Increased risk of chronic liver failure in adults with heterozygous ?-antitrypsin deficiency

Abstract

Controversy exists whether patients who are genetically heterozygous for ␣ 1 -antitrypsin deficiency (␣ 1 ATD), carrying a single PI*Z allele, are at increased risk of developing chronic liver disease. In these investigations, we determined the prevalence of heterozygous ␣ 1 AT phenotypes (PI MZ, PI SZ) in a well-characterized cohort of patients presenting with chronic liver failure before orthotopic liver transplantation (OLT). We analyzed data collected from all adult patients (n ‫؍‬ 641) who underwent OLT at our tertiary referral center between March 1985 and December 1996. Study patients entered a prospective protocol designed to test for all known etiologies of liver disease. Complete testing including ␣ 1 AT phenotyping was successfully performed in 599 adults. We compared the overall number of heterozygous PI*Z carriers in our OLT cohort with established prevalence figures for general and regional American populations, and examined their distribution among various liver disease subgroups. Fifty-one patients were found to be heterozygous carriers of a single PI*Z allele for ␣ 1 AT. The predominant phenotype in our transplantation cohort was PI MZ, identified in 49 patients (8.2%), which is a significantly higher prevalence than that reported from previous American population studies (2%-4%). Additionally, a significantly greater number of PI MZ carriers existed in patients with cryptogenic cirrhosis compared with other liver disease categories (26.9%; P F .001). These data suggest that individuals carrying a single PI*Z allele for ␣ 1 AT may be at increased risk of developing cirrhosis and liver failure, even in the absence of an identifiable coexisting liver disease. (HEPATOLOGY 1998;28:1058-1063

Liver disease in adults with α1‐antitrypsin deficiency

“…This confirms a previous report of Graziadei et al, who observed a prevalence of 26.9% in patients who underwent liver transplantation for cryptogenic cirrhosis. 7 Thus, heterozygosity for the Z-allele might have implications in patients without a known aetiology. This prompts SERPINA1 genotyping in patients with cryptogenic cirrhosis, as well as in patients with findings indicative of an otherwise unexplained chronic liver disease.…”

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

“…Although homozygous individuals are more likely to develop liver disease, even a single ␣1-ATZ mutation may predispose patients to hepatic injury 3,4,7,32 and act as a modifier gene in the progression of liver disease in patients suffering from cystic fibrosis, 8 non-alcoholic fatty liver disease, and hepatitis C. 5 However, most patients homozygous for the Z mutation never develop clinically relevant liver disease. The development of liver injury in this model therefore must require an environmental or genetic factor in addition to the Z mutation.…”

“…1,2 Homozygosity for the ␣1-ATZ mutation (also referred to as PiZZ) is generally required for the development of liver disease, although several studies report an increased risk to heterozygous individuals. [3][4][5][6][7] A single ␣1-ATZ mutation may also predispose patients with cystic fibrosis to significant liver disease. 8 Therefore, the ␣1-ATZ mutation not only may cause liver injury but it may act as a modifier gene that exacerbates other forms of liver disease.…”

α1-Antitrypsin mutations in NAFLD: High prevalence and association with altered iron metabolism but not with liver damage

“…15,16 These amino acid substitutions lead to abnormal folding and spontaneous protein polymerization, determining endoplasmic reticulum stress and hepatocellular damage. Heterozygosity for the PiZ, and to a lesser extent for the PiS 17 allele has been associated with cirrhosis and hepatocarcinoma in the presence of other hepatotoxic factors in adulthood, 18,19 and increased prevalence of the PiZ allele has been reported in patients with cryptogenic cirrhosis, now recognized to be frequently related to NASH, [17][18][19] and in HHC, 20,21 although evidence is controversial. 15,22 AAT is involved in the regulation of the innate immunity and its deficiency may promote a pro-inflammatory status.…”