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Received: 27 January 2016 / Accepted: 22 February 2016 / Published online: 25 March 2016 UDC 616.234-002:577.212
ALPHA-1 ANTITRYPSIN DEFICIENCY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Ardak N. Zhumagaliyeva, http://orcid.org/0000-0002-4928-1339
Semey State Medical University, Semey, Kazakhstan, A PhD student on the specialty "Medicine"
Abstrakt
Introduction. Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population.
Chronic obstructive pulmonary disease (COPD) is one of the most essential causes of morbidity and mortality. In 2008, COPD was the fourth leading cause of death in the world, but the number of patients is still increasing and the World Health Organization (WHO) predicts that COPD will get the third most common cause of mortality in 2030.
The Aim. To acquaint the students and specialists of practical healthcare with a genetic disease, deficiency of alpha-1-antitrypsin
Methods. The study of publications on this subject included in the evidentiary basis the Cochrane Library EMBASE and MEDLINE, databases during the last 30 years.
Results. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been associated to an accelerated progression of this condition. AATD is caused by mutations in the SERPINA 1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing, PCR. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage lung disease can be treated by organ transplantation.
Conclusions. Preventive measures, such as smoking cessation, avoiding contact with pollutants, vaccine prevention of infections are measures that reduce the rate of progression of the disease. It is advisable to pre-clinical diagnostic of alpha1 -antitrypsin deficiency that could determine the choice of occupation, place of residence, the lifestyle of an individual.
Keywords: alpha-1 antitrypsin, alpha-1 antitrypsin deficiency, chronic obstructive pulmonary disease, genetics, diagnostics.
Резюме
ДЕФИЦИТ АЛЬФА-1 - АНТИТРИПСИНА И ХРОНИЧЕСКАЯ ОБСТРУКТИВНАЯ БОЛЕЗНЬ ЛЕГКИХ
Ардак Н. Жумагалиева, http://orcid.org/0000-0002-4928-1339
Государственный медицинский университет г.Семей, Казахстан. Докторант PhD по специальности «Медицина»
Введение. Дефицит альфа-1 - антитрипсина (ДААТ) является генетическим заболеванием, проявляется эмфиземой, циррозом печени и в редких случаях как панникулит и характеризуется низким уровнем ААТ в сыворотке, который является основным ингибитором протеазы в сыворотке человека (PI). Распространенность в Западной Европе и в США оценивается примерно в 1: 2500 и 1: 5000 новорожденных, а в значительной степени зависит от скандинавского происхождения населения.
Хроническая обструктивная болезнь легких (ХОБЛ) является одним из наиболее важных причин заболеваемости и смертности. В 2008 году ХОБЛ была по значимости четвертой причиной смерти в мире, но количество больных продолжает расти и Всемирная организация здравоохранения (ВОЗ) прогнозирует, что ХОБЛ будет на третьем месте по наиболее распространенной причиной смертности в 2030 году.
Цель. Ознакомить студентов и специалистов практического здравоохранения с генетическим заболеванием, дефицитом альфа-1-антитрипсина.
Методы. Изучение публикаций по данной теме, вошедших в доказательную базу Кокрановской библиотеки, базы данных EMBASE и MEDLINE. Глубина поиска составляла 30 лет.
Результаты. Наиболее распространенные аллели дефицита в Северной Европе PIZ и PIS, и большинство людей с тяжелым ДААТ типа PIZZ. ДААТ ZZ и SZ являются факторами риска развития респираторных симптомов (одышки, кашля), раннего начало эмфиземы и обструкции дыхательных путей у взрослых. Экологические факторы, такие как курение, и воздействие пыли являются дополнительными факторами риска и связаны с ускорением прогрессирования данного заболевания. ДААТ вызывается мутациями в гене SERPINA1 кодирующих ААТ, и наследуется по аутосомно-рецессивному признаку. Диагноз может быть установлен при обнаружении низкого уровня сывороточного ААТ и методами ПЦР и изоэлектрофокусирования. Для лечения болезни легких внутривенно вводят заместительную терапию альфа1 -антитрипсином, рекомендуется ежегодная вакцинация против гриппа и пневмококковая вакцина, каждые 5 лет. Одышка уменьшается назначением бронходилататоров длительного действия и ингаляционных кортикостреоидов. Трансплантация легких применяется в конечной стадии заболевания.
Выводы. Профилактические мероприятия, такие как отказ от курения, исключение контактов с поллютантами, вакцинопрофилактика инфекции являются мерами, уменьшающими темпы прогрессирования заболевания. Желательна доклиническая диагностика серпинопатии, что могло бы определять выбор профессии, место жительства, образ жизни индивидуума.
Ключевые слова: альфа-1-антитрипсина, дефицит альфа-1-антитрипсина, хроническая обструктивная болезнь легких, генетика, диагностика.
ТYЙiндеме
АЛЬФА-1 - АНТИТРИПСИН ТАПШЫЛЫГ Ы ЖЭНЕ еКПЕШН СОЗЫЛМАЛЫ ОБСТРУКТИВТ1 АУРУЫ
Ардак Н. Жумагалиева, http://orcid.org/0000-0002-4928-1339
Семей каласыньщ мемлекетлк медицина университет^ Семей, Казакстан. «Медицина» мамандыгы бойынша PhD докторанты.
К1р1спе. Альфа-1-антитрипсин тапшылыгы (AAT^ генетикалык; ауру болып табылады, екпе эмфиземасы, бауыр циррозы, панникулит тYрiнде байкалады жэне сарысудагыпротеаз ингибиторы болып саналатын AAT децгейшН теменде^мен сипатталады. Батыс Еуропада жэне А^Ш-та аурудыц таралуы шамамен 1: 2500 и 1: 5000 жаца туган нэрестеге багаланады жэне кебшесе скандинавиядан шыгу тепмен байланысты.
ЭкпенН созылмалы обструктивт ауруы (0СОА) аурушацды; пен ел1м-жтмнН мацызды себебi болып табылады. 2008 жылы ЭСОА элемде ел1м-жтмнН тертiншi себебi болды, бiрак
наукастар саны есуде, ДYниежYзiлiк денсаулык сактау уйымыныц (ДД¥) болжамы бойынша, 2030 жылы ЭСОА елiм-жmмнiц Yшiншi себебi болады деп кYтiлуде.
Максаты. Студенттер мен практикалык денсаулык сактау мамандары осы генетикалык альфа1-антитрипсин тапшылыгымен таныстыру.
Эдiстер. Бул жумыстыц дэлелдемелер базасы Кокрандык ютапхананыц, EMBASE жэне MEDLINE мэлiметтер базасына осы такырып бойынша жарияланымдар зерттеу болып табылады. 1здеу терецдт 30 жыл.
Нэтижелерк СолтYCтiк Еуропада барынша кец таралган PI Z жэне PI S аллельдерi жэне кептеген адамдарда ауыр ААТТ PI ZZ тYрi байкалады. ZZ жэне SZ ААТТ респираторлык белгi (ентiгу, жетел), ересектереде эмфиземаныц, тыныс жолдары обструкциясыныц ерте дамуыныц катер факторлары болып табылады. Шылым шегу, жэне шац-тозац сиякты коршаган орта факторлары косымша катер факторлары болып табылады жэне аурудыц YДеуiне Yлес косады. ААТТ ААТ кодтайтын SERPINA 1 гендегi мутациянэтижесiнде туындайды жэне аутосомды-рецессивтi белгi бойынша бершедк Диагноз сарысудагы ААТ темен децгей жэне изоэлектрлiк фокустеу, ПТР эдiсi бойынша аныкталады. Экпе ауруларын кектамырiшiлiк альфа1-антитрипсинмен орнын толтыру емiн жYргiзу аркылыемдеудi жэне эрбiр 5 жыл сайын пневмококк карсы вакцина, жыл сайын тумауга карсы вакцина егудi усынады. Ентiгудi бэсецдету узак эсер ететiн бронх кецейткiштерi жэне ингаляциялык кортикостероидтар аркылы жYзеге асады. Экпе трансплантациясы аурудыц соцгы сатысында колданылады.
Корытынды. Шылым шегуден бас тарту, поллютанттармен байланысты болдырмау, алдын-ала вакцина егу ауру YДеуiн баялатудыц шаралары болып табылады.
Альфа-1-антитрипсин тапшылыгыныц клиникага дейiнгi нактамалауы адамныц кэсiп, тургылыкты жерi, емiр салтын тацдауын аныктайды.
Heri3ri сездер: альфа-1-антитрипсин, альфа-1-антитрипсин тапшылыгы, екпенiц созылмалы обструктивтi ауруы, генетика, диагностика.
Библиографическая ссылка:
Жумагалиева А. Н. Санитарно-эпидемиологическая характеристика медицинских отходов лечебно-профилактических учреждений города Семей / / Наука и Здравоохранение. 2016. №1. С. 127-131.
Zhumagaliyeva A. N. Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease. Nauka i Zdravookhranenie [Science & Healthcare]. 2016, 1, pp. 127-131.
Жумагалиева А. Н. Альфа-1 - Антитрипсин тапшылыгы жэне екпенщ созылмалы обструктивт1 ауруы / / Гылым жэне Денсаулык сактау. 2016. №1. Б. 127-131.
Chronic obstructive pulmonary disease.
Hundreds of millions worldwide suffer from asthma and chronic obstructive pulmonary disease (COPD) alone [6, 58]. One half of those who die prematurely from non-communicable diseases are in their productive years and the social costs and economic consequences in terms of lost productivity are considerable [67]. In 2010, COPD alone was estimated to have cost the global economy $400 billion [33].
In Kazakhstan, the number of patients with COPD has increased more than twofold in the last 10 years, constituting 321patients out of 100 thousand people in 2011. To compare, one of the most common diseases, diabetes is found 158.3 people per 100 thousand [38].
Chronic obstructive pulmonary disease (COPD) is defined as airflow obstruction that is not fully reversible. It results from abnormal inflammation following exposure to noxious particles or gases [48]. This is typically exposure to cigarette smoke but may also include exposure to biomass fuels and some industrial dusts. COPD clusters within families, suggesting that heritable factors play a role in the pathogenesis of this disease [1, 57]. The only genetic factor that is widely accepted to be associated with COPD is severe deficiency of ai-antitrypsin [32, 42].
Objective. Conducting a search of literature on the study of the pathogenesis, clinical manifestations, epidemiology and treatment of
alpha1 -antitrypsin deficiency in patients with chronic obstructive pulmonary disease
Methods. To achieve this goal was performed a systematic search of literature in the online resource. Were found 300 sources, including for analysis were selected - 68. Key points of forming search queries for the formation of the literature review were presented to the following elements: "alphal -antitrypsin", "alphal -antitrypsin deficiency", "genetics", "chronic obstructive pulmonary disease".
Criteria for inclusion in the review of publications:
• Publications in the last 30 years;
• Publications indexed in the MEDLINE database, EMBASE;
• Publications with clearly formulated and statistically proven conclusions.
• Publications in English languages;
Exclusion criteria in the review of publications:
• Newspaper publications;
• unpublished observations;
• Summary reports.
Results and discussion
Structure and function of ai - antitrypsin
Alpha 1 - Antitrypsin (AAT) is a 52-kDa glycoprotein produced by hepatocytes and, to a lesser extent, by mononuclear monocytes whose main role is to effectively inhibit neutrophil elastase [13]. It is synthesised by hepatocytes [14, 28] and secreted into the plasma at a concentration of 1.9-3.5 mg/ml.It is also synthesised by and secreted from macrophages [13] and intestinal [36] and bronchial epithelial cells [16, 45]. The protein was initially named because of its ability to inhibit pancreatic trypsin [54]. Subsequently it has been detected to be an effective inhibitor of a variety of other proteinases including neutrophil elastase, [49] cathepsin G, [52] and proteinase 3 [26]. The broad spectrum of proteinase inhibition gave increase to its alternative name of a1-proteinase inhibitor, [26] although this too is inaccurate as other proteins in the a1 band of serum (such as a1-antichymotrypsin) are also proteinase inhibitors. Crystal structures have shown that AAT is composed of three p-sheets (A-C) and an exposed mobile reactive loop that presents a peptide sequence as a pseudosubstrate for thetarget proteinase [39,50]. The AAT gene
spans 12.2 kb in length and has three non-coding (IA, IB, IC) and four coding (II, III, IV, V) exons; exon V includes the sequence coding for the reactive site of the AAT protein (Met358-Ser359). There is a close genetic linkage between the AAT and AACT genes, and it is likely that the two loci differentiated relatively recently (100-250 million years ago) [59, 60].
ai-antitrypsin (AAT) deficiency Alpha-1 antitrypsin (AAT) deficiency is a hereditary disorder first reported in the early 1960s when emphysema was described in patients with low plasma levels of AAT protein [4, 10, 13].The condition is related with substantially increased risk for the development of pulmonary emphysema by the third or fourth decades of life and is also associated with risks for development of hepatic disease [34], cutaneous panniculitis [25], bronchiectasis [37], vasculitis [40], Wegener's granulomatosis [7], and lung cancer [68]. AAT deficiency is characterized by misfolding of the AAT protein and belongs to a class of genetic diseases termed conformational disorders [18, 27].
The SERPINA1 gene is high pleomorphic with over 100 alleles identified to date [44].The most common mutation causing AATD is the Z mutation, with the S mutation weakly linked with lung disease. AAT deficiency is under-diagnosed and prolonged delays in diagnosis are common. ATS/ERS guidelines advocate screening all COPD, poorly-controlled asthma, and cryptogenic liver disease patients, as well as first degree relatives of known AATD patients [12].
Epidemiology of ai - antitrypsin deficiency The low frequency of the Pi ZZ phenotype in the general normal population makes firm data collection with respect to prevalence of affected individuals difficult to recieve. The prevalence of AAT deficiency in newborns has been expected from large population studies, with a screening of all newborns in Sweden in 1972 to 1974 being most comprehensive [15, 22]. Of 200,000 children in that study, 127 had the PiZZ phenotype, yielding a prevalence rate of approximately 1 in 1,600 newborns. Studies from various regions of Europe have shown a large variation in frequency of the Z gene in different countries [35].The gene frequency is highest on the northwestern seaboard of the European continent and the mutation seems likely to have arisen in southern
Scandinavia. In the USA, therefore, Z gene frequencies are highest in individuals of northern of western European descent [40]. Over all, the prevalence in the general population in Western Europe is approximately 1 in 2,500. The distribution of the S gene is quite different: the gene frequency is highest in the Iberian Peninsula and the mutation is likely to have arisen in that region [9, 43]. The belief that AAT deficiency is a disorder which mostly affects white subjects has been, inpart, shaken by the analysis of the worldwide surveys performed by de Serres [22]. He provided evidence for a significant prevalence of both PI*Z and PI*S in populations from the Middle East and North Africa, Central and Southern Africa, and Central and South-East Asia, suggesting that AAT deficiency has prevailed over racial and ethnic boundaries [22]. a1-antitrypsin deficiency is widespread throughout the world, with significantly high prevalence in countries throughout the continent of Asia. It also is clear that a1-antitrypsin deficiency is not just a disease of Caucasians (or whites), but is prevalent in many different races throughout the world [23,56].
Clinical description
COPD and alpha 1 - antitrypsin deficiency. The lung manifestations of AAT deficiency include emphysema and chronic obstructive pulmonary disease (COPD) [19]. Variations in the gene coding for a1-antitrypsin (AAT), the most abundant protease inhibitor circulating in the blood, is the only established genetic risk factor for COPD [2, 31]. Emphysema is a chronic progressive lung disease characterised by abnormal permanent enlargement of airspaces as a result of destruction of alveolar walls[9,65]. Emphysema usually develops by the third to fourth decade in affected individuals who smoke cigarettes and may appear in the fifth or sixth decade in individuals who have never smoked [11, 47].
Children and adolescents with a-1 antitrypsin deficiency have not been shown to have significant lung function abnormalities [62]. Although a study of affected children with liver disease suggested a tendency to hyperinflation [64].
Registries of patients with AAT deficiency show that as many as 43% of patients have chronic sputum expectoration, as defined by
Medical Research Council (MRC) criteria, even in non-smokers. Patients with chronic bronchitis tend to have more severe airflow obstruction and more extensive emphysema than those without, despite similarities in age and smoking history [46, 52, 53].
Deficient Z Variant Individuals who are homozygous for the deficient Zvariant have circulating concentrations of AAT that areless than 15% of normal values and an accelerated rateof deterioration of lung function, even in the absence of smoking [5]. However, pulmonary emphysema develops at an earlier age in those individuals who are also smokers [20]. The low plasma and tissue concentrations of AAT are insufficient to protect the connective tissue of the lung from the action of neutrophil proteases. Although the PIZZ phenotype is undoubtedly a genetic risk factor for the development of COPD, there is considerable variation in the clinical expression of the deficiency [41]. This variability is not entirely attributable to the difference in exposure to tobacco smoke, since the rate of deterioration of lung function in ZZ individuals who are nonsmokers is also highly variable [8]. The clinical expression of AAT deficiency is also modified by polymorphisms in glutathione S-transferase P1, a subfamily of glutathione S-transferase that is widely expressed in all types of epithelial cells, including those of the lung, [16, 66] and that participates in the detoxification of electrophilic substances and products of oxidative stress caused by tobacco smoke [54].
Methods for the diagnosis of ai-at deficiency
Procedures for testing for a1-AT deficiency have been available since the 1960s, and new techniques have been introduced during the intervening years. These advances in methodology should facilitate the widespread application of more rapid, convenient and cost-effective tests for a1-AT deficiency and thus lead to an increase in the numbers of individuals diagnosed with the disorder [12, 46].
The primary diagnostic test for AAT deficiency is an immunoassay that measures AAT concentration in plasma or serum [29]. Typically, AAT-deficient patients homozygous for the Z allele have plasma or serum concentrations 85% below normal; whereas, patients who are
heterozygous for both the Z and S alleles can have intermediate AAT concentrations (~60% below normal) [49].
Methods:
Alpha-1 -Antitrypsin PhenotypR™ - Isoelectric Focusing (IEF)
Alpha-1 -Antitrypsin (Serum) - Nephelometry (NEPH)
Alpha-1 -Antitrypsin GenotypR™ - INVADER®-based detection of Pi Z and S alleles in genomic DNA [30]
Individuals with MZ and SS phenotypes have AAT concentrations that are 40% below normal [38]. The MZ and SS phenotypes are indicative of intermediate AAT deficiency and an increased risk of developing AAT deficiency-associated diseases [33]. The ZZ phenotype is associated with a severe AAT deficiency1 and predisposes children to liver disease and emphysema [31].
Although over 70 European alleles in the Pi gene are reported, most are private or rare. Approximately 95% of AAT-deficient patients are either homozygous for the Z allele or are heterozygous for both the Z and S alleles.2,9 This assay detects both of these common alleles, and can identify carriers and individuals at risk for AAT deficiency that is independent of AAT concentrations [21].
Clinical Utility: Diagnosis of AAT deficiency in the symptomatic patient and concomitant identification of familial mutation; The mutation in the Z allele accounts for 95% of AAT-deficient patients; The World Health Organization (WHO) recommends screening for AAT deficiency at least once in all Chronic Obstructive Pulmonary Disease (COPD) patients and in adults and children with asthma [50].
Genetic counseling and prenatal testing
When patients are identified as a new case of homozygous type Z alpha-1-antitrypsin deficiency, the issue of heritability for their children is frequently raised. It is less inconvenient for the children when first the other parent is investigated by isoelectric focusing or genotyping for alpha-1-antitrypsin. Since about 95% of individuals carry the Mm phenotype, all children from parents with ZZ and MM type will carry the MZ type alpha-1 -antitrypsin. If the parent is not MM, but is carrying a deficient allele next to the M allele (i.e. MZ), there is a 50% chance of ZZ genotype for every newborn from
these parents and this can be confirmed in the child by isoelectic focusing of serum. Prenatal testing is not a routine procedure due to the low penetration of liver disease shortly after birth [61].
Treatment
At present, treatment options for alpha-1-antitrypsin deficiency are very limited. There are no randomized, placebo-controlled studies that provide proof of an effective cure [35]. Specific therapy for AATD-related lung disease, called augmentation therapy, is the periodic intravenous infusion of pooled human serum alpha-1antitrypsin (AAT). Concordant observational studies show that AAT augmentation therapy can slow the rate of FEV1 decline among individuals with AATD-related emphysema [3, 17]. For treatment of lung disease, the ATS/ERS Statement recommends intravenous alpha-1-antitrypsin augmentation therapy for Pi ZZ individuals with FEV1 between 35 and 65% of predicted [51]. In addition, the World Health Organization (WHO) recommends annual flu vaccination and a pneumococcal vaccine every 5 years [66]. Like in emphysema patients without alpha-1-antitrypsin deficiency, relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids [63].
Natural history and prognosis
Alpha-1-antitrypsin deficiency with its many genotypes and its manifestation in various organs is rarely observed in daily clinical practice and is frequently not diagnosed or misdiagnosed. On average, the delay from the first signs of disease to the correct diagnosis is several years [55].Several studies have shown that FEV1 is the most important predictor of survival of patients with emphysema due to alpha-1-antitrypsin deficiency (AATD). For individuals with an FEV1 below 20% of predicted, the 2 year mortality is 40% if not treated by a lung transplant [69]. Patients who have never smoked and who are detected by screening of affected family members turn out to have a normal life expectancy. Most of these AATD individuals (83%) are clinically healthy throughout adulthood and most will have liver enzyme abnormalities in early life [71]. All of these observations were performed more than 15 years ago and in the mean time computed tomography of the chest provided new analytical information on the quality of lung parenchyma, including the extent of emphysema. Dawkins et
al. reported that lung density values assessed by computed tomography have better associations with mortality in type Z alpha-1-antitrypsin deficiency than FEV1 [24].
Conclusion
Alpha-1-antitrypsin deficiency (AATD) is an underdiagnosed condition in patients chronic obstructive pulmonary disease (COPD). Preventive measures, such as smoking cessation, avoiding contact with pollutants, vaccine prevention of infections are measures that reduce the rate of progression of the disease. It is advisable to pre-clinical diagnostic of alphal-antitrypsin deficiency that could determine the choice of occupation, place of residence, the lifestyle of an individual.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
The authors equally contributed to this review article. They read and approved the final version of the manuscript.
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Contact Information:
Zhumagaliyeva Ardak Nazilovna - a PhD student on the specialty "Medicine", State Medical University of Semey, Kazakhstan.
Mailing address: East Kazakhstan region, 071412, Semey, Riskulov Str 1B-64. E-mail: [email protected] Tel: 87051459307
