Fetal and infantile hemochromatosis†

Hemochromatosis is the term coined by Von Recklinghausen in the late 19th century to describe the association of endocrine dysfunction (i.e., diabetes), cirrhosis, and abnormally bronze-colored skin. Observed mainly in adult men,1 it was later determined that abnormal iron deposition in diseased tissues was involved in its pathogenesis and that it was a familial condition. It was not until 1996 that the hemochromatosis gene HFE was discovered and that the homozygous mutation C282Y was determined to be the cause of the vast majority of cases of hereditary hemochromatosis.2 In the intervening decade, mutations of other genes whose products are involved in the regulation of the body's iron status have been identified in patients expressing the phenotype of hemochromatosis, resulting in several disorders that now constitute “hereditary hemochromatosis.” There are few patients with the classic hemochromatosis phenotype in whom no gene defect can be identified. Children—particularly young children—have never fit into the classic hemochromatosis phenotype. Clinical observation has shown that many years are required for patients with hereditary hemochromatosis to accrue the amount of excess iron that causes disease. Thus, decades before the discovery of HFE, rare patients with iron overload and organ failure or dysfunction beginning in childhood were classified differently. Children presenting signs of the disorder some years after birth were diagnosed with “juvenile hemochromatosis” while newborns simply had “neonatal hemochromatosis”. Mutations of newly described genes whose products are important in iron homeostasis have been determined to cause most cases of juvenile onset hereditary hemochromatosis. These findings have helped unravel the complexities of the system that regulates iron metabolism. Yet, the clinical and pathological findings in these children who rapidly accrue iron, perhaps even during intrauterine life, have shed some doubt as to whether neonatal hemochromatosis could possibly result from iron overload. This review covers the clinical gamut of hemochromatosis as it affects fetuses and infants. The distinct clinical and pathological findings of neonatal hemochromatosis are the main focus of discussion. The subjects of hereditary hemochromatosis and iron homeostasis have been ably reviewed by Pietrangelo1 and Fleming and Bacon.3 Herein, brief overviews of these subjects will set the stage for discussing emerging concepts related to the pathogenesis of neonatal hemochromatosis. Controlling the accrual of dietary iron involves a complex system for sensing iron status and signaling whether increased or decreased enterocyte iron export is indicated—a kind of “ferro-stat.” The 2 central figures in the ferro-stat are hepcidin, the sensor signal, and ferroportin, the regulator of enterocyte iron export. Hepcidin is synthesized by the liver and acts on ferroportin to cause its cellular internalization and destruction.4, 5 Ferroportin is essential for the export of iron from any cell, including enterocytes, hepatocytes, and macrophages.6 In times of iron sufficiency, the liver limits the further uptake of dietary iron by increasing the synthesis and export of hepcidin, which in turn reduces the amount of ferroportin available for export of iron from enterocytes. Hepcidin similarly acts on macrophages to reduce the amount of systemic iron available from recycling. Hemojuvelin appears to be upstream of hepcidin in the hepatic system of sensing cellular iron stores and regulating available iron and is critically involved in signaling the upregulation of hepcidin synthesis in conditions of iron sufficiency.7, 8 The function of HFE in the regulation of iron homeostasis is not clearly understood. In conditions of iron sufficiency, it may act directly by programming enterocytes to not export iron to the circulation or indirectly by regulating hepcidin synthesis and export by hepatocytes. Serum transferrin receptor 2 may function along with HFE to modulate hepatic hepcidin expression.9 The fetus parasitizes the mother to insure adequate iron for the growth and oxygen-carrying capacity of the fetus and newborn.10 The placenta acts as an active interface between the mother's huge iron pool and the highly controlled and relatively small fetal iron pool, insuring adequate iron supply to the fetus and protecting against potentially toxic iron overload.11 Concepts regarding how the flux of iron from mother to fetus is regulated are currently unfolding. It appears that the ferro-stat that functions after birth to control accrual of dietary iron also functions during fetal life, with the placental trophoblast functioning in analogy to the duodenal mucosa.12 Ferroportin is highly expressed and colocalizes with HFE in placental trophoblast cells.13, 14 Ferroportin expression increases with gestational age in parallel with the fetus' increasing demand for iron.13 Fetal hepcidin evidently regulates fetal iron stores. Disruption of the gene encoding for the transcription factor upstream stimulatory factor 2 (Usf2) in the mouse results in complete absence of hepcidin expression and a hemochromatosis phenotype.15 Usf2−/− mice have massive iron overload in the liver that is significantly greater than that of wild-type mice as early as 2.5 months of age, suggesting fetal iron overload.15 In contrast, mice exhibiting an overexpression of transgenic hepcidin are born profoundly anemic and iron-deficient.16 NH, neonatal hemochromatosis; AFP, alpha-fetoprotein; IgG, immunoglobulin G. The vast majority of hemochromatosis results from homozygous C282Y mutation of HFE located on chromosome 6 (OMIM 235200; hereditary hemochromatosis type 1).1 In homozygous affected individuals, defective HFE function results in poor control of dietary iron assimilation, with approximately 3 mg/d of excess iron being assimilated. When accumulating in critical excess, the iron produces tissue damage and organ dysfunction, particularly involving the liver, endocrine glands, and heart. The age of onset and expression of clinical disease are highly variable but are usually in the fifth and sixth decades of life. The most common clinical presentation is with liver disease. HFE-associated hemochromatosis is one of the most common hereditary diseases; the rate for the homozygous C282y mutation is approximately 5 per 1,000 persons in populations of European descent. Hemochromatosis with relatively early onset of clinical disease in adolescence and early adulthood has been termed juvenile hemochromatosis.1 Juvenile onset hereditary hemochromatosis is exceedingly rare, with at most a few dozen cases recorded. The mutations of 2 genes have been shown to produce juvenile hemochromatosis (OMIM 602390, hereditary hemochromatosis type 2): HJV, located on chromosome 1,17, 18 whose product is hemojuvelin (hereditary hemochromatosis type 2A), and HAPM, located on chromosome 19,19 whose product is hepcidin (hereditary hemochromatosis type 2B). The majority of cases are due to HJV mutations. The rate of iron accretion in juvenile hemochromatosis has not been determined, but is presumed to be much greater than in HFE-associated hemochromatosis. The clinical features are dictated by the rapidly accumulating iron overload. Iron parameters and tissue iron distribution in adolescents are similar to middle-aged adults with HFE-associated hemochromatosis. Endocrine manifestations (particularly hypogonadism) and cardiac disease are the most common presenting clinical features. The liver is involved as well, but significant liver dysfunction or cirrhosis is rarely seen, presumably because the other organ dysfunction dictates the natural history. It is important with regard to the potential role of iron overload in the pathogenesis of neonatal hemochromatosis to note the lack of liver injury in human juvenile hemochromatosis (Fig. 1). Furthermore, the hepcidin-deficient Usf2−/− mouse shows virtually no hepatic injury at 19 months of age despite having a liver iron content of 1,000 μg/g dry tissue, which is 10 times the wild-type value.15 It seems that it may take considerable time for acquired excess iron to produce liver injury. This may contribute to the lack of liver disease at clinical presentation of juvenile hemochromatosis compared with HFE-associated hemochromatosis. A 2-year-old girl was discovered to have increased serum iron indices (serum ferritin 3,600 ng/mL; transferrin saturation 79%) and elevated alanine aminotransferase levels during a work-up of failure to thrive. (A) Perl's Prussian blue stain of the liver biopsy showed marked iron overload (original magnification ×100). (B) This overload primarily involved hepatocytes, but it affected Kupffer cells as well (arrows) (original magnification ×400). A clinical diagnosis of juvenile hemochromatosis was made and phlebotomy therapy was instituted. An evaluation of the possible gene defects involved is underway. Examination of standard histological preparations showed little if any disturbance of hepatic architecture, and hepatocytes showed no evidence of cellular injury despite the massive iron overload. Neonatal hemochromatosis (NH) (OMIM 231100) has been clinically defined as severe neonatal liver disease in association with extrahepatic siderosis in a distribution similar to that seen in hereditary hemochromatosis.20 Considerable evidence exists to suggest that it is a gestational disease in which fetal liver injury is the dominant feature.21 It has also been called “congenital hemochromatosis.” NH is associated with severe fetal liver injury, and one of its most common presentations is late second and third trimester fetal loss as evidenced by the gestational histories of women who have had an infant diagnosed with NH.22 We have diagnosed NH in necropsies of stillborns as early as 22 weeks' gestation. Most affected live-born infants show evidence of fetal insult (i.e., intrauterine growth restriction and oligohydramnios), and premature birth is common. Liver disease is generally apparent within hours of birth, though in rare cases the liver disease takes a subacute course and manifests days to weeks after birth. There is a spectrum of disease, and some infants recover with supportive care.23, 24 Indeed, it may be that some “affected” infants have no clinical disease. We have shown that twins may have disparate clinical findings, with one severely affected and the other minimally so.25 It is one of the most commonly recognized causes of liver failure in the neonate.26 The presenting findings are those of acute liver failure and usually multiorgan failure. Affected infants are frequently diagnosed as having overwhelming sepsis of the newborn even with negative cultures. Hypoglycemia, marked coagulopathy, hypoalbuminemia and edema with or without ascites, and oliguria are prominent features. Jaundice develops during the first few days after birth. Most cases exhibit significant elevations of both conjugated and nonconjugated bilirubin. Serum aminotranferase concentrations are disproportionately low for the degree of hepatic injury, whereas circulating concentrations of alpha-fetoprotein (AFP) are characteristically very high, usually 100,000 to 600,000 ng/mL. Elevated concentrations of AFP in NH could be due to a failure to downregulate the synthesis of AFP, and perhaps both high AFP and low aminotransferase activities reflect a failure of the diseased liver to switch from fetal to neonatal metabolic patterns. Studies of iron status often show hypersaturation of available transferrin, with hypotransferrinemia and hyperferritinemia (>800 ng/mL), which though characteristic in NH are nonspecific in liver disease of the newborn infant.20 The low transferrin levels probably reflect severe liver disease. Notably, several patients in our experience have received the diagnosis of tyrosinemia based on elevated serum tyrosine levels, which are reflective of failed hepatic metabolic function. Urinary succinylacetone is absent. The prognosis in severe NH is generally very poor. The average life expectancy of a severely affected infant is days to a few weeks with good care. A cocktail of antioxidants and an iron chelator has been used as a treatment. Success rates with medical treatment have been reported to be 10% to 20%, though it is not clear what factors determine a successful outcome.23, 24 No controlled trial of the use of this cocktail has been undertaken. Within the spectrum of severe NH, it may be that patients with more hepatic reserve profit from it, while more severely affected patients fail to respond.23 It is clear that patients with clinical liver failure due to NH can fully recover with no residual liver disease.23 NH is a frequent indication for liver transplantation in the neonate.26, 27 However, both patient and allograft survival are poor in neonatal liver transplantation, and neurological function is often impaired in survivors.27 When performed for NH, the difficulties attendant to transplanting newborns are frequently compounded by prematurity, small size for gestational age, and multiorgan failure. Liver injury in NH is very severe and out of proportion to that seen in hereditary hemochromatosis (Fig. 2). Autopsy materials from stillbirths and newborns have provided most of the pathological descriptions of the disease. Cirrhosis is universally described. The liver is generally small and deeply bile-stained. Its contours may be irregular as a result of hepatocellular loss, collapse of stroma, and varying degrees of regeneration. Fibrosis is pronounced, particularly in the lobule and around the central vein. Regenerative nodules may be present. In some instances, almost no hepatocytes remain. The residual and/or regenerating hepatocytes may exhibit either giant cell or pseudoacinar transformation with canalicular bile plugs. Considerable acute and chronic inflammation is usually evident. The pattern of injury is strongly reminiscent of subacute or acute hepatic failure in postnatal life. Liver failure was noted at birth in a 2,900-g, 38 weeks' gestation male infant. Decreased fetal movement and oligohydramnios had been noted at 36 weeks' gestation. Refractory hypoglycemia and severe coagulopathy were the most prominent signs of liver failure. NH was suspected. On magnetic resonance imaging performed at 8 days of age, the liver (left arrow) and pancreas (right arrow) had a markedly reduced T2 signal intensity (dark area) relative to the spleen. Serum iron indices were not measured. Supportive therapy failed, and the infant expired on day 9. The composite image shows the most prominent histological findings on the postmortem examination. (a) Severe liver damage. A trichrome stain shows a fibrotic portal tract on the upper left. The hepatic parenchyma has been replaced by necrotic and fibrous tissue (blue-stained areas) and ductules; there were very few preserved hepatocytes (original magnification ×100). Perl's Prussian blue stain showed abnormal iron deposition in the (b) liver (original magnification ×200), (c) pancreas (original magnification ×200), (d) myocardium (original magnification ×400), (e) Hassall's corpuscles of the thymus (original magnification ×400), and (f) thyroid follicles (original magnification ×400). The liver iron content was modestly elevated at 4,559 μg/g wet weight (reference normal 200–2,000). R, right; L, left. Hepatocytes often—though not always—show siderosis, while Kupffer cells are spared. The siderosis is coarsely granular, which is in contrast to the hazy iron staining of normal newborn liver. Siderosis may affect any of several tissues outside the liver (Fig. 2).20, 28 The most consistently affected are the acinar epithelium of the exocrine pancreas, myocardium, epithelia of thyroid follicles, and the mucosal (“minor salivary”) glands of the oronasopharynx and respiratory tree. Less affected are the gastric and Brunner glands, parathyroid glands, choroid thymus and in The and of There appears to be little tissue damage associated with the extrahepatic siderosis (Fig. and no organ dysfunction (i.e., endocrine or cardiac has been reported to result from These findings it that the universally severe liver injury could be the result of iron overload a of severely affected infants exhibit with of and of with the of normal this of to 24 weeks' gestation. It is that this stage of is liver the liver failure to the late second and early third NH be in infants who liver disease or very after of extrahepatic siderosis is for siderosis in the liver is not and its absence not the NH is often diagnosed at siderosis of many tissues can be of extrahepatic siderosis in infants can be tissue biopsy or magnetic resonance of the is a clinically to tissue in which to in magnetic between and normal tissues on magnetic resonance imaging can siderosis of particularly the pancreas and liver (Fig. though the of these has never been mucosal biopsy often because are either or not In our adequate some iron amount is in approximately of cases to have NH, whereas magnetic resonance imaging abnormal iron distribution in approximately of The of NH is not understood. it was to be the of any severe fetal liver injury (i.e., due to intrauterine or possibly a 36 However, NH has an pattern and a high rate of in the of affected women that be by these The of NH and the an affected infant has on a for further it to determine an However, it is generally that after the there is an approximately that infant born to that mother will be In our more than of women have had more than one affected infant or an fetal There are several of a birth to affected infants with male but not There have been no of of women having an infant with NH having affected infants. In NH appears to be and but not We have and have supportive evidence that NH is an gestational disease that results from during to a common human liver that is expressed mainly in fetal The pattern of which is much that of and with hereditary disease, to this of the immunoglobulin are the placenta to the fetus from approximately 18 weeks' gestation. The function of this is to for the fetus and newborn against a of to which there has been no The of involves of a to a fetal NH it to be a liver that to as which results in and of immunoglobulin of the of and to the In of to the fetus this and is by movement of liver to the fetal it the in liver and results in injury of the fetal liver. Liver injury results in the of iron that the liver, which to siderosis and the NH phenotype. In this injury of the fetal liver to the of iron, as to iron overload to liver damage. It has been from clinical that liver disease iron deposition in which well with this In this the hemochromatosis phenotype results from iron deposition in extrahepatic It be noted that it is not if newborns with NH are iron which is to that iron content has never been There are 2 with regard to the of siderosis in is that the infants are as a result of poor control of iron flux the fetal hepcidin is involved in regulating placental ferroportin which is involved in regulating iron It is to that reduced hepcidin synthesis by the severely liver could to poor regulation of ferroportin in the placenta and to iron overload. The failure to ferroportin could also contribute to the lack of and Kupffer cell The other is that the infants are not have an abnormal but deposition of iron in severe liver injury, the central and distribution for iron in the fetus is Iron to fetal transferrin, the of which is usually low in NH, in the placenta a tissue to use or In transferrin saturation is high in NH, iron may also be in The tissues siderosis are those of iron from These and possibly further We have a treatment for women to NH during gestation based on the that it is an disease. The treatment of immunoglobulin from of at a of weight from 18 weeks' gestation until the of This is a treatment commonly used to the of other gestational We have for treatment women whose most gestation was affected with NH in of any other for high of infants have been born to gestational treatment to our No intrauterine growth fetal liver disease, or other evidence of fetal have been in any This is in contrast to the of NH, in which severe intrauterine growth restriction and oligohydramnios are 6 infants showed significant clinical evidence of liver disease. However, there was evidence that 24 infants were affected with NH, as evidenced by elevated serum AFP and/or elevated serum ferritin Liver were from 2 showed severe with and iron and 2 hepatic and of giant cells with We have reported the results of women When on a of to affected gestational immunoglobulin therapy was associated with infant survival We from this experience that treatment with immunoglobulin during gestation appears to have NH that it was not to the fetus or These results evidence for an for if NH is siderosis has been in cases of fetal and neonatal liver injury due to and However, extrahepatic siderosis has not been in these There to be a for a gene associated with NH with no to 36 In there is little evidence to suggest that more than a small of cases result from the There is to that the majority a fetal liver injury, though a for is to a be to determine if cases of NH a if are there some cases that are to perhaps fetal liver injury. This the lack of or most NH is could a with a newborn in which liver failure is a The to treatment at and the of the immunoglobulin It also in the of affected the of be cause to from the infant or as is performed for other severe fetal and it be a in because at the to if a is at is for to have an affected infant. show that severe NH is have significant The figures were by of