It is reasonably well accepted that compound heterozygotes for S and Z alleles of AATalpha-1 antitrypsin More (SZ) may develop progressive liver disease similar to ZZ patients (e.g., PAS-positive globules resistant to diastase digestion). However, due to the lack of specific evidence-based studies the risk of disease in SZ patients is not well defined. The S allele is commonly found in North America and Western Europe, particularly among the populations of Portugal and Spain. Studies have demonstrated that mutant S protein can only heteropolymerize within the cell if it is co-expressed with another mutant Z protein. Thus, this fact may explain why progressive liver injury occurs in SZ patients while liver disease is absent in SS individuals (6,23,25). Therefore, it is reasonable for clinicians to evaluate and monitor SZ children in a pattern identical to ZZ patients.
Alpha-1 antitrypsin deficiency liver disease – Translational Gastroenterology and Hepatology
A study of AATD-related liver transplantation in 50 PI*ZZ and 23 PI*SZ cases [65], reported that PI*SZ patients were older at the time of transplant (53 versus 47 years), and a greater proportion of patients had an underlying concomitant cause of liver disease (such as hepatitis C virus or alcohol-induced liver damage) compared with PI*ZZ patients (43.5% versus 8%). In addition, despite age being a modifying factor, PI*SZ patients had better survival than PI*ZZ patients (although not statistically significant) [65]. Compared with the PI*MZ genotype, there is evidence to suggest that the PI*SZ genotype confers greater risk of liver disease [65] which may be due to higher levels of heteropolymers as in vivo studies suggest that the M and S proteins colocalise with the Z variant within liver cells, but with greater accumulation of ZZ complexes than the SZ and MZ complex (ZZ>SZ>MZ) [66]; however, further research should be undertaken to confirm this. Liver comorbidities such as hepatitis B and C have given rise to the “second hit” theory, whereby the associated liver pathology could be worsened in the presence of AATD [67]. Preventative measures such as vaccination and alcohol avoidance/moderation may help to minimise these liver-associated complications later in life.
Overall, the risk of liver disease in PI*SZ individuals is much lower than that of PI*ZZ individuals; however, it remains an important aspect of the disease risk associated with PI*SZ genotype.
Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype – The European Respiratory Journal