#945;1-Antitrypsin Deficiency

GENERAL PRINCIPLES

• #945;₁-Antitrypsin (#945;₁AT) deficiency is an autosomal recessive disease associated with accumulation of misfolded #945;₁AT in the endoplasmic reticulum of hepatocytes.

• The most common allele is protease inhibitor M (PiM—normal), followed by PiS and PiZ (deficient variants). African Americans have a lower frequency of these alleles.

• The most prevalent deficiency alleles Z and S are derived from European ancestry.²⁰

• #945;₁AT deficiency can also be associated with emphysema in early adulthood, as well as other extrahepatic manifestations including panniculitis, pancreatic fibrosis, and membranoproliferative glomerulonephritis.

DIAGNOSIS

Clinical Presentation

• The disease may present as neonatal cholestasis or, later in life, as chronic hepatitis, cirrhosis, or HCC.

• The presence of significant pulmonary and hepatic disease in the same patient is rare (1%-2%).

Diagnostic Testing

• Low serum #945;₁AT level (10%-15% of normal) will flatten the #945;₁-globulin curve on serum electrophoresis.

• Deficient #945;₁AT phenotype (PiSS, PiSZ, and PiZZ).

• Elevated AST and ALT.

DIAGNOSTIC PROCEDURES

Liver biopsy shows characteristic periodic acid-Schiff-positive diastase-resistant globules in the periportal hepatocytes.

TREATMENT

Currently, there is no specific medical treatment for liver disease associated with #945;₁AT deficiency. Gene therapy for #945;₁AT deficiency is a potential future alternative.

Surgical Management

Liver transplantation is an option for those with cirrhosis and is curative, with survival rates of 90% at 1 year and 80% at 5 years.

Outcome and Prognosis

• Chronic hepatitis, cirrhosis, or HCC may develop in 10%-15% of patients with the PiZZ phenotype during the first 20 years of life.

• Controversy exists as to whether liver disease develops in heterozygotes (PiMZ, PiSZ, PiFZ).