Neonatal hemochromatosis (NH; OMIM* 231100) is defined by the coexistence of liver disease of antenatal onset with excess iron at extrahepatic sites in a tissue distribution parallel to that seen in HFE-associated hemochromatosis (OMIM 235200). NH is not a single disorder, but a syndrome. While the etiology of most cases is unclear, NH is not an unusual manifestation of HFE disease. Some instances of NH may be due primarily to defects in tissue iron handling. Most appear to represent fulminant hepatic failure of fetal onset, with altered iron storage as a sequela. In selected cases, mitochondrial DNA analysis or searches for infective agents harbored by parents of NH patients may prove rewarding. Genomic screening for candidate genes has yet to be attempted. Until recently, NH was diagnosed only at autopsy. It now can be identified antenatally, though to date only in the third trimester of pregnancy, and patients have survived with either supportive care or orthotopic liver transplantation.
As discussed elsewhere in this text, hemochromatosis was identified in adults who absorbed dietary iron in excess of body needs and in whom excess tissue iron led to organ dysfunction . (In Europe and the Americas, the great majority of instances of hemochromatosis in adults are due to mutations in HFE, a gene at 6p21.3 with a product of unknown function .) With respect to the tissue distribution of iron, the phenotype in hemochromatosis (hemochromatotic siderosis) is different from that seen in iron overload owing to blood transfusions (transfusional siderosis). In transfusional siderosis *OMIM: Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/Omim/). reticuloendothelial elements in spleen, lymph nodes, bone marrow, and along hepatic sinusoids, which take up erythrocytes from the circulation, are the
first site of iron deposition. Siderosis of parenchymal tissues of various organs develops secondarily, and is associated with myocardial and endocrine-system failure . In hemochromatosis periportal hepatocytes, which take up iron absorbed into portal venous plasma from chyme, are the first site of iron deposition. Over time, siderosis extends throughout the hepatic lobule and involves pancreatic parenchyma, myocardium, and some endocrine epithelia. Reticuloendothelial elements remain strikingly iron-free. As in transfusional siderosis, myocardial and endocrine-system failure are seen ; cirrhosis, however, seems to be a feature of hemochromatosis rather than of transfusional siderosis uncomplicated by infective hepatitis 
It is the phenotype of advanced liver disease together with extrahepatic parenchymal rather than reticuloendothelial siderosis that Hans Cottier was the first to recognize in infants as mimicking late-stage hemochromatosis of adults. In 1957 he described “a disease picture comparable to
hemochromatosis in newborn infants” . Similar observations were published in English for the first time some years later [6, 7], and many reports of NH have since appeared worldwide [8 – 10].
NH recurs in sibships. Infants with NH may be stillborn and often are born prematurely or exhibit intrauterine growth retardation. Placental edema and oligohydramnios are frequent complications, although polyhydramnios also has been reported [11, 12]. Liver disease is generally apparent at birth or only hours thereafter: Tests of umbilical cord serum have confirmed that liver disease is present antenatally [13, 14]. It may be that liver disease of fetal onset takes a subacute course and is manifest as NH only days to weeks after birth [10, 14, 15], but such cases are highly exceptional. Liver disease may antedate the development of extrahepatic siderosis in NH .
Presenting conditions in NH include hypoglycemia, hypoalbuminemia and edema with or without ascites and oliguria, and a hemorrhagic diathesis with or without elevated levels of fibrin split products, thrombocytopenia, and anemia [8 – 10]. The initial manifestations of NH thus reflect hepatic disease, with presumedly reduced capacity to store glycogen, to release glucose, and to synthesize albumin and clotting factors. Placental edema may be due to decreased oncotic pressure, as may fetal oliguria, manifest as oligohydramnios (but see “Anatomic-pathology findings”, below). Hyperbilirubinemia, which develops during the first few days after birth, may be due to impaired hepatic synthesis and excretion of bilirubin as well as (given a hemorrhagic diathesis) to a burden of extravasated blood. Concentrations of transaminase activity in serum are disproportionately low for the degree of hepatic dysfunction , while circulating concentrations of a-fetoprotein may be high; these reflect, respectively, reduced hepatocellular mass and attempted regeneration. Other evidence of hepatocellular synthetic insufficiency includes decreased circulating concentrations of a1-antitrypsin, ceruloplasmin, and transferrin . Abnormal serum bile acid profiles have been seen in NH as well. It has been suggested that D4-3-oxosteroid 5b-reductase deficiency, a primary defect in bile acid synthesis, may underlie some instances of NH , but the argument that abnormalities in bile acid handling are a sequela of severe hepatocellular disease also can be made [19, 20]. Until mutational analysis of the gene encoding this enzyme is available, the question will remain moot .
The liver is generally small and deeply bile-stained at biopsy or autopsy. Its contours may be irregular as a result of hepatocellular loss, collapse of stroma, and varying degrees of regeneration. On microscopy, the residual hepatocytes may exhibit either giant-cell or pseudoacinar transformation, with canalicular bile plugs. Regenerative nodules may be present and may contain hepatocytes with severe atypism; hepatocellular carcinoma has been reported [22, 23]. In some instances almost no hepatocytes remain . There is generally very little bile duct proliferation, and portal tracts are not distorted, while perisinusoidal fibrosis and central-vein sclerosis are pronounced [10, 24]. Hepatocytes show siderosis, while Kupffer cells are spared; tissue macrophages in regions of scarring, however, may contain abundant hemosiderin. Transmission electron microscopy to date has not been contributory.
At extrahepatic sites, siderosis may affect, in approximate order of severity, acinar epithelium of the exocrine pancreas; myocardium; epithelia of thyroid follicles, mucosal (“minor salivary”) glands of the oronasopharynx and respiratory tree, gastric and Brunner glands, parathyroid glands, choroid plexus, thymus (Hassall corpuscles), pancreatic islets, and adenohypophysis; and chondrocytes in hyaline cartilage. The spleen, lymph nodes, and bone marrow contain comparatively trivial quantities of stainable iron. The placenta is not siderotic and villitis has not been reported [8 – 10].
Other associated findings often include splenomegaly (probably a sequela of portal hypertension) and pancreatic islet-cell hyperplasia with apparent hypertrophy of islets, possibly a sequela of abnormal glucose handling owing to hepatic disease. More rarely recognized is dysgenesis (“absence”) of proximal renal tubules, which is thought to reflect hypoperfusion of the kidney during later fetal development ; an association among this finding, underdevelopment of the calvaria, and NH has been described . Such dysgenesis, which may contribute to oliguria, has been found only at autopsy to date.
Isolated reports exist of other malformations in association with NH [12, 27, 28], but these may be coincidences. The phenotype designated as trichohepatoenteric syndrome appears exceptional . Down syndrome must be mentioned, in which transient myeloproliferative disorder in utero can cause hepatic and pancreatic fibrosis [30 – 32] associated with hemochromatotic siderosis .
Siderosis of hepatocytes is entirely physiologic in the term infant . This finding in isolation does not permit the diagnosis of NH. In adults or older children, siderosis of hepatocytes is not physiologic, and even without fibrosis or cirrhosis it can mark early stages of hemochromatosis
due to HFE disease ; “juvenile hemochromatosis” (HFE2), which maps to chromosome 1q  (OMIM 602390); or HFE3, linked to neither 6p21.3 nor 1q  (OMIM 605250). Failure to appreciate that criteria for iron overload differ with stage in life can lead to misdiagnosis in the fetus or infant [37 – 39]. In addition, prenatal growth retardation may accentuate hepatocellular siderosis, as in Finnish lethal neonatal metabolic syndrome  (OMIM 603358) or leprechaunism* (OMIM 246200), and postnatal growth failure may impede dispersal of hepatic iron stores by dilution;* we attribute both these phenomena to normal iron uptake with subnormal body mass. These considerations also must be taken into account in evaluating iron within the liver. * Personal observations
APPROACHES TO DIAGNOSIS AND TREATMENT
At this writing, NH is an idiopathic syndrome. The diagnosis of NH should be suspected in infants who manifest liver disease antenatally or very shortly after birth, but NH can be diagnosed only after infective, metabolic, and hematologic disorders are excluded by usual testing [8 – 10]. Some infrequently encountered conditions that can be mistaken for NH and should be borne in mind include liver-predominant mitochondriopathies , hepatic infarction , and hemophagocytic lymphohistiocytosis [43, 44].
The clinical-chemistry finding most characteristic of NH is hypersaturation of available transferrin, with relative hypotransferrinemia [9, 10, 12, 14, 17, 45 – 48]. By contrast, hyperferritinemia is nonspecific in liver disease of the newborn infant [10, 47, 48] and may even be misleading [43, 44]. The term infant liver is physiologically iron-laden, and immediately after birth, as the hematocrit drops, tissue iron stores appear to increase further . Hence, in the neonate, hepatocellular injury of whatever etiology can be expected to cause hyperferritinemia. Hypotransferrinemia, however, in all but rare instances reflects severe liver disease with reduced synthetically functional hepatocellular mass. Serum concentrations of iron, total iron-binding capacity, and, specifically, transferrin should be determined when NH is under consideration [10, 46 – 48].
Imaging studies can be used to support the diagnosis of NH. Differences in magnetic susceptibility between iron-laden and normal tissues on MRI can document siderosis of the pancreas and myocardium and, at the same time, can demonstrate the absence of splenic (reticuloendothelial) siderosis, establishing that hemochromatotic siderosis is present [14, 17, 47 – 51]. In the liver, as stated above, siderosis is physiologic in the neonate; failure to appreciate this, and to understand that severe liver disease is a requisite for diagnosis, can lead to wrongly assigning the diagnosis of NH.
Also characteristic of NH is persistent patency of the ductus venosus, which can be demonstrated by sonography [52, 53]. Hepatocellular injury in the fetus may be potentiated by portocaval shunting through the ductus venosus: We hypothesize that in the presence of a large-bore portocaval shunt, even slight increases in intrasinusoidal pressure such as those produced by hepatocellular swelling  can be expected to decrease blood flow within sinusoids and, in turn, to worsen hypoxemic – ischemic stress in centrilobular zones. The perisinusoidal fibrosis and central-vein sclerosis that characterize NH [10, 24] thus may reflect the peculiar hemodynamics of the fetal liver. In postnatal life, such fibrosis and sclerosis increase intrahepatic resistance to portal blood flow and, as a result, the ductus venosus fails to close.
Liver biopsy in NH is difficult to conduct safely, owing to the hemorrhagic diathesis associated with the disorder. Biopsy of the mucosa of the oral cavity has been used to demonstrate extrahepatic parenchymal siderosis consistent with hemochromatotic siderosis and to support the diagnosis of NH [17, 48, 50, 55]. A 3-mm punch biopsy specimen of lower lip mucosa generally suffices. Frozen section, with examination for minor salivary gland tissue, can determine adequacy . Hemostasis can be procured under direct vision.
Because a fetus in a mother who has borne an infant with NH is at risk for liver disease, antenatal diagnosis in NH has been attempted [47 – 51]. In several pregnancies at such risk that have been monitored closely, evidence of liver injury, in particular placental or fetal edema, has been found in the third trimester and follow-up studies have identified fetal distress. Studies of blood obtained both by funipuncture and at emergent delivery documented abnormalities characteristic of NH, with NH confirmed at buccal mucosal biopsy, hepatectomy, or autopsy [47, 48, 50, 51]. To our knowledge, MRI studies have not yet identified hemochromatotic siderosis in utero, nor has evidence of fetal disease in a pregnancy at risk for NH been found before the third trimester. It is an open question if intervention in such a pregnancy, or early delivery when fetal disease is identified, can reliably improve outcome [10, 48, 51]. Preliminary results of immunoglobulin administration during pregnancies at risk (see below) are reportedly favorable.
The prognosis in NH is poor. Some infants have recovered with supportive care [45, 51, 56], and reports of good results ascribed to an antioxidant and chelator regimen have been published [50, 57, 58].* Outcomes with the regimen have not been uniformly
* The agents and doses employed to date are available elsewhere [47, 57]. Caution is recommended in the use of the iron chelator desferrioxamine, which as a siderophore can potentiate bacterial infection [47, 59, 60].
happy: It may be that less severely ill patients profit from it, while more severely ill patients fail to respond [47, 48, 51]. Other infants have been treated by whole-liver or split-liver transplantation [17, 19, 21, 47, 51, 61, 62]. While siderosis may develop in the allograft, this appears to reflect equilibration of body iron from extrahepatic sites into the engrafted organ rather than increased postnatal iron absorption , and liver disease ascribed to the effects of siderosis has not been
reported after liver transplantation in NH.
PERTURBED IRON METABOLISM OR LIVER DISEASE: WHICH COMES FIRST?
Two hypotheses on the cause of NH can be entertained. One proposes that in the fetus liver injury leads to abnormalities in iron handling. Clinical evidence supporting this hypothesis has been found in association with tyrosinemia [55, 63], cytomegalovirus infection , and maternal
transfusion-associated hepatitis  as well as in the subset of NH associated with Down syndrome . The other proposes that in the conceptus abnormalities in iron handling lead to liver injury. Clinical evidence supporting this hypothesis has not been found; it rests on analogy
with HFE disease.
The body acquires iron through different routes antenatally and postnatally. Antenatal iron uptake by the conceptus occurs via endocytosis of iron – apotransferrin (transferrin) complexes bound to transferrin receptors on the surface of placental trophoblast in contact with maternal blood . The transferrin receptor, b2-microglobulin, and HFE (the protein encoded by HFE) are physically associated within the cell [2, 66]; full details of their interaction are not yet elucidated. This observation is consonant with the fact that the phenotype of HFE disease is partially expressed, with hemochromatotic siderosis but without liver disease, in murine deficiency of b2-microglobulin (OMIM 109700) .
Within endocytotic vacuoles, or endosomes, acidification leads to release of iron from transferrin; the freed iron is then moved across the endosomal membrane into cytoplasm via DMT1 (divalent metal transporter 1) . The molecular species are not yet defined that prevent oxidative damage to cellular constituents while chaperoning ionic iron through the cytoplasm to sites of use (metalloproteins, mitochondria), storage (apoferritin), or export across basolateral membranes; nor are the species known that export iron from phagolysosomes. Basolateral export is mediated, but not conducted, by hephaestin, a putative ferroxidase ; the actual transport protein is not yet definitively known . Iron exported into the extracellular medium must then, whether in the form of transferrin or complexed with some other carrier, traverse endothelium to gain access to the intravascular space. The steps involved in this process also are obscure.
Each of the steps by which iron passes through the placenta is expected to be under genetic control, and can theoretically be altered by mutation to result in greater iron uptake, which in turn might cause fetal liver injury. The genes encoding proteins known to participate in these processes and the proteins themselves have not been thoroughly studied in families affected by NH, although usual mutations in HFE have not been found in NH patients . It should be noted that neither maternal or paternal HFE disease has been shown to be associated with increased transplacental iron uptake .
Postnatal iron uptake occurs in the brush border of enterocytes in the proximal duodenum. An incompletely characterized ferrireductase mediates this process [73, 74]; DMT1 is the transporter of iron from chyme into cytoplasm [75, 76]. As with trophoblast, iron carrier species and phagolysosomal export species in enterocytes are not known; basolateral export is effected by hephaestin and an unknown transport protein; and exported iron must traverse endothelium, by routes that are not understood, to gain access to the intravascular space. Transferrin receptors at the basolateral aspects of crypt enterocytes, again ssociated with HFE and b2 microglobulin , are not thought to participate directly in efflux of iron from the cell.
HFE disease leads to increased transfer of iron from chyme into plasma , and in turn to increased body iron content, with siderosis of a variety of cell types. Paradoxically exempt from siderosis in HFE disease are tissue macrophages (reticuloendothelial cells). This pattern of tissue
siderosis also is seen in mice deficient in b2-microglobulin . It can be hypothesized that defective function of the HFE / b2-microglobulin / transferrin-receptor complex leads – by an unknown route, possibly involving increased release of iron from transferrin within the acidified endosome  – to altered regulation of iron export proteins in both enterocytes and macrophages . If iron thus is exported from both cell types at accelerated rates in HFE disease and in deficiency of b2-microglobulin, the observed phenotype can be understood.
This, however, leaves the question of why hemochromatotic siderosis is a feature of both human and murine atransferrinemia / hypotransferrinemia (OMIM 209300) [80 – 82]. Why should lack of functional apotransferrin should impair function of the HFE / b2-microglobulin / transferrin-receptor complex when the elements of this complex are themselves intact? Perhaps a clue lies in shifts of plasma iron from an apotransferrin-bound pool to a labile or low-molecular-weight pool in the absence of functional apotransferrin, as seen in both HFE disease and hypotransferrinemia [82, 83].
Liver disease in the fetus can lead to reduced hepatocellular mass. This shrinks both the capacity of the physiologic depot for iron storage in utero and the capacity for hepatic synthesis of a variety of proteins. Both absolute hypotransferrinemia and hypersaturation of available transferrin [9, 10, 12, 14, 45 – 48], with expansion of a low-molecular-weight iron pool , are features of NH. Iron in this plasma pool is available to DMT1 on cell surfaces. Cellular iron uptake via DMT1 may bypass usual controls imposed by iron-responsive elements in transferrin-receptor mRNA, which decrease translation when intracytoplasmic iron concentrations rise . Like transferrin-receptor mRNA, one form of DMT1 mRNA contains sequences that are exposed, leading to degradation, when an iron-binding protein dissociates from mRNA; another, however, does not [75, 76].
We speculate that patterns of tissue siderosis at extrahepatic sites in NH, as in atransferrinemia, reflect constitutive differential expression of DMT1. Translation of DMT1 mRNA in epithelia and myocardium at rates greater than in macrophages and reticuloendothelial cells may be manifest as hemochromatotic siderosis when iron is displaced from transferrin into low-molecular-weight species within plasma.
The corollary conclusion is that the effects of severe liver disease in utero, in particular hypotransferrinemia, probably suffice to explain aberrant iron distribution within the tissues of patients with NH. We believe that most instances of NH represent subacute or fulminant hepatic
failure of fetal onset, with survival to birth made possible by the support provided by placenta and mother [48, 85].
ETIOLOGY AND COUNSELING: POSSIBILITIES AND APPROACHES
The pattern in which NH occurs within populations is unusual for a recessively inherited disorder; consanguine demes in which NH is common have not been reported. The pattern in which NH occurs within sibships also is unusual for a recessively inherited disorder; once a proband has
manifested NH, the empiric rate of recurrence in the sibship exceeds 75% (P. McKiernan, personal communication). These observations suggest that alternate inheritance patterns need to be considered, or that an acquired and persistent parental factor may play a role.
It is possible that marked variability in penetrance of a dominant gene underlies the unusual pattern in which NH occurs. Other observations, however, must be considered: No man has ever been reported to have fathered infants with NH on different women, but several kindreds are known in which a woman has borne infants with NH to different men [51, 86 – 88]. This may indicate that some instances of NH are due to gonadal mosaicism for new and dominant mutations lethal in spermatogenesis but not in oogenesis. It also may indicate that mitochondrial disease, inherited through the mother , or maternal transmission of an imprinted gene accounts for some instances of NH. Finally, it is compatible with an acquired and persistent maternal factor.
Such a factor might be an antibody against a fetal hepatocellular antigen or, less likely, one of the proteins involved in iron handling within the conceptus. (One kindred has been reported in which maternal autoimmune disease was associated with NH; antibodies complexed with liver tissue were not detected in an affected child .) When mothers who have borne infants with NH have received immunoglobulin by vein during subsequent pregnancies, to ablate a postulated anamnestic response, fetal liver disease has not been entirely eliminated. To date, however, the liver dysfunction present has not been lethal in any instance (P. Whitington, personal communication).
Instances of maternal blood exposure and hepatitis associated with NH have been reported [5, 16], and we have encountered other instances of NH in which one or both parents have histories of blood exposure or intravenous drug abuse, with or without clinically manifest hepatitis. These observations, together with the occurrence pattern described above, suggest that infective hepatotropic agents, probably viral, harbored by the mother may be responsible for some instances of NH. It should be noted that immunoglobulin treatment might be expected to alter the course of an infectious insult as well as that of an alloimmune response. It may be possible prospectively to look for evidence of viral infection or unusual antibodies in maternal and fetal or infant sera of pregnancies at risk.
To postulate a persistent maternal factor, either an infective agent or an antibody, has implications for counseling prospective parents and for the outcome of either supportive care or liver transplantation. It is apparent that to cite a recurrence rate of one in four may be misleading. In addition, when a woman wants to bear a healthy child, donor gamete or embryo transfer can help evade the risk of an inherited disorder but may be ineffective in an acquired one. Finally, if an infective agent is responsible for some instances of NH, it may affect an allograft liver;
immunosuppression might be expected to facilitate such infection. Therefore it is of interest that liver disease has not been reported to recur in survivors of NH.
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