PiZZ Phenotype Research Articles

Характеристика захворювань у дітей при спадковому дефіциті альфа 1-антитрипсину

The article presents the current views on genetics, features of metabolic disorders, course of various clinical manifestations, diagnostic criteria, and treatment principles for monogenic enzymopathy — an inherited α1;antitrypsin (AAT) deficiency. Inherited AAT deficiency manifests itself as four clinical syndromes: respiratory disease (pulmonary emphysema, chronic obstructive pulmonary disease (COPD), bronchial asthma, spontaneous pneumothorax, bronchiectasis); liver disease and blood vessel damage. Respiratory disease manifests itself between the ages of 20–40 years. Chronic pulmonary emphysema is typical for homozygous PiZZ gene carriers. The most unfavorable clinical course variant including persistent cough, COPD development, bronchial asthma, pneumonia, co-existence of various respiratory diseases and severe disorders of external respiration is the PISZ phenotype. Bronchial asthma has severe clinical course with torpid purulent endobronchitis; is often uncontrolled despite background therapy. In COPD patients, exacerbations are frequent, severe, and prolonged. The reduction in the vessels of the pulmonary circulation results in pulmonary hypertension, right ventricular failure. In AAT deficiency, there is a high incidence of bronchiectasis, lung cancer. Liver diseases manifest themselves as neonatal hepatitis, biliary atresia, liver cirrhosis, infectious complications. Chronic form is characterized by subclinical changes in the biochemical parameters of liver function most of which (up to 70%) normalize before the age of 18 years. In patients until the age of 20 years, disease slowly progresses and leads to the development of liver cirrhosis in 30% of cases, while older patients develop liver cirrhosis in 30–50% of cases. Some patients have a benign course of liver disease and present with hepatomegaly. Hemorrhagic syndrome occurs when protease inhibitor gene product acquires the properties of antithrombin. Vascular disease manifests itself as necrotizing panniculitis, severe hemorrhagic vasculitis with serum antineutrophil cytoplasmic antibodies to proteinase (С-АNСА). AAT deficiency may coexist with systemic vasculitis, vascular aneurysm, many other diseases, as well as with the development of aplastic processes of various localization. In addition to clinical manifestations, diagnosis of inherited AAT deficiency includes screening programs, instrumental (X-ray, spirometry, ECG, ultrasound), laboratory (liver function, coagulation profile, immunogram, serum AAT concentration), genetic investigations, exclusion testing for cystic fibrosis, viral hepatitis, and other diseases. Treatment of patients with inherited AAT deficiency consists in adequate nutrition and physical activity; treatment of pre-existing conditions; prevention and timely therapy for respiratory infections; pathogenetic therapy. Pathogenetic therapy for AAT deficiency is a replacement (augmentation) therapy with exogenous α1-antitrypsin concentrate. Replacement therapy is indicated only in patients >18 years of age with the PiZZ phenotype or other rare AAT phenotypes. No conflict of interest was declared by the author. Key words: children, inherited α1-antitrypsin deficiency, diagnosis, therapy.

Liver disease in adults with severe alpha-1-antitrypsin deficiency

BackgroundThe proportion of adults with liver disease due to severe alpha-1-antitrypsin deficiency (AATD), with PiZZ phenotype, is not clear. The markers of the AATD liver disease, how it progresses, and measures for its prevention have not been established. The aim of this study was to analyze the risk of liver disease in individuals with severe AAT deficiency (PiZZ).MethodsLongitudinal clinical and laboratory data were obtained from the Swedish National registers, by cross-linkage between the Swedish national AATD register, the Swedish National Patient Register, the National Cancer Register and the National Causes of Death Register.ResultsA total of 1595 PiZZ individuals were included in the analyses. The mean follow-up time was 12 years (range 0.3–24). The mean number of follow-ups was 5 (range 2–15). Two or more liver function tests (LFTs) were available in 1123 individuals, and 26% of them (n = 290) had repeated elevated LFTs during the follow-up. The prevalence of any liver disease was 10% (n = 155). Liver cirrhosis was found in 7% of the individuals (n = 116) and hepatocellular carcinoma in 2% (n = 29). The mean age at the onset of liver disease was 61 (SD 15) years. In multivariate analyses, the male gender, age over 50 years, repeated elevated LFTs, hepatitis virus infection, and a diagnosis of diabetes were associated with increased risk of developing liver disease in adulthood (p < 0.01).ConclusionThe prevalence of liver disease in adult PiZZ individuals is 10%. Age over 50 years, the male gender, repeated elevated liver enzymes, hepatitis, and the presence of diabetes mellitus are risk factors for developing liver disease.

Alpha-1 antitrypsin deficiency panniculitis: clinical and pathologic characteristics of 10 cases.

Alpha-1 antitrypsin deficiency (AATD) may be associated with liver and lung disease and rarely causes panniculitis. We evaluated the clinicopathologic and laboratory findings of AATD panniculitis in 10 patients. We conducted a retrospective review of all cases of AATD panniculitis at Mayo Clinic, Rochester, MN, from 1989 to 2016. Ten patients with AATD panniculitis were included. Seven of ten were women. Clinical lesions were most commonly nodular (100%), erythematous (90%), ulcerated (90%), and painful (90%) subcutaneous nodules and plaques. Extracutaneous associations were rare. PiZZ phenotype was most commonly identified (50%). Histopathologically, lobular panniculitis (80%) with associated septal involvement (60%) and a predominant neutrophilic infiltrate (100%) were most common. Treatments varied; dapsone and alpha-1 proteinase inhibitor infusions were each used in five (50%) patients, respectively. In patients with greater than 6-month follow-up (n = 4), one patient continued to have disease activity despite treatment. AATD panniculitis should be considered in the differential for a painful, ulcerative panniculitis with a predominantly neutrophilic histopathologic infiltrate. Diagnosis can be made with clinicopathologic correlation and genetic and laboratory evaluations. Serum AAT level and phenotype assists in diagnosing patients with suspected AATD panniculitis.

Autophagy in Hepatocytes in Infants With Alpha-1 ATD and Different Liver Disease Outcomes: A Retrospective Analysis.

It is unclear whether a distinct activity of pathways removing the antitrypsin (AT) protein in Alpha-1-Antitrypsin Deficiency (α1ATD) are associated with an unfavorable predisposition to liver disease in the future. The aim of this study was to determine whether liverspecific activity of AT protein disposal occurs at infancy in α1ATD with PiZZ phenotype (ATZ). Liver samples of 17 infants with unfavorable ATZ outcome (Group I, n = 8, median age = 0.35 year) and good outcome (Group II, n = 9, 0.17 year), and 9 with biliary atresia (BA, median age = 0.17 year) as control, were enrolled. For each subject were investigated autophagy activity by mRNA, protein expression (Calnexin, Beclin-1, p62, and Parkin), and hepatocyte ultrastructure with morphometric analyses. No significant differences in gene expression in the liver of infants were found between the 2 ATZ groups. Although a correlation between patients' age and protein expression was observed, the ATZ groups differed Parkin immunohistochemical expression. Moreover, the hepatocytes in ATZ infants with unfavorable outcome were characterized by low Parkin expression and the presence of isolated mitophagosoms and numerous enlarged mitochondria. The mentioned findings differed in patients with BA. Thus, mentioned specific features occurring at infancy may suggest association with poor liver outcome. Parkin low expression could have a potential for disease prognosis and treatment; however, further studies in a greater number of patients are needed.

Liver Involvement in Patients With PiZZ-Emphysema, Candidates for Lung Transplantation.

Information about the prevalence and nature of liver disorders in adults with alpha1-antitrypsin deficiency is scarce. At our center, systematic liver biopsy screening is part of the evaluation before lung transplantation (LT) in the emphysema patients with the PiZZ phenotype. Our aim was to report our experience with this prospective screening. Clinical, liver function, and imaging parameters as well as liver histology data were analyzed for 23 consecutive adult patients with PiZZ severe emphysema referred to our center for consideration of LT from 2006 to 2014. Overall 20 (87%) featured chronic liver disease characterized by a chronic inflammation and/or a significant portal fibrosis on histology. Two of the 23 patients (8.7%) had septal fibrosis according to the Metavir and Ishak scores and met our definition of severe chronic liver disease. They were both clinically asymptomatic with normal liver function tests. On abdominal ultrasonography, the liver appeared normal in one patient and with abnormal contours in the other. Our data indicate that in adults with PiZZ-related emphysema being evaluated for LT, most patients had some histologic involvement. The prevalence of severe liver dysfunction is <10%.

PECULIARITIES OF EXTERNAL RESPIRATION FUNCTION IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITH DEFICIT OF ALPHA-1-ANTITRYPSIN

Chronic obstructive pulmonary disease (COPD) is one of the leading reasons of mortality in the whole world. The insufficiency of alpha-1-antitrypsin (А1АТ) protein is an important factor of genetic predisposition to COPD development. А1АТ deficit can be diagnosed with the help of phenotyping. Detection of PiZZ phenotype of А1АТ preconditions 95% of А1АТ deficit cases whereas PiMM phenotype testifies about the conservation function of the protein. Detection of A1AT in case of COPD might be accompanied by a graver course of the diseases, it is characterized by peculiarities of complex study parameters of the external respiratory function and densitometric values of the pulmonary tissue determined by computer tomography. The objective of this study is comparison of external respiratory function in COPD patients with PiZZ and PiMM phenotype of А1АТ. Materials and methods: COPD patients with PiZZ phenotype of А1АТ (N = 6) and PiMM phenotype of A1AT (N = 75) were studies. The following spirometric values were evaluate: forced expiratory volume per 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, maximum expiratory flow rate (MEFR), peak flow rates (PFR50 and PFR75), mean flow rate (MFR), as well as the total lung capacity (TLC) etc. Spiral computer tomography was performed with application of the densitometric analysis software. Evaluation of the intensity of dyspnoe and effect of symptoms on the quality of life was done. Results. Comparison of spirometric values showed that for patients at PiZZ phenotype of А1АТ showed lower values of FEV1/ FVC, PFR50, PFR75, MFR, DLco, va and higher parameters of MEFR, FVC and TLC than in PiMM phenotype of А1АТ (p < 0,05*). Conclusions: in COPD patients with PiZZ phenotype of А1АТ more intense deviations of bronchial obstruction, reduction of elastic properties of the pulmonary tissues, hyperinflation, reduction of the capillary bed due to emphysematous pulmonary involvement are observed.

Cholestasis in the newborn and infant

Neonatal cholestasis occurs in approximately 1 in 2500 term infants, the most common underlying disease being biliary atresia, viral infections and α1-antitrypsin deficiency. The incidence of cholestasis is much higher in extremely premature newborns. The etiology of biliary atresia remains unclear, which in turn makes the search for additional treatments to surgery challenging. Reliable non-invasive tools to differentiate biliary atresia from other forms of neonatal cholestasis need to be further investigated. Despite important findings in the last decades, the pathogenesis of cholestatic liver disease in α1-antitrypsin deficiency remains to be clarified. Any such explanation would also need to explain why only a minority of individuals with PiZZ phenotype develop liver disease. For other genetic diseases causing neonatal cholestasis, such as Alagille's syndrome and progressive familial intrahepatic cholestasis the breakthrough within the field of molecular biology has definitely deepened our understanding of both etiology and pathogenesis. However, the correlation between genotype and phenotype is rarely obvious and for several patients with the seemingly correct phenotype no known genetic mutation is detected. A stepwise approach to the management of cholestasis in the newborn and infant is suggested, where percutaneous liver biopsy is of value to select patients with suspected biliary atresia for laparotomy.

Increased Outer Arm and Core Fucose Residues on the N-Glycans of Mutated Alpha-1 Antitrypsin Protein from Alpha-1 Antitrypsin Deficient Individuals

Alpha-1 antitrypsin (AAT) is the major physiological inhibitor of a range of serine proteases, and in the lung, it maintains a protease-antiprotease balance. AAT deficiency (AATD) is an autosomal co-dominant condition with the Z mutation being the most common cause. Individuals homozygous for Z (PiZZ) have low levels of circulating mutant Z-AAT protein leading to premature emphysematous lung disease. Extensive glycoanalysis has been performed on normal AAT (M-AAT) from healthy individuals and the importance of glycosylation in affecting the immune modulatory roles of AAT is documented. However, no glycoanalysis has been carried out on Z-AAT from deficient individuals to date. In this study, we investigate whether the glycans present on Z-AAT differ to those found on M-AAT from healthy controls. Plasma AAT was purified from 10 individuals: 5 AATD donors with the PiZZ phenotype and 5 PiMM healthy controls. Glycoanalysis was performed employing N-glycan release, exoglycosidase digestion and UPLC analysis. No difference in branched glycans was identified between AATD and healthy controls. However, a significant increase in both outer arm (α1-3) (p = 0.04) and core (α1-6) fucosylated glycans (p < 0.0001) was found on Z-AAT compared to M-AAT. This study has identified increased fucosylation on N-glycans of Z-AAT indicative of ongoing inflammation in AATD individuals with implications for early therapeutic intervention.

S76 Proteinase 3 activity in sputum from alpha-1-antitrypsin deficient subjects

IntroductionTissue destruction in emphysema is widely believed to result from an imbalance between serine proteinases and their inhibitors, the antiproteinases. Previous work has studied the role of neutrophil elastase (NE),...

Factors Associated With the Evolution of Lung Function in Patients With Alpha-1 Antitrypsin Deficiency in the Spanish Registry

Introduction The present study intends to describe the characteristics of patients diagnosed with severe alpha-1 antitrypsin deficiency (AATD) in Spain, to observe the rate of decline in forced expiratory volume in 1 s (FEV1) with and without substitutive therapy, and to identify factors associated with a rapid rate of decline in FEV1. Method A retrospective study of the evolution of individuals with AATD was carried out based on data collected from the Spanish registry. The primary response variable was the annual rate of decline in FEV1, calculated using the baseline and last postbronchodilator FEV1 values in an endpoint analysis. Results Three hundred and three patients with severe AATD and Pi ZZ phenotype were identified. Follow-up spirometric data were collected for 117 subjects. Being a smoker or ex-smoker vs never smoker (odds ratio [OR]=10.31; 95% confidence interval (CI)=1.8–58.8; P=.008) and having a higher baseline postbronchodilator FEV1 (% predicted) (OR=1.03; 95% CI=1.005–1.06; P=.018) were independently associated with a more rapid rate of decline in FEV1. There was also a trend towards a relationship between low body mass index (BMI) and a greater rate of deterioration in lung function (OR=1.14; 95% CI=0.98–1.33; P=.085). Conclusion Being a smoker or ex-smoker, greater baseline lung function, and low BMI were the main risk factors associated with an accelerated rate of decline in FEV1. This finding warrants the close observation of younger patients with a better-preserved FEV1.

Factores asociados a la evolución de la función pulmonar en pacientes con déficit de alfa-1-antitripsina del registro español

Introduction The present study intends to describe the characteristics of patients diagnosed with severe alpha-1 antitrypsin deficiency (AATD) in Spain, to observe the rate of decline in forced expiratory volume in 1 second (FEV1) with and without substitutive therapy, and to identify factors associated with a rapid rate of decline in FEV1. Method A retrospective study of the evolution of individuals with AATD was carried out based on data collected from the Spanish registry. The primary response variable was the annual rate of decline in FEV1, calculated using the baseline and last postbronchodilator FEV1 values in an endpoint analysis. Results 303 patients with severe AATD and Pi ZZ phenotype were identified. Follow-up spirometric data were collected for 117 subjects. Being a smoker or ex-smoker versus never smoker (odds ratio [OR] = 10.31; 95% confidence interval (CI) = 1.8-58.8; p = 0.008) and having a higher baseline postbronchodilator FEV1 (% predicted) (OR = 1.03; 95% CI = 1.005-1.06; p = 0.018) were independently associated with a more rapid rate of decline in FEV1. There was also a trend towards a relationship between low body mass index (BMI) and a greater rate of deterioration in lung function (OR = 1.14; 95% CI = 0.98-1.33; p = 0.085). Conclusion Being a smoker or ex-smoker, greater baseline lung function, and low BMI were the main risk factors associated with an accelerated rate of decline in FEV1. This finding warrants the close observation of younger patients with a better-preserved FEV1.

Severe ulcerative panniculitis caused by alpha 1-antitrypsin deficiency: Remission induced and maintained with intravenous alpha 1-antitrypsin

To the Editor: Panniculitis caused by homozygosity of ZZ alpha 1-antitrypsin (A1AT) deficiency is extremely rare despite the relatively common presence of ZZ phenotype affecting approximately 1 in 3500 people among whites in Western Europe. This phenotype deficiency can be associated with emphysema (greatly enhanced by smoking), hepatic cirrhosis, hepatitis, and angioedema.1 We present a case of a boy who developed extremely tender and debilitating recalcitrant panniculitis secondary to PiZZ phenotype A1AT deficiency requiring regular intravenous infusions of A1AT enzymes (Prolastin; Talecris Biotherapeutics, Research Triangle Park, NC) to maintain remission.

Traitement substitutif par alpha-1 antitrypsine : suivi sur 20 ans d’un patient déficitaire: Cas du 1er patient traité en France

Alpha one antitrypsin deficiency is a rare genetic disorder occurring principally in patients with the PiZZ phenotype. This deficiency can lead to pulmonary emphysema which impairs quality of life and which may progress to respiratory failure. The diagnosis is based on the presence of emphysema typically with a basal preponderance and airflow obstruction and is confirmed by measuring A1AT levels. A1AT replacement is the only specific therapy for this condition.We describe the 1st patient with A1AT deficiency treated in this way in France. The patient was 52 years old at the start of treatment with A1AT replacement, initially in hospital and then at their place of residence. Treatment was initiated in the context of progressive breathlessness, the presence of emphysema and confirmation of the biochemical deficit. The patient received 4 g of AIAT per week in combination with inhaled corticosteroids and ongoing physical rehabilitation. Follow up over 20 years has revealed a slowing in the decline in spirometric measurements. No problems with tolerating the treatment have been reported.In this clinical case replacement therapy appeared to show clinical benefits and was well tolerated.

LIVER TRANSPLANTATION IN A LUNG TRANSPLANT RECIPIENT FOR ALPHA-1-ANTITRYPSIN DEFICIENCY

INTRODUCTION:Alpha-1 antitrypsin is a protein with inhibitory capability over the proteolytic enzyme elastase. Since its first description in 1963, over 100 different AAT alleles have been described, each producing a different phenotypic variant of AAT. The most severe form of deficiency is the homozygous expression of the Z allele or PI*ZZ. When this expression occurs, it accounts for 95% of cases of severe AAT deficiency. The three organs most commonly affected by AATD are the lungs, liver and skin. Alpha-1 antitrypsin deficiency (AATD) is the most frequently recognized genetic risk factor for chronic obstructive pulmonary disease (COPD). Even though it remains underdiagnosed, its importance continues to grow in the field of solid organ transplantation, accounting for 8-9% of all lung transplants. Individuals with the PiZZ phenotype are also at risk of hepatitis as neonates and cirrhosis as adults. AATD is the most common metabolic liver disease requiring liver transplantation in children. However, in a recent population study, with self-report questionnaires, the prevalence of liver disease was 7.6% (165/2175), and severe liver disease was 1.8% (40/2175) among the participants of the Alpha-1 Foundation Registry. Furthermore, a mortality analysis found that liver disease was included as a cause of death in 21% of death certificates listing AAT deficiency, and autopsy studies have shown cirrhosis in 37% of patients with AAT. We describe a unique case of a 59 year-old woman with severe AATD who required single lung transplant and then 5 years later developed AATD cirrhosis requiring sequential liver transplantation.

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

Alpha-1 antitrypsin (alpha1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous alpha1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The alpha1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic alpha1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P = 0.0003) and hydroxyproline (P = 0.007) than wild-type mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P = 0.02, P = 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in alpha1-AT deficiency, and the alpha1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.

ALPHA-1 ANTITRYPSIN PHENOTYPE AND GENOTYPE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

PURPOSE: Alpha-1 Antitrypsin (AAT) deficiency is one common lethal genetic cause of emphysema in adults. The World Health Organization (WHO) recommends detection of AAT level in patients with Chronic Obstructive Pulmonary Disease (COPD) and Asthma. The abnormally low plasma concentrations of AAT in individuals predisposes them to elevated risk of early pulmonary emphysema and in some occasions hepatic damage. The PiZZ phenotype is the most frequently associated with low plasma concentrations of AAT.However much of this data comes from fully developed regions such as North America and Europe.

Variable Degree of Liver Involvement in Siblings With PiZZ Alpha‐1‐Antitrypsin Deficiency‐related Liver Disease

PiZZ alpha-1-antitrypsin deficiency is the commonest genetic cause of chronic liver disease, but only 10-15% of PiZZ individuals develop liver disease in childhood. Studies have demonstrated varying patterns of disease progression within siblings with the PiZZ phenotype. We retrospectively analysed the case-notes of all patients diagnosed with PiZZ A1ATD between 1978-2002 and compared the pattern of liver disease between affected siblings. We identified 29 families with more than 1 child with the PiZZ phenotype. Twenty-one (72%) PiZZ siblings of the 29 probands had liver disease, which was concordant for severity in 6 (29%), while 8 (28%) had no liver involvement. Five of 7 children requiring liver transplantation had siblings with no persistent liver dysfunction. This study suggests that there is a variable degree of liver involvement in siblings with PiZZ A1ATD-related liver disease and environmental and/or other genetic factors must be involved in determining disease severity.

EXPERIENCE WITH ALPHA -1 ANTITRYPSIN DEFICIENCY FOLLOWING LIVER TRANSPLANTATION

Purpose: Alpha-1 Antitrypsin Deficiency is an inborn metabolic disorder with different clinical presentations starting usually at childhood or adulthood. Single liver transplant center's experience with presentation, complication and survival rates following orthotopic livertransplantation is retrospectively reviewed Methods: From 1994 to 2003,10 patients with preoperative diagnosis of A1AT Deficiency have undergone orthotopic liver transplantation at Nazih Zuhdi Transplant Institute, INTEGRIS Baptist Medical Center in Oklahoma City, OK. Five patients were males, 5 were females, Mean age was 42 where ages ranged from 2 to 61 years. There were total of 2 pediatric cases; a 2-year-old girl with PiZZ phenotype and a 16 year-old boy with PiMZ phenotype. They were both referred with initial diagnosis of A1AT Deficiency. Most adult patients were initially referred for transplantation with diagnosis of cryptogenic cirrhosis. During the pre-transplant work up, PiMZ pheno-types were detected. None of the patients had evidence of pulmonary disease upon initial presentation. Results: The Mean MELD score was 21.2 with a range of 7 to 34. Ascites was present in all cases before transplantation. Mean platelets count was 75000, signifying portal hypertension. The 16-year-old boy needed a second orthotopic liver transplant 3 months after his first transplant because of hepatic artery thrombosis. All patients are currently alive. Mean survival is 3.8 years with a range of 4 months to 9 years. In all of the cases, diagnosis of A1AT Deficiency was later confirmed using PAS staining of the liver tissue obtained from the explanted organ. Conclusions: 1) A1AT Deficiency is often considered as a pediatric disease process. We hereby have reported 8 adult cases with cirrhosis due Alpha-1 Antitrypsin Deficiency. Therefore, this metabolic disorder needs to be diligently searched among adult cirrhotic patients as well, especially in cases that have been previously labeled as cryptogenic cirrhosis. 2) In our center, one year patient and graft survival of such cases is similar to orthotopic liver transplantation due to other factors.

P0214 PHENOTYPIC EXPRESSION OF LIVER DISEASE IN FAMILIES WITH PIZZ ALPHA-1-ANTITRYPSIN DEFICIENCY

Introduction: PiZZ alpha-one-antitrypsin deficiency (A1ATD) is the commonest genetic cause of chronic liver disease leading to liver transplantation in children. The pathogenic mechanism appears to involve abnormal loop sheet polymerisation of the aberrant PiZ alpha-1-antitrypsin and its retention in the hepatocyte endoplasmic reticulum, with consequent progression to chronic inflammation and cirrhosis. Only 10–15% of PiZZ individuals develop clinical symptoms and additional genetic and environmental modifiers have been postulated. Methods: The database of 279 children diagnosed with A1ATD at our centre between 1978–2002 was reviewed to identify families in which there was more than one child with the PiZZ phenotype. A retrospective analysis of their notes was carried out to assess the severity of their liver disease. Results: Forty-two children (24 boys) from twenty-one families were identified, including 2 pairs of monozygotic and 1 pair of dizygotic twins. The children were followed up for a median of 66 months (range, 8–185 months). The patients were divided into the following categories: (A) asymptomatic/family screening –4.8%; (B) no clinical liver disease after neonatal biochemical dysfunction – 30.9%; (C) mild ongoing liver dysfunction – 35.7%; (D) moderate chronic liver disease – 19.1% and (E) end stage liver disease/liver transplant – 9.5%. There were no significant differences in the length of breastfeeding or frequency of infection between the siblings. Only 5/21 sibling pairs (23.8%) were within the same category. Of note, of those children requiring liver transplant 3/4 had siblings within categories A or B. Of the three pairs of twins identified, the twins were in different categories in 2 out of 3. Six out of 12 children in the D and E categories were male. Amongst the families where a child had end stage liver disease (E), 6 sought an antenatal diagnosis. Two of the foetuses were PiZZ and the pregnancies were terminated, the remainder were heterozygotes. Two of the families with moderate chronic liver disease (D) were also tested antenatally: one was a heterozygote and the other a PiZZ foetus was lost as a consequence of a mid-trimester spontaneous abortion. Conclusion: In the relatively small sample of families reviewed, the clinical course of liver disease within siblings with PiZZ A1ATD was highly variable. This observation, if confirmed in a larger sample, is important because antenatal diagnosis of PiZZ A1ATD may not predict the extent of liver involvement in families where one child has been affected by end stage liver disease, as has been previously reported.

Z α1-Antitrypsin Polymerizes in the Lung and Acts as a Neutrophil Chemoattractant

Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs. In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT. Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.