RESUMEN
INTRODUCTION: Pulmonary emphysema and liver disease are the clinical expressions of alpha 1-antitrypsin deficiency, an autosomal recessive genetic disease. STATE OF THE ART: Alpha 1-antitrypsin deficiency is usually associated with the homozygous Z variant of the SERPINA1 gene. Its clinical expression always consists in a substantial reduction of alpha 1-antitrypsin serum concentration and its variants are analyzed by isoelectric focalization or molecular techniques. Assessed by CO transfer alteration and CT scan, risk of pulmonary emphysema is increased by tobacco consumption. Assessed by transient elastography and liver ultrasound, risk of liver disease is increased by alcohol consumption or obesity. Treatment of COPD-associated alpha 1-antitrypsin deficiency does not differ from that of other forms of COPD. In patients presenting with severe deficiency, augmentation therapy with plasma-derived alpha 1-antitrypsin reduces the progression of emphysema, as shown in terms of CT-based lung density metrics. Patients with alpha 1-antitrypsin deficiency with a ZZ genotype should refrain from alcohol or tobacco consumption, and watch their weight; so should their close relatives. PERSPECTIVES: Modulation of alpha 1-antitrypsin liver production offers an interesting new therapeutic perspective. CONCLUSION: Homozygous (Z) variants of the SERPINA1 gene confer an increased risk of pulmonary emphysema and liver disease, particularly among smokers, drinkers and obese persons.
Asunto(s)
Enfisema Pulmonar , Deficiencia de alfa 1-Antitripsina , Genotipo , Humanos , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/epidemiología , Enfisema Pulmonar/etiología , alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/epidemiologíaRESUMEN
INTRODUCTION: Several studies have investigated the clinical feature of COPD in subjects carrying the common alpha-1 antitrypsin deficiency mutations PIS and PIZ. However, there are few data on COPD due to rarer deficient variants. In this study, we aimed to explore the features of COPD in subjects carrying the PIMMmalton mutation, which is the most prevalent alpha-1 antitrypsin variant in Tunisia. MATERIAL AND METHODS: Five individuals, heterozygous for PIMMmalton were analyzed and compared to 97 non-deficient COPD patients. Demographic data as well as clinical and functional outcomes from subjects were collected. Blood gases and plasma alpha-1 antitrypsin levels were recorded. RESULTS: PIMMmalton subjects did not show any significant difference in terms of predicted FEV1 (35±13.2%), predicted forced vital capacity (34.2±9.6%) and FEV1 decline (148.6±114mL/year) compared to usual COPD patients (respectively 41.7±17.2%, P=0.500; 43.8±18.8%, P=0.300; 197.9±191mL/year, P=0.800). However, PaO2 was significantly reduced in PIMMmalton subjects (58.8±4.0mmHg) compared to usual COPD (69.9±10.6mmHg; P=0.029) and those patients with chronic bronchitis and centrolobular emphysema (71.0±10.9mmHg; P=0.038). CONCLUSION: PIMMmalton subjects were significantly hypoxic, similar to that observed in PiZZ homozygous rather than observed in heterozygous individuals.
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Mutación , Enfermedad Pulmonar Obstructiva Crónica/genética , alfa 1-Antitripsina/genética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Alpha-1 antitrypsin deficiency is a hereditary disease defined at the biological level by a serum alpha-1 antitrypsin level below 11µM/L. The null variants are characterized by undetectable circulating alpha-1 antitrypsin levels. Suspicion of a null variant requires the use of appropriate diagnostic techniques. CASE REPORT: We report the case of a 33-year old patient presenting with dyspnea on exertion, associated with a moderate airflow obstruction, incompletely reversible. His tobacco use was less than 3pack-years. The thoracic CT-scan showed emphysema. The serum alpha-1 antitrypsin level was collapsed. Phenotyping by isoelectrofocusing on agarose gels did not show any band. The study of the SERPINA1 gene, by PCR-sequence of the II, III, IV and V exons and the flanking intronic sequences, allowed identification of the NullQ0ourém allele in homozygous state. This mutation was found in heterozygous state in both parents of the index case and in one of his brothers. The index case showed a rapid aggravation of the airflow obstruction. CONCLUSION: In the case of a serum alpha-1 antitrypsin deficiency, the analysis of the phenotype of the protein by isoelectrofocusing must be performed as a first-line investigation. The detection of an atypical profile may suggest the presence of deficient alleles other than the PI S and PI Z alleles that can only be characterized by sequencing of the whole SERPINA1 gene. The patients carrying a null mutation have a high risk of severe chronic obstructive pulmonary disease.
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Codón sin Sentido , Deficiencia de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adulto , Disnea/genética , Humanos , Masculino , Fenotipo , Deficiencia de alfa 1-Antitripsina/patologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) is currently the ninth leading cause of death in France and is predicted to become the third leading cause of worldwide morbidity and mortality by 2020. Risk factors for COPD include exposure to tobacco, dusts and chemicals, asthma and alpha-1 antitrypsin deficiency. This genetic disease, significantly under-diagnosed and under-recognized, affects 1 in 2500 live births and is an important cause of lung and, occasionally, liver disease. Alpha-1 antitrypsin deficiency is a pathology of proteostasis-mediated protein folding and trafficking pathways. To date, there are only palliative therapeutic approaches for the symptoms associated with this hereditary disorder. Therefore, a more detailed understanding is required of the folding and trafficking biology governing alpha-1 antitrypsin biogenesis and its response to drugs. Here, we review the cell biological, biochemical and biophysical properties of alpha-1 antitrypsin and its variants, and we suggest that alpha-1 antitrypsin deficiency is an example of cell autonomous and non-autonomous challenges to proteostasis. Finally, we review emerging strategies that may be used to enhance the proteostasis system and protect the lung from alpha-1 antitrypsin deficiency.
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Deficiencia de alfa 1-Antitripsina , Homeostasis , Humanos , Modelos Biológicos , Deficiencias en la Proteostasis/etiología , alfa 1-Antitripsina/fisiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/terapiaRESUMEN
INTRODUCTION: Alpha-1 antitrypsin, secreted by the liver, inhibits neutrophil elastase. Its deficiency favours the development of emphysema. Restoring a "protective" serum level in deficient patients should make it possible to inhibit the development of emphysema. STATE OF THE ART: Human plasma-derived alpha-1 antitrypsin is a blood-derived drug sold in France under the name Alfalastin(®). The recommended posology is an I.V. administration of 60 mg/kg once a week. Human plasma-derived alpha-1 antitrypsin restores anti-elastase protection in the lower lung and prevents experimental emphysema induced by the elastasis of human neutrophils in hamster. The low number of patients with alpha-1 antitrypsin deficiency is one of the difficulties to perform sufficiently powerful randomised studies. However, randomised studies have reported the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on mortality, FEV1 decline and the frequency of exacerbations. Randomised control trials have demonstrated the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on the loss of lung density assessed by CT scan. CONCLUSION: Augmentation therapy is simple in its conception and implementation, but it is expensive. However, there are currently no other solutions.
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Enfisema Pulmonar/tratamiento farmacológico , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , alfa 1-Antitripsina/uso terapéutico , Animales , Sinergismo Farmacológico , Humanos , Pulmón/efectos de los fármacos , Pulmón/patologíaRESUMEN
Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.
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Deficiencia de alfa 1-Antitripsina/genética , Animales , Humanos , Modelos Moleculares , Estructura Terciaria de Proteína , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/terapia , alfa 1-Antitripsina/química , Deficiencia de alfa 1-Antitripsina/patología , Deficiencia de alfa 1-Antitripsina/terapiaRESUMEN
Alpha-1 antitrypsin (α1-AT) deficiency is an autosomal recessive genetic disorder, which predisposes affected patients to development of pulmonary emphysema or liver cirrhosis. Despite the guidelines from the American Thoracic Society and the European Respiratory Society about α1-AT deficiency screening, it remains significantly under recognized. So, it seems necessary to propose an efficient and suitable biological approach to improve diagnosis and management of α1-AT deficiency. α1-AT is a 52 kDa glycoprotein predominantly produced in the liver and its physiological serum concentration for adults ranges from 0.9 to 2.0g/L (17-39 µmol/L). It is encoded by the SERPINA1 gene, which is highly pleomorphic, and to date, more than 100 alleles have been identified. α1-AT testing would initially involve quantification of serum α1-AT concentration with possible complementary measurement of the elastase inhibitory capacity of serum. If the serum α1-AT concentration is reduced below the reference value, two strategies for laboratory testing can be used: (i) serum α1-AT phenotyping by isoelectric focusing which allows identification of the most common variant designated as the PI M variant but also of various deficient variants besides the predominant PI S and PI Z ones; (ii) genotyping by allele-specific PCR methods which allows only identification of the deficient PI S and PI Z alleles. Identification of the null alleles or of other rare deficient alleles can be performed by direct sequencing of the whole SERPINA1 gene as a reflex test.
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Técnicas y Procedimientos Diagnósticos , Deficiencia de alfa 1-Antitripsina/diagnóstico , Adulto , Técnicas y Procedimientos Diagnósticos/normas , Técnicas y Procedimientos Diagnósticos/estadística & datos numéricos , Pruebas Genéticas , Genotipo , Técnicas de Genotipaje/métodos , Humanos , alfa 1-Antitripsina/química , alfa 1-Antitripsina/fisiologíaRESUMEN
Apha-1-antitrypsin deficiency is an autosomal recessive genetic disorder seen in all races. The molecular defect is a specific mutation of the SERPINA1 gene leading to synthesis of an abnormal protein (alpha-1-antitrypsin Z) that cannot be secreted and polymerizes in the endoplasmic reticulum of hepatocytes. The inter-individual variability in the responses to intracellular stress induced by the accumulation of abnormal polymers and the mechanisms allowing their degradation is, without doubt, responsible for the different clinical manifestations of the disease. The disease affects the liver where the abnormal protein is synthesized and the lung, which is its place of action. Liver involvement is well recognized in homozygous infants of the phenotype ZZ. In this situation the disease may present a varying picture from neonatal cholestasis (about 15% of neonatal defects) to cirrhosis. However, evolution towards cirrhosis affects less than 3% of infants with the ZZ phenotype and it is preceded in 80% of cases by neonatal cholestasis. In adolescents or adults the manifestations associated with alpha-1-antitrypsin deficiency are usually limited to biochemical abnormalities but may lead to cirrhosis or hepatocellular carcinoma. The hepatic disorder and its complications are treated symptomatically though the pulmonary involvement may benefit from substitution treatment. More specific treatments targeting the molecular and cellular abnormalities are the subject of research.