Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alpha-1 antitrypsin deficiency (AAT) is a hereditary recessive autosomal disease caused by mutations in the AAT gene. This disease is characterized by abnormally low AAT concentrations in plasma, which, in its homozygote form, carries a high risk for the development of early pulmonary emphysema and liver damage. Since the end of the 1980s augmentation therapy with AAT from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has been demonstrated to be safe and weekly infusions of AAT have resulted in plasma AAT concentrations above those considered protective for the lungs. However, life-long weekly infusions are not well accepted by patients, therefore pharmacokinetic studies have been performed to try to individualize the therapeutic regimen in order to obtain adequate trough serum AAT levels with prolonged intervals of administration. Therapeutic regimens administered every two weeks appear to be safe and result in adequate trough serum concentrations, but less-frequent administrations result in trough levels below the target. Alpha-1-antitrypsin deficiency is largely unrecognized and underdiagnosed. The foundation of national and international registries is a valid strategy to increase awareness about the disease and collect information about the natural history of this deficiency. Furthermore, the identification of a large number of patients will allow the development of new clinical trials aimed at finding better treatments for this infrequent condition.
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PMID:Augmentation therapy for emphysema due to alpha-1-antitrypsin deficiency. 1912 55

Panniculitis is a recognized but unusual complication of a severe deficiency of alpha1-antitrypsin (AAT), with fewer than 100 cases described to date. Like the pathogenesis of emphysema in severe PiZZ deficiency of AAT, panniculitis has been hypothesized to be an inflammatory process, possibly related to Z AAT polymer formation and to an unopposed anti-inflammatory screen in the context of deficient serum levels of AAT. The current report presents a 31-year-old woman with PiZZ AAT deficiency-associated panniculitis. Our case extends current knowledge of AAT-associated panniculitis in 2 ways: (1) we demonstrate Z-type AAT polymers in the skin, which supports the inflammatory pathogenesis of panniculitis and the potential pro-inflammatory role of polymers; (2) we show that a high dose and long-term use of intravenous augmentation therapy (90 mg/kg body weight once weekly during 3 years) can ameliorate the frequency and severity of panniculitis associated with AAT deficiency.
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PMID:New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy. 1921 87

Alpha-1-antitrypsin deficiency is associated with variable development of airflow obstruction and emphysema. Index patients have greater airflow obstruction than subjects detected by screening, but it is unclear if this reflects smoking differences and/or ascertainment bias, or is due to additional genetic factors. In this study 72 sibling pairs with alpha-1-antitrypsin deficiency were compared using lung function measurements and HRCT chest. Tag single nucleotide polymorphisms to cover all common variation in four genes involved in relevant inflammatory pathways (Tumour necrosis factor alpha, Transforming growth Factor beta, Surfactant protein B and Vitamin D binding protein) were genotyped using TaqMan technology and compared between pairs for their frequency and relationship to lung function. 63.5% of non-index siblings had airflow obstruction and 59.5% an FEV(1) < 80% predicted. Index siblings had lower FEV(1) and FEV(1)/FVC ratio, a higher incidence of emphysema (all P <or= 0.001) and lower gas transfer (P = 0.02). There was no correlation of FEV(1) between siblings but KCO was significantly correlated (r = 0.42, P = 0.002). Quantitative analyses against lung function showed that a polymorphism in Surfactant protein B was associated with FEV(1) (P = 0.002). This result was replicated in a non-sibling group (P = 0.01). Our results show that clinical differences in families with alpha-1-antitrypsin deficiency are not solely explained by smoking or ascertainment bias and may be due to variation within genes involved in inflammatory pathways.
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PMID:Phenotypic differences in alpha 1 antitrypsin-deficient sibling pairs may relate to genetic variation. 1935 49

Alpha-1 antitrypsin (AAT) is synthesised in the liver and has half-life of 4-5 days. AAT has antiprotease activity, with particular affinity for neutrophil elastase. Its deficiency leads to a lack of effective lung protection against activated neutrophil enzymes. Deficiency of AAT is a genetic disorder that occurs as a result of the inheritance of two protease inhibitor deficient alleles. Of the deficient alleles, Pi*Z is the most common, and the homozygous form Pi*ZZ results in the lowest serum levels, usually below 50 mg/ dl. The "protective threshold" is 80 mg/dl. Smoking increases the risk of emphysema. The current goal of augmentation therapy is to raise the plasma levels, above protective threshold and slow disease progression. The authors present the experience of the Day Care Hospital of the Pulido Valente Hospital with five male patients presenting emphysema due to AAT deficiency, receiving weekly intravenous treatment with Prolastin. We performed a clinical, respiratory functional and radiological evaluation between 2003 and 2007. The results point to a slower progression of the disease, with clinical and radiological stability and a reduced rate of FEV1 decline. Augmentation therapy is an expensive treatment and its use is lacking supportive evidence of efficacy by randomized controlled clinical trials. Evidence that it confers benefits is based on observational studies. Our experience is positive, showing clinical, radiological and functional benefits. The literature available points to a decrease in mortality, but we could not affirm so in our small population.
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PMID:[Alpha-1 antitrypsin deficiency. The experience of Pulido Valente Hospital with augmentation therapy]. 1940 96

Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT) variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 microM) and evidence of obstructive lung disease. In this article, we review the published evidence of A1AT augmentation therapy efficacy, side effects, and safety profile.
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PMID:Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. 1970 8

alpha(1)-Antitrypsin (AAT), a 52 kDa plasma protein, is produced mainly in the liver. It is the most abundant circulating serine proteinase inhibitor (serpin). It has also previously been called protease inhibitor to reflect its function as a general inhibitor of serine proteases. Its main physiological role is to inhibit neutrophil elastase and it contributes to the innate immune system as an anti-inflammatory protein. Severe AAT deficiency is most prevalent in northern Europeans affecting about 1 in 3000 of the population. AAT deficiency predisposes individuals who smoke to developing pulmonary emphysema in the fourth-fifth decade of adult life and to childhood cirrhosis in about 10% of cases, with the initial presentation being prolonged neonatal jaundice. The mean interval from presentation with symptoms to diagnosis in adults is about 8 years. The condition is under-recognised and under-diagnosed. The only effective current treatment for the severe liver disease that occurs in childhood currently is liver transplantation. Replacement therapy with purified AAT from human plasma is being used in clinical practice for the lung disease though it is not known whether this influences the outcome of this chronic condition. The liver pathology arises from intracellular polymerisation of mutant protein, and attenuation of polymerisation is a potential target for therapy.
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PMID:alpha1-Antitrypsin deficiency: best clinical practice. 1978 16

Alpha-1 antitrypsin (AAT) deficiency is an under-recognized genetic condition that predisposes to liver disease and early-onset emphysema. Although AAT is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most common mutation responsible for severe AAT deficiency, the so-called Z variant, reduces serum levels by promoting polymerization of the molecule within the hepatocyte, thereby reducing secretion. Serum levels below the putative protective threshold level of 11 micromolar (mumol/L) increase the risk of emphysema. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma represents a specific therapy for AAT deficiency and raises serum and epithelial lining fluid levels above the protective threshold. Substantial evidence supports the biochemical efficacy of this approach, particularly for the weekly infusion regimen. Definitive evidence of clinical efficacy is still needed, as the two available randomized controlled trials showed non-significant trends towards slowing rates of loss of lung density on lung computerized axial tomography. However, concordant results of prospective cohort studies suggest that augmentation therapy has efficacy in slowing the rate of decline of lung function in patients with moderate airflow obstruction and severe deficiency of AAT. Overall, augmentation therapy is well-tolerated and, despite its failure to satisfy criteria for cost-effectiveness, is recommended because it is the only currently available specific therapy for AAT deficiency.
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PMID:Alpha-1 antitrypsin (AAT) deficiency - what are the treatment options? 1982 90

The time delay between the start of respiratory symptoms and the correct diagnosis of alpha-1-antitrypsin (AAT) deficiency is often 6 to 8 years. Most patients are misdiagnosed as having COPD or asthma. Recent estimates suggest that only 15 % of patients have already been identified. The PiZZ genotype leads to severely decreased AAT serum concentrations, and is associated with a high risk of pulmonary emphysema. Disease manifestation is earlier in smokers than in non-smokers. Since cigarette smoke is able to reduce AAT activity by a factor of 2000, it can accelerate the progression of emphysema. Patients are therefore recommended to stop smoking. The EXACTLE study assessed the development of emphysema by means of CT densitometry in 77 patients with severe AAT deficiency over a period of 2.5 years. CT densitometry was able to detect the progressive loss of lung tissue, and it was found to be more sensitive than pulmonary function or quality of life variables. With weekly intravenous supplementation of alpha-1-antitrypsin, emphysema progressed more slowly compared to placebo (albumin) infusions. In Germany, of about 900 patients are currently receiving supplementation therapy with human AAT. The treatment is well tolerated and well accepted by the patients. Symptomatic treatment consists of long- and short-acting beta-agonists, anticholinergic bronchodilators, and inhaled corticosteroids. Alpha-1 centres provide particular expertise, and it is recommended that every patient should be seen in one of these specialised outpatient clinics.
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PMID:[Update: Alpha-1-antitrypsin deficiency. Summary of a scientific symposium at the conference of the Swiss Pneumologic Society on April 16th, 2009]. 1994 Dec 65

Alpha-1-antitrypsin (AAT) deficiency results from mutations on the Protease Inhibitor (PI) locus located in chromosome 14 and has been associated with pulmonary early-onset emphysema and chronic obstructive pulmonary disease (COPD). African populations show a lower prevalence of AAT deficiency compared to Europeans. Two hundred and two (202) unrelated samples from the Cape Verde archipelago (Northwest Africa) were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using PCR - Mediated Site-Directed Mutagenesis. PI*S mutation in Cape Verde (3.2%) presents one of the highest frequencies in sub-Saharans, similar to South Africa (3.3%) but lower than Angolans (18.8%), Namibians (14.7%), Nigerians (6.4%) and Botswains (4.5%). The PI*Z mutation shows lower values (0.2%) than other sub-Saharan populations, namely Somalia (1.15%), Mali (0.98%)or Nigeria (0.36%). However, many other sub-Saharan populations, like Botswana, Congo, Cameroon, Angola, Gambia, South Africa, Mozambique and Namibia, lack the PI*Z mutation. The frequency of all the AAT deficiency genotypes in the Cape Verde archipelago (PI*ZZ, PI*SS, and PI*SZ) was estimated to be one of the highest in sub-Saharans (15 per 1000), only lower than Angola (54 per 1000) and Namibia (22 per 1000). The results obtained show a high prevalence of the AAT deficiency in Cape Verdeans when compared to other sub-Saharans a condition that can be explained by a heavy European genetic influence, characteristic of that population.
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PMID:Alpha-1-antitrypsin deficiency in the Cape Verde islands (Northwest Africa): High prevalence in a sub-Saharan population. 2022 49

The hereditary disorder alpha-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-kappaB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease-anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.
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PMID:Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. 2022


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