Gestational alloimmune liver disease reconsidered: Advocating for a new nomenclature and enhanced diagnosis accuracy

Abstract

Gestational alloimmune liver disease (GALD), previously known as neonatal hemochromatosis, is a rare antenatal immune condition in which maternal antibodies target the fetal liver, leading to a spectrum of liver injury. Although GALD in the leading cause of neonatal liver failure, recent evidence highlights its association with milder phenotypes. A maternal history of miscarriages or stillbirths may be present. GALD is characterized by hepatic and extrahepatic iron overload sparing the reticuloendothelial system. The transferrin saturation coefficient is the most reliable marker of iron overload, and salivary gland biopsy may assist in diagnosis. Early recognition is crucial, as GALD is treatable. Management involves both acute neonatal treatment and preventive strategies for future pregnancies. Recurrence may reach 90% but can be effectively prevented with antenatal intravenous immunoglobulin therapy. We report four cases of GALD managed in gastroenterology unit of the Sainte-Justine center in Montreal, Canada. A literature review was also conducted to explore the etiopathogenesis, diagnosis, treatment options, and outcomes of the GALD. A total of 39 studies published between 2008 and 2024 were identified through PubMed, Google Scholar, and EMBASE using the terms “gestational alloimmune liver disease” and “neonatal hemochromatosis”.

Key Words: Gestational allo-immune liver disease; Neonatal liver failure; Neonatal hemochromatosis; Intravenous immunoglobulin therapy; Liver transplantation

Core Tip: Gestational alloimmune liver disease is a rare neonatal hepatic condition with clinical manifestations ranging from benign presentations to fulminant liver failure. Curative treatments include intravenous immunoglobulin (IVIG) and double-volume plasma exchange; liver transplantation may be necessary in severe cases. The recurrence rate in subsequent pregnancies is as high as 90%, but it can be effectively prevented with antenatal IVIG administration. In this review, we summarize the latest available literature to raise awareness among pediatricians and pediatric hepatologists, ensuring early recognition and appropriate management of this condition.

INTRODUCTION

Gestational alloimmune liver disease (GALD), previously referred to as neonatal hemochromatosis (NH), is a rare antenatal and neonatal allo-immune disease. It is the primary cause of neonatal liver failure and has a broader spectrum than previously thought, covering from mild to severe liver damage[1,2]. The pathophysiology of GALD is characterized by the production of maternal antibodies [immunoglobulin G (IgG)] damaging the fetal hepatocytes in response to fetal antigens. In opposition to initial belief, the iron accumulation in the liver and extrahepatic tissues sparing the reticuloendothelial system, is probably associated to the liver injury and is not the primary mechanism, therefore explaining the appellation change from NH to GALD[3,4].

Practioner’s main goal is to obtain a prompt diagnosis, through liver biopsy, iron status and salivary glands biopsy[1,5]. A timely initiation of effective treatment is also required to improve survival with native liver as delayed diagnosis can be associated with a liver transplant and death[5].

Management should address both immediate newborn treatment and future pregnancies. Recurrence can be as high as 90% and can be prevented with intravenous immunoglobulin (IVIG) therapy[4].

Given the limited official practice recommendation on GALDs diagnosis and treatment strategies, and limited data on outcomes for neonates and subsequent pregnancies, we present here a cohort of patients diagnosed in our gastroenterology unit of the CHU Sainte-Justine in the last ten years, to illustrate the variability and complexity of diagnosis and treatment of this disease. In addition, we conducted a literature review of related GALD articles to present the etiopathogeneses, clinical presentation, signs and symptoms, diagnosis, treatment and prognosis of those patients.

CASE REPORTS

Case 1

A female newborn was delivered at 39 weeks of gestation to a 26-year-old mother gravida 2, para 2, following an uneventful pregnancy. The Apgar score was 9 at 1 minute, 5 minutes, and 10 minutes, and birth weight was within the normal range.

Shortly after birth, the infant developed hypoglycemia and thrombocytopenia, which was attributed to platelet alloimmunization, confirmed by the presence of positive anti-human leukocyte antigen antibodies. During her hospitalization in the neonatal intensive care unit (NICU), she exhibited severe coagulopathy, requiring repeated transfusions of fresh frozen plasma (FFP) to maintain an international normalized ratio (INR) below 5. Additionally, she developed hyperammonemia and showed signs of portal hypertension.

A portosystemic shunt embolization was performed on day 14 of life due to portal hypertension, but this intervention led to worsening hyperammonemia and progressive splenomegaly. Laboratory investigations revealed elevated transferrin saturation.

A salivary gland biopsy performed on day 18 showed no evidence of iron overload. Then, a liver biopsy performed on day 21 demonstrated fibrosis, significant remodeling of the hepatic parenchyma with only two remaining portal tracts, and iron overload. Findings were consistent with GALD.

The patient underwent a successful liver transplant at the age of 3 months from a cadaveric donor. Now, at 8 years old, she has normal liver function with no major complications apart from mild signs of portal hypertension secondary to a portal vein stenosis. Her growth and development are within normal parameters.

Case 2

A female infant born from parents of Haitian origin. The mother was 34 years old with a history of five pregnancies, including three live births and two miscarriages. The pregnancy was complicated by oligohydramnios and asymmetric intrauterine growth restriction.

At birth, the infant presented with persistent hypoglycemia, requiring continuous enteral nutrition. Laboratory tests showed normal alanine aminotransferase (ALT) levels, cholestasis with normal gamma-glutamyl transferase levels, a normal INR, and thrombocytopenia. Ferritinemia was markedly elevated (4103 μg/L), raising suspicion of GALD. Liver ultrasound revealed a patent ductus venosus.

Further investigations included magnetic resonance imaging (MRI), which showed no evidence of hepatic or extrahepatic siderosis. A salivary gland biopsy was normal, and liver biopsy revealed nonspecific hepatitis. The clinical course was marked by spontaneous improvement in liver function. At the last follow-up, liver ultrasound was normal. There were no subsequent pregnancies from the mother’s patient.

Case 3

A female newborn was delivered at 33 weeks of gestation due to placental abruption to a 31-year-old mother, gravida 2, para 1 (G2P1), with a history of miscarriage. Prenatal ultrasounds showed no evidence of oligohydramnios or growth restriction. The Apgar scores were 2, 6, and 7. Birth asphyxia was diagnosed by the neonatology team.

At birth, the infant presented with hepatomegaly, with the liver palpable 4 cm below the costal margin and hypoglycemia. Laboratory investigations revealed cholestasis, mild elevation of ALT, elevated INR, hypoalbuminemia, and renal failure, most likely secondary to hepatorenal syndrome. Coagulopathy was not improved by repeated doses of vitamin K and required FFP transfusions.

MRI showed no hepatic or extrahepatic siderosis. Salivary gland biopsies revealed no iron deposits. Liver biopsy confirmed siderosis and fibrosis, consistent with a diagnosis of GALD. Immunohistochemical staining for C5b-9 was negative.

The patient received two doses of IVIG with a favorable outcome, without requiring double-volume exchange transfusion or liver transplantation. At the last follow-up at two years of age, growth and liver function were normal, as was liver elastography (FibroScan). However, liver ultrasound showed a heterogeneous liver texture.

The mother had a subsequent pregnancy at 33 years old and received IVIG at 14 weeks of gestation, followed by weekly infusions until 37 weeks. No side effects were noted. She gave birth to a healthy boy with normal liver function.

Case 4

A male newborn was born at 34 weeks of gestation to a 32-year-old mother (G2P1), with a history of one miscarriage. Delivery was induced due to maternal N-methyl-D-aspartate receptor encephalitis, diagnosed at 30 weeks of gestation, which did not improve with corticosteroids and IVIG. Antenatal ultrasound revealed intrauterine growth restriction.

At birth, the infant was admitted to the NICU for severe hypoglycemia, requiring high glucose infusion through total parenteral nutrition. He developed severe coagulopathy, requiring twice-daily transfusions of FFP. Laboratory tests showed cholestasis, hypoalbuminemia, thrombocytopenia, and an elevated ferritin level of 2515 μg/L.

Liver ultrasound demonstrated a patent ductus venosus, which required embolization, and a heterogeneous liver. MRI confirmed hepatic siderosis (Figure 1), while salivary gland biopsy was normal.

Figure 1 T2 signal loss in liver (case 4).

Despite receiving three doses of IVIG and undergoing double-volume exchange transfusion, the patient showed no improvement. He was listed for liver transplantation on day 16 of life but unfortunately succumbed to a cerebral hemorrhage.

Autopsy confirmed the diagnosis of GALD with evidence of hepatic and pancreatic siderosis.

The mother had a subsequent pregnancy, and she received IVIG weekly from 18 weeks of gestation. She gave birth to a healthy child. Table 1 summarizes the characteristics of each patient.

Table 1 Gestational alloimmune liver disease cases summary table.

	Case 1	Case 2	Case 3	Case 4
Mothers’ characteristics	26-year-old, gravida 2, para 2	34-year-old, gravida 5, para 3A2	31-year-old, gravida 2, para 1A1	32-year-old, gravida 2, para 0A1, N-methyl-D-aspartate encephalitis at 30 gestation weeks
Antenatal findings	None	Oligoamnios, asymmetric intrauterine growth restriction	None	Intrauterine growth restriction
Term of birth (weeks of gestation)	39	37	33	34
Preterm birth cause	N/A	N/A	Placental abruption	Maternal encephalitis
Major clinical presentation	Hypoglycemia	Hypoglycemia	Hypoglycemia, birth asphyxia, hepatorenal syndrome, hepatomegaly	Hypoglycemia
Laboratory findings	Thrombocytopenia, coagulopathy, hyperammonemia, iron saturation level 86%	Thrombocytopenia, cholestasis, high ferritin (4103 μg/L)	Thrombocytopenia, cholestasis, coagulopathy, hypoalbuminemia, high ferritin (3347 μg/L), iron saturation level 88%	Thrombocytopenia, cholestasis, coagulopathy, hypoalbuminemia, high ferritin (2515 μg/L)
Liver ultrasound findings	Portosystemic shunt: Patent ductus venosus	Portosystemic shunt: Patent ductus venosus	Heterogenous liver	Heterogenous liver, portosystemic shunt: Patent ductus venosus
Magnetic resonance imaging findings	Not performed	No hepatic or extrahepatic siderosis	No hepatic siderosis. Nonspecific for GALD	Hepatic siderosis
Salivary glands pathology	No iron deposits	No iron deposits	No iron deposits (Prussian blue)	No iron deposits
Liver pathology	Fibrosis, remodeling of the hepatic parenchyma, iron overload. Conclusion: GALD confirmed	Portal fibrosis, giant hepatocytes, siderosis. Conclusion: Nonspecific hepatitis	Membrane attack complex negative, fibrosis, siderosis. Conclusion: GALD confirmed	On autopsy: Fibrosis, siderosis +++, siderosis of pancreas
Treatments	Embolization of porto-systemic shunt and liver transplantation	None	Two doses of IVIG	Three doses of IVIG. Double volume exchange transfusion. Listed for liver transplantation
Outcomes	Normal liver function and normal growth	Spontaneous amelioration of liver function. Now: Normal liver function	Now: Normal liver function	Dead from cerebral hemorrhage
Subsequent pregnancy	No	No	Yes	Yes
Antenatal IVIG	N/A	N/A	Yes (14-16-18-19 weeks then every week)	Yes
Outcome for subsequent pregnancy	N/A	N/A	Healthy child	Healthy child

GALD: Gestational alloimmune liver disease; IVIG: Intravenous immunoglobulin; N/A: Not applicable.

DISCUSSION

GALD is the leading treatable cause of liver failure in newborns[2]. However, it presents with a broad-spectrum of clinical manifestations. NH, is the most common, but not the only, presentation of GALD, this explains why the appellation NH has been replaced by GALD[1]. The incidence of GALD is estimated to be 4 per 10000 live births, in the United States, according to Kasko et al[6].

Etiopathogeneses

GALD is attributed to the transplacental transfer of maternal IgG antibodies, which induce fetal hepatocyte injury through the membrane attack complex (complement component 5Cb-9 complex)[3]. The specific fetal liver antigen targeted by these antibodies remains unknown, despite extensive research efforts[7].

Destruction of fetal hepatocytes leads to dysregulation of iron homeostasis, resulting in siderosis of hepatic and extrahepatic tissues[4]. Additionally, it contributes to congenital collapse of liver lobules and acute liver failure with or without iron overload[4]. Depressed hepcidin expression in fetal liver disrupts placental iron regulation[8]. Specifically, the absence of hepcidin reduces negative feedback on ferroportin, resulting in increased transplacental iron flux[1]. Moreover, decreased transferrin gene expression, results in an excess of non-transferrin-bound iron (NTBI)[1]. Siderosis occurs in tissues capable of absorbing NTBI but unable to expel it[8].

Clinical presentation

The onset of GALD manifestation ranges from 18 weeks of gestation to three months of age[9]. Most often children present within hours of birth[9]. GALD should be considered in cases of unexplained stillbirth, fetal loss and early postnatal death, particularly in the context of severe liver disease[1]. In these cases, autopsy can be valuable in diagnosing GALD and may guide the decision to administer IVIG in subsequent pregnancies.

As observed in our cases, prenatal signs of GALD, including oligohydramnios, fetal growth restriction, hepatomegaly and fetal hydrops can be observed from 18 weeks of gestation[3,10]. Additional fetal ultrasound findings may include ascites, abnormalities of the liver and spleen[3]. Staicu et al[3] and Sciard et al[11] reported that in fetuses who present these features, MRI can aid in the diagnosis of GALD, after excluding placental vascular pathology and infectious fetopathies. Prenatal MRI typically reveals hepatic atrophy and significant iron overload in both hepatic and extrahepatic tissues[3,11].

In our cohort, we presented patients with a range of GALD severity, from benign, self-resolving case to patient who required liver transplantation or had fatal outcome. The clinical spectrum of GALD is broad, spanning from asymptomatic affected infants to those born with acute liver failure, and remains partially understood[12]. This variability is exemplified by Casas-Alba et al[13] who reported a case of GALD diagnosed in a newborn presenting with tachypnea and lactic acidosis. Additionally, discordant disease presentation in twins has been observed, suggesting that in utero alloimmune process may act independently in each fetus[14]. A better prognosis has been reported in preterm infants with GALD[15,16]. Mulzer et al[15] hypothesized that this improved outcome may be attributed to a shorter duration of exposure to maternal complement-fixing antibodies.

Signs and symptoms

Coagulopathy with a high INR with or without hemorrhagic manifestations as well as recurrent hypoglycemia are frequent manifestations. These manifestations are followed by progressive edema, hypoalbuminemia, cholestasis and renal impairment[17]. They typically appear within the first few hours to days after birth, due to the antenatal onset of the disease[17].

Laboratory findings in GALD, beyond cholestasis and features of acute liver failure, typically include mild elevation of aminotransferase levels, rarely exceeding 100 UI/L[17]. Ferritin (> 800 ng/mL), serum iron, and transferrin saturation (> 70%) are elevated, while transferrin levels are decreased[12,18]. Although ferritin is a sensitive marker for NH, it lacks specificity[1].

Alpha foeto-protein levels may be markedly elevated, ranging from 100000 ng/mL to 600000 ng/mL[1]. Thrombocytopenia is frequently observed[6].

Doppler ultrasound commonly demonstrates a patent ductus venosus in affected neonates[4].

Diagnosis

The diagnosis relies on identification of extrahepatic iron overload sparing the reticuloendothelial system[5], in the context of severe liver disease, with or without iron overload[1]. T2-weighted MRI typically reveals iron deposition in the brain, pancreas and liver[5]. Iron staining of salivary gland tissue using Perls’ Prussian blue may aid in diagnosis[1]. However, salivatory gland biopsies can be negative in 30% of cases[12].

Histopathological findings in the liver include hepatocyte loss, siderosis, giant cells and pseudoacinar transformation[1]. Panlobular parenchymal colapse and regenerative nodules may also be observed[1].

A definitive diagnosis requires immunohistochemical detection of the membrane attack complex (C5b-9) in hepatocytes and giant cells[1,5]. However, this technique is not widely available[12]. Absence of these finding does not allow to rule out the diagnosis of GALD[17].

Treatment

The current standard of care for GALD is IVIG therapy, with or without exchange transfusions, achieving a survival rate of approximately 75% without the need for liver transplantation[17]. Feldman and Whittington[1] recommend administering a single dose of IVIG (1 g/kg) to any infant presenting with liver failure when GALD is suspected. Following diagnosis confirmation, a second IVIG dose should be administered, accompanied by a double volume exchange transfusion[19,20]. Normalization of INR can take up to 6 weeks[19].

Liver transplantation remains the definitive treatment for infants with acute liver failure who do not respond to medical therapy[9]. In our cohort one patient was successfully transplanted. Due to the overall severity of illness and the small size of affected infants, liver transplantation can be particularly challenging[9].

Neonates often receive left lateral segment graft. ABO-incompatible liver transplantation is a viable option, as newborns have not yet developed blood group sensitization[9]. However, liver transplantation in the group of age 0 day to 90 days is associated with prolonged hospitalizations, extended intensive care units stays, longer mechanical ventilation and high reoperation rates, compared to older children[21].

Survival rates of liver transplant in infants with GALD were reported to be 35% in the cohort studied by Rand et al[19], while Taylor et al[8] observed a 43% survival rate among infant transplanted. In contrast, Kelgeri et al[22] reported a 100% survival rate in their cohort of GALD-transplanted infants.

Prognosis

The recurrence risk of GALD in subsequent pregnancies is estimated to be as high as 90%, irrespective of paternal changes[4,10]. This risk can be significantly reduced through antenatal administration of IVIG starting at 14 weeks, 16 weeks, 18 weeks of gestation and continuing weekly until birth. The effectiveness of IVIG in preventing adverse outcome has been well established[8,23].

Whitington et al[23] reported a 94% of healthy offspings in treated pregnancies compared to 30% in untreated ones (P < 0.0001). A review of 73 pregnancies treated with antenatal IVIG confirmed that all resulted in live births, with no infant requiring liver transplantation[24]. Beyond reducing the frequency of affected live-born infants, antenatal IVIG has also been shown to lower stillbirth rates[23].

Baruteau et al[16] documented an 8/8 survival rate among newborns of treated mothers, compared to 0/9 among untreated cases. Of the eight surviving infants, five exhibited mild, transient liver disease[16].

While IVIG therapy is generally well tolerated, mild side effects have been reported, including headaches, rash, shivering, tinnitus and burn sensation at the injection site[16]. More severe side effects, such as pancytopenia, have also been described, as reported by Sarker et al[25], with a few additional cases documented in the literature[26].

CONCLUSION

GALD must be considered in any newborn with coagulopathy or signs of liver failure. Prompt laboratory and radiological investigations are essentials to ensure early diagnosis and timely intervention. GALD is a serious condition that can have life-threatening consequences potentially leading to liver transplant or death if not promptly diagnosed and treated. Careful management of future pregnancies is crucial for optimizing outcomes. Antenatal IVIG prophylaxis, administered to mothers starting at 14 weeks of gestation, has demonstrated excellent results, significantly improving outcomes for the unborn child. Further research is needed to enhance our understanding of this rare disease and develop more effective therapeutic strategies.

ACKNOWLEDGEMENTS

The authors would like to thank the members of the gastroenterology unit at the Sainte Justine Center for their valuable support in the management of the reported cases. We also acknowledge the contributions of the radiology and pathology departments for their expertise and collaboration.