Gestational Alloimmune Liver Disease

Gestational alloimmune liver disease is foetal liver injury caused by maternal IgG antibodies that cross the placenta and activate complement against foetal hepatocyte antigens.

It is the leading cause of neonatal haemochromatosis, now defined as a clinical syndrome with extrahepatic iron overload.

It is rare. Recurrence in later pregnancies of the same mother is about 90% or more once an affected child has been born, and recurrence with a different partner is rare.

The cause is maternal alloimmunisation to a foetal liver antigen that is not yet identified. Other conditions that can cause a neonatal haemochromatosis picture include mitochondrial disease (for example DGUOK and MPV17 variants), infection and metabolic liver disease.

Pathophysiology

Maternal IgG binds the foetal hepatocyte antigen and activates the classical complement cascade, forming the membrane attack complex (C5b-9) on hepatocytes.

Hepatocyte death produces liver failure, impaired hepcidin synthesis and iron accumulation in the liver, pancreas, heart, thyroid and salivary glands, though not in the reticuloendothelial system.

• Onset in utero or within 24 to 48 hours of birth, with growth restriction, prematurity and oligohydramnios during pregnancy.

• Severe coagulopathy, hypoglycaemia, hypoalbuminaemia, oedema, ascites and jaundice.

• Hypotonia, lethargy and encephalopathy.

• Liver tests: modestly raised transaminases relative to the degree of failure, raised conjugated bilirubin, very high INR, low albumin and fibrinogen, and raised alpha fetoprotein.

• Ferritin over 800 ng/mL and transferrin saturation over 80% support the diagnosis. Both are nonspecific.

• Extrahepatic iron on MRI (pancreas, heart, adrenals) or on buccal mucosa biopsy (salivary gland siderosis).

• Liver biopsy with C5b-9 immunostaining confirms complement mediated injury, but is often unsafe with coagulopathy.

• Metabolic and infectious screens to exclude other causes.

Immediate treatment.

• Double volume exchange transfusion followed by IV immunoglobulin 1 g/kg, repeated once at 1 week if no response. Treatment started early gives the best chance of native liver survival.
• Correct hypoglycaemia, coagulopathy (fresh frozen plasma 10 to 15 mL/kg, cryoprecipitate for fibrinogen under 1 g/L, platelets for thrombocytopenia), and treat sepsis.
• Intravenous aciclovir 20 mg/kg every 8 hours until herpes simplex is excluded.
• Antioxidant therapy (N-acetylcysteine, selenium, vitamin E, desferrioxamine, prostaglandin E1) has been used but evidence is limited.

Liver transplantation. For infants who do not respond within 1 to 2 weeks or who develop progressive failure. Refer early to a liver transplant centre.

Prevention in later pregnancy. IV immunoglobulin 1 g/kg to the mother at 14 weeks and 16 weeks, then weekly from 18 weeks until delivery. This is highly effective at preventing recurrence.

Monitoring. INR, glucose, ammonia, electrolytes, liver function and ferritin daily. Foetal growth and amniotic fluid in subsequent pregnancies.

Referral and escalation. Urgent referral to a liver unit. Genetic counselling and obstetric review for the family.