alloimmune model, was a breakthrough in the history of the disease because it reduced the severity of the disease in a series of at-risk pregnancies so that none of the babies needed liver transplantation. In a recent updated report, 52 of 55 newborns born to treated pregnancies survived with only medical treatment and 3 failures were for causes other than NH. On the contrary, 92% of untreated pregnancies resulted in intrauterine fetal demise, neonatal death, or liver failure requiring transplantation (10). Although the prevention of the recurrent NH appears to be effective, a medical approach remains to be codified for newborns born to mothers with no positive family history of this condition.
We first reported a case of NH treated with respect to an alloimmune cause. The newborn showed acute liver disease with severe worsening coagulopathy, and the diagnosis was based upon elevated serum ferritin, low transferrin, high transferrin saturation, and documented siderosis on liver and placenta. The baby was treated with 2 exchange transfusions as supportive intensive care with a good outcome (11). Additional care consisted of continuative substitutive therapy, acetylcisteine, selenium, and vitamin E. In the present issue of JPGN, Escolano-Margarit and coworkers describe a case of a newborn affected by NH, in whom exchange transfusion administered at admission because of high serum indirect bilirubin concentration seems to have improved the course of the disease. Exchange transfusion has long been considered nonspecific supportive care for NH. The mounting evidence for NH to be an alloimmune humoral condition allows its administration as specific treatment, with the rationale that exchange transfusion would act as plasmapheresis, removing the antifetal liver antigen causing this acute liver disease.
The strongest evidence so far for the efficacy of treating NH “immunologically” is represented by the trial conducted by Rand et al (12), in which exchange transfusion and intravenous high-dose immunoglobulin were used. The survival rate without liver transplantation was 75% in children who received the treatment versus 17% in children who did not. Even with the limits of a multicenter study with a control group represented by a historical cohort, this report showed that an effective medical treatment exists.
The report by Escolano-Margarit and colleagues represents one of the first experiences of the successful use of exchange transfusion in NH. This procedure, associated or not with immunoglobulin administration, appears to be a promising approach to a rare and scarcely understood condition. Considering the concerns linked to liver transplantation in the neonatal period and the lack of both efficacy and safety of the previously accepted treatment using iron chelators and antioxidants, a convincing and codified medical treatment could represent a turning point in the management of NH. Future studies will be probably drawn to confirm this emerging and encouraging evidence.
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