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Background: Neonatal hemochromatosis caused by a gestational alloimmune mechanism or gestational alloimmune liver disease (GALD) is a rare perinatal disorder characterized by intra- and extrahepatic iron overload. It is believed to result from complement-mediated liver injury, in which the classical complement pathway is activated by maternal antibody/fetal antigen complexes, leading to hepatocyte lysis by the membrane attack complex C5b9. According to some authors, C5b9 expression in more than 75% of liver parenchyma is specific for GALD., Methods: We conducted a retrospective multicentric immunohistochemical study with anti-C5b9 in GALD cases (n = 25) and non-GALD cases with iron overload (n = 36) and without iron overload (n = 18)., Results: C5b9 was expressed in 100% of GALD cases but involved more than 75% of the liver parenchyma in only 26% of the cases. C5b9 was detected in 26.75% of the non-GALD cases with more than 75% of positive parenchyma in maternal erythrocytic alloimmunization, herpes and enterovirus hepatitis, bile acid synthetic defect, DGUOK mutation, Gaucher disease, cystic fibrosis, and giant-cell hepatitis with autoimmune hemolytic anemia., Conclusion: Diagnosis and therapeutic management of GALD cannot only be based on C5b9 expression in liver samples as it is not specific of this disease.

Objectives: Neonatal haemochromatosis is a rare gestational disease that results in severe foetal liver disease with extrahepatic iron overload, sparing the reticuloendothelial system. Recurrence can be prevented with intravenous immunoglobulin (IVIG) infusions during pregnancy, supporting an alloimmune aetiology. The aim of the study was to assess the effect of antenatal treatment with IVIG infusion on the outcome of pregnancies in women with a history of documented neonatal haemochromatosis likely owing to gestational alloimmune disease and to analyse IVIG tolerance., Methods: From 2004 to 2012, 8 pregnant women were treated with IVIG at 1 g/kg body weight weekly from 18 weeks' gestation until birth in a prospective multicentre study., Results: All 8 neonates born to the treated women survived. Five developed mild neonatal liver disease with hepatomegaly (n = 1), hyperechogenic liver (n = 2), abnormal liver function tests (n = 1), raised serum ferritin (n = 3) and α-fetoprotein (n = 5) levels, or mild iron overload on liver magnetic resonance imaging (n = 1). Ferritin and α-fetoprotein levels normalised before 14 days and 2 months, respectively. A per-mother-basis analysis comparing outcomes of treated (n = 8) and untreated (n = 9) gestations showed a significant improvement in the survival of neonates with gestational IVIG therapy (survival 8/8 vs 0/9, P < 0.001). Adverse effects of IVIG infusion occurred in 5 mothers leading to discontinuation of treatment in 1 case. Preterm neonates born before 37 weeks' gestation had a decreased risk of neonatal liver disease (P = 0.04)., Conclusions: Antenatal treatment with IVIG infusion in women at risk for gestational alloimmune disease recurrence improves the outcome of pregnancies despite mild signs of transient neonatal liver disease.

The vascular architecture of the human liver is established at the end of a complex embryological history. The hepatic primordium emerges at the 4th week and is in contact with two major venous systems of the fetal circulation: the vitelline veins and the umbilical veins. The fetal architecture of the afferent venous circulation of the liver is acquired between the 4th and the 6th week. At the end of this process, the portal vein is formed from several distinct segments of the vitelline veins; the portal sinus, deriving from the subhepatic intervitelline anastomosis, connects the umbilical vein, which is the predominant vessel of the fetal liver, to the portal system; the ductus venosus connects the portal sinus to the vena cava inferior. At birth, the umbilical vein and the ductus venosus collapse; the portal vein becomes the only afferent vein of the liver. The efferent venous vessels of the liver derive from the vitelline veins and are formed between the 4th and the 6th week. The hepatic artery forms at the 8th week; intrahepatic arterial branches progressively extend from the central to the peripheral areas of the liver between the 10th and the 15th week. Hepatic sinusoids appear very early, as soon as hepatic cords invade the septum transversum at the 4th week. They then progressively acquire their distinctive structural and functional characters, through a multistage process. Vascular development and differentiation during liver organogenesis is, therefore, a unique process; many of the cellular and molecular mechanisms involved remain poorly understood.

We report here four cases of pediatric patients in whom the diagnosis of cystic fibrosis was made only after the histological examination of a liver specimen obtained by biopsy (three cases) or at autopsy (one case). There were two boys and two girls, aged 13 months to 7.5 years. None had a personal or familial history suggestive of cystic fibrosis. One patient, presenting with myocardial lesion and hepatomegaly, died of heart failure; at autopsy, the liver showed a typical aspect of focal biliary cirrhosis. In the three other cases, liver disease was the only manifestation of cystic fibrosis at the time of diagnosis. Liver biopsy examination showed focal biliary cirrhosis in one case and massive steatosis in two. In all four cases, the diagnosis was confirmed by the existence of known pathogenic mutations in the CFTR gene. The evolution was variable; one patient had progressive liver disease with severe portal hypertension after 7 years; another one had lung complications after 1 year. In conclusion, our experience recalls that the diagnosis of cystic fibrosis must be considered in children presenting with unexplained liver disease; its confirmation by molecular techniques makes it possible to set up an appropriate follow-up.