From Birth to Midlife-Liver Function, Fibrosis and Mortality in Individuals with Severe Alpha-1-Antitrypsin...

Background: Severe Alpha-1-Antitrypsin deficiency (AATD), phenotype PiZZ, is a leading cause of liver disease in neonates, children, and adults. Nevertheless, the prevalence of liver disease and mortality within PiZZ adults remains unclear. Between 1972 and 1974, a cohort of 129 individuals with severe AATD (PiZZ) was identified through the Swedish national screening of 200,000 newborns. The cohort has been followed up regularly since birth. This prospective cohort follow-up study, with a cross-sectional comparison at 50 years of age, aims to characterize the natural history of liver disease and mortality in this cohort in their early fifties, compared with an age-matched control group (PiMM) randomly selected from the population registry. Methods: Study participants completed questionnaires regarding occupation, medical history, medication, and alcohol consumption. They underwent physical examination and measurement of liver stiffness using transient elastography (TE, FibroScan^®). Blood samples were obtained for evaluation of liver function, alcohol consumption, calculation of liver fibrosis scores, and detection of viral hepatitis and autoimmune liver disease. Results: Ninety-five PiZZ and 124 PiMM individuals participated in the study, of whom 47 PiZZ and 96 PiMM underwent TE measurement. PiZZ individuals had significantly higher median liver stiffness compared with PiMM individuals (5.9 kPa vs. 4.5 kPa, p < 0.01). No significant differences were found in Fib-4 score or the Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS) between the groups. Since identification of the cohort at birth, 13 (10%) of the 129 PiZZ individuals have died. Of these, liver disease was the main or underlying cause of death in 8 individuals (6%). Conclusions: In their early fifties, PiZZ individuals show a small but significant increase in liver stiffness measured by TE, indicating early liver fibrosis. In contrast, conventional fibrosis scores, such as Fib-4 and NFS, do not differ between PiZZ individuals and PiMM, suggesting that serum-based fibrosis scores may underestimate fibrosis in AATD. In this cohort, liver disease and its complications represented the main cause of death in PiZZ individuals by the age of 50, an observation that is uncommon in the general population at this age.