Pulmonary function associated with the Mmalton deficient variant of alpha 1-antitrypsin

We have studied 78 members of a large family in which the Mmalton deficiency allele of alpha 1-antitrypsin (alpha 1AT) is present. Four patients of PI type MmaltonZ (alpha 1AT concentration, 16.4% of normal) had severe emphysema and marked depression in all flow and gas exchange parameters, significantly different from other members of the same family who were normal or had intermediate concentrations of alpha 1AT. Fourteen subjects with PI type MMmalton (alpha 1AT concentration, 63.3% of normal) were compared with 46 PI MM relatives (alpha 1AT, 103.8% of normal) and 14 relatives of PI type MZ (alpha 1AT concentration, 66.5% of normal). Spirometry, flow-volume loops, plethysmography, gas exchange at rest and exercise, and xenon 133 regional lung function were similar in those partially deficient when compared with the normal subjects. There was a trend for impairment of tests of lung function between smoking partially deficient (PI MZ, PI Mmalton) and normal (PI MM) relatives.     

Liver disease associated with alpha1-antitrypsin deficiency

Alpha1-ATD is the most common metabolic liver disease in children for which liver transplantation is performed and, in adults, is associated with cirrhosis, hepatocellular carcinoma, and emphysema. It appears that only a proportion of patients with the deficiency develop clinical manifestations of this disease. Moreover, recent characterization of specific cellular and physiologic events have provided the basis for future potential therapeutic interventions.     

Lung disease associated with alpha1-antitrypsin deficiency

α(1)-Antitrypsin (A1AT) is a polyvalent, acute-phase reactant with an extensive range of biological functions that go beyond those usually linked to its antiprotease (serpin) activities. Genetic mutations cause a systemic deficiency of A1AT, leading to liver and pulmonary diseases, including emphysema and chronic bronchitis. The pathogenesis of emphysema, which involves the destruction of small airway structures and alveolar units, is triggered by cigarette smoke and pollutants. The tissue damage caused by these agents is further potentiated by the mutual interactions between apoptosis, oxidative stress, and protease/antiprotease imbalance. These processes lead to the activation of endogenous mediators of tissue destruction, including the lipid ceramide, extracellular matrix proteins, and abnormal inflammatory cell signaling. In this review, we propose that A1AT has a range of actions that are not restricted to protease inhibition but rather extend to mitigate a range of these pathological processes involved in the development of emphysema. We discuss the evidence indicating that A1AT blocks apoptosis by binding and inhibiting active caspase-3 and modulates a broad range of inflammatory responses induced by neutrophils and by lipopolysaccharide and tumor necrosis factor-α signaling.     

Hepatocellular carcinoma and the alpha 1-antitrypsin phenotype

To determine whether or not alpha 1-antitrypsin phenotype PiMZ is a predisposing factor for hepatocellular carcinoma alpha 1-antitrypsin phenotype was studied in 83 French patients with hepatocellular carcinoma compared with 1,030 blood donors. In 66 patients, alpha 1-antitrypsin phenotype was determined by isoelectric focusing which allows the distinction between subtypes of phenotype M. No difference has been shown between the two groups for alpha 1-antitrypsin alleles or subtypes of allele Pi*M. The authors conclude that phenotype PiMZ is not a significant predisposing factor for hepatocellular carcinoma in French people. As well, a review of literature suggests that, in contrast with the conclusion of previous reports, the link between alpha 1-antitrypsin phenotype PiMZ and hepatocellular carcinoma is either nonexistent or very weak.     

Panniculitis associated with histoplasmosis and alpha 1-antitrypsin deficiency

A patient with mediastinal histoplasmosis, alpha 1-antitrypsin deficiency, and panniculitis is presented. The patient showed dramatic response to treatment with ketoconazole. The associations of panniculitis with histoplasmosis and alpha 1-antitrypsin deficiency are discussed.     

Differential detection of PAS-positive inclusions formed by the Z, Siiyama, and Mmalton variants of alpha1-antitrypsin

Several point mutations of alpha(1)-antitrypsin cause a perturbation in protein structure with consequent polymerization and intracellular accumulation. The retention of polymers of alpha(1)-antitrypsin within hepatocytes results in protein overload that in turn is associated with juvenile hepatitis, cirrhosis, and hepatocellular carcinoma. The detection of alpha(1)-antitrypsin polymers and understanding the molecular basis of polymer formation is of considerable clinical importance. We have used a monoclonal antibody (ATZ11) that specifically recognizes a conformation-dependent neoepitope on polymerized alpha(1)-antitrypsin to detect polymers within hepatocytes of individuals with alpha(1)-antitrypsin deficiency. Paraffin-embedded liver tissue specimens were obtained from individuals who were homozygous for the Z (Glu342Lys), Mmalton (52Phe del), and Siiyama (Ser53Phe) alleles of alpha(1)-antitrypsin that result in hepatic inclusions and profound plasma deficiency. Immunohistological staining with a polyclonal anti-human alpha(1)-antitrypsin antibody showed hepatic inclusions in all 3 cases, while ATZ11 reacted with hepatic inclusions formed by only Z alpha(1)-antitrypsin. Polymers of plasma M and Z alpha(1)-antitrypsin prepared under different conditions in vitro and polymers of recombinant mutants of alpha(1)-antitrypsin demonstrated that the monoclonal antibody detected a neoepitope on the polymerized protein. It did not detect polymers formed by a recombinant shutter domain mutant (that mirrors the effects of the Siiyama and Mmalton variants), polymers formed by cleaving alpha(1)-antitrypsin at the reactive loop, or C-sheet polymers formed by heating alpha(1)-antitrypsin in citrate. In conclusion, the ATZ11 monoclonal antibody detects Z alpha(1)-antitrypsin in hepatic inclusions by detecting a neoepitope that is specific to the polymeric conformer and that is localized close to residue 342.     

Molecular abnormality of human alpha1-antitrypsin variant (Pi-ZZ) associated with plasma activity deficiency.

A human alpha1-antitrypsin variant protein was purified to homogeneity from homozygous variant subjects (Pi-ZZ) who had a deficiency of plasma trypsin inhibitory capacity. Molecular weight, specific trypsin inhibitory capacity, and immunologic activity of the variant protein were identical to those of normal. Amino acids, N-acetylglucosamine, and hexose contents were closely similar in the normal and variant proteins, but the sialic acid content in the variant protein was significantly lower than normal. The structural difference between the normal and the variant alpha1-antitrypsin was elucidated by fingerprinting of their tryptic peptides. Two amino acid substitutions, i.e., glutamic acid in the normal protein to lysine in the variant protein, and glutamic acid in the normal protein to glutamine in the variant protein, were found.     

Lack of increase in heterozygous alpha 1-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma.

Homozygous alpha 1-antitrypsin deficiency (PiZZ phenotype) is known to be associated with increased risk of cirrhosis and primary liver cancer. Although a relationship between heterozygous alpha 1-antitrypsin deficiency and chronic liver disease was suggested recently, it is still a matter of controversy whether such patients are at increased risk of liver cancer. The goal of this study was to determine the prevalence of heterozygous alpha 1-antitrypsin deficiency of different phenotypes among patients with primary hepatobiliary cancers. We studied 82 patients with primary hepatobiliary cancer; 59 had hepatocellular carcinoma and 23 had bile duct carcinoma. alpha 1-Antitrypsin quantitation and phenotyping were performed in each patient using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds-ratio and chi 2 tests were used to measure the relative risk and the significance of association, respectively, between primary hepatobiliary cancers and heterozygous alpha 1-antitrypsin deficiency. Four patients in each of the cancer groups were heterozygous. Among the hepatocellular carcinoma patients, three had the PiMS phenotype and one had the PiMZ phenotype. Of these four heterozygous patients, only two had cirrhosis; one had cryptogenic cirrhosis and the other had hepatitis B virus-related cirrhosis. One noncirrhotic patient with a PiMZ phenotype had a fibrolamellar carcinoma. Of the four patients with bile duct carcinoma, three had the PiMS phenotype and one had the PiMZ phenotype. Of the four heterozygous patients, two had primary sclerosing cholangitis without associated inflammatory bowel disease and one patient had had previous biliary operations.(ABSTRACT TRUNCATED AT 250 WORDS)     

The source of a minor alpha 1-antitrypsin in variant serum.

An antiserum produced against human alpha1-antitrypsin gave 2 precipitin lines by immunodiffusion when tested against sera displaying MZ or MS phenotypes. Only one line (major antigen) was seen with sera displaying M phenotype, but a second line (minor antigen) became evident when the serum was concentrated 5-fold. The minor antigen appeared to be a denatured form of alpha1-antitrypsin, because the major antigen was converted to the minor one when purified alpha1-antitrypsin was incubated between pH 2.95 and 4.0. Such incubation inactivated the protein irreversibly. The purified protein was also inactivated completely within 1 hour at pH 4.95, but the activity was recovered completely by incubation for 2 to 4 hours at pH 8.0. The immunologic properties of the reactivated a1-antitrypsin were the same as those of the original untreated protein.     

Fatal liver disease associated with alpha 1-antitrypsin deficiency PiM1/PiMduarte

A 53-yr-old man with a rare form of partial alpha 1-antitrypsin deficiency, PiM1/PiMduarte, died of endstage cirrhosis. Typical cytoplasmic alpha 1-antitrypsin globules were present in the hepatocyte cytoplasm. Initial protease inhibitor phenotyping on the patient was reported as normal PiM1 in more than one laboratory. This case emphasizes the diagnostic importance of alpha 1-antitrypsin and illustrates the point that protease inhibitor phenotyping without family genotyping may be misleading in heterozygous patients with liver disease.     

Alpha1-antitrypsin gene polymorphisms are not associated with renal arterial fibromuscular dysplasia

OBJECTIVE: We previously showed that fibromuscular dysplasia (FMD) of the renal artery may be familial. Case reports have associated alpha1-antitrypsin deficiency and FMD. The aim of this study was to test the implication of the alpha1-antitrypsin (AAT) gene in a large cohort of patients with renal FMD. MATERIALS AND METHODS: A case-control study comparing the genotype frequencies in 161 consecutive patients with angiographically proven renal FMD with those observed in three sets of controls (353 hypertensive patients, 288 normotensive patients, 444 normotensive women) was conducted. High-resolution echotracking of the carotid and radial arteries was performed in a subset of 77 FMD patients. Three functional polymorphisms of the AAT gene (PiM1, PiZ, PiS) were investigated. RESULTS: Clinical (age 44.3 +/- 13.8 years, 85.1% women) and radiological (77.1% of multifocal lesions) characteristics of the FMD population were consistent with those previously published. No differences were found in AAT genotype frequencies in the FMD subjects compared with the 1085 controls. We found no correlation between the AAT genotypes and the clinical and angiographical characteristics of the FMD patients. Echotracking results confirmed our previously published results in FMD patients with a specific pattern and a mean arterial phenotypic score greater than 3. However, no difference in the arterial score was observed across the genotypes. CONCLUSION: Polymorphisms PiM1, PiZ and PiS of the AAT gene are not associated with renal FMD or infraclinical carotid lesions detected by echotracking methods. As the true prevalence of renal FMD is not precisely known and alpha1-antitrypsin deficiency is not infrequent in the general population, the association of the two may occur by chance.     

Tracheobronchial clearance in patients with emphysema associated with alpha1-antitrypsin deficiency.

Tracheobronchial clearance was studied in five patients who had emphysema associated with deficiency of serum alpha1-antitrypsin but no history of chronic bronchitis. After the patients had inhaled an aerosol of 6 micrometer teflon particles tagged with 99mTc, the radioactivity in the lungs was followed externally during 2 h. Clearance in the emphysematous patients was normal or even rapid as compared with clearance in healthy subjects, and was significantly more rapid than clearance in patients with a history of chronic bronchitis. The results indicate that emphysema can develop in patients with alpha1-antitrypsin deficiency without their having an impairment of mucociliary transport.     

Antithrombin Pittsburgh: an alpha1-antitrypsin variant causing hemorrhagic disease.

A 10-year-old boy had a severe lifelong hemorrhagic disorder that had necessitated more than 50 hospitalizations. Laboratory examination showed prolonged bleeding, clotting, partial thromboplastin, prothrombin, and thrombin times. These findings were due to a potent inhibitor of the thrombin-fibrinogen reaction. This inhibitor was similar to heparin in that it acted immediately and did not interfere with the coagulant activities of certain venoms. It differed from heparin in not being adsorbed to barium citrate or neutralized by protamine sulfate. The inhibitory effect was found in the alpha1-globulin fraction. It was identified immunologically and functionally as a double-banded alpha1-antitrypsin of a previously unreported phenotype. The inhibitory effects were depressed by trypsin and heterologous anti-alpha1-antitrypsin.     

Alpha-1-antitrypsin deficiency resulting in a hitherto unseen presentation of hepatocellular carcinoma： Polycythemia but with normal alpha fetoprotein

Polycythemia is a known paraneopastic manifestation of hepatoma, but only in the presence of alpha-fetopro (AFP). We present a case of polycythemia in the absence of AFP, and suggest concurrent alpha-1-antitrypsin deficiency as the cause for breaking this rule. We also suggest a reason for the apparent constant conjunction between polycythemia and AFP in hepatoma.     

A novel alpha1-antitrypsin null variant （PiQ0Milano）nt (PiQ0Milano)

Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasionally,chronic liver disease.We report an incidental finding of a novel null AAT allele,Q0Milano,consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene,in an Italian child with persistently increased liver enzymes,a mild decrease in circulating AAT levels and without any pulmonary disease.Q0Milano variant results in an unfunctional protein lacking of AAT active site,as the resultant protein is truncated near PiS locus involved in AAT protein stability.     

Alpha-1-antitrypsin deficiency resulting in a hitherto unseen presentation of hepatocellular carcinoma: Polycythemia but with normal alpha fetoprotein

Polycythemia is a known paraneopastic manifestation of hepatoma, but only in the presence of alpha-fetopro (AFP). We present a case of polycythemia in the absence of AFP, and suggest concurrent alpha-1-antitrypsin deficiency as the cause for breaking this rule. We also suggest a reason for the apparent constant conjunction between polycythemia and AFP in hepatoma.     

Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency.

BACKGROUND & AIMS: Alpha 1 -antitrypsin deficiency (AAT) is an autosomal recessive disease that affects 1 in 2500 persons and might lead to cirrhosis. Our study aim was to characterize the liver disease in AAT and identify factors associated with advanced liver disease. METHODS: A cohort of the Alpha-1 Foundation Registry who reported liver disease was surveyed with a liver disease questionnaire to obtain information related to liver disease, liver transplantation, and AAT phenotype. RESULTS: One hundred sixty-five of the 2175 participants in the registry reported a history of jaundice or liver disease, and 139 (84.2%) completed the questionnaire. Of these, 71.3% were PiZZ, 18.0% were PiMZ, and 5.7% did not know their phenotype. Analysis of 104 participants with a known age of diagnosis included 30 participants diagnosed with liver disease before 18 years, of whom 15 had advanced liver disease defined as liver transplantation or listed for liver transplantation. No differences in age, age at diagnosis, gender, race, phenotype, or infant jaundice were identified. Seventy-four participants were diagnosed after age 18 years, of whom 25 had advanced liver disease. In this group, advanced liver disease was associated with male gender ( P = .006) and a greater mean body mass index ( P = .01), but not with race, Pi phenotype, infant jaundice, diabetes, or hypercholesterolemia. Viral hepatitis was more frequently reported in the nontransplant group (34.7% vs 8.0%, P = .01), and the mean daily alcohol use was significantly greater in this group ( P = .04). CONCLUSIONS: Our results suggest that male gender and obesity but not alcohol or viral hepatitis predispose to advanced liver disease in adults with AAT.