Hepatocytic PAS-positive diastase-resistance inclusions in the absence of alpha-1-antitrypsin deficiency--high prevalence in alcoholic cirrhosis

The presence of PAS-positive, diastase-resistant inclusions in the cytoplasm of the hepatocytes is characteristic of alpha-1-antitrypsin deficiency. The purpose of this investigation was to determine whether the presence of these inclusions is a specific feature, permitting the recognition of alpha-1-antitrypsin deficiency in patients with liver disease. We examined the liver specimens from 20 patients suffering from alcoholic cirrhosis with the Pi M phenotype, i.e., in whom alpha-1-antitrypsin deficiency was excluded. In seven of these patients, PAS-positive, diastase-resistant inclusions were seen in the hepatocytes; in two patients, these inclusions contained a material antigenically similar to alpha-1-antitrypsin. These inclusions might represent deposits of glycoproteins poorly excreted by the diseased hepatocytes. It is concluded that, in patients with liver disease, the presence of PAS-positive, diastase-resistant inclusions--even containing alpha-1-antitrypsin--in the cytoplasm of the hepatocytes does not permit the hepatic lesions to be ascribed to alpha-1-antitrypsin deficiency.     

Place of genotyping in addition to the phenotype and the assay of serum α-1 antitrypsin

The diagnosis of deficiency of alpha-1 antitrypsin (A1AT) is based on isoelectric focusing of serum proteins and the extent of serum. However, the focusing is technically difficult and a greatly reduced concentration in abnormal A1AT tapeless does not differentiate an unstable variant of a variant called 'null' (that is to say without any phenotypic expression) to 'heterozygous' state. In this study, we compared the results of the assay, the phenotype and genotype of A1AT in 50 patients. Normal A1AT alleles (Pi*M1 to Pi*M4) or loss of the most common (Pi*S and Pi*Z) were clearly identified in phenotyping. However, genotyping was necessary to characterize: (i) certain alleles rarer A1AT (S-Munich, X-Christchurch); (ii) a null allele and; (iii) two new alleles A1AT not yet described in the literature. In conclusion, although the A1AT genotyping is generally not necessary, it is necessary to resolve complex cases and to obtain witnesses validated for isoelectric focusing.     

Alpha-1-antitrypsin (Pi) types in Down''s syndrome

Alpha-1-antitrypsin (Pi) phenotypes have been determined in 40 patients suffering from Down's syndrome. Thirty-six of the patients were found to have a normal M phenotype, whereas two deficient phenotypes of the MS variety were observed. In addition, two M variants were noted. The significance of an M variant phenotype in some patients with Down's syndrome is not completely understood and is currently under investigation. Since the majority of the patients had a normal alpha-1-antitrypsin phenotype, the results of this study indicate that a deficiency in alpha-1-antitrypsin plays no role in the respiratory fragility of individuals with Down's syndrome.     

Alpha-1-antitrypsin phenotypes in malignant lymphoma.

The alpha-1-antitrypsin (alpha 1 AT) Pi phenotypes have been determined by isoelectric focusing in a series of 228 patients having a histologically diagnosed malignant lymphoma and in 250 healthy controls. The Pi MZ phenotype occurred in 13 patients with lymphoma (5 . 8%) and in five of 250 healthy individuals (2%). Furthermore, one patient with a Pi SS and three patients with an abnormal unknown phenotype, migrating slower than Z, were found in the lymphoma group. No prevalence for a special lymphoma type was observed among the abnormal Pi phenotype patients. The increased incidence of abnormal Pi phenotypes in malignant lymphoma's support the hypothesis of the possible role of alpha 1 AT in development of immunopathological disorders.     

The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency.

To further define the clinicopathologic spectrum and pathogenetic mechanism of the nephropathy associated with alpha 1-antitrypsin (A1AT) deficiency, we evaluated renal specimens from 34 patients with chronic hepatic disease, including 20 with A1AT deficiency (study patients), and correlated these findings with urinalysis evaluation. Glomerular lesions were noted in 79% (15 of 19) of A1AT patients with the PiZZ phenotype, including seven with mesangio-capillary glomerulonephritis (MPGN and focal segmental MPGN), six with mesangial proliferative glomerulonephritis (Mes GN), one with diffuse endocapillary proliferative glomerulonephritis (DPGN), and one with focal segmental mesangial proliferative glomerulonephritis with segmental necrosis (FS Nec GN). One A1AT patient with the PiMZ phenotype did not demonstrate glomerular abnormalities. Focal segmental Mes GN was found in 43% (six of 14) of patients in an age-matched group with chronic hepatic failure unrelated to A1AT deficiency. In nine study patients, glomerular pathology was noted in the presence of a normal urinalysis. Immunofluorescence studies revealed the presence of immunoproteins and the A1AT protein isoelectric forms, PiM and PiZ, in the subendothelial region of glomerular basement membranes in A1AT patients with MPGN, Mes GN, and DPGN. Our results emphasize the heterogeneity of glomerular lesions associated with A1AT deficiency and hepatic disease and the relatively high incidence of MPGN in these children. The presence of abnormal PiZ protein in the subendothelial region of the glomerular basement membrane in A1AT patients with glomerulonephritis suggests a possible role for this protein in the pathogenesis of this lesion.     

Reference and Interpretive Ranges for α1-Antitrypsin Quantitation by Phenotype in Adult and Pediatric Populations

Laboratory evaluation of α(1)-antitrypsin (A1AT) deficiency involves measurement of circulating A1AT protein (quantitation) and characterization of A1AT genetic polymorphisms (phenotyping or genotyping). This study compared adult and pediatric A1AT reference ranges in patients with nondeficiency alleles and examined A1AT concentrations in multiple other phenotypes. A1AT phenotype and quantitation were retrospectively collected on adult (n = 21,444) and pediatric (n = 2,469) samples that were submitted for laboratory evaluation of A1AT deficiency. The 95% reference ranges for normal adult and pediatric populations with the M/M phenotype were determined to be 100 to 273 mg/dL (18.4-50.2 μmol/L) and 93 to 251 mg/dL (17.1-46.2 μmol/L), respectively (P < .0001). Decreased concentrations of A1AT correlated with heterozygosity and homozygosity for the S and Z alleles in both the adult and pediatric groups. Other rare alleles, such as I, were also associated with decreased concentrations of A1AT, particularly in the context of a Z allele, and may warrant monitoring for symptoms of deficiency.     

Inherited defect of alpha-1-antitrypsin associated with chronic liver and respiratory tract diseases in children

The frequency of occurrence of alpha-1-antitrypsin (A1AT) deficiency among total of 3228 Polish children with chronic liver diseases and chronic disease of respiratory tract was determined. It was observed that among children with chronic liver diseases which disclosed more frequent defect (concentration of A1AT below 150 mg/dl was found in 10.3% of children), the highest occurrence of deficiency was in children with neonatal hepatitis (23.1%). The deficiency was connected with the presence of ZZ and MZ phenotypes of A1AT.     

"M" alpha-1-antitrypsin at term of pregnancy in an African population: concentration and microheterogeneity

For 19 multipars in Ivory Coast alpha-1-antitrypsin (A1AT) has been determined in mother's serum as well as in the cord serum and the amniotic fluid. In all cases the type of A1AT was MM. In 15 cases the pregnancies were normal and full term while four were premature (28th week). The A1AT levels obtained were found to be similar to the literature values and thereby do not seem to be influenced by the ethnic origin. Crossed electroimmunodiffusion analyses demonstrate a distribution of the different fractions of A1AT which is characteristic for each of the above groups of samples analysed. The similarity of the fractions in mother's serum and amniotic fluid indicate a maternal origin for A1AT of the latter. The cord blood shows a very characteristic increase in the peak M6. In the author's experience, they have only noticed such a peak in the blood of patients with primary liver cancer of the phenotype MM.     

Cirrhosis associated with partial deficiency of alpha-1-antitrypsin: A clinical and autopsy study

A 63 year old woman with cryptogenic cirrhosis, astiles, portal hypertension, and intermediate levels of alpha-l-antitrypsin of prolease inhibitor SZ phenotype who died of esophageal variceal hemorrhage is described. The partial deficiency of alpha-1-arrtihypsin and the diagnosis of cirrhosis were suspected one year prior to death because a needle biopsy liver showed PAS positive, diastase resistant cyloplasmic bodies within hepatocyles. This report illustrates three previously undescribed features: (1) Heterozygous protease inhibitor SZ phenotype may be associated with coarsely nodular cirrhosis in the older adult. (2) The large intracytoplasmic glycoprotein droplets that are distinctive by light microscopy are probably formalin induced aggregates of submicroscopic flocculent material. (3) 1n the older patients with aberrant alpha-1-anlilrypsin theflocculent material is present not only in the granular endoplasmic reticulmn but also in smooth endoplasmic reticulum vesicles and cytolysosomes.     

Occurrence of alpha-1-antitrypsin deficiency in 155 patients with alcoholic liver disease

Liver biopsies from 155 patients with alcoholic liver disease were examined for periodic-acid-Schiff-positive, diastase-resistant (PAS-DR) intracytoplasmic globules in hepatocytes. Seven patients had these PAS-DR globules: each was a heterozygote for a deficiency allele of alpha-1-antitrypsin (AAT), or alpha-1-protease inhibitor, with the PAS-DR globules distributed in a pattern characteristic of this deficiency. One further patient with normal AAT had a few intracytoplasmic PAS-DR globules in occasional hepatocytes. The prevalence of AAT heterozygotes in this series did not differ from that in the reference population. The seven heterozygotes included five of PI (protease inhibitor) type MZ, one of PI type SZ, and one heterozygous for a rare deficiency allele, PI type MMmalton. The M and Mmalton alleles may be difficult to distinguish because they have similar mobilities with isoelectric focusing technics. Therefore, if PAS-DR inclusions are found in the liver of a patient with an apparently normal phenotype, the presence of a defective M variant allele, such as Mmalton, should be considered.     

Alagille syndrome associated with a paracentric inversion 20p12.2p13 disrupting the JAG1 gene

Mutations in the human gene Jagged1 (JAG1) localized in 20p12 have been recently identified as causal for the anomalies found in patients with Alagille syndrome (AGS). This gene encodes a ligand for the Notch1 transmembrane receptor, which plays a key role in cell-to-cell signaling during differentiation and is conserved from C. elegans to human. We report a paracentric inversion (PAI) of chromosome 20p12.2p13 in an individual with AGS who also had alpha-1-antitrypsin deficiency. To our knowledge, this is the first published case of PAI involving the short arm of chromosome 20. Using FISH, fiberFISH, and molecular studies with a approximately 40 kb cosmid clone encompassing the entire 36 kb JAG1 gene, we demonstrate that the gene was disrupted by the inversion breakpoint between exons 5 and 6. An unusual association between two most common causes of chronic liver disease in childhood, AGS and alpha-1-antitrypsin deficiency, as well as their influence on the proband's abnormal phenotype are discussed.     

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.     

Therapy for α1-Antitrypsin Deficiency

alpha(1)-Antitrypsin (A1AT) deficiency is inherited as an autosomal codominant disorder characterised by reduced levels of A1AT in the serum. Low levels of A1AT in blood perfusing the lung cause low levels in the lung interstitium, making it susceptible to proteolytic damage from resident neutrophil elastase. A 'protective threshold' serum A1AT level of 11 micromol/L has been identified by epidemiological studies as a minimum value below which there is an increased risk of emphysema. Intravenous augmentation therapy for patients with severe deficiency of A1AT has been shown to have biochemical efficacy. Although the clinical efficacy of intravenous augmentation therapy has not been demonstrated in a randomised clinical trial, available studies suggest that augmentation therapy is associated with a slowed rate of decline of lung function and enhanced survival. The criteria for patient selection include: age >18 years, serum A1AT level 相似文献   

Alpha-1-antitrypsin in islet cell tumors of the pancreas

The presence of alpha-1-antitrypsin (A1AT) in normal pancreatic islets recently has been demonstrated, and serum elevation of A1AT in patients having pancreatic tumors has been reported. In the present study, the presence of A1AT in 12 of 33 islet cell tumors was demonstrated. The possible utility of A1AT as a marker for islet cell tumors is suggested.     

alpha-1 antitrypsin phenotypes by isoelectric focusing in a metropolitan southern Chinese population

AIMS/BACKGROUND: alpha-1 antitrypsin (alpha1AT) is an abundant protease inhibitor in human plasma. Its phenotypic variability has been reported to be associated with pulmonary emphysema and chronic liver diseases. However, alpha1AT deficiency is an uncommon condition in the Chinese population. The aim of this study was to describe the phenotypic distribution of alpha1AT in a southern Chinese population. METHODS: A total of 1085 healthy blood donors underwent alpha1AT phenotyping by isoelectric focusing. RESULTS: Two thirds (66.1%) were homozygous for either M1 or M2, whereas 32.6% were heterozygous for two different M phenotypes. The frequency of allelic variants was only 0.007, and deficiency variants were absent. Compared with earlier studies on southern Chinese populations, this study found a lower frequency of M2, and a higher number of allelic variants, including E, L, N, P, and S. This phenomenon can be attributed to population migration and mixing. CONCLUSIONS: An understanding of the alpha1AT pattern is important for evaluating the predisposition of the population to selected clinical diseases.     

Purification of alpha-1-antitrypsin monomer by preparative electrophoresis.

Alfa-1-antitrypsin (alpha 1AT) was purified by pseudoligand chromatography and preparative electrophoresis from the serum of a patient with alpha 1AT deficiency. The combination of the two techniques yielded a high grade batch of alpha 1AT monomer and this was successfully used to purify the protein from the serum of PiMIM1, PiMIM2, and PiZZ phenotype subjects. This procedure should facilitate structural studies of alpha 1AT variants susceptible to intracellular accumulation.     

Alpha1-antichymotrypsin globules within hepatocytes in patients with chronic hepatitis C and cirrhosis

Alpha1-antichymotrypsin (A1AC) is an acute phase serine protease inhibitor, similar to alpha1-antitrypsin (A1AT) in amino acid sequence. A1AT deficiency is known to be associated with emphysema and cirrhosis; deficiency of serum A1AC has been reported to be associated with emphysema, childhood asthma, and cryptogenic cirrhosis. The hepatocyte globules associated with A1AT deficiency have been well described; A1AC deficiency also has been reported to be associated with hepatocyte globules. The aim of this study was to describe the globules of A1AC and to compare them with A1AT globules. Immunohistochemistry for A1AC and A1AT was performed on liver biopsy specimens from 15 hepatitis C virus (HCV)-positive cirrhotic patients, 14 non-HCV cirrhotic patients, and 12 other patients with chronic hepatitis C but no cirrhosis, all of whom had known serum levels of A1AC; most had known serum levels of A1AT. Five of 15 HCV-positive cirrhotic patients, 1 of 14 non-HCV cirrhotic patients, and 1 of 12 noncirrhotic chronic hepatitis C patients had A1AC globules. Two of 15 HCV-positive cirrhotic patients and 2 of 14 non-HCV cirrhotic patients had A1AT globules. Histologically, the globules of A1AC were similar to those of A1AT but were smaller and fewer; the PAS/D stain was not as helpful for A1AC as it was for A1AT; immunohistochemistry was most useful. There was not a good correlation between serum levels of A1AC and its globules in hepatocytes. A1AC globules should be included in the differential diagnosis of hepatocyte inclusions.     

Fine structural observations of the liver in alpha-1-antitrypsin deficiency.

Morphologic studies of liver tissue in individuals deficient in alpha-1-antitrypsin (alpha-1-AT) have established the presence of membrane-delimited deposits which are diastase resistant, perodic acid-Schiff positive, sialic acid deficient, and immunologically related to serum alpha-1-AT. The molecular basis for the accumulation alpha-1-AT-like substance in hepatocytes and the serum deficiency in alpha-1-AT patients is unknown.In an effort to gain insight into the membrane sites involved in the storage of the alpha-1-AT-like material, we examined liver biopsies by light and electron microscopy from 3 children with homozygous PiZZ deficiency and varying degrees of liver pathology. Contrary to the more widely held belief that accumulation occurs primarily in the rough endoplasmic reticulum, we find the earliest and greatest accumulation of alpha-1-AT-like material in smooth endoplasmic reticulum of hepatocytes. We have combined our ultrastructural observations with the current knowledge which is available concerning the structural properties of M-type and Z-type alpha-1-AT and have proposed a model which may explain the basis for the hepatic accumulation of alpha-1-AT-like material and the serum deficiency state in the PiZZ genotypes.     

Liver cirrhosis caused by alpha-1-antitrypsin deficiency

The authors present 2 patients with cirrhosis of the liver associated with alpha-1-antitrypsin deficiency. The patients are two children (brother and sister aged 4 and 13). The manifestation of the disease in these two children was a prolonged neonatal icterus. The symptoms of a decompensated cirrhosis of the liver appeared at the age of 2 and 4 years. There were several attacks of obstructive bronchitis etiologically associated with the same cause. The boy died at the age of four of hepatic coma preceded by several bleedings from esophageal varices. Splenectomy was performed in the girl on account of distinct signs of hyperplenism and two and a half years later mesentericocaval shunt because of the extensive bleeding from esophageal varices and the fundus of the stomach. The diagnosis of alpha-1-antitrypsin deficiency was made on the basis of low values in the serum and on the basis of liver biops? and findings of typical PAS positive inclusions in the endoplasmic reticulum of hepatocytes. The values of A1A parents are also lower. The finding of Pi phenotypification is significant--the SZ phenotype was found in two patients (brother and sister), which is seldom described in patients with cirrhosis of the liver.     

Alpha-1-antitrypsin and the liver: a routine immunohistological screen.

One hundred and eighty five consecutive liver biopsies were immunostained using anti-alpha-1-antitrypsin to assess the use of routine immunohistochemistry in the diagnosis of alpha-1-antitrypsin (AAT) deficiency. About half the livers showed staining of hepatocytes for alpha-1-antitrypsin, but most of these livers showed a panlobular pattern, possibly indicating increased synthesis of AAT. Only ten contained periportal granules, said to be typical of AAT deficiency. In cases in which serum was also available for quantitation and phenotyping there was no absolute relation between staining pattern, phenotype, and serum concentrations: the immunohistological screening technique, therefore, has limitations in the diagnosis of AAT deficiency in liver biopsy specimens.