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)

(1) Deficiency of alpha AT is one of the most common hereditary diseases affecting Caucasians in Europe. The alpha 1AT protein is extremely pleomorphic, and around 90 variants due to mutations have been recognized. The prime functions of alpha 1AT is to inhibit neutrophil elastase, and a proportion of individuals who are deficient in alpha 1AT develop emphysema. The most common deficiency variant (Z) is also associated with liver disease. The main site of alpha 1AT synthesis is in the liver. Not all deficient individuals are affected by lung or liver disease, however, so that other factors (genetic and environmental) are clearly important. (2) Investigation of alpha 1AT status is essential in any child or adult presenting with chronic liver disease. The genetic cause cannot be identified clinically or by any other laboratory investigation. The diagnosis carries important prognostic consequences and is important for other family members. Patients with emphysema should have their Pi type determined, especially if they are under the age of 50, have never smoked or there is a suggestive family history. Asymptomatic individuals who are homozygous type Z should be referred to a chest physician for a clinical and radiological assessment together with lung function tests. (3) Several laboratory tests are available to detect alpha 1AT deficiency, and the choice of test(s) will depend on circumstances. Quantitation of the serum protein is simple and cheap. Because alpha 1AT is an acute phase protein, however, quantitation used in isolation may give false negative results which are clearly unacceptable, particularly in association with paediatric liver disease. Phenotyping by isoelectric focusing requires some experience in distinguishing SZ and ZZ phenotypes, and phenotyping should ideally be used in conjunction with quantitation because heterozygous null phenotypes may appear identical to homozygous normal phenotypes. (4) Prenatal diagnosis is usually performed by DNA analysis of CVS samples obtained at 11-13 weeks. Because of the risk that CVS samples might be contaminated by maternal tissue, assays which are less likely to detect minor contaminants are preferable. At present, use of DNA tests is confined to prenatal diagnosis, but the availability of simple tests and the possibility of unequivocal identification of S and Z alleles means that these tests are likely to find greater use in the near future.
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PMID:Molecular basis, clinical consequences and diagnosis of alpha-1 antitrypsin deficiency. 968 Oct 66

alpha 1-Antitrypsin (AAT) deficiency, also known as alpha 1-antiprotease inhibitor deficiency, is a disease caused by genetically determined AAT deficiency. It occurs as a result of inheritance of two protease inhibitor (PI) deficiency alleles from the AAT gene locus (designated PI) on chromosomal segment 14q32.1. The most common deficiency allele is PI*Z and a large majority of individuals with severe AAT deficiency are PI type ZZ. The disease occurs predominantly in white persons of European origin and its frequency in Europe and North America is comparable to that of cystic fibrosis (1 in 2000 to 1 in 7000.) Persons with AAT deficiency may have no clinical manifestations. Chronic obstructive pulmonary disease (COPD) with a high frequency of panacinar emphysema is the most prevalent clinical disorder associated with AAT deficiency and the most frequent cause of disability and death. Tobacco smoking is the major risk factor for developing COPD, which generally begins by the third decade of life, much earlier than "usual" COPD that occurs in AAT-replete individuals. Liver disease, the second most frequent clinical manifestation of AAT deficiency, typically presents as cholestasis in infancy but is usually not severe and generally remits by adolescence. Chronic liver disease develops infrequently, although AAT deficiency is the commonest cause of chronic liver disease in childhood. Cirrhosis and carcinoma of the liver affect at least 25% of AAT-deficient adults over the age of 50 years. AAT deficiency appears to be widely underdiagnosed and based on predicted gene frequencies even in the most intensely studied populations, only a small proportion of those predicted to have AAT deficiency have been diagnosed. Human AAT is available in limited quantity for augmentation therapy. This Memorandum summarizes the discussions and recommendations made by participants at a WHO meeting held in Geneva on 18-20 March 1996 to review existing knowledge about this highly prevalent genetic disorder, develop a strategy for enhancing awareness of it among health-care-givers and the general public, and explore new case-finding and disease-prevention strategies.
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PMID:Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. 944 74

Homozygous PIZZ alpha 1-antitrypsin deficiency, which has an incident of 1 in 1600 to 1 in 2000 live births, is the most common genetic cause of liver disease in children. It is also associated with chronic liver disease and hepatocellular carcinoma in adults. It is a well-known cause of pulmonary emphysema. Although emphysema is due to uninhibited proteolytic destruction of the connective tissue backbone of the lung, liver disease is thought to result from the toxic effects of the mutant alpha 1AT molecule retained within the endoplasmic reticulum of liver cells. Screening studies done by Sveger in Sweden have shown that only 10 to 15% of the PIZZ population develop clinically significant liver disease over the first 20 years of life. Recent studies have suggested that a subgroup of PIZZ individuals are predisposed to liver injury because of an inefficient degradation of mutant alpha 1ATZ within the endoplasmic reticulum. Altered migration of the abnormal alpha 1ATZ molecule in isoelectric focussing gels is the basis of the diagnosis of alpha 1AT deficiency. Treatment of alpha 1AT deficiency-associated liver disease is mostly supportive. Liver replacement therapy has been used successfully for severe liver injury. An increasing number of patients with severe emphysema have undergone lung transplantation.
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PMID:Alpha-1-antitrypsin deficiency. 977 22

Alpha 1-Antitrypsin deficiency (PiZ) is frequent in Caucasian populations. The predominant clinical correlates of this inborn error, i.e. chronic liver disease, emphysema, and vasculitic syndromes including their pathogenetic background are discussed in the present review.
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PMID:Alpha 1-antitrypsin deficiency. 989 72

Alpha 1-antitrypsin deficiency is the most common genetic cause of liver disease in children. It is also associated with chronic liver disease, hepatocellular carcinoma, and pulmonary emphysema in adults. Liver injury is caused by hepatotoxic effects of retention of the mutant alpha 1-antitrypsin molecule within the endoplasmic reticulum of liver cells, and emphysema is caused by uninhibited proteolytic damage to elastic tissue in the lung parenchyma. Recent studies of the biochemistry and cell biology of the mutant alpha 1-antitrypsin molecule have led to advances in understanding susceptibility to liver injury and in developing new strategies for prevention of both liver and lung disease.
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PMID:Liver injury in alpha 1-antitrypsin deficiency. 1123 97

Alpha-1-antitrypsin (AT) deficiency was first described in the late 1960s in patients with severe pulmonary emphysema. The recognition of AT deficiency as a cause of emphysema then led to what is still the prevailing theory for the pathogenesis of emphysema, the protease-antiprotease theory. Soon it was found that AT deficiency accounted for a significant number of cases of neonatal liver disease that were previously categorized as idiopathic. We now know that AT deficiency is the most common genetic cause of neonatal liver disease and the most frequent diagnosis necessitating liver transplantation. It has also been shown to cause chronic liver disease, cryptogenic cirrhosis, and hepatocellular carcinoma in adults never previously known to have liver disease in infancy or childhood. Observations indicate that genetic traits unlinked to the AT gene or environmental factors predispose to or protect AT-deficient individuals from liver disease.
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PMID:Alpha-1-antitrypsin deficiency: diagnosis and treatment. 1546 58

Alpha1-antitrypsin deficiency (AATD) is a common hereditary disorder associated with high risk of developing pulmonary emphysema early in life and, to a lesser extent, chronic liver disease and cirrhosis. Among Northern Europeans and Northern Americans, more than 95% of individuals with emphysema associated with AATD carry the most frequent AAT deficient gene variants, PI*Z and PI*S. Rare AAT deficient variants account for 2-4% of AATD individuals. We extend the sequence data on AAT by characterizing a novel Null allele detected in 3 subjects: a carrier belonging to an Italian/Egyptian family and 2 members of a family originating from Southern Italy. The mutation raised on a M1 (Ala213) base allele and it is characterized by an A-->T transversion at exon III, nt 218, codon 259 (AAA-->TAA) (GeneBank accession number AY 256958). The transversion results in a premature stop codon (Lys259AAA-->Stop259TAA). The proposed nomenclature of Q0cairo is from the birthplace of the father of first recognized subject. Serum levels and isoelectric focusing of AAT were consistent with the presence of the Null variant.
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PMID:Identification of a novel alpha1-antitrypsin null variant (Q0Cairo). 1590 97

In 3 patients, 2 men aged 51 and 40 years and a 50-year-old woman, with liver-function disorders due to excessive consumption of alcohol, the liver function deteriorated rapidly resulting in the patients' death. All 3 were found to be heterozygous for alpha1-antitrypsin (AT) deficiency. Alpha1-AT deficiency can lead to cirrhosis of the liver and pulmonary emphysema. There are indications that heterozygous alpha1-AT deficiency can contribute to the development of a chronic liver disease, even when the serum level of alpha1-AT is within the normal range, especially in association with other risk factors such as alcohol abuse or chronic viral hepatitis. Persons with this mutation also have an increased risk for the development of cryptogenic cirrhosis and primary liver-cell carcinoma. Determination of the alpha1-AT phenotype should perhaps be recommended for all patients with a chronic liver disease, especially if the liver function deteriorates more rapidly than expected, even in the presence of a normal alpha1-AT serum level. A liver biopsy remains the gold standard for establishing the presence of alpha1-AT deposits in the liver.
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PMID:[Heterozygosity for alpha1-antitrypsin deficiency as a cofactor in the development of chronic liver disease]. 1618 48

Alpha1-antitrypsin (D,1AT) is the most abundant circulating protease inhibitor (Pi) in human plasma. It has central function in controlling tissue degradation by inhibiting a large number of proteases including neutrophil elastase and proteinase 3 (PR3). PR3, the Wegner's autoantigen, has been suggested to be involved in the pathogenesis of small-vessel systemic vasculitides. alpha1 AT deficiency (PiZ) is frequent in Caucasian populations, and its homozygous state (PiZZ) is known to predispose to lung emphysema and chronic liver disease. A strong correlation between heterozygous (PiZ) and homozygous (PiZZ) alpha1 AT deficiency and anti-neutrophil cytoplasmic autoantibodies (ANCA) associated systemic nocrotizing vasculitides has recently been reported in various populations. In this review the pathogenesis of small-vessel vasculitides is outlined, focusing on the role of alpha1 AT deficiency. alpha1 AT has been suggested to have a crucial role as a protective protein in ANCA-associated vasculitic syndromes.
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PMID:The role of alpha1 -antitrypsin Deficiency in the Pathogenesis of Antineutrophil Cytoplasmic Antibodies Associated Systemic Necrotizing Vasculitides. 1821 13

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. 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. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. 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 linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 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. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. 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 liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.
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PMID:Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. 1856 11


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