Management of Alpha-1 Antitrypsin Deficiency-Related Liver Disease
For patients with significant alpha-1 antitrypsin deficiency affecting the liver, management should include regular monitoring with liver function tests, ultrasound examinations, and preventive measures such as hepatitis A and B vaccinations, while liver transplantation remains the only definitive treatment for advanced disease. 1
Pathophysiology and Risk Factors
- Alpha-1 antitrypsin deficiency liver disease results from accumulation of mutant AAT Z protein molecules within the endoplasmic reticulum of hepatocytes, leading to liver injury through the "accumulation theory" 1
- The Z allele and several others (e.g., S iiyama, M malton) are associated with intrahepatocytic accumulation of unsecreted, polymerized AAT that forms characteristic periodic acid–Schiff-positive inclusions, while other deficiency alleles (null variants, S) do not predispose to liver disease 1
- Male sex appears to confer an increased risk for developing cirrhosis in PI*ZZ AAT-deficient individuals 1
- The individual progression of liver cell damage in AAT deficiency is extremely variable, with genetic or environmental factors potentially promoting rapid progression in some patients 1
- Risk factors for disease progression in adults include age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome (including obesity and type 2 diabetes mellitus) 2
Diagnosis
- Serum phenotyping by isoelectric focusing performed by a reliable laboratory is the accepted "gold standard" for diagnosing AAT deficiency 1
- Liver biopsy is not indicated for establishing the diagnosis of AAT deficiency but is useful for staging liver disease in individuals with clinically overt liver disease 1
- The incidental finding of periodic acid–Schiff-positive globules in a liver biopsy should prompt suspicion of the Z allele or other rare deficiency alleles associated with intra-hepatocyte inclusions 1
- In heterozygotes with active liver disease, the plasma AAT level may be normal; performing isoelectric focusing is required for diagnosing such individuals who may be PI*Z heterozygotes 1
Monitoring and Management
- Clinical management should include regular assessment by physical examination, liver function tests, and ultrasound examination 1
- Hepatitis A and B vaccinations are recommended for all patients with AAT deficiency-related liver disease 1
- In older individuals (≥50 years of age) with decompensated cirrhosis due to AAT deficiency and increased risk for hepatoma, periodic computed tomography imaging of the liver is recommended because of the insensitivity of other tests (e.g., α-fetoprotein measurement) 1
- Regular assessment of simple liver function tests is recommended in elderly individuals with AAT deficiency who lack liver symptoms 1
- For MZ phenotype individuals (intermediate deficiency), clinical evaluation every 1-2 years, liver function tests every 1-2 years, and more frequent monitoring if risk factors are present 3
Treatment Options
- Currently, no specific medical therapy for liver disease is available; intravenous augmentation therapy with α1-antiprotease does not confer benefits for liver disease 1, 4
- Liver transplantation remains the only definitive treatment for individuals with advanced AAT deficiency-related liver disease 1
- Research on therapeutic alternatives is focused on prevention and reversion of the conformational abnormalities that lead to formation of pathogenic proteins 1
- Promising approaches under investigation include:
- Gene therapy aimed at both achieving effective expression of the normal gene and suppressing expression of the Z protein 1
- Chemical chaperones such as trimethylamine N-oxide and citrate that can retard the rate of AAT polymerization 1
- Butyric acid derivatives such as 4-phenylbutyrate that mediate increased secretion of mutant Z AAT 1
Special Considerations
- Most PI*ZZ AAT-deficient individuals are clinically healthy throughout childhood but may have liver enzyme abnormalities in early life 1
- The PI*ZZ phenotype is a common cause of neonatal cholestasis, and despite spontaneous resolution in most cases, AAT deficiency is a frequent indication for liver transplantation in childhood 1
- Cirrhosis in PI*ZZ AAT-deficient individuals may become clinically apparent at any age, with peak incidence occurring in elderly never-smokers who have survived without developing severe emphysema 1
- In heterozygotes carrying the Z allele, there is a much smaller risk for cirrhosis, for which toxic liver injury from alcohol and viruses (especially hepatitis C) may be risk factors 1
- Coexisting viral hepatitis, particularly hepatitis C, may significantly worsen prognosis in patients with AAT deficiency 5