Neonatal cholestasis : clinical and aetiological aspects, with special reference to viral infections transmitted from mother to infant

Abstract: Although the list of possible causes for neonatal cholestasis is long, in many cases the aetiology remains unknown. The aim of this thesis was to examine the pathogenetic role of viral infections in the early infantile cholestasis. Fifty-nine cholestatic infants, of whom 21 had extrahepatic biliary atresia (EHBA), were examined for a large number of viral infections. Serum samples from their mothers and from controls of pregnant women and of noncholestatic infants were included. Cytomegalovirus (CMV) IgM was more often detected in infants with EHBA (8/21=38%) and with intrahepatic cholestasis (I 1/38=29%) than in controls (2/35=6%, p<0.01). The rate of CMV-IgG positive mothers was higher than in controls (94% v.s. 75%, p<0.01). CMV-DNA was detected by polymerase chain reaction (PCR) in the liver tissue in 9 of 18 (50%) patients with EHBA and in 3 of 7 (43%) patients with intrahepatic cholestasis. CMV-DNA was detected by PCR on stored Guthrie cards in 2 of 39 infants with CMV-associated cholestasis. All eight positive controls, i.e. children with a documented congenital CMV infection tested positive, and all four adult negative controls tested negative. Fifty-eight infants to 5 5 mothers with antibodies to hepatitis C virus (HCV) were followed from 0- 18 months of age. All children had negative HCV-RNA tests on all occasions. Passively transferred matemal anti-HCV was still detectable at 9 months in 22%, but undetectable in all at 18 months. One of six tested siblings was found to be HCV infected at 4.5 years of age. GB virus C/hepatitis G virus (GBV-C/HGV) RNA was detected in 7 of 42 (17%) anti-HCV positive mothers. One of their eight children, a twin boy, had GBV-C/HGV RNA in serum samples from 3-42 months of age, without biochemical signs of persistent liver disease. Sequence analysis of the detected virus genomes suggested vertical transmission as the route of infection. The twin sister was repeatedly negative for GBV-C/HGV from 0-42 months of age. In a following study GBV-C/HGV RNA was detected in I of 38 (3%) cholestatic infants, in 4 of 95 (4%) children investigated for malabsorption, and in none of 30 children with chronic autoimmune hepatitis. Sequence analysis suggested vertical transmission of GBV-C/HGV to the cholestatic infant. The medical records of 85 cholestatic infants were reviewed. EHBA was diagnosed in 30 patients (35%), alpha-1-antitrypsin deficiency in 11 (13%) and progressive familial intrahepatic cholestasis in I I patients. The mothers in the EHBA group had a higher mean age than the non-EHBA mothers (31.4 v.s. 28.3, p=0.02) and a higher incidence of gestational diabetes. The EHBA patients had a different seasonal variation in the calendar months of birth than expected. Nine of all patients (10%) presented with non-cerebral bleedings. At the endpoint of follow-up 49% of all patients had none or minor liver disease, 22% had a chronic compensated liver disease and 28% were either liver transplanted or had died from their liver disease. In the EHBA group, the age at portoenterostomy did not correlate to the outcome.