P0214 PHENOTYPIC EXPRESSION OF LIVER DISEASE IN FAMILIES WITH PIZZ ALPHA-1-ANTITRYPSIN DEFICIENCY

Abstract

Introduction: PiZZ alpha-one-antitrypsin deficiency (A1ATD) is the commonest genetic cause of chronic liver disease leading to liver transplantation in children. The pathogenic mechanism appears to involve abnormal loop sheet polymerisation of the aberrant PiZ alpha-1-antitrypsin and its retention in the hepatocyte endoplasmic reticulum, with consequent progression to chronic inflammation and cirrhosis. Only 10–15% of PiZZ individuals develop clinical symptoms and additional genetic and environmental modifiers have been postulated. Methods: The database of 279 children diagnosed with A1ATD at our centre between 1978–2002 was reviewed to identify families in which there was more than one child with the PiZZ phenotype. A retrospective analysis of their notes was carried out to assess the severity of their liver disease. Results: Forty-two children (24 boys) from twenty-one families were identified, including 2 pairs of monozygotic and 1 pair of dizygotic twins. The children were followed up for a median of 66 months (range, 8–185 months). The patients were divided into the following categories: (A) asymptomatic/family screening –4.8%; (B) no clinical liver disease after neonatal biochemical dysfunction – 30.9%; (C) mild ongoing liver dysfunction – 35.7%; (D) moderate chronic liver disease – 19.1% and (E) end stage liver disease/liver transplant – 9.5%. There were no significant differences in the length of breastfeeding or frequency of infection between the siblings. Only 5/21 sibling pairs (23.8%) were within the same category. Of note, of those children requiring liver transplant 3/4 had siblings within categories A or B. Of the three pairs of twins identified, the twins were in different categories in 2 out of 3. Six out of 12 children in the D and E categories were male. Amongst the families where a child had end stage liver disease (E), 6 sought an antenatal diagnosis. Two of the foetuses were PiZZ and the pregnancies were terminated, the remainder were heterozygotes. Two of the families with moderate chronic liver disease (D) were also tested antenatally: one was a heterozygote and the other a PiZZ foetus was lost as a consequence of a mid-trimester spontaneous abortion. Conclusion: In the relatively small sample of families reviewed, the clinical course of liver disease within siblings with PiZZ A1ATD was highly variable. This observation, if confirmed in a larger sample, is important because antenatal diagnosis of PiZZ A1ATD may not predict the extent of liver involvement in families where one child has been affected by end stage liver disease, as has been previously reported.