Neonatal Liver Cirrhosis Without Iron Overload Caused by Gestational Alloimmune Liver Disease

Abstract

Gestational alloimmune liver disease has emerged as the major cause of antenatal liver injury and failure. It usually manifests as neonatal liver failure with hepatic and extrahepatic iron overload, a clinical presentation called neonatal hemochromatosis. We report on a newborn in whom fetal hepatomegaly was detected during pregnancy and who presented at birth with liver cirrhosis and mild liver dysfunction. Liver biopsy showed the absence of iron overload but strong immunostaining of hepatocytes for the C5b-9 complex, the terminal complement cascade neoantigen occurring specifically during complement activation by the immunoglobulin G-mediated classic pathway, which established the alloimmune nature of the hepatocyte injury. The infant survived with no specific therapy, and follow-up until 36 months showed progressive normalization of all liver parameters. This case report expands the recognized clinical spectrum of congenital alloimmune liver disease to include neonatal liver disease and cirrhosis, even in the absence of siderosis. Such a diagnosis is of utmost importance regarding the necessity for immunotherapy in further pregnancies to avoid recurrence of alloimmune injury.

Transient Neonatal Liver Disease After Maternal Antenatal Intravenous Ig Infusions in Gestational Alloimmune Liver Disease Associated With Neonatal Haemochromatosis

“…Pathological reports that have highlighted the absence of a correlation between iron overload and severity of foetal liver disease raise further questions (14,25). Indeed, previous observations of NH-GALD that demonstrated the onset of liver injury before (39) or without (14) the demonstration of iron overload corroborate this view. By increasing cellular iron stocks, a secondary oxidant injury would worsen foetal hepatocyte damage (33).…”

“…Autopsy should be promoted in discussions with families and always be performed in neonates who died of unexplained liver or multiorgan failure to assess the diagnosis of NH (25). Immunostaining in hepatocytes for C5b-9, the terminal complement cascade neoantigen occurring specifically after complement classical pathway activation, is a highly suggestive biomarker of the disease (13,14) even if recent observations in a galactosemic family have raised the question of its specificity (38). Pathophysiological mechanisms involved in NH-GALD suggest transplacental transfer of a specific maternal immunoglobulin G (IgG) activating the foetal complement classical pathway and the formation of membrane attack complex (13).…”

“…Other forms of NH have to be ruled out, mainly mitochondrial oxidative phosphorylation disorders that can lead to a similar phenotype of neonatal cirrhosis with intrahepatic and extrahepatic iron overload (33)(34)(35)(36)(37). Pathological reports that have highlighted the absence of a correlation between iron overload and severity of foetal liver disease raise further questions (14,25). Immunostaining in hepatocytes for C5b-9, the terminal complement cascade neoantigen occurring specifically after complement classical pathway activation, is a highly suggestive biomarker of the disease (13,14) even if recent observations in a galactosemic family have raised the question of its specificity (38).…”

“…It is characterised by high rates of mortality and recurrence (80%-92%) in the progeny of affected women (5,6). Most instances of NH have been ascribed to gestational alloimmune disease (GALD) (11)(12)(13)(14). Most instances of NH have been ascribed to gestational alloimmune disease (GALD) (11)(12)(13)(14).…”

Distinguishing primary from secondary Δ4‐3‐oxosteroid 5β‐reductase (SRD5B1, AKR1D1) deficiency by urinary steroid analysis

“…Although liver function values such as alanine aminotransferase may be moderately elevated, the process of cirrhosis has begun and normal values are common. Importantly, biopsy specimens show no histopathologically demonstrable iron deposition but only severe fibrosis or cirrhosis . Detection of glyceroluria by organic acid analysis using GC‐MS may be useful for diagnosis of NH .…”