What is the association between alpha-1 antitrypsin (A1AT) SS phenotype and neonatal cholestasis or liver disease?

From the Guidelines

Alpha 1 antitrypsin (A1AT) SS phenotype has not been associated with neonatal cholestasis or liver disease. The SS phenotype is considered a normal variant of alpha 1 antitrypsin and does not cause liver or lung disease. Unlike the ZZ or SZ phenotypes, which are associated with alpha 1 antitrypsin deficiency and can lead to liver disease including neonatal cholestasis, hepatitis, cirrhosis, and hepatocellular carcinoma, the SS phenotype produces normal levels of functional alpha 1 antitrypsin protein.

Key Points

• Alpha 1 antitrypsin is a protease inhibitor that primarily protects lung tissue from neutrophil elastase.
• In deficiency states like ZZ, the abnormal protein can accumulate in hepatocytes, causing liver damage.
• However, the SS phenotype produces a normal protein that is properly secreted from the liver, preventing such accumulation and subsequent liver injury.
• Therefore, if a patient with SS phenotype develops liver disease, other causes should be investigated as the SS phenotype itself would not be the underlying etiology, as supported by 1.

Clinical Implications

• Patients with MZ, MS, SZ, or homozygous SS phenotypes do not present with neonatal cholestasis unless associated with another cause.
• Serum a1-antitrypsin concentrations alone are an insufficient test because a1-antitrypsin is an acute phase reactant and, during illnesses, may be increased in serum, as noted in 1.
• The evaluation of patients with α-1-antitrypsin disease requires careful assessment for liver disease, but this does not apply to the SS phenotype, as stated in 1.

From the Research

Association of Alpha 1 Antitrypsin SS Phenotype with Neonatal Cholestasis or Liver Disease

• The Alpha 1 Antitrypsin SS phenotype has been associated with liver disease, but its connection to neonatal cholestasis is not well-established 2, 3.
• A study from 2005 found that liver disease was present in 8 out of 12 patients with the PiZZ phenotype and in 15 out of 24 patients with heterozygous alpha1-AD, but it did not specifically examine the SS phenotype 2.
• Another study from 2013 investigated the frequencies of defective alleles, including the S allele, in Iranian children with idiopathic neonatal cholestasis and found that 2.2% of the patients were heterozygous for the S allele, but no SS individuals were found 3.
• A review from 2023 discussed the natural history and management of alpha-1 antitrypsin deficiency-associated liver disease, but it did not provide specific information on the SS phenotype 4.
• A study from 2020 found that neonatal cholestasis was a poor predictor of future portal hypertension in young patients with alpha-1 antitrypsin deficiency, but it did not examine the SS phenotype specifically 5.
• An overview from 1993 discussed the mechanisms of alpha-1 antitrypsin deficiency and its effects on the liver, but it did not provide information on the SS phenotype 6.

Key Findings

• The SS phenotype is not commonly associated with neonatal cholestasis or liver disease in the available studies 2, 3.
• The PiZZ and PiMZ phenotypes are more commonly linked to liver disease and neonatal cholestasis 2, 4.
• Further research is needed to fully understand the relationship between the Alpha 1 Antitrypsin SS phenotype and liver disease 3, 5.