Alpha 1-antitrypsin Phenotype Research Articles

Alpha-1 Antitrypsin Phenotyping: An Unmet Educational Need of Healthcare Providers.

Diagnosing alpha-1 antitrypsin deficiency (A1ATD) involves two-step laboratory testing, determination of serum alpha-1 antitrypsin (A1AT) level and phenotyping if A1AT < 100 mg/dL. Whether these guidelines are effectuated in clinical practice is uncertain. To begin to address this issue, we determined whether A1AT phenotyping is performed in patients with serum A1AT 57 - 99 mg/dL at our institution. We reviewed the medical records of patients seen at Jesse Brown Veterans Affairs Medical Center from January 2019 to October 2022 with serum A1AT between 57 and 99 mg/dL. In each case, pertinent demographic, clinical, and pulmonary function tests data were extracted. Data were presented as means and standard deviation (SD) where appropriate. The Student's t-test was used for statistical analysis. P < 0.05 was considered statistically significant. Thirty patients (90% males; 60 ± 18 years) with serum A1ATD < 100 mg/mL were identified. Fourteen were African Americans, four Hispanics, and 12 non-Hispanic Whites. The majority were current or ex-smokers. Fourteen (47%) patients had lung disease, 14 (47%) liver disease and one had concomitant lung and liver diseases. Mean ± SD forced expiratory volume in 1 s (FEV1) and lung diffusing capacity were 2.57 ± 1.41 L (67±19% predicated) and 18.7 ± 10 mL/min/mm Hg (64±28% predicted), respectively. Only 13 patients (43%) underwent phenotype testing (seven African Americans, five Whites, and one Hispanic). Six patients had MZ phenotype, four MS, and three SZ. One patient died from acute respiratory failure during the study period. Phenotyping of patients with serum A1AT 57 - 99 mg/dL at our institution is inadequate. Accordingly, regular continuous medical educational programs on A1AT phenotyping targeting healthcare providers are warranted.

Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, for example, cirrhosis and hepatocellular carcinoma, caused by the accumulation of mutant forms of AAT retained within the liver. As with lung disease, the only treatment option for end-stage liver disease is liver transplantation. Survival rates for patients with AATD undergoing liver transplantation are also favorable, and patients, particularly pediatric patients, have benefitted from advancements in peri-/post-surgical care. As the majority of AAT is produced by the liver, the AAT phenotype of the recipient becomes that of the donor, meaning that AAT serum levels should be normalized (if the donor is AAT-replete), halting further lung and liver disease progression. However, post-liver transplant respiratory function may continue to decline in line with normal age-related lung function decline. In the most severe cases, where patients have simultaneous end-stage lung and liver disease, combined lung and liver transplantation is a treatment option with favorable outcomes. However, there is very little information available on this procedure in patients with AATD.

RECURRENT PNEUMOTHORACES IN A YOUNG, NON-SMOKING WOMAN

SESSION TITLE: Medical Student/Resident Genetic and Developmental Disorders Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is known to affect the lungs and liver by causing the early development of emphysema and liver disease. We present a case of a non-smoker who developed emphysema in her early 40s. CASE PRESENTATION: 42 year old non-smoking female with a past medical history of multiple spontaneous pneumothoraces presented to her primary care physician (PCP) with complaints of right-sided chest pain and was found to have decreased breath sounds on the right side. She was sent for a 2-view chest x-ray and d-dimer. The posteroanterior and lateral chest x-ray showed a right side pneumothorax and she was instructed to go to the emergency department (ED) for chest tube placement. Examination in the ED revealed normal vital signs and no breath sounds on the right chest. D-dimer was unremarkable. She was seen by pulmonology who recommended further imaging. CT chest with contrast demonstrated small subpleural blebs along the medial aspect of the right lung apex, the suspected source of the spontaneous pneumothorax, and a lobulated lesion in the posterior segment of the right lobe of the liver. Given the liver findings, a MRI abdomen was done showing a mildly complex, septated cyst in the posterior right hepatic lobe measuring up to 4.4cm without enhancement consistent with a biliary cystadenoma. Serial chest x-rays were done to monitor the pneumothorax regression. The chest tube was removed three days later after absence of pneumothorax on water seal. She was discharged with a referral to thoracic surgery and had an office visit two weeks later for right-sided robotic-assisted thoracoscopic surgery with wedge excision of right apical bleb and mechanical pleurodesis. Pathology from the bleb tissue showed subpleural fibrosis and emphysematous change. AATD testing sent during her hospitalization was significant for alpha-1 antitrypsin (AAT) phenotype of SS, with an incidence of 0.1% and an AAT level of 105 mg/dL, the lower end of the normal range for her age. Pulmonary function testing did not reveal any obstructive findings. DISCUSSION: Our case demonstrates a rare presentation of the development emphysema in a non-smoker found to have the SS phenotype with low normal level of alpha-1 antitrypsin. This patient developed emphysema earlier than expected given the phenotype of AATD. Although our patient did not have classic liver manifestations, she was found to have a biliary cystadenoma. Patients with the SS phenotype are at risk to develop liver disease and early manifestations of emphysema; however they have a minimally increased risk of developing COPD, as the SS allele is related to a mild decrease in alpha-1 antitrypsin levels. CONCLUSIONS: Given the rarity of the SS phenotype, more research is needed in order to truly determine the incidence of developing lung and/or liver disease. It will be vital to help prognosticate and treat patients with alpha-1 antitrypsin deficiency. Reference #1: Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008;3:16. Reference #2: Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of Emphysema Distribution in alpha1-Antitrypsin Deficiency Influences Lung Function Impairment. Am J Respir Crit Care Med. 2004;170:1172-8. Reference #3: Kelly E, Greene CM, Carroll TP, McElvaney NG, O’Neill SJ. Alpha-1 antitrypsin deficiency. Respir Med. 2010;104:763-72. DISCLOSURES: No relevant relationships by Patrick Koo, source=Web Response No relevant relationships by Jetina Okereke, source=Web Response

High Serum Level of IL-17 in Patients with Chronic Obstructive Pulmonary Disease and the Alpha-1 Antitrypsin PiZ Allele.

Chronic obstructive pulmonary disease (COPD) is multifactorial disease, which is characterized by airflow limitation and can be provoked by genetic factors, including carriage of the PiZ allele of the protease inhibitor (Pi) gene, encoding alpha-1 antitrypsin (A1AT). Both homozygous and heterozygous PiZ allele carriers can develop COPD. It was found recently that normal A1AT regulates cytokine levels, including IL-17, which is involved in COPD progression. The aim of this study was to determine whether homozygous or heterozygous PiZ allele carriage leads to elevated level of IL-17 and other proinflammatory cytokines in COPD patients. Materials and Methods. Serum samples and clinical data were obtained from 44 COPD patients, who included 6 PiZZ, 8 PiMZ, and 30 PiMM A1AT phenotype carriers. Serum concentrations of IL-17, IL-6, IL-8, IFN-γ, and TNF-α were measured by the enzyme-linked immunosorbent assay (ELISA). All A1AT phenotypes were verified by narrow pH range isoelectrofocusing with selective A1AT staining. A turbidimetric method was used for quantitative A1AT measurements. Results. COPD patients with both PiZZ and PiMZ phenotypes demonstrated elevated IL-17 and decreased IFN-γ levels in comparison to patients with the PiMM phenotype of A1AT. Thereafter, the ratio IL-17/IFN-γ in PiZZ and PiMZ groups greatly exceeded the values of the PiMM group. Homozygous PiZ allele carriers also had significantly higher levels of IL-6 and lower levels of IL-8, and IL-6 values correlated negatively with A1AT concentrations. Conclusions. The presence of the PiZ allele in both homozygous and heterozygous states is associated with altered serum cytokine levels, including elevated IL-17, IL-17/IFN-γ ratio, and IL-6 (only PiZZ), but lower IFN-γ and IL-8.

Clinical Effect of Alpha-1 Antitrypsin Deficiency in Antineutrophil Cytoplasmic Antibody-associated Vasculitis: Results from a French Retrospective Monocentric Cohort.

Deficiency in alpha-1 antitrypsin (AAT) is a possible pathogenic cofactor in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the clinical effect of AAT deficiency remains poorly established in this setting. This study aimed to describe the clinical phenotypes and outcomes of AAV according to AAT phenotypes. This study was conducted retrospectively at Caen University Hospital and included all consecutive granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with positive proteinase 3-ANCA or myeloperoxidase-ANCA, from January 2000 or September 2011, respectively, to June 2016. AAT dosage (nephelometry) and phenotyping (isoelectric focusing in agarose gel) were performed. Among the 142 patients with AAV, including 88 GPA and 54 MPA, 102 (72%) had the MM phenotype, 5 (4%) had a nonpolymerogenic M-variant phenotype, 18 (13%) had the deficient allele MZ, 12 (8%) had MS, 2 (1%) had ZZ, 2 (1%) had SZ, and 1 (1%) had SS. M, Z, and S allele frequencies were 84%, 8%, and 6%, respectively. No association was observed between AAT deficiency and ANCA subtype or AAV phenotype, except for intraalveolar hemorrhage (IAH), which was more frequent in patients harboring at least 1 of the deficient Z or S alleles than in those without any deficient alleles (p < 0.01). Global, renal, or relapse-free survival rates were similar for all subgroups. This study shows that AAT deficiency confers, independently of ANCA subtype, a higher risk of IAH. Prospective studies are required to refine these data and to assess the need for replacement therapy in AAT-deficient patients with AAV.

Alpha 1 Antitrypsin Deficiency, Two Cases of Heterozygous S and Clayton Null Alleles

Alpha-1 antitrypsin deficiency (AATD) is a disorder that can lead to early onset lung and liver disease and is considered to be underdiagnosed. The purpose of this paper is to demonstrate the importance of early detection using genotyping of AATD by presenting two very rare cases of this disorder and to remind clinicians to maintain a high level of suspicion for this disorder. Two unrelated patients presented to different pulmonology offices in Grand Blanc, MI and were screened for AATD for different reasons. Testing for both patients included alpha-1 antitrypsin enzyme levels, phenotyping, and genotyping. Both individuals were heterozygotes for S allele and Q0Clayton allele. The Q0Clayton allele is a very rare Null allele that is defined this way because these individuals do not produce any alpha-1 antitrypsin. These cases highlight the need for early testing of patients with risk factors for AATD. Also demonstrated is the need to include genotype testing to accurately identify the risk of developing emphysema and cirrhosis. Lower morbidity and mortality may result if AATD is detected early.

Alpha-1 antitrypsin Pi*SZ genotype: estimated prevalence and number of SZ subjects worldwide.

The alpha-1 antitrypsin (AAT) haplotype Pi*S, when inherited along with the Pi*Z haplotype to form a Pi*SZ genotype, can be associated with pulmonary emphysema in regular smokers, and less frequently with liver disease, panniculitis, and systemic vasculitis in a small percentage of people, but this connection is less well established. Since the detection of cases can allow the application of preventive measures in patients and relatives with this congenital disorder, the objective of this study was to update the prevalence of the SZ genotype to achieve accurate estimates of the number of Pi*SZ subjects worldwide, based on studies performed according to the following criteria: 1) samples representative of the general population, 2) AAT phenotyping characterized by adequate methods, and 3) selection of studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop tables and maps with an inverse distance-weighted (IDW) interpolation method, to provide numerical and geographical information of the Pi*SZ distribution worldwide. A total of 262 cohorts from 71 countries were included in the analysis. With the data provided by these cohorts, a total of 1,490,816 Pi*SZ were estimated: 708,792 in Europe; 582,984 in America and Caribbean; 85,925 in Africa; 77,940 in Asia; and 35,176 in Australia and New Zealand. Remarkably, the IDW interpolation maps predicted the Pi*SZ prevalence throughout the entire world even in areas lacking real data. These results may be useful to plan strategies for future research, diagnosis, and management of affected individuals.

Genotyping diagnosis of alpha-1 antitrypsin deficiency in Saudi adults with liver cirrhosis.

The acute phase protein alpha-1 antitrypsin (AAT) is mainly produced in liver cells. AAT deficiency affects the lungs and liver. We conducted a case-control study to define a valuable method for the proper diagnosis of alpha-1 antitrypsin deficiency (AATD), as well as the association of liver cirrhosis with AATD in Saudi adults.Blood samples from 300 liver cirrhosis patients and 400 controls were analyzed according to serum AAT concentration, phenotyping, and genotyping. Nephelometry was used for AAT quantification, isoelectric focusing electrophoresis was used for phenotyping detection, and real-time PCR was used for genotyping to determine the Z and S deficiency alleles.This study highlights the accuracy of using genotyping in addition to AAT quantification, since this technique has proven to be successful in the diagnosis of AATD for 100% of our cases. A significant deviation in AAT genotypes frequencies from the Hardy–Weinberg equilibrium in the adult cirrhosis group occurred due to a higher observed frequency than expected for the Pi ZZ homozygous genotype.Pi ZZ in adults may be considered as the risk factor for liver cirrhosis. However, we could not establish this relationship for heterozygous AATD genotypes (such as Pi MZ and Pi SZ).

Association of alpha-1 antitrypsin level and lung function in patients with chronic obstructive pulmonary disease

Introduction/Objective. Alpha-1 antitrypsin deficiency is a well established inherited risk factor for chronic obstructive pulmonary disease (COPD); however, alpha-1 antitrypsin level may result in different lung function reduction. The aim of our study was to evaluate possible associations of alpha-1 antitrypsin level and lung function in COPD patients with different alpha-1 antitrypsin phenotypes. Methods. Serum alpha-1 antitrypsin concentration from patients (n = 1,167) with COPD, defined according to the GOLD criteria, were analyzed by nephelometry, and alpha-1 antitrypsin phenotype was determined by means of isoelectric-focusing. Results. In COPD patients without alpha-1 antitrypsin deficiency (MM), a significant negative association of lung function (FEV1) with serum alpha-1 antitrypsin (r = -0.511; p &lt; 0.05) and C-reactive protein (CRP) concentrations (r = -0.583; p &lt; 0.05) was detected; moreover, the level of alpha-1 antitrypsin positively correlated with CRP concentration (r = 0.667; p &lt; 0.05). Conclusions. In patients without alpha-1 antitrypsin deficiency, detected negative association of alpha-1 antitrypsin level with FEV1 and positive association with the CRP level defined the importance of alpha-1 antitrypsin for lung function in COPD patients.

Closing volume and flow volume abnormalities in alpha(1)-antitrypsin phenotype groups in a community population.

Alpha1-antitrypsin phenotype groups, found in a community population studied in Tucson, were compared by using the maximum expiratory flow volume curve and the single-breath nitrogen test, alone and in combination. Subjects 25 to 54 years of age were used for the comparison, among whom there were 728 Pi M, 29 Pi MZ, and 62 Pi MS phenotypes. None of the flow volume parameters or closing volume parameters was able to differentiate among the phenotype groups; subjects in groups heterozygous for alpha1-antitrypsin did not differ from individuals homozygous for Pi M with regard to any or all flow volume or closing volume parameters.

Serum concentration of alpha-1 antitrypsin is significantly higher in colorectal cancer patients than in healthy controls.

BackgroundThe association between alpha-1 antitrypsin (AAT) deficiency and colorectal cancer (CRC) is currently controversial. The present study compares AAT serum concentrations and gene frequencies between a group of CRC patients and a control group of healthy unrelated people (HUP).Methods267 CRC subjects (63% males, 72 ± 10 years old) were enlisted from a Hospital Clinic setting in Asturias, Spain. The HUP group comprised 327 subjects (67% males, mean age 70 ± 7.5 years old) from the same geographical region. Outcome measures were AAT serum concentrations measured by nephelometry, and AAT phenotyping characterization by isoelectric focusing.ResultsSignificantly higher serum concentrations were found among CRC (208 ± 60) than in HUP individuals (144 ± 20.5) (p = 0.0001). No differences were found in the phenotypic distribution of the Pi*S and Pi*Z allelic frequencies (p = 0.639), although the frequency of Pi*Z was higher in CRC (21%) than in HUP subjects (15%).ConclusionsThe only statistically significant finding in this study was the markedly higher AAT serum concentrations found in CRC subjects compared with HUP controls, irrespective of whether their Pi* phenotype was normal (Pi*MM) or deficient (Pi*MS, Pi*MZ and Pi*SZ). Although there was a trend towards the more deficient Pi* phenotype the more advanced the tumor, the results were inconclusive due to the small sample size. Consequently, more powerful studies are needed to reach firmer conclusions on this matter.

Misdiagnosis of Alpha-1 Antitrypsin Phenotype in an Infant with CMV Infection and Liver Failure

A 4-month-old female with a history of neonatal cholestasis was initially evaluated with jaundice, ascites, coagulopathy, and worsening aminotransferase levels. At 5 weeks of age, her parents had noticed ‘‘yellowing’’ of her eyes and skin accompanied by a slightly more pale appearance of her regularly yellow-colored stools. Initially, she was noted to have conjugated hyperbilirubinemia, with total bilirubin 6.5 and conjugated 4.5, aspartate aminotransferase (AST) 163, alanine aminotransferase (ALT) 103, and elevated alkaline phosphatase. Liver ultrasound was normal. A percutaneous liver biopsy, obtained due to her continued unexplained cholestasis, was reported as showing possible large duct obstruction and bile duct proliferation, suggestive of extrahepatic biliary atresia. A subsequent endoscopic retrograde cholangiopancreatography (ERCP) and intraoperative cholangiogram showed no anatomic abnormalities in the intrahepatic and extra hepatic biliary system, inconsistent with the diagnosis of biliary atresia (Fig. 1). During her hospital admission, a serum alpha-1 antitrypsin (A1AT) concentration was 34 mg/dl (normal 100–250 mg/dl), with A1AT MZ phenotype reported. Her conjugated hyperbilirubinemia improved slightly, and her liver numbers stabilized. She was discharged home with a close follow-up outpatient appointment in the pediatric gastroenterology clinic. The remainder of her evaluation for neonatal cholestasis, including an echocardiogram and ophthalmology examination for Alagille’s syndrome, was negative. Infectious studies were negative as well. Hepatosplenomegaly or ascites were not detected by physical examination, with reassuring and age-appropriate biometrics noted. Ongoing outpatient medical care revealed elevated cytomegalovirus (CMV) IgM titers (0.97). Due to persistent cholestasis, a repeat A1AT serum concentration was low level at 32 mg/dl, although a repeat ELISA was now reported as the Z phenotype consistent with the ZZ genotype. Due to conflicting tests of mutant serum A1AT proteins, her liver biopsy was re-analyzed with intrahepatic positive periodic acid–schiff stain (PAS) granules now reported, consistent with the diagnosis of A1AT deficiency (Fig. 2). Concomitantly, CMV viremia was confirmed with an elevated CMV polymerase chain reaction (PCR) assay of 12,800. In the clinic, she exhibited significantly increased abdominal distension and marked ascites. Her bilirubin (total 8.8 mg/dl; conjugated 5.3 mg/dl) and aminotransferases (AST/ALT 500/309 units/l) were elevated. Additionally, a significant coagulopathy was noted with an international normalized ratio (INR) of 2.2 and low fibrinogen of 88. Hyponatremia (119 mg/dl) and metabolic acidosis were also present. She did not have any changes in her mental status, and her venous ammonia concentration was mildly elevated to 68 lmol/l. She was admitted to Lucile Packard Children’s Hospital at Stanford for correction of her electrolyte abnormalities and coagulopathy. She was treated with ganciclovir for CMV viremia. During her first 48 h in the hospital, despite the use of IV phytonadione, her hepatic synthetic liver function deteriorated rapidly, with daily doses of fresh-frozen plasma required to treat her coagulopathy. Due to her P. Arias (&) J. Kerner M. Christofferson W. Berquist K. T. Park Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Lucile Packard Children’s Hospital, Stanford University Medical Center, 750 Welch Road, Suite 116, Palo Alto, CA 94304, USA e-mail: parias@stanford.edu

A rare variant of alpha 1 antitrypsin mutations detected in Vietnamese children with liver disease

Alpha 1 antitrypsin (A1AT) is the major plasma serine protease inhibitor that is produced in liver cells. A1AT deficiency is recognized globally as a common genetic cause of liver disease in children, which results from mutations in the SERine Protease INhibitor A1 (SERPINA1) gene. The importance of A1AT deficiency in Viet Nam is unclear. The aim of this study was to determine the A1AT variants present in paediatric patients with liver diseases in order to clarify whether A1AT deficiency is present in Viet Nam. A1AT studies were carried out in 130 children with liver disease of indeterminate aetiology. A1AT levels were determined by immunoturbidimetry. Phenotype analysis of A1AT was performed by isoelectric focusing (IEF) in all patients. Genotype analyses to determine A1AT mutations were performed by direct sequencing. We identified a rare variant of A1AT named Zbristol. The Zbristol appeared to be deficient in the plasma to about the same degree as the PI S protein resulting in low concentration of A1AT in one of these two Vietnamese patients. No other deficient A1AT allele was detected, although 11 patients (8.5%) showed a reduced serum concentration of A1AT. These are the first two cases of a rare A1AT deficiency allele to be found in Viet Nam clearly inferring that A1AT deficiency is not just a disease of Caucasians. As such, the laboratory diagnosis of A1AT deficiency including A1AT concentration determination and phenotype and genotype testing should form part of the routine differential diagnosis of paediatric liver disease of indeterminate aetiology in Vietnamese patients.

Imaging of the jaundiced child

•. In infants and older children ultrasound remains the initial radiological investigation and further imaging is dependent upon the sonographic findings. •. Advances in MRI technique in the evaluation of the biliary tract in children avoids more invasive investigations. •. Imaging primarily aims to differentiate extrahepatic from intrahepatic causes. •. Any neonate with jaundice persisting beyond 2 weeks warrants investigation to exclude biliary atresia as diagnosis prior to 8-weeks-old achieves the best long term surgical success. •. Gallstones are increasingly prevalent in older children but underlying choledochal cysts should be sought when bile duct stones are found. •. Hepatic and pancreatic masses are a rare but important differential in the investigation of jaundice and require evaluation by CT or MRI. This article outlines a practical approach to the investigation of the jaundiced child and reviews the imaging modalities and findings that can establish a diagnosis or narrow the differential. A systematic approach to the work-up of the jaundiced child prevents unnecessary tests and facilitates prompt treatment. Imaging of the jaundiced neonate and infant is reviewed separately to that of the older child and adolescent owing to different aetiologies in the two age groups. There are wide and varied differential diagnoses for the cause of jaundice in a child, which are broadly classified as pre-hepatic, hepatic and post-hepatic. Imaging does not play a significant role in elucidating the cause of pre-hepatic (unconjugated hyperbilirubinaemia); the underlying causes include physiological jaundice, breast milk jaundice, haemolysis and sepsis. Imaging does, however, play an important role in the investigation of conjugated hyperbilirubinaemia, which nearly always reflects hepatic dysfunction. One of the major roles of imaging is to differentiate intrahepatic from extrahepatic causes of jaundice although the underlying diagnosis is often ultimately established by a combination of clinical presentation and findings, laboratory tests, imaging and histology. Initial laboratory tests include liver function tests (including conjugated bilirubin fraction), hepatitis screening, TORCH (Toxoplasmosis, Other (syphilis, hepatitis, zoster), Rubella, Cytomegalovirus and Herpes) titres, a sepsis screen (blood, urine and cerebrospinal fluid (CSF)), metabolic screen (e.g. alpha1-antitrypsin phenotype testing) and sweat test, and in older children a toxic screen and autoantibodies. These results help to determine the most appropriate imaging.

Alpha 1-antitrypsin activity is markedly decreased in Wegener’s granulomatosis

Alpha 1-antitrypsin (A1AT) is the most abundant proteinase inhibitor in plasma and the main inhibitor of Proteinase 3, the target antigen of antineutrophil cytoplasmic antibodies (ANCAs) that predominant in Wegeners' granulomatosis. Α1AT deficiency correlated with ANCA-associated vasculitis. This study explores the trypsin inhibitory capacity (TIC), specific activity, and phenotypic deficiency of Α1AT in Wegener's granulomatosis. Twenty-seven WG patients were studied. ANCA was tested by IIF and ELISA. Serum a1-anti-trypsin levels were quantified in WG patients and healthy controls by immunoturbidimetric assay. Serum TIC was assessed by the enzymatic colorimetric assay. Phenotypes of A1AT were detected by Isoelectric Focusing. A1AT concentration was equivalent in patients and controls; however, serum TIC (P = 0.001) and specific activity of A1AT (P = 0.001) were dramatically lower in WG patients. Five patients had deficient phenotypes of A1AT: MZ (n = 3), MS (n = 1) and SS (n = 1). This was correlated with an increase in the prevalence of deficient phenotypes of A1AT in WG (P = 0.01). Trypsin inhibitory capacity and specific activity of A1AT were decreased in WG patients and may be involve in disease pathogenesis and can worsen the clinical manifestations. This A1AT deficiency probably resulted from oxidative inactivation and/or enzymatic degradation of A1AT. This could result in localized deficiency of A1AT in vessel wall interfaces and lead to severe disease.

Prevalence of an Abnormal Alpha-1 Antitrypsin Phenotype in a Rural Community in Southwest Missouri

SESSION TYPE: COPD Posters I

Alpha-1 antitrypsin deficiency in patients with chronic hepatitis

Alpha-1 antitrypsin deficiency causes accumulation of mutant alpha-1 antitrypsin molecules in hepatocytes, and is attributed to severe liver injury even in heterozygous state. However, there is a question as to whether alpha-1 antitrypsin deficiency is only a cause of liver injury or has a worsening effect on the underlying liver disease. We aimed to determine the role of alpha-1 antitrypsin deficiency in the ongoing chronic hepatitic process. Fifty-four patients with the diagnosis of chronic hepatitis by liver biopsy (36 chronic hepatitis B virus, 8 chronic hepatitis C virus, 7 non-alcoholic steatohepatitis, 2 primary biliary cirrhosis, and 1 autoimmune hepatitis) and 51 age- and sex-matched control subjects chosen from among healthy blood donors were included in the study. Isoelectric focusing for identifying alpha-1 antitrypsin phenotypes was performed in all patients and control subjects, whereas the histopathological examination was done only in patients. Alpha-1 antitrypsin-deficient variant was absent in patients and controls. The mean serum alpha-1 antitrypsin level was significantly lower in patients (157.4 ± 33 mg/dl) than controls (134.8 ± 30 mg/dl) (p<0.00). Histological activity index and fibrosis grade in the liver were not related to the serum alpha-1 antitrypsin level (p: 0.276 and 0.902, respectively). Additionally, the serum alpha-1 antitrypsin levels among normal variants of alpha-1 antitrypsin did not differ according to the underlying liver diseases (p: 0.928). This prospective case-control study could not define any additional effect of alpha-1 antitrypsin deficiency on liver histopathology in chronic hepatitis patients.

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.

Role of Alpha-1 Antitrypsin (AAT) in Ocular Allergy and Uveitis

Ocular allergy and uveitis are varied groups of inflammatory eye disorders characterized by complex and as yet ill-defined pathogeneses. Alpha-1 antitrypsin (AAT) is the archetype of the serine protease inhibitor supergene family. AAT deficiency is one of many factors that may be involved in abnormalities such as liver and lung disease, inflammatory joint diseases, and inflammatory eye diseases. In the present review, the role played by AAT in ocular inflammation is analyzed, particularly in vernal keratoconjunctivitis (VKC) and uveitis. Tear trypsin inhibitory capacity was shown to be reduced in VKC patients. In uveitis patients, a significant difference in AAT phenotypes was found compared to normal subjects. We propose that a reduced inhibitory capacity of ATT and AAT might facilitate or prolong different types of ocular inflammation. Keywords: Ocular allergy, uveitis, alpha-1-antitrypsin deficiency, vernal keratoconjunctivitis, HLA-B27 typing.

Alpha-1 Antitrypsin Deficient Squamous Cell Carcinoma of Esophagus in the Azeri Population of Iran

Background: Alpha-1 antitrypsin (AAT) deficiency is an inherited disease characterized by reduced levels of AAT in the serum. The 2 common genotypes of AAT deficiency are type Z (PiZ) and type S (PiS), which are associated with several malignancies. Methods: We assessed the AAT phenotype as well as genotypes Z and S in squamous cell carcinoma of the esophagus (SCCE) and their association with malignancy in Azeri patients of Iran. Alpha-1 antitrypsin phenotype identification was done using isoelectric focusing (IEF); its genotype was identified by RFLP. Results: The results indicated that the mean range of trypsin inhibitory capacity (TIC) and AAT nephlometry are significantly different in patients (P<0.05). In addition, while AAT levels are higher in the serum of patients they are not functional. This accounts for further dysfunction and reduction of its proper protease inhibitory activity in patients when compared with the healthy controls. Moreover, 97.3% of SCCE patients were homozygote for MM (PiMM), and only 2.7% were MS heterozygous. Neither of the PiZ and PiS genotypes were identified in the patients (P<0.05). Conclusion: Alpha-1 antitrypsin is a suitable prognostic rather than early stages diagnostic tumor marker in SCCE as its correlation with the disease could significantly be seen in the advanced stages of the esophageal tumorigenesis. As a tumor marker, AAT is highly sensitive but less tissue specific, thus its application is useful in combination with a panel of tumor markers in SCCE diagnosis, treatment, and follow up.