Α1-antitrypsin Phenotypes Research Articles

Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2-18 years) diagnosed with AATD and 18 controls (aged 3-16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity, hTERT expression and AATD phenotypes; high-risk patients showed shorter telomeres, lower hTERT expression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.

Circulating polymers in 1-antitrypsin deficiency

To the Editor: Most individuals carry two wild-type M alleles of the SERPINA1 gene which encodes α1-antitrypsin. 95% of severe deficiency of α1-antitrypsin is associated with the Z allele (Glu342Lys; denoted PiZZ in the homozygote), and with the retention and polymerisation of α1-antitrypsin within hepatocytes [1]. These polymers are contained within periodic acid–Schiff-positive, diastase-resistant inclusions that are associated with neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The concomitant lack of circulating α1-antitrypsin predisposes the Z α1-antitrypsin homozygote to early-onset emphysema. Polymers of α1-antitrypsin form within the lung as a result of local inflammation and exposure to cigarette smoke [2]. They have also been identified in the skin of an individual with α1-antitrypsin deficiency and panniculitis [3] and in a renal biopsy from an individual with α1-antitrypsin deficiency and vasculitis [4]. It is unknown whether these polymers form locally or are deposited in these tissues from a circulating source, and whether extrahepatic polymers are associated with any disease phenotypes. We have assessed whether polymers of α1-antitrypsin are present within serum, from where they originate, and whether they are associated with clinical features in individuals with PiZZ α1-antitrypsin deficiency. In this investigation we used ELISA with the anti-α1-antitrypsin polymer monoclonal antibody (2C1) [5] to assess the presence of polymers in the plasma of 1) 518 individuals with PiZZ α1-antitrypsin deficiency; 2) an individual with α1-antitrypsin deficiency who underwent liver transplantation; and 3) 293 individuals with a mixture of α1-antitrypsin phenotypes. The specificity of the 2C1 antibody was confirmed by using it to immunoprecipitate polymers from the plasma of individuals with and without a positive signal …

Index of Suspicion

The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu. A 2-year-old boy with a history of eczema and food allergies to nuts and soy presents to the emergency department with a 10-day history of generalized edema. The swelling began in the periorbital area but soon progressed to involve his entire body. There have been no fevers or any recent illnesses other than 1 day of cough and a few watery stools. He has had no new exposures to foods or other substances. His family history is remarkable for multiple allergies and eczema. Physical examination reveals a temperature of 98.8°F (37.1oC), heart rate of 98 beats per minute, respiratory rate of 36 breaths per minute, blood pressure of 103/65 mm Hg, and an oxygen saturation of 97% on room air. His weight is 12.6 kg (34th percentile). He is noted to have a moderate amount of periorbital edema, decreased breath sounds at the lung bases bilaterally, a protuberant abdomen, and 2+ pitting edema on his lower extremities. The rest of his physical examination findings are within normal limits. Laboratory evaluation reveals a white blood cell count of 23,800/μL (23.8 × 109/L), with 37% neutrophils, 49% lymphocytes, 4% bands, 7% monocytes, and 3% eosinophils; hemoglobin level of 13.3 g/dL (133 g/L); and platelet count of 427 × 103/μL (427 × 109/L). Serum electrolyte, blood urea nitrogen, and creatinine levels are normal. Sodium level is 132 mEq/L (132 mmol/L). Serum albumin level is 1.7 g/dL (17 g/L) (reference range, 3.4-5.4 g/dL [34-54 g/L]). Total protein level is 3.8 g/dL (38 g/L). Aspartate aminotransferase, alanine aminotransferase, and coagulation profiles …

Nasobiliary Drainage in an Episode of Intrahepatic Cholestasis in a Child With Mild ABCB11 Disease

Nasobiliary Drainage in an Episode of Intrahepatic Cholestasis in a Child With Mild <i>ABCB11</i> Disease

Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: results of a case-control study.

The role of the viral genotype, especially genotype 1b, in the severity of liver injury induced by chronic hepatitis C virus (HCV) infection is unclear, probably because of confounding factors such as the date and mode of contamination. Host genetic or environmental factors such as heterozygous MZ alpha1-antitrypsin deficiency or alcoholism, could also be potential risk factors for the development of cirrhosis. The aim of this study was to compare the prevalence of genotypes, alpha1-antitrypsin phenotype, past hepatitis B virus infection, and alcohol consumption in cirrhotic and noncirrhotic patients with chronic hepatitis C. We conducted a case-control study comparing 84 consecutive cirrhotic patients with chronic hepatitis C (cases) with 84 noncirrhotic patients with chronic hepatitis C (controls) selected from a cohort of 464 patients hospitalized during the same period. Controls were paired with cases according to age, sex, risk factors, and date of infection. HCV genotypes were determined using the InnoLiPA technique (Innogenetics, Zwijnaarde, Belgium) and classified according to the method of Simmonds. Patients were divided in three groups according to alcohol consumption: <30 g/d (light), 30 to 80 g/d (moderate), and >80 g/d (heavy). Cirrhotic and noncirrhotic patients were not significantly different in terms of genotype distribution (1a/1b/2a/3a/others/undetermined: 10/48/7/17/0/2 versus 11/43/10/10/5/5), alpha1-antitrypsin phenotype distribution (MM/MS/MZ: 84%/14%/2% vs. 87%/11%/2%, respectively), and prevalence of antibody to hepatitis B core antigen positivity (29% vs. 23%). Alcohol consumption was significantly different between cases and controls (L/M/H: 58%/27%/16% vs. 76%/15%/9%, respectively; P < .05). Two conclusions regarding patients with chronic hepatitis C virus infection can be drawn from this study: 1) viral genotype, especially 1b, past hepatitis B virus infection, and heterozygous MZ alpha1-antitrypsin deficiency are not risk factors for cirrhosis; and 2) alcohol consumption, even moderate, is a risk factor for cirrhosis.

Lack of association between porphyria cutanea tarda and alpha 1-antitrypsin deficiency.

To determine whether alpha 1-antitrypsin deficiency is involved in the pathogenesis of chronic liver disease in patients with porphyria cutanea tarda and in their recently described high prevalence of hepatitis C virus infection. Consecutive patients diagnosed as having porphyria cutanea tarda and chronic liver disease. A northern Italian hospital. alpha 1-antitrypsin phenotypes were characterized by isoelectric focusing and the results confirmed by DNA analysis in 63 Italian patients with porphyria cutanea tarda. alpha 1-antitrypsin phenotypes different from the normal one were found in 13% of the patients. This prevalence did not differ from that in control subjects (9%). Clinical characteristics of patients with porphyria cutanea tarda with normal or altered alpha 1-antitrypsin phenotype, including age of presentation of the disease, prevalence of hepatitis C virus infection, liver histology, prevalence of iron overload and hepatocellular carcinoma occurrence, did not differ significantly. alpha 1-antitrypsin does not seem to play a role in the pathogenesis of chronic liver disease and hepatitis C virus infection in patients with porphyria cutanea tarda. Patients in whom the two defects coexist do not have a more severe disease.

Alpha 1-antitrypsin phenotypes in coeliac patients and a control population in the west of Ireland.

alpha 1 antitrypsin or protease inhibitor (Pi) phenotyping was carried out on 111 coeliac disease patients (CD) and 250 controls. The Pi MM phenotype was present in 95 (85.6%) of the coeliacs and 225 (90%) of the controls. The groups did not differ significantly with regard to Pi phenotypes. In the CD group the Pi Phenotype did not relate to HLA B8 or DR3 status. Associated diseases in the CD patients did not correlate with Pi phenotype.

α1-Antitrypsin phenotypes in patients with abdominal aortic aneurysms

The α 1-antitrypsin phenotypes were determined in 47 patients with abdominal aortic aneurysms. The MM phenotype was present in 85%, the MS phenotype in 4%, the MZ phenotype in 11%, and the ZZ phenotype not present in any patients. The MZ phenotype occurred significantly more often in patients with aneurysms than would be expected in the general population. The current data would support a genetic mechanism of either autosomal-dominant or multifactorial influences but not an X-linked mechanism for families with a history of abdominal aortic aneurysms.

Alpha-1-antitrypsin phenotypes in acute anterior uveitis.

α1-Antitrypsin phenotypes were investigated in 65 patients with acute anterior uveitis. These patients did not suffer from any additional systemic disease and showed a highly significant increase of HLA antigen B27. No association with the α1 antitrypsin phenotype MZ, as described by other authors, or with other phenotypes of this system was detected

PiPclifton: a new α1-antitrypsin allele in an American Negro family*

Serum specimens from eight females and two males representing three generations of an American Negro family exhibited an α1-antitrypsin phenotype that we labelled MPclifton because of its electrophoretic mobility. The...

Selective IgA Deficiency and Pi ZZ-Antitrypsin Deficiency: Association with Recurrent Sinopulmonary Infections, Emphysema, and Bronchiectasis

We describe a patient in whom selective IgA deficiency and homozygous α1-antitrypsin deficiency were discovered. Clinically, the patient suffered from chronic sinopnlmonary infections, destructive emphysema, and bronchiectasis. The interrelation of IgA and α1-antitrypsin was studied. Twenty-three α1-antitrypsin-deficient sera were screened for IgA deficiency. None of these sera were deficient in IgA. Fifteen IgA-deficient sera were screened for α1-antitrypsin deficiency. In this group, three patients were found to have variant α1-antitrypsin phenotypes. Respiratory infections were a prominent complaint in all three of these patients, with bronchiectasis in two patients. We believe that the combination of IgA and α1-antitrypsin deficiencies should be considered in the evaluation of any patient with idiopathic bronchiectasis. We describe a patient in whom selective IgA deficiency and homozygous α1-antitrypsin deficiency were discovered. Clinically, the patient suffered from chronic sinopnlmonary infections, destructive emphysema, and bronchiectasis. The interrelation of IgA and α1-antitrypsin was studied. Twenty-three α1-antitrypsin-deficient sera were screened for IgA deficiency. None of these sera were deficient in IgA. Fifteen IgA-deficient sera were screened for α1-antitrypsin deficiency. In this group, three patients were found to have variant α1-antitrypsin phenotypes. Respiratory infections were a prominent complaint in all three of these patients, with bronchiectasis in two patients. We believe that the combination of IgA and α1-antitrypsin deficiencies should be considered in the evaluation of any patient with idiopathic bronchiectasis.