Alpha-1 Antitrypsin (AAT) deficiency

Related Subjects: | Chronic liver disease | Cirrhosis | Alkaline phosphatase (ALP) | Liver Function Tests | Ascites Assessment and Management | Budd-Chiari syndrome | Autoimmune Hepatitis | Primary Biliary Cirrhosis | Primary Sclerosing Cholangitis | Wilson disease | Hereditary Haemochromatosis | Alpha-1 Antitrypsin (AAT) deficiency | Non alcoholic steatohepatitis (NASH) | Spontaneous Bacterial Peritonitis | Alcoholism and Alcoholic Liver Disease

Screen anyone with COPD age < 40, It is inherited in an autosomal recessive pattern, which causes emphysema and cirrhosis and has a prevalence of 1 in 2500. Causes 1% of Emphysema. Patients who manifest disease usually have PiZZ genotype

About

• Deficiency of Alpha-1-antitrypsin due to a genetic mutation leads to a failure to inhibit neutrophil elastase
• Leads to emphysema and possibly cirrhosis depending on genotype. Normal is PIMM Worst is PIZZ

Aetiology

• Alpha-1-antitrypsin (AAT) is produced in the liver
• It is an inhibitor of the proteolytic enzyme elastase
• The gene for AAT is on chromosome 14
• PiZZ seen in 1 in 2500 in Europe

Pathophysiology

• Elastase may be released by neutrophils
• Elastase causes local damage which is reduced by AAT
• AAT deficiency leads to increased tissue damage.
• Normal = PiMM
• Homozygous PiSS (50% normal A1AT levels)
• Homozygous PiZZ (10% normal A1AT levels

Genetics - many alleles

• AAT Enzymes Defined by electrophoresis
• Medium (M) Slow (S) Very Slow (Z)
• Alleles M is normal, S intermediate and Z is severe decrease
• Best: Normal are MM/MS/MZ
• Intermediate: SZ and Worst: ZZ

Clinical

• Panacinar emphysema, Bronchiectasis
• Lung disease commoner at lung bases
• 10% have liver disease and Cirrhosis
• Hepatocellular carcinoma
• Onset age 30-40 in smokers and 50-60 in non smokers
• Lungs: pan]acinar emphysema, most marked in lower lobes
• Liver: cirrhosis and hepatocellular carcinoma in adults, cholestasis in children

Investigations

• Low AAT Serum levels below 50 to 80 mg/dL (11 µmol/L)
• Genotyping: With a severe deficient genotype
• The liver biopsy shows PAS-positive diastase resistant globules and cirrhosis.

Management

• Stop smoking and reduce alcohol intake
• Treat as for emphysema/cirrhosis
• Infusion of pooled human AAT (alpha-1 antiprotease) in moderate disease
• Gene therapy - future possibility
• Lung and liver transplantation available as therapeutic options
• New liver produces normal AAT - curative