Alpha 1 Antitrypsin Heterozygosity and Cirrhosis

Abstract

Purpose: A 47 yo female with cryptogenic cirrhosis was seen after TIPS placement. She complained of forgetfulness and fatigue. Past history included insulin-dependent diabetes and hypothyroidism. She had no history of hepatitis or alcohol use. Family history was significant for asthma in her mother and brother, and presumed alcoholic cirrhosis in her father. She was an obese female with normal vital signs and cardiovascular exam, and mild hepatomegaly. No cutaneous stigmata of liver disease were found. Laboratory evaluation: AST 135 U/L, ALT 105U/L, AP 136 U/L, bilirubin 0.8 mg/dL, albumin 2.3 g/dL, ammonia 129 umol/dL, and INR 1.5. Tests for viral hepatitides, ANA, anti-smooth muscle, and AMA antibodies were negative; ceruloplasmin was normal. Alpha-1-antitrypsin (AAT) level was low at 67 mg/dL, and she had heterozygous MZ Pi phenotype. Liver biopsy showed cirrhosis with PAS positive diastase resistant granules in the cytoplasm of the hepatocytes especially at the periphery of the regenerative nodules. There was no increased intrahepatic fat, Fe, or Cu. AAT, a serine protease inhibitor is synthesized by hepatocytes in quantities second only to albumin. It inhibits proteases, including neutrophil elastase. AAT deficiency (AATD) is a common genetic condition caused by a single nucleotide substitution in the AAT gene on chromosome 14. Loss of inhibitory function results in lung damage in AATD. Multiple allelic variations of the AAT gene exist; the most common normal allel is PiM. The most frequent genetic variant, PiZ, caused by a substitution of lys to glu342 results in an abnormally folded and polymerized protein that accumulates in the endoplasmic reticulum of hepatocytes. 1.5-3% of the Caucasian population are heterozygous. Liver disease is more common in PiZZ patients, but heterozygotes may develop various degrees of liver abnormalities. Concomitant viral hepatitis or alcohol abuse may accelerate the development of cirrhosis in AATD, but even in their absence patients with abnormal genotype may develop cirrhosis or hepatic malignancy. AAT infusion is helpful in the treatment of AATD associated lung disease, but liver transplant is the only treatment for AATD cirrhosis. Patients with cryptogenic advanced liver disease should undergo thorough clinical investigation and AATD should always be considered in the differential diagnosis. Clinicians should remember that ATT granules are not readily detectable by routine liver histology and special staining with PAS and diastase is needed. Even with normal AAT levels patients with abnormal phenotype may develop hepatic injury. When AATD is diagnosed, both the patient and their family need to be referred for genetic counseling and screening for AATD.