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[página principal] [portugués] [deficiencia de alfa-1] [boletín informativo] [donativos] [entérate] [grupos de apoyo] [enlaces] [detección y registro] [historias para compartir] [articulos médicos] [mailing list] [otros temas de interés] [nuevo] [contáctanos] Alpha-1-Antitrypsin Deficiency: June 22-23, 1999, Cernobbio-Como, Italy Editorial: Professor Robert Stockley, University Hospital, Birmingham, UK
It is some thirty-six years since the first cases of Alpha-1-Antitrypsin (AAT) Deficiency were recognised and described. Since that time studies have confirmed that patients identified with the deficiency have an accelerated loss of lung function typically due to the development of emphysema. Other studies have shown that AAT Deficiency is associated with neonatal jaundice (which usually settles giving no further problem) cirrhosis of the liver and hepatocellular carcinoma, necrotising panniculitis and more recently systemic vasculitis. Most of these associations have been determined by the study of patient groups collected by enthusiastic and inquisitive individuals over time. However, despite these many associations, the relationship between AAT Deficiency and lung disease predominates.
In recent years the exact mechanism resulting in deficiency in the common Pi Z type of AAT Deficiency has been clarified. AAT accumulates within the liver cells causing hepatocellular damage. In most individuals this is only a pathological finding and it remains largely sub-clinical. The lung disease is thought to be a result of a reduction in the protection of lung tissues from damage by the enzymes normally inhibited by AAT. More recently studies have indicated that AAT can retain its protective function if the concentrations are 11 µM. However, in the common Pi Z type of AAT Deficiency the concentration is typically 5 µM and this places individuals at increased risk of the development of destructive lung disease in the presence of inflammation involving the neutrophil.
With the exception of the observations made above our understanding of the relationship of AAT Deficiency to disease is still relatively superficial. For instance, we know from limited pathological studies that individuals have evidence of emphysema and bronchiectasis. However, in large studies of patients with these conditions AAT Deficiency remains an uncommon cause and most of the patients predicted to be present within the population remain unidentified. It is only in areas where extensive active screening has taken place (such as in the city of MaImö, Sweden) that the majority of patients with the deficiency are identified (approx. 70 percent).
From the point-of-view of lung disease it is well recognised that only 10-15 percent of non deficient smokers are susceptible to the development of emphysema. In this group the exact mechanisms are unknown, although genetic susceptibility is believed to be important. It is possible that the same genetic causes determine the susceptibility of AAT deficient subjects to the development of chronic lung diseases. If so, the smoking susceptible deficient individual (perhaps also 10-15 percent of the AAT deficient population) develops more rapidly accelerated destructive lung disease. Hence the majority of deficient subjects may never present to the health care system with lung disease.
It is also possible however, that many patients are being missed because they present with what appears to be the wrong diagnosis. For instance, in young breathless patients the most likely diagnosis is asthma and patients with AAT Deficiency may therefore be misdiagnosed for many years until clinical suspicion arises. However, studies of deficiency have shown that a reversible degree of airflow obstruction is often present. Furthermore, it is quite possible that patients may develop asthma in their early years and that the inflammation associated with the asthma and perhaps smoking leads to permanent lung damage at a later date. The final alternative is that both cigarette smoking induced emphysema and asthma are common and may therefore coincide in many patients confusing the clinical picture. Whatever the situation these relationships remain to be clarified. Furthermore, the relationship between bronchiectasis and AAT Deficiency is uncertain. Small clinical studies suggest it may be common affecting up to 40-50 percent of the patients, whether this is an incidental finding and hence atypical remains to be determined.
It has been nearly twenty years since the first deficient individuals were given AAT augmentation therapy. The logic of replacing a deficient protein and thereby reversing the risk of the development or progression of lung disease remains compelling. However, no sufficiently powered controlled clinical trial has been carried out to date. There is little doubt that the theory of augmentation therapy is correct. However, in the absence of a clinical trial there will always remain doubt as to the efficacy of such therapy. It is unknown which patients require augmentation therapy. The optimal dosage and dosing interval has not been rigorously established. It is not known whether augmentation should be given by the intravenous or inhaled route. These questions can only be answered by clear adequately powered controlled clinical trials. Most doctors have not looked after patients with AAT Deficiency. Indeed, many specialists may see few cases and even those with an interest may only see 10-15 patients at any one time. However, over the years many national registries have been established, some including up to 1,000 subjects. The establishment and maintenance of registries has always depended on the enthusiasm of the individuals and the goodwill of their colleagues. These registries have undoubtedly provided important epidemiological data, but their relevance to other countries remains unknown. We are rapidly approaching the end of the twentieth century and about to start a new one. Arguably this could be the most exciting time for AAT Deficiency since its original discovery. It is a time to rethink many of our concepts of what deficiency really means and whether it, alone, is a risk factor for the development of disease. International collaboration is currently underway providing an opportunity to study thousands of patients rather than a few. New methods of assessment have been developed, including extensive physiology, the introduction of exercise testing, quality of life and most specifically high resolution CT which can identify the pathological changes in life. New concepts on how to deliver AAT augmentation therapy are being developed and we now approach a time when we can realistically expect controlled clinical trials to take place and hence provide greater insight into the role of AAT and its deficiency in health and disease.
THE HISTORY OF THE ALPHA ONE INTERNATIONAL REGISTRY (AIR)
Discovery of AAT Deficiency
In 1963 Laurell and Eriksson discovered AAT Deficiency by noticing an association between the development of early pulmonary emphysema and a missing alpha-1-band when running a patient's protein electrophoresis. The missing protein was alpha-1-antitrypsin, named after its function as a trypsin inhibitor. Soon after this discovery it was found that this was capable of inhibiting a number of serine proteases other than trypsin. Therefore, the protein has also been referred to as an alpha-1-protease inhibitor. However, the main target of AAT is the inhibition of neutrophil elastase. Smokers and patients with lower respiratory tract infections have an abundance of neutrophils in their lungs, which in turn release neutrophil elastase. Without the inhibition of this protease, by AAT, neutrophil elastase can cause significant damage to the lungs. The question then arose, how can this imbalance of AAT be reversed? Harvesting AAT from human plasma, which is subsequently administered to AAT deficient patients intravenously, has been used to approach this problem.
Epidemiology
AAT Deficiency is an autosomal recessive disease caused by mutations in the gene coding for AAT. This genetic disorder is characterised by a very low (<20 percent normal) serum level of antiprotease. AAT is primarily produced in the liver by hepatocytes, following which it enters into the general circulation and reaches the pulmonary tissue. AAT Deficiency often results in the development of emphysema, caused by the imbalance between elastase (released by neutrophils) and the AAT protease inhibitor. As a consequence of this imbalance, the alveolar structures are inadequately protected from chronic exposure to elastase; elastin and perhaps other tissues are destroyed resulting in the development of emphysema as the eventual outcome. Liver cirrhosis is also known to occur and is probably due to liver cell damage as a result of AAT accumulation.
People with AAT serum levels <50 mg/dL have an increased risk of developing emphysema in their lifetime; however, those with >80 mg/dL are at no greater risk than the general population. It is therefore thought that the protective threshold of AAT is >80 mg/dL. With augmentation therapy (human plasma-derived AAT (Prolastin®) it is possible to increase AAT levels above this threshold and, therefore, theoretically, to provide protection of the lungs. It should be noted that, to date, no randomised placebo-controlled trials have been conducted to assess the efficacy of augmentation therapy with AAT. However, data strongly suggest that AAT augmentation therapy is both efficacious and can improve quality of life.
A variety of mutations are known to occur within the AAT gene - being one of the most commonly inherited genetic abnormalities in humans. People of northern European descent have one of the highest incidences of mutation - one in 50 - with the Z allele, and the PiZZ variant, typically reduces patients' AAT levels to <20 percent of normal. The next most common deficiency mutation is S, but the deficiency related to this allele is milder than with Z. Homozygous S individuals are not at any greater risk than the general population of developing emphysema, but SZ heterozygotes may be at mild risk, which is increased by smoking.
An under-diagnosed disease
Calculations from population screening studies in Sweden and the United States suggest that one in 1700-5000 Caucasians are PiZZ, with severe AAT Deficiency thought to be present in approximately 3 percent of outpatients with chronic obstructive pulmonary disease (COPD). From these screening studies it has been predicted that >100,000 Americans have severe AAT, but that <10 percent of these individuals have been diagnosed. This is perhaps not surprising when considering that a physician may only encounter one of two AAT deficient patients within their career, with patient symptoms commonly attributed to asthma, smoking, lack of physical fitness or even nerves. In fact, it has been reported that the mean interval between the first onset of symptoms and diagnosis of AAT Deficiency is 7.2 years. To begin to resolve this problem AAT Deficiency should be suspected in any adult or adolescent with obstructive airways disease and all individuals with unexplained liver disease. It should also be considered in individuals with panniculitis (deep ulcerating skin lesions), and in individuals with vasculitis. Mortality data concerning AAT Deficiency in terms of its severity have been firmly established by the WATL (Westdeutsche Arbeitsgemeinschaft zur Therapie von Lungenkrankheiten) Alpha-1-Antitrypsin (AAT) Study Group in Europe (Eur Respir J 1998;11:428). They calculated that whilst the average American has a 95 percent probability of being alive at 50 and an 85 percent probability of living to 60, these chances are significantly reduced to 52 percent and 16 percent, respectively, for AAT deficient individuals.
Alpha-1 International Registry (AIR)
After the first description of an association between pulmonary emphysema with a missing alpha-1-band in the protein electrophoresis the first national registries collecting data on patients with AAT Deficiency were formed. Although each of these national registries are collecting data on AAT Deficiency they are all unique in their own ways. The largest registries in Europe are located in Sweden and Denmark, (900 and 700 patients with severe AAT Deficiency, respectively). Germany has a substantial registry, including nearly 900 patients, some of them receiving augmentation therapy with human plasma-derived AAT. The total number of patients identified by registries today is approximately 3500, with an average new identification rate of between 5-10 percent in established registries and up to 100 percent in newly formed registries such as South Africa.
In addition to the differences in the numbers of patients in the various national registries, inclusion criteria also tend to be different. For example, in Sweden only patients with a PiZZ phenotypes are entered into the registry, whereas other countries include phenotypes such as PiSZ and other rare deficiency types. Follow-up periods and therapeutic treatment are also variable from country-to-country. After the WHO meeting on AAT Deficiency in 1996 an Alpha-1 International Registry (AIR) was established; addressing one of the WHO recommendations. The AIR began with 12 founding countries: Australia, Canada, Denmark, Germany, Italy, New Zealand, South Africa, Spain, Sweden, Switzerland, The Netherlands, and the United Kingdom.
The initial aims of the AIR were defined as:
The AIR has established a central database in Malmö, Sweden for the collection of initial data including, demographics, smoking history, lung function measurements and other parameters of patients with severe AAT Deficiency and follow this up. The first Chairperson of the AIR, Professor Nikolaus Konietzko (Essen, Germany), remarked that the "formation of the AIR is a unique opportunity to collect a large body of follow-up data on this disorder and jointly address pressing research questions that could not be solved by smaller, national registries alone." He openly invited other countries to join the AIR (four other countries -Austria, Belgium, Japan and Northern Ireland -have either recently joined or have expressed interest in joining).
Conclusions and Recommendations WH0 (World Health Organization)
AIR: a new committee and a new direction
In San Diego in May 1999 the new AIR committee was elected. The new Chairperson of the AIR, Professor Robert Stockley (Birmingham, UK), committed himself to taking the AIR into the 21st Century whilst guiding the future progress of the International Registry. He set out a series of goals for the AIR to strive for, including:
Data and patients need to be collected and enrolled into the AIR registry, so that realistic and achievable clinical trials can be conducted. Professor Stockley explained that the strength of the AIR is in the diverse nature of its national registries, with enthusiastic and highly motivated individuals in each country having contributed their personal interests and direction onto 'their' national registries. With the development of the AIR, it should be possible to perform the first large-scale international controlled trials based on the characterisation of the natural history of the disease and identification of risk factors. These should, in turn, help with the development of appropriate therapies and standards of care. A standard of care for patients is already being developed, with the American Thoracic Society and European Respiratory Society currently formulating an up-to-date consensus document (described later). In addition, the AIR is pushing for the implementation of the W.H.O recommendations (as outlined earlier), such as those stating that all-adult COPD, asthma and bronchiectasis patients should be tested at least once in their lifetime for AAT Deficiency.
THE CURRENT STATUS - NATIONAL REGISTRIES, SCREENING
Sweden
Professor Sten Eriksson (MaImö, Sweden) has been at the leading edge of research in AAT Deficiency since he co-discovered this genetic disorder in 1963. It is therefore not surprising that the Swedish national registry is both the largest and longest running AAT Deficiency registry in Europe, with over 900 AAT deficient patients. More than 20 percent of AAT deficient patients in Sweden have been identified, with 70 percent of AAT deficient patients from the 240,000 population of Malmö identified. Compared with the detection rate of < 5 percent in most European countries and the USA this is a considerable achievement.
Professor Eriksson plans to continue enrolling AAT deficient patients onto the Swedish registry and the AIR. He is hopeful that, with the large number of AAT deficient patients grouped together for the first time on the single AIR database, that basic clinical and experimental studies on liver and lung disease can at last be undertaken.
Professor Eriksson and Dr Sternby (Malmö, Sweden) conducted one of the most detailed investigations into the natural history of AAT to date, having examined the causes of death among AAT deficient patients in the City of Malmö between 1962 and 1997. In 41 PiZZ cases (21 female, 20 male), it was found that smoking significantly (p<0.01) shortened survival in AAT deficient patients (Figure 1), with the main cause of death in smokers being emphysema and bronchitis (74 percent). In contrast, in neversmokers cirrhosis is the main cause of death.
In terms of screening, Sweden has conducted the most complete neonatal study. Between 1972 and 1974 all newborn children - 200,000 - were screened for AAT by taking 5 µl blood samples and testing at a central laboratory in Malmö. Children with AAT levels less than 40 percent of normal were phenotyped. The aim of the study was to identify PiZZ homozygotes and to give effective anti-smoking advice to parents and children. Smoking -as illustrated in Figure 1 - has clearly been demonstrated to exacerbate the disorder and ultimately shorten AAT deficient patients' lives. The prognosis of patients at the age of 20 has been shown to be excellent, with only 3 patients having severe liver disease at this age. Lung function at 16 was also calculated to be normal as compared with controls. Smoking advice was shown to be effective at 18, with 6 percent of patients actively smoking compared to 17 percent of the background population.
Professor Eriksson concluded, however, that this study did not advocate screening from birth. He based this conclusion on cost benefits (17,600 patients would need to be screened to find one who would benefit from antismoking advice) and on the significant psychosocial side effects observed in terms of parental stress and anxiety concerning their child's condition. He did confirm, however, that AAT deficient patients at 18-20 were normal in terms of their mental and physical well being. He recommended that, if screening was to be performed, it should be on a basis of informed consent and in individuals aged between 12 and 15 years.
Denmark
The national registry in Denmark was formed in 1976 with now over 900 (100 heterozygous) patients and between 30 and 50 new ones enrolled each year. No active screening programme exists in Denmark, with no uniform adherence to the W.H.O recommendations to screen all COPD, asthma and bronchiectatic patients. Patients enter the Danish registry based on reports from chest physicians throughout Denmark. The Danish registry has a unique feature, namely the examination of AAT deficient patients' family genetics, with the Z gene followed along the patients' family tree. Some family trees include more than 100 individuals, with several thousand heterozygote members in the registry. Professor Asger Dirksen (Copenhagen, Denmark) commented upon the value of the AIR, and expressed delight at the progress and contribution it has already made. He remarked that "the AIR has already been very valuable as it has brought people together who otherwise would not have met, and together we are learning more about the disorder and developing new collaborations." He said that AIR has already had an impact in Denmark as it has indirectly brought about the creation of a patients' organisation which is actively pursing new treatments (human plasma-derived AAT is not currently licensed in Denmark). Professor Dirksen was optimistic that the AIR will help to bring AAT Deficiency to the attention of physicians and the general public alike. He is confident that the AIR will promote scientific research into AAT Deficiency, will become a powerful lobby and will be successful in acquiring the funds necessary to undertake this research.
The Netherlands
The Dutch registry was set up ten years ago and has now recruited over 400 patients. Those referred to Doctor Jan Stolk (Leiden, The Netherlands) by pulmonary physicians and other doctors are now being included in the AIR.
In October 1998 Doctor Stolk began collaborating with the central phenotyping laboratory in Amsterdam, which indirectly alerts him to any homozygous AAT patients. The laboratory includes a letter with their phenotype report to the referring physician, asking them to contact Doctor Stolk and to make an additional appointment for the patient at his hospital for further screening. This has enabled him to recruit approximately 60 percent of Dutch patients found to be PiZZ or PiSZ, into the AIR. These patients are given full pulmonary tests and CT scans and complete a St George's questionnaire. A blood sample is obtained and stored for further assays.
In an effort to replicate the Danish registry experience in terms of family genetics, Doctor Stolk asks AAT deficient patients whether their families can also be screened. Unfortunately, family doctors - mainly through ignorance of AAT Deficiency - are tardy in co-operating and, suggests Doctor Stolk, the one way to change this could be to publish a review in the Dutch Journal of Family Practitioners and increase awareness of the condition.
Two years ago, Doctor Stolk examined whether it was possible to set up a national neonatal screening programme in The Netherlands. He found that it was impossible to embark on such a programme as he was twenty-fifth in line and that a series of ethical and legal barriers stood in his way. In an effort to increase awareness and screening for AAT Deficiency at 'grass roots', he addresses all trainee pulmonologists in The Netherlands each year and asks them to phenotype young patients with signs of emphysema. In addition, he asks all paediatricians to request phenotyping when neonatal icterus occurs and all gastroenterologists to request phenotyping in patients with a family history of cirrhosis. Reiterating Professor Dirksen's comments, he is both confident and optimistic that the AIR will help perform the simple clinical studies that need to be conducted to move the understanding of AAT Deficiency forward and that the AIR will become both a powerful lobby in acquiring funding for research and in bring AAT Deficiency to the attention of the physicians and general public in The Netherlands.
United Kingdom
It has been calculated there may be approximately 25,000 AAT deficient patients in the UK although only 500 have been identified - because either physicians are unable to diagnose them or individuals with the disorder have so far not shown signs of illness. Indeed, diagnosis remains one of the most common problems in all countries. Professor Stockley, co-ordinator of the AAT registry in the UK, hopes that, via the AIR, national opinion leaders can be brought together to resolve these problems and help AAT deficient patients avoid 'contraindicated' socioeconomic factors.
Human plasma-derived AAT is not licensed in the UK and, as Professor Stockley explained, until controlled clinical trials prove it to be efficacious, this will remain the case. As the Chairperson of the AIR and the head of the registry in the UK, he is confident that the AIR will be able to accrue enough patients internationally for trials powered to address the question of augmentation therapy. He also hopes that, with the establishment of the AIR and with the expertise within the group, new endpoints to evaluate lung function can be adopted (e.g., CT evaluation of lung density).
Italy: the mainland
AAT Deficiency was considered extremely rare in Italy until 1993, when a targeted nation-wide screening programme was started to determine the prevalence of the disease. Of some 850 patients screened, 70 were found to be AAT deficient, 80 percent of whom were PiZZ. Based on these results, a national registry for AAT Deficiency was established in February 1996. Six years after the beginning of their initial screening programme, over 1000 patients have been screened, with 160 AAT deficient patients identified. Dr. Maurizio Luisetti (Pavia, Italy) hopes that the AIR will help gather further information on the epidemiology of this condition and quantify further the natural history and prevalence of the disease.
Italy: Sardinia
The situation in Sardinia differs from both mainland Italy and the rest of Europe. The population is about 1.5 million, with the majority of people living in small villages with less than 1000 individuals. Sardinia has experienced a significant degree of geographical isolation over the centuries and many relatives inter-marry, thus it is not surprising that some of the highest incidences of rare genetic diseases occur in this population.
An AAT registry set up in Sardinia found that, of 865 individuals examined, 32 had low AAT serum levels and eight were severely AAT deficient. Unlike most severely AAT deficient patients, these individuals were M-like variants, characterised by a deletion of the TTC in the second exon. It is now apparent that M-like variants in the Sardinian population are more important than the Z-form, in the development of AAT. It has also been confirmed that normal phenotyping techniques are not sufficient to characterise these M-like variants and that direct sequencing of PCR products of the AAT gene is mandatory. Ongoing research is examining the epidemiology of this variant, in order to establish its relevance in terms of liver and lung disease. The Sardinia registry acknowledges the role of Professor Gavino Faa, Cagliari, Italy in this screening programme.
Spain
AAT deficient patients in Spain were identified in Barcelona in 1987, with the first patients receiving augmentation therapy in 1989. The Spanish national registry was founded in 1993 with its main objectives:
A total of 248 AAT deficient patients have now been found--representing 5 percent of the patients predicted in Spain. Of the AAT deficient patients identified, 239 are PiZ, with a predominance of men (73 percent) and individuals who smoke or are ex-smokers (68.5 percent). The registry in Spain covers 63 centres (an additional centre in Andorra has one patient) with a central laboratory and national database. The co-ordinator of the Spanish registry and Spanish representative of AIR is Dr. Marc Miravitlles who will assume the Chair for the next scientific AIR meeting.
Germany
The German registry was set up in the 1980s well before augmentation therapy was available and comprises two groups--those recruited before augmentation therapy and those afterwards, some of whom now receive human plasma-derived AAT. Dr Marion Wencker (Essen, Germany) explained that the registry and database are being reorganised so that their data can feed into the AIR. No active screening programme for AAT takes place in Germany, but 25 pulmonary centres across Germany report patients to the national registry. Or Wencker has considerable first hand experience of AAT Deficiency, having treated over 100 patients over many years. In terms of augmentation therapy, she has no doubt that human plasma-derived AAT has significantly helped her patients. This was well illustrated when during early 1998 the supplies of human plasma-derived AAT were temporarily disrupted--patients who had been stable on augmentation therapy for more than seven years rapidly declined when not on therapy for six months. On recommencing therapy, these patients did not return to their previous state.
Or Wencker said that she is excited about the AIR and feels that this group will be able to answer some of the important questions concerning AAT Deficiency, such as:
AIR will also be able to assess, via controlled trials, new technological advances such as aerosol treatment.
USA: the Salt Lake City experience
Professor Edward Campbell (Salt Lake City, USA) explained that since 1991 they have operated a centre for the diagnosis of AAT Deficiency. In that time they have tested over 29,000 samples and identified more than 900 PiZ patients. This programme was started because in the USA (as in many countries) more than 90 percent of AAT deficient patients are presently undiagnosed.
Professor Campbell expressed a hope that the AIR will help bring the USA into the international fold in terms of an international registry and in initiating controlled clinical trials. He expressed a real sense of excitement with the thought that, for the first time in the short history of the AAT Deficiency, significant steps can be made with this international collaboration. He explained that "there is a general understanding within the AIR that co-operation can lead to greater individual achievements. There is a strong spirit of optimism that the group can become a success in terms of advancing our knowledge and in developing treatment strategies for AAT Deficiency."
ATS/ERS CONSENSUS DOCUMENT
Considerable progress has been made concerning the understanding of AAT Deficiency since 1989 when the first consensus document on AAT Deficiency was published. The ATS and ERS have, therefore, co-sponsored a new consensus of care document regarding the diagnosis and management of the condition.
The task force preparing this new consensus document comprises 21 international experts from seven countries. The purpose of the updated document is to present, to the ATS/ERS and other interested professional groups, a summary of the current views, diagnosis and treatment strategies for AAT Deficiency. It is not intended to be a "cutting edge" scientific document but one that can guide clinical care with a consensus on how to manage patients.
The consensus document is currently being prepared with submission to the ATS/ERS for publication targeted in early 2000. The issues being addressed are:
Professor James Stoller (Cleveland, USA) stressed that this document should be seen as a springboard to move current thinking forward.
THE DREAMS OF THE AIR CHAIRPERSON
The new Chairperson of the AIR, Professor Stockley, hopes that, over the next 5-10 years, AIR will be able to:
He stated that "even if we don't achieve these dreams in our efforts to strive towards them, I am sure we will get pretty close--this in itself will be a significant advancement." He closed the First Scientific Meeting of the AIR by concluding that it is now on its way to making a difference. He also announced that AIR will not remain in its current state for long, as new countries such as Austria, Belgium, Japan and Northern Ireland are already on their way to joining and adding their voice and strength to the registry. "Over the next five to ten years we are going to see the positive impact of the AIR, with controlled trials and an updated consensus document as our foundation."
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