Liver failure in neonates is a rare but often fatal event. Causes include inborn errors of metabolism, perinatal infections, hypotension/shock, and hematological conditions like TMD, congenital leukemia and hemophagocytic lymphohistiocytosis [4, 5]. Whereas metabolic liver diseases typically present weeks to months after birth and infectious diseases weeks after birth, neonatal NH presents soon after birth. In NH, the onset of the liver disease is in utero, with end-stage liver disease already established even in the prematurely born infant [6, 7]. It is the most frequently recognized cause of liver failure in neonates and the commonest indication for neonatal liver transplantation.
In NH, severe fetal liver injury often leads to fetal loss as evidenced by the obstetric histories of women who have had an infant diagnosed with NH [7, 8]. Intrauterine growth restriction, oligohydramnios or polyhydramnios, fetal distress and placental edema may be present. Infants who are not stillborn exhibit liver and multiorgan failure within the first few days of life. Jaundice with significant elevations of both conjugated and nonconjugated bilirubin, hypoglycemia, marked coagulopathy, thrombocytopenia, anemia, hypoalbuminemia, edema, ascites, and oliguria are prominent features . Typical biochemical findings include an extremely high serum ferritin level (usually > 800 ng/mL), and extremely high levels of AFP (usually > 200 ng/mL). An unusual characteristic given the degree of liver injury is low or absent serum transaminases. Hepatocellular synthetic insufficiency leads to hypoglycemia, coagulopathy (factors V and VII usually less than 10% of normal, low fibrinogen), hypoalbuminemia (usually less than 2 gm/dL) and decreased iron-binding capacity. Liver histology is characterized by intense fibrosis and cirrhosis without acute necrosis. However, none of these findings is diagnostic of NH.
The diagnosis of NH is based on the clinical features of liver failure at birth with extrahepatic siderosis and sparing of the reticuloendothelial system in the absence of other causes of liver failure. Extrahepatic siderosis can be demonstrated non-invasively in these critically ill infants on magnetic resonance imaging (MRl) and lip biopsy [6, 9–11]. Hepatic siderosis is not specific for NH, rather it is observed in the normal infant liver and more prominently in a multitude of liver diseases. Therefore liver biopsy, a hazardous procedure in the presence of coagulopathy, is not diagnostic for NH.
The prognosis for patients with NH is grim; most succumb to the complications of end-stage liver disease within the first few weeks of life if not successfully rescued by liver transplantation [7, 12–16]. Treatment with either anti-oxidant/chelator cocktail, or exchange transfusion and IVIG has been reported to be successful in small series of patients but these therapies have not been systematically evaluated. The survival after liver transplantation is 50% (median follow up 7.8 years, range 3-10 years). There is a high recurrence rate (~80%) of NH in families following the birth of an affected child.
The case presented here had several typical features of NH. The unique features of the infant presented in this report are the association of NH with Trisomy 21 (tenth reported case in literature) and the association of NH with PPH. Although PPH has been reported with end-stage liver disease (ESLD) in adults and older children, this is the first report of PPH in association with liver failure secondary to NH, an end-stage liver disease seen in the neonatal period . The diagnosis of PPH in adults and older children requires the presence of pulmonary hypertension in the setting of liver disease or portal hypertension. It has been proposed that binding of endothelin-A receptors by increased circulating levels of endothelin 1 (ET-1) produced by the cirrhotic liver lead to vasoconstriction and vascular smooth muscle proliferation which manifests as PPH. Although the diagnosis of PPH is made on the basis of hemodynamic criteria, presence of morphologic features of pulmonary hypertension has been described in a few case series of pediatric ESLD [18, 19]. Because of the rarity of PPH, diagnosis is often delayed. Clinical diagnosis requires a high degree of suspicion and deliberate follow-up by echocardiography for the timely detection of pulmonary hypertension before irreversible vascular damage occurs. In our patient, pulmonary hypertension that was present since the first day of life worsened progressively inspite of treatment. Infants with Trisomy 21 have an increased risk for developing persistent pulmonary hypertension in the neonatal period as well as primary pulmonary hypertension later in life even in the absence of structural heart disease [20, 21]. The predisposition to neonatal pulmonary hypertension has been attributed to a combination of reduced alveolar count (as was observed on autopsy in our patient), reduced capillary surface area and an abnormal pulmonary vasculature. Pulmonary hypertension in neonates with Trisomy 21 typically responds to medical therapy. Several features suggest that the pulmonary hypertension observed in this neonate was attributable to ESLD, with the presence of Trisomy 21 being a contributory factor - the fact that the hypoxemia responded to supplemental oxygen in the first two days and then worsened progressively with worsening liver failure despite treatment with assisted ventilation and inhaled nitric oxide. The neonate with ESLD differs from adults and children with ESLD in that pulmonary hypertension is normal during fetal life because the placenta, not the lung, serves as the organ of gas exchange and the presence of ESLD may prevent the normal postnatal drop in pulmonary vascular resistance soon after birth. Therefore hemodynamic criteria for porto-pulmonary hypertension may be present in the absence of morphologic criteria because of presentation of liver failure soon after birth. The importance of recognizing PPH is that it is reversible with liver transplantation but at the same time increases the risk of post-operative mortality. It has been suggested that screening with echocardiography be considered for all adults and children with ESLD for early diagnosis of PPH. We suggest that this recommendation be also applied to newborns with fulminant liver failure to improve outcomes.