Alpha 1-antitrypsin and hepatic fibrosis

The administration of alpha 1-antitrypsin, both sialo and asialo types, to rats with chronic liver injury accelerated hepatic fibrosis. More fibrosis was seen histologically and the amount of hydroxyproline in the liver increased. Moreover, the growth of HEL cells (human embryonal lung fibroblast) in culture was promoted by alpha 1-antitrypsin though the action of the asialo type was very weak by contrast with the sialo type.     

Alpha-1-antitrypsin deficiency in adults

A clinicopathological examination was carried out on eight adult patients with alpha-1-antitrypsin (ATT) deficiency. Phenotyping confirmed five patients with PiMZ, two patients with PiZ-, and one patient with PiZZ. Cirrhosis was found in six of the patients, four of whom had a history of excessive ethanol consumption. Hepatitis B surface antigen was positive in two patients with cirrhosis. Dysplastic change was present in four patients, although no neoplasia in the liver was found in all patients. All patients had periodic acid-Schiff positive and diastase resistant inclusions of hepatocytes, which were identified as ATT by indirect immunoperoxidase stain. The possibility of the combined effects of ATT inclusions and such harmful stimuli such as alcohol or viral hepatitis infection may render the hepatocytes more susceptible to damage, and may contribute to development of cirrhosis.     

Alpha-1-antitrypsin in human macrophages

Preliminary studies have suggested that alpha-1-antitrypsin (A1AT) is a useful immunohistochemical marker of histiocytes (monocytes/macrophages) and malignant tumours derived from them. To confirm the reliability of this marker a wide variety of benign and malignant lymphoreticular cells and tissues have been stained by the immunoperoxidase technique for A1AT and positive staining was found to be confined to histiocytes. Immunodiffusion, isotope labelling, and isoelectric focusing studies performed on cell lysates confirmed that the positive staining shown by monocytes and malignant histiocytes is due to the presence of A1AT identical with serum A1AT and that this material is synthesised by these cells rather than taken up from their environment. Positive immunoperoxidase staining for A1AT is thus a reliable marker of lymphoreticular neoplasms of true histiocytic origin.     

Adult alpha1-antitrypsin deficiency.

Three adults with alpha 1-antitrypsin deficiency are described. In two of the cases the deficiency was genetically determined (cases 1 and 2), and each demonstrated unusual features of the disease. The liver in case 1 (homozygous) showed cholangiolar hyperplasia which has been recorded only once before. Case 2 (heterozygous) had emphysema and cirrhosis, a combination not previously documented in a heterozygote, in addition to malabsorption. Case 3 represents a case of spurious alpha 1-antitrypsin deficiency with cirrhosis included to emphasize the diagnostic improtance of phenotyping in such cases.     

Alpha 1-antitrypsin and hepatic fibrosis.

The administration of alpha 1-antitrypsin, both sialo and asialo types, to rats with chronic liver injury accelerated hepatic fibrosis. More fibrosis was seen histologically and the amount of hydroxyproline in the liver increased. Moreover, the growth of HEL cells (human embryonal lung fibroblast) in culture was promoted by alpha 1-antitrypsin though the action of the asialo type was very weak by contrast with the sialo type.     

Alpha-1-antitrypsin immunoreactivity in gastric carcinoid

Alpha-1-antitrypsin (AAT) was demonstrated in tumour cells in three out of five cases of gastric carcinoma showing the histological characteristics of carcinoid tumour. It was also detected in normal stomach mucosa, but was not found in 10 cases of adenocarcinoma of intestinal or mucous cell type. The AAT-positive tumour cells were argyrophilic, PAS-positive and were negative for pancreatic and gastric hormones. These findings suggest a possible malignant proliferation of alpha-1-antitrypsin-containing cells in the stomach.     

Alpha-1-antitrypsin globules in liver biopsies

In order to examine the frequency of alpha-1-antitrypsin (AAT) deficiency of phenotype Pi-Z in a consecutive liver biopsy material, PAS/diastase resistent globules with positive immunohistochemical reaction for AAT (AAT globules) were used as a marker of the Pi-Z gene. 34 (4%) of 850 liver biopsies contained AAT globules. More than half of the biopsies with globules had chief histological diagnoses within the groups fibrosis, suspicion of cirrhosis and cirrhosis. Micronodular cirrhosis was significantly more frequent in biopsies with AAT globules. The results support the assumption that AAT deficiency of phenotype Pi-Z as well in homozygous as heterozygous form is associated with development of liver cirrhosis.     

Alpha-1-antitrypsin types and rheumatoid arthritis

Frequencies of alpha-1-antitrypsin (Pi) phenotypes were studied in 100 female and 100 male Swedish patients with classical rheumatoid arthritis and compared with the population frequencies. A significant increase of rare Pi types (MS, MZ, MF and SZ) was found among the patients. However, the increase concerned mainly Z heterozygotes and was more strongly pronounced in male patients. The M-subtypes showed no association with rheumatoid arthritis. Previous investigations of Pi types in rheumatoid arthritis have shown somewhat variable results. The results so far indicate, however, that an association between the Z allele and rheumatoid arthritis is likely to exist, while the evidence for a relationship between rheumatoid arthritis and other Pi alleles is considerably weaker.     

Alpha 1-antitrypsin phenotypes in homosexual men

The alpha 1-antitrypsin (AAT) phenotype was determined by isoelectric focusing in 215 male homosexuals and compared with those in 208 male heterosexuals. The incidence of abnormal phenotypes was 16.3% in the homosexual group which was significantly different (p less than 0.03) than the 8.7% in the heterosexual group. There was no difference in the phenotype distribution between homosexuals who were anti-human immunodeficiency virus reactive and those who were non-reactive. It suggests that investigation into the interplay of factors associated with homosexuality could include genetic as well as psychological and social factors.     

Laboratory diagnosis of alpha1-antitrypsin deficiency

The laboratory diagnosis of alpha(1)-antitrypsin (AAT) deficiency (AATD) has evolved over the last 40 years since the first cases of the disorder were reported. It is currently performed in specialized centers, and it requires a combination of different biochemical methods: nephelometric AAT concentration, isoelectric focusing, genotyping, and sequencing. The availability of matrices such as the dried blood spot have facilitated the implementation of laboratory analyses for AATD, but they have also challenged laboratories to develop more reliable and reproducible techniques starting from dried blood. In this article, we describe the protocols we have optimized for AATD diagnosis from dried blood spot, in an attempt to hopefully provide useful information for physicians and scientists involved in this diagnostic line. We also describe the diagnostic flowchart for AATD detection that we have developed accordingly.     

Acquired alpha-1-antitrypsin deficiency and dysgammaglobulinemia

Alpha-1-antitrypsin (AAT) levels were measured in patients with three types of dysgammaglobulinemia: monoclonal gammopathy, polyclonal hypergammaglobulinemia and hypogammaglobulinemia. A fourth group comprised of subjects with normogammaglobulinemia served as a control. The frequency of hypoalpha-1-antitrypsinemia was significantly higher in those with monoclonal gammopathy compared with controls. The basis for this evaluation is unknown. It was not associated with phenotypic variation nor was it related to sex, age, total protein, albumin and immunoglobulin levels, liver function, bone marrow and bone x-ray findings.     

Characterization of alpha1-antitrypsin in the inclusion bodies from the liver in alpha 1-antitrypsin deficiency.

alpha1-antitrypsin was isolated from periodic acid-Schiff-positive inclusion bodies from the hepatocytes of patients with alpha1-antitrypsin deficiency and further purified to enable more detailed chemical analysis. Amino acid and cyanogen bromide fragmentation studies showed a close similarity between hepatic and serum (PiMM) antitrypsin in contrast to the carbohydrate analysis, which revealed markedly deficient glycosylation of hepatic antitrypsin. A complete lack of sialic acid and a relative deficiency of all other carbohydrate components could fully explain the difference of approximately 6000 daltons in molecular size between the two proteins. The accumulation of hepatic globules is probably related to the physical properties of the defective antitrypsin, which include marked insolubility and tendency toward aggregation. The results strongly suggest an abnormal amino acid sequence in the peptide chain of the deficient antitrypsin. The interference with glycosylation may be related to steric hindrance.