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Serum levels of alpha-1-antitrypsin were measured by radial immunodiffusion, and phenotypes were determined by electrofocusing in acrylamide gel in 160 subjects who were used as controls in a case-control study of hepatocellular carcinoma (HCC). The results were studied in relation to age, sex, diagnostic category, tobacco smoking, consumption of alcoholic beverages, presence of hepatitis B surface antigen (HBsAg), and serum levels of alphafetoprotein (AFP) by modeling the data through multiple regression. There was no relation of serum alpha-1-antitrypsin values with sex, HBsAg, AFP, consumption of alcoholic beverages, and diagnostic category (p |is greater than~ 0.25). By contrast, there were statistically significant dose-dependent positive associations of serum alpha-1-antitrypsin with age and tobacco smoking (p |is less than~ 0.01 in both instances). The positive association of serum alpha-1-antitrypsin with tobacco smoking and the previously reported excessive elevation of serum alpha-1-antitrypsin in hepatitis B-negative tobacco-related cases of HCC suggest that alpha-1-antitrypsin is intimately related to the pathogenetic process linking tobacco smoking to HCC., Alpha-1-antitrypsin is one of at least nine plasma proteins that have been characterized as protease inhibitors (Harpel 1983). Alpha-1-antitrypsin is under genetic control, and more than 50 codominant alleles at [...]

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The IgG pattern in CSF was studied in 11 patients with multiple sclerosis who exhibited an oligoclonal banding upon thin-layer polyacrylamide gel isoelectric focusing followed by silver stain of unconcentrated CSF. Each patient received beta-interferon intrathecally during a 2 month period. No modification was observed over a 6 month period. In addition, the oligoclonal pattern was remarkably unique for each individual representing a typical "fingerprint" which allowed the identification of any single CSF. [ABSTRACT FROM AUTHOR]

We report 12 cases of lymphomas which occurred among 1670 patients with kidney or combined renal and pancreatic transplantation. Group 1 comprised nine patients presenting with the diffuse form of the disease where immunoblasts or mature plasma cells massively infiltrated all organs. The first symptom was a viral syndrome, associated with a restriction of heterogeneity of immunoglobulins; oligoclonal to monoclonal peaks of immunoglobulins appeared about 50 days after transplantation. All patients received antilymphocyte globulins (ALG), and seven were treated with cyclosporin. EBV infection could be demonstrated in almost all patients; three EBV lymphoblastoïd cell lines were established, their HLA phenotype being the same as the recipient of the graft. All patients finally died with renal and hepatic failure. Group 2 comprises three patients who presented solid B cell tumours of tonsils, lungs, and spleen at onset, extending to liver, kidney graft, lymph nodes, and brain. All received cyclosporin; two patients were treated with ALG, and one with OKT3. Immunoglobulins were polyclonal, oligoclonal, or decreased. Cell surface immunoglobulins were monoclonal on two tumours. EBV-DNA was positive within two tumours. Two patients presented EBV and CMV primary infection. CD4+T lymphocytes subsets were diminished at onset, and increased after cessation of immunosuppressive therapy. One patient died because of brain involvement; the two others are alive, one with perfect graft function. Therapy consisted of stopping immunosuppressive treatment, Acyclovir, and in two patients of group 2, monoclonal antibodies to pan-B and EBV receptor antigens. [ABSTRACT FROM PUBLISHER]

The two major protease inhibitors in human serum, alpha1-antitrypsin (α1AT) and alpha2- macroglobulin (α 2m), were analysed for their effects on antibody-dependent cell-mediated cytotoxocity (ADCC) and natural killing (NK). The results indicate that both α 1AT and α 2m decrease ADCC and NK in a dose-responsive pattern. [ABSTRACT FROM AUTHOR]

The existence of alpha-1 antitrypsin variants with apparently unremarkable phenotypes and serum concentrations, contrasting with a clinical picture suggestive of a severe deficiency, led us to investigate whether in these cases there was a reduction or even suppression of the capacity of alpha-1 antitrypsin to inhibit elastase. To this end, in two different laboratories, we adapted and validated a method for measuring the functional activity of alpha-1 antitrypsin, based on spectrophotometric kinetic analysis of the inhibition by serum alpha-1 antitrypsin of the hydrolytic activity of porcine pancreatic elastase on a chromogenic substrate. This method has proved to be robust, reproducible and transferable and made possible to define, on the basis of an analysis of a hospital population, a functionality index with a confidence interval comprised between 0.87 and 1.2, allowing to identify subjects likely to have a functional deficiency of alpha-1 antitrypsin, whether this deficiency being of a genetic origin without any quantitative or phenotypic translation, or whether being acquired under the effect of external agents (cigarette smoke or viruses).

Introduction: Alpha1-antitrypsin deficiency is a predisposing factor for pulmonary disease and under-diagnosis is a significant problem. The results of a targeted screening in patients with respiratory symptoms possibly indicative of severe deficiency are reported here., Methods: Data were collected from March 2016 to October 2017 on patients who had a capillary blood sample collected during a consultation with a pulmonologist and sent to the laboratory for processing to determine alpha1-antitrypsin concentration, phenotype and possibly genotype., Results: In 20 months, 3728 test kits were requested by 566 pulmonologists and 718 (19 %) specimens sent: among these, 708 were analyzable and 613 were accompanied by clinical information. Of the 708 samples, 70 % had no phenotype associated with quantitative alpha1- antitrypsin deficiency, 7 % had a phenotype associated with a severe deficiency and 23 % had a phenotype associated with an intermediate deficiency. One hundred and eight patients carried at least one PI*Z allele which is considered to be a risk factor for liver disease., Conclusions: The results of this targeted screening program for alpha1- antitrypsin deficiency using a dried capillary blood sample reflect improvement in early diagnosis of this deficiency in lung disease with good adherence of the pulmonologists to this awareness campaign., (Copyright © 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background & Aims: To identify prognostic factors for liver disease in children with alpha-1 antitrypsin deficiency, irrespective of phenotype, using the DEFI-ALPHA cohort., Methods: Retrospective, then prospective from 2010, multicentre study including children known to have alpha-1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Clinical and biological data were collected. Liver disease was classified as "severe" (portal hypertension, liver failure, liver transplantation or death); "moderate" (persistent abnormal liver biology without portal hypertension); and "mild/none" (normal or almost normal liver biology and native liver). Prognostic factors for severe liver disease were evaluated using a Cox semiparametric model., Results: In January 2017, 153 patients from 19 centres had been included; genotypes were PIZZ in 81.9%, PISZ in 8.1%, other in 10.0%. Mean ± SD follow-up was 4.7 ± 2.1 years. Half of patients had moderate liver disease. Twenty-eight children (18.3%) had severe liver disease (mean age 2.5 years, range: 0-11.6): diagnosis of alpha-1 antitrypsin deficiency was made before two months of age in 65.4%, genotypes were PIZZ in 25 (89.3%), PISZ in 2, PIM like Z in 1, 15 children underwent liver transplantation, 1 child died at 3 years of age. Neonatal cholestasis was significantly associated with severe liver disease (P = 0.007)., Conclusion: Alpha-1 antitrypsin-deficient patients presenting with neonatal cholestasis were likely to develop severe liver disease. Some patients with non-homozygous ZZ genotype can develop severe liver disease, such as PISZ and M variants, when associated with predisposing factors. Further genetic studies will help to identify other factors involved in the development of liver complications., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Alpha-1-antitrypsin deficiency (A1ATD) is a common genetic condition which predisposes to emphysema and liver disorders. It is estimated that 10-15% of homozygous individuals for the Z allele (PiZZ) may develop liver fibrosis. The optimal modalities to detect liver disease in PiZZ adult patients need to be defined. The aim of this prospective study was to perform a systematic non-invasive evaluation of the liver fibrosis by elastometry using Fibroscan ® in a cohort of A1ATD patients with emphysema., Methods: Patients followed in our respiratory unit were enrolled in this prospective study and underwent on the same day a physical examination, a biochemical profiling, an abdominal ultrasound (US) and a Fibroscan ® ., Results: Twenty-nine PiZZ adults (19 male) were included. Median age was 50.4 yrs (21.5-67.2). Median serum A1AT level was 0.20 g/L (0.15-0.33). Liver Function Tests (LFT) were not normal in 2 patients and US was abnormal in 6 patients. Two patients had both abdnormal LFT and US. Fibroscan ® was technically feasible in 28/29 (97%) patients. Median liver stiffness was 4.5 kPa (2.8-32.8), and was > 7.2 kPa in 5/28 (18%) and > 14 kPa in 2/28 (7%) patients. Liver stiffness was increased in 2/2 (100%) patients with abnormal LFT and US, in 1/4 (25%) with abnormal LFT or US and in 2/22 (10%) patients with normal LFT and US., Conclusions: Fibroscan ® is an easy and repeatable tool which can be used in PiZZ patients to screen for the presence of significant liver fibrosis and to identify patients at higher risk to develop liver complications in the future and who may benefit from a closer surveillance., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background & Aims: Fifteen to twenty percent of alpha-1 antitrypsin deficiency patients (A1ATD) have a severe liver outcome (portal hypertension - PHT) during childhood. Since they all share the same ZZSERPINA1 genotype and that environmental factors such as alcohol cannot be advanced, the presence of modifier genes is now well recognized. SNPs located on the SERPINA1 and MAN1B1 genes have already been tested in very few studies with contradictory or not replicated results., Methods: Our genotype-phenotype correlation study, performed on 92 ZZ children, aimed at determining once and for all if SERPINA1 and MAN1B1 polymorphisms may be implied in the onset of PHT. To do so, we also performed for the first time a complete haplotype reconstruction for data analysis., Results: The two genetic associations with severe liver disease that had been suspected previously (one SNP for SERPINA1 and another for MAN1B1) were not confirmed in our cohort. Moreover, the haplotype analysis identified only one major genetic background for the SERPINA1 Z-allele, allowing us to exclude the presence of a frequent modifier SNP within. For MAN1B1, four major haplotypes were identified but the prevalence of PHT did not significantly differ between them., Conclusion: We conclude that genetic polymorphisms in these two genes probably do not influence the onset of severe liver disease in A1ATD., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Serum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients., Methods: In a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL., Results: One hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations., Conclusion: An elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

Background: Alpha 1 antitrypsin (A1AT) deficiency (A1ATD) is potentially associated with a high degree of liver and/or lung disease. Apart from the most frequent deficiency alleles, Pi S and Pi Z, some A1AT alleles of clinical significance may be easily misdiagnosed. This is typically the case of the Pi Mmalton variant which shares the same 'gain-of-function' liver toxicity than Pi Z and the same 'loss of function' lung disease as well., Methods: The biological diagnosis of A1ATD typically relies on a low serum concentration associated with an abnormal isoelectric focusing (IEF) pattern of migration. However, Sanger direct DNA sequencing may be required for deficiency alleles without biochemical expression (Null alleles) or for A1AT variants whose IEF profiles resemble the wild-type and sub-types M allele but with a low concentration., Results: We report four cases of A1ATD involving the deficient Pi Mmalton allele with very different clinical expressions: (i) one Mmalton/Mmalton with liver fibrosis and cirrhosis, (ii) two Mmalton/Z with chronic pulmonary obstructive disease in one case and (iii) one M/Mmalton without liver or lung disease. In both cases, the correct diagnosis has necessitated a genetic analysis., Conclusions: Our study provides another example of Pi Mmalton homozygosity associated with a severe liver disease that emphasizes the necessity of a not delayed diagnosis. The great clinical heterogeneity of the other genotypes (which is in agreement with the literature data) questions about the role of environmental and other modifier genes in the pathogenicity of A1ATD.

Introduction: The alpha-1 antitrypsin (α1-AT) deficiency, most frequently caused by homozygosity for the Z variant (SERPINA1: c.1096 G>A; Glu342Lys), can give rise to two clinical patterns: (i) respiratory impairment with emphysema (mainly in adulthood) because of a pulmonary quantitative defect in anti-elastase activity; (ii) hepatic impairment (mainly in childhood) due to the misfolding of the PiZ protein which accumulates in hepatocytes thus providing cytotoxicity., Current Knowledge: To date, the clinical and genetic factors responsible for the development of major hepatic injuries (fibrosis and portal hypertension) during childhood in PiZ patients are not known., Methods: The DEFI-ALPHA cohort, created in 2008, aims to inventory and prospectively study all α1-AT deficient children diagnosed and included after occurrence of a hepatic sign. The POLYGEN DEFI-ALPHA PHRC has recently (2013) been added to the project to identify modifiers genes by two complementary approaches: (i) the candidate genes strategy with the SERPINA1, CFTR (cystic fibrosis gene), MAN1B1 and SORL1 genes, these two latter being implied in the degradation of misfolding proteins; (ii) the whole exome sequencing (WES) strategy in families in which the PiZ proband has a PiZ brother or sister free of any hepatic sign., Expected Results: The clinical parameter we want to explain is the apparition of a portal hypertension in PiZ children. In the DEFI-ALPHA project, three criteria will be tested: (i) age of inclusion in the cohort, (ii) the way of inclusion (neo-natal icterus or later hepatic impairment) and (iii) treatment or not with ursodesoxycholic acid and, if so, its duration. Genetically, polymorphisms on the SERPINA1 and MAN1B1 genes have already been associated in the literature with different clinical evolutions of the A1ATD but very inconstantly. Our study thus aims to confirm or not this association. The CFTR and SORL1 genes have never been studied in the α1-AT deficiency. Finally, the whole exome sequencing strategy could allow the discovery of new unexpected modifiers genes in this disease., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Alpha- 1-antitrypsin (A1AT) deficiency is a hereditary autosomal codominant genetic disorder resulting in low circulating levels of A1AT and leading to lung and/or liver disease. It remains underdiagnosed and only 5 to 10% of PIZZ patients, the most common form of severe A1AT deficiency, would be actually identified in France. Facilitating early diagnosis of A1AT deficiency would allow a better management of this disease; therefore we have developed and standardized in three laboratories involved in this study, a diagnostic test on dried blood spots (DBS) including quantitative A1AT measurement, phenotyping by IEF electrophoresis and, if necessary, genotyping by SERPINA1 gene sequencing. We performed a quantitative assay on 90 DBS samples by immunoturbidimetric or immunonephelometric methods. We demonstrated that both methods were suitable for this type of sampling and the results obtained were highly correlated (R(2)>0.9) between the three laboratories: for a target value of 1.00 g/L, the results obtained from the three laboratories were between 1.00 and 1.02 g/L. Phenotyping and genotyping were performed under redefined operating conditions and adapted to the analysis of DBS samples. The results were comparable with those obtained for venous blood samples. Following this work, it becomes possible to provide pulmonologists with a reliable kit to perform a capillary blood sampling on filter paper which would allow a large-scale screening of A1AT deficiency in the population particularly affected by this genetic condition.

Unlabelled: Renal dysfunction is frequent in liver cirrhosis and is a strong prognostic predictor of orthotopic liver transplantation (OLT) outcome. Therefore, an accurate evaluation of the glomerular filtration rate (GFR) is crucial in pre-OLT patients. However, in these patients plasma creatinine (Pcr) is inaccurate and the place of serum cystatine C (CystC) is still debated. New GFR-predicting equations, based on standardized assays of Pcr and/or CystC, have been recently recommended in the general population but their performance in cirrhosis patients has been rarely studied. We evaluated the performance of the recently published Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPI-Pcr, CKD-EPI-CystC, and CKD-EPI-Pcr-CystC) and the more classical ones (4- and 6-variable MDRD and Hoek formulas) in cirrhosis patients referred for renal evaluation before OLT. Inulin clearance was performed in 202 consecutive patients together with the determination of Pcr and CystC with assays traceable to primary reference materials. The performance of the GFR-predicting equations was evaluated according to ascites severity (no, moderate, or refractory) and to hepatic and renal dysfunctions (MELD score  ≤ or >15 and KDOQI stages, respectively). In the whole population, CystC-based equations showed a better performance than Pcr-based ones (lower bias and higher 10% and 30% accuracies). CKD-EPI-CystC equation showed the best performance whatever the ascites severity and in presence of a significant renal dysfunction (GFR <60 mL/min/1.73 m(2))., Conclusion: Pcr-based GFR predicting equations are not reliable in pre-OLT patients even when an IDMS-traceable enzymatic Pcr assay is used. Whenever a CystC-assay traceable to primary reference materials is performed and when a true measurement of GFR is not possible, CystC-based equations, especially CKD-EPI-CystC, may be recommended to evaluate renal function and for KDOQI staging., (© 2013 by the American Association for the Study of Liver Diseases.)