Alpha1-antitrypsin deficiency: biological answers to clinical questions

Alpha1-antitrypsin (alpha1AT) deficiency is a common lethal hereditary disorder of white persons of European descent. The condition is characterized by reduced serum levels of alpha1AT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. Alpha1AT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase cathepsin G and proteinase 3. The clinical manifestations of alpha1AT deficiency occur chiefly in the lung, with a high risk of emphysema occurring by the third or fourth decade of life. Cigarette smoking accelerates the development of emphysema in persons with alpha1AT deficiency. There is also an increased risk of liver disease in alpha1AT deficiency, which occurs mostly in childhood. In this review, we will define further the diagnosis of alpha1AT deficiency and its clinical manifestations and describe the therapeutic strategies that are currently being developed to treat the hepatic and pulmonary disease associated with this condition.     

Alpha1-antitrypsin deficiency and hepatic carcinoma.

A patient with homozygous ZZ alpha1-antitrypsin deficiency and severe pulmonary emphysema was discovered to have a mixed hepatocellular and cholangiolar hepatic carcinoma arising in a noncirrhotic liver. Because of the increasing frequency of hepatomas in patients with alpha1-antitrypsin deficiency, it is suggested that a causal relationship may exist.     

Alpha1-antitrypsin deficiency and pancreatic fibrosis.

A 39-year-old woman with homozygous ZZ alpha1-antitrypsin deficiency was found to have pancreatic fibrosis in addition to the recognized pulmonary and hepatic abnormalities. Pancreatic exocrine function was normal but endocrine studies showed glucose intolerance. Pancreatic fibrosis may be another manifestation of alpha1-antitrypsin deficiency.     

Alpha1-antitrypsin deficiency in childhood

Alpha (1)-antitrypsin deficiency is a common genetic disease in which individuals homozygous for the mutant Z allele are at risk for the development of liver disease and emphysema. The mutant Z protein product is synthesized in hepatocytes but then accumulates intracellularly rather then being appropriately secreted. The effects of the intracellular accumulation of the mutant Z protein in the liver include the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation, which progress in a cascade causing hepatocellular injury. Liver disease can occur at any age, although the majority of children are free of significant liver dysfunction. The variable clinical presentations suggest an important contribution of genetic and environmental disease modifiers. The heterozygous carrier state for the mutant Z gene, present in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.     

Alpha 1-antitrypsin deficiency associated with PZ and MP phenotypes. Clinical and laboratory correlations

In a large kindred we have identified two siblings with the hitherto unreported PZ phenotype and eight other subjects with the MP phenotype. In subjects with the MP phenotype serum alpha₁-antitrypsin levels are near the lower limits of normal. In contrast, subjects with the PZ phenotype have severely depressed alpha₁-antitrypsin levels. One subject with the PZ phenotype at age 34 already shows evidence of obstructive lung disease. We found no convincing evidence of obstructive lung disease in family members with the MP phenotype. After purification of alpha₁-antitrypsin from the serum, isoelectric focusing and acrylamide gel electrophoresis can be used to distinguish normal protein from the products of the Pi^P and Pi^Z alleles. Subjects with the PZ phenotype have more Pi^P than Pi^Z product.     

Alpha 1-antitrypsin deficiency and pancreatitis in a juvenile

An 18-year-old female with PiSZ phenotype alpha 1-antitrypsin deficiency presented with pancreatitis and a pancreatic pseudocyst. There were no other causative factors. Deficiency of alpha 1-antitrypsin may predispose to pancreatitis or exacerbate existing pancreatic disease.     

Alpha1-antitrypsin deficiency: situation in Spain and development of a screening program

Studies undertaken in Spain indicate that 9% of the general population aged between 40 and 70 years is affected by chronic obstructive pulmonary disease (COPD). Although tobacco smoke is the causative factor in more than 90% of cases, it is estimated that only 10% to 20% of smokers develop COPD. This may be explained by the existence of genetic or environmental factors that modulate the toxic effects of tobacco. The best known genetic factor is alpha1-antitrypsin deficiency, which is associated with an increased risk of developing pulmonary emphysema in smokers. The most recent guidelines from both the World Health Organization and the American Thoracic Society/European Respiratory Society recommend the establishment of screening programs for the detection of alpha1-antitrypsin deficiency in patients with COPD. This strategy is crucial in Spain, where the disease is under diagnosed, mainly due to a low index of suspicion among doctors.     

Alpha1-antitrypsin deficiency: current perspective on research, diagnosis, and management

The Alpha One International Registry (AIR), a multinational research program focused on alpha₁-antitrypsin (AAT) deficiency, was formed in response to a World Health Organization recommendation. Each of the nearly 20 participating countries maintains a national registry of patients with AAT deficiency and contributes to an international database located in Malmö, Sweden. This database is designed to increase understanding of AAT deficiency. Additionally, AIR members are engaged in active, wide-ranging investigations to improve the diagnosis, monitoring, and treatment of the disease and meet biennially to exchange views and research findings. The fourth biennial meeting was held in Copenhagen, Denmark, on 2–3 June 2005. This review covers the wide range of AAT deficiency-related topics that were addressed encompassing advances in genetic characterization, risk factor identification, clinical epidemiology, inflammatory and signalling processes, therapeutic advances, and lung imaging techniques.     

Alpha 1-antitrypsin deficiency with bronchiectasis in two sisters]

Two sisters with alpha 1-antitrypsin deficiency and bronchiectasis are reported. The 53-year-old older sister (propositus) had pneumonia 3 times during her forties. She developed dyspnea on exertion in February, 1988, and a few months later she was seen at our hospital. Her serum alpha 1-antitrypsin level was 11 mg/dl. Vascular markings on chest X-ray were mildly decreased. Bronchography showed generalized cystic bronchiectasis. The younger sister was seen at our hospital at the age of 50. She had been in good health until one year previously when she had developed pneumonia, and thereafter she had suffered from productive cough and dyspnea on exertion. Her alpha 1-antitrypsin level was 22 mg/dl. Chest X-ray showed ring-like shadows and tram lines. Chest CT scans of both sisters revealed cystic changes, dilatation of bronchi, and the connection of these lesions diffusely. The alpha 1-antitrypsin phenotype of these sisters was found to be PiSiiyama (homozygote). Family study revealed that alpha 1-antitrypsin levels of 7 members were intermediate and no members had symptoms. We consider that bronchiectasis may have been related to alpha 1-antitrypsin deficiency in these sisters.     

Alpha 1-antitrypsin deficiency and increased susceptibility to elastase-induced experimental emphysema in a rat model.

Administration of 200 mg of D-galactosamine/kg intraperitoneally to rats produced a decrease in the serum concentrations of trypsin and elastase inhibitory capacities. Induction of emphysema by intravenous injection of pancreatic elastase resulted in significantly increased severity of the disease in the animals depleted of alpha 1-antitrypsin. The degree of severity of the disease determined by mean linear intercept suggested a correlation with trypsin and elastase inhibitory capacities at the time of elastase injection.     

Alpha1-antitrypsin deficiency with severe panniculitis. Report of two cases.

Two patients with profound decrease of alpha1-antitrypsin (PiZZ) presented with severe pannicultis (Weber-Christian disease); one had systemic panniculitis including pancreatitis. Another possible case is quoted from the literature. Although milder forms of panniculitis can have normal Pi phenotypes and alpha1-antitrypsin levels, the marked reduction of antiproteolytic activity found in PiZZ homozygotes may predispose to or aggravate the lesions of Weber-Christian disease.     

Alpha 1-antitrypsin deficiency and the liver (author's transl)

Alpha 1-antitrypsin (alpha 1 AT) is a glycoprotein of hepatic origin which functions as a systemic protease inhibitor (Pi). Its production is controlled by two autosomal-codominantly transmitted alleles. Among the numerous genetic variants some alleles (predominantly PiZ) may induce alpha 1 AT-deficiency, facultatively associated with childhood liver disease. However, the pathogenesis of this congenital disorder, which may progress to complete cirrhosis remains obscure at present. In addition, no clear cut relationship has been proven between alpha 1 AT-deficiency and deranged liver architecture, observed in advanced aged adults. Possibly this may reflect a more accidental coincidence with the consequences of chronic viral hepatitis (Non A-Non B-type). Nevertheless, this hypothesis is hitherto unestablished as it holds for the supposed association between alpha 1 AT-deficiency and the occurrence of malignant hepatoma.     

Association between heterozygous alpha 1-antitrypsin deficiency and genetic hemochromatosis.

Primary hemochromatosis is a genetically determined autosomal recessive disorder characterized by the excessive accumulation of body iron, most of which is deposited in the parenchymal cells of various organs. alpha 1-Antitrypsin deficiency is characterized among others by defective secretion of alpha 1-antitrypsin from liver cells. Whereas the risk of cirrhosis is increased in homozygous patients (PI ZZ) and possible in heterozygous patients (non-PI MM) as well, a greater risk for hepatocellular carcinoma has been suggested only in homozygous patients. Because these two metabolic disorders are relatively common, it has been difficult to determine whether they are associated with each other. In this study, we tried to determine the relationship between these two disorders using the case material seen at the University of Pittsburgh during a 7-yr period. We studied 15 patients with genetic hemochromatosis. alpha 1-Antitrypsin quantitation and phenotyping were performed in each case using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds ratio and chi 2 tests were used to measure the relative risk and significance of association, respectively. Eleven patients (73%) were found to be PI M and four (27%) were identified as being heterozygotes: three (20%) were PI MZ, and one (7%) was PI MS. The prevalence of the PI MS phenotype was similar to that in the general population (7% vs. 6.4%; NS). The PI MZ phenotype, however, was statistically more common in patients with hemochromatosis than in the general population (20% vs. 2.2%; p less than 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha-1-antitrypsin deficiency: a biological enigma.

The association of certain forms of liver disease and a deficiency of alpha-1-antitrypsin is an observation which raises the possibility that other forms of liver disease ultimately will be found to have as their proximate cause a defined metabolic aberration, which may in turn be inherited. Although alpha-1-antitrypsin deficiency is a genetically determined error of protein synthesis, environmental factors, unrecognised at present, are required for the disease to become overt. Thus, this interesting association may herald an increasing number of clinical diseases in which the interaction of environmental stimuli and single genetically determined aberrations are crucially important. The diseases to which we succumb may be largely determined by a genetically determined susceptibility, a point of view which was stated so well by Archibalt Garrod in his essay Inborn Factors in Disease published nearly half a century ago.     

Alpha 1-antitrypsin in acute myocardial infarction.

Alpha 1-antitrypsin serum levels were measured in 48 patients with acute myocardial infarction and in 19 control patients either with coronary heart disease without necrosis, or with neither coronary disease nor inflammation. Alpha 1-antitrypsin was significantly raised in the group of patients with acute myocardial infarction. As some patients individually showed no change in alpha 1-antitrypsin levels, however, they were divided into two groups according to the maximum serum levels attained. Patients with non-increasing levels of alpha 1-antitrypsin showed increased mortality and a higher incidence of cardiogenic shock, whereas reinfarction occurred more frequently in the group with high alpha 1-antitrypsin levels. Our findings may suggest that the course of a myocardial infarction is determined not only by the severity of the ischaemic event, but also by the response of the "acute" phase reaction" mechanism. We conclude that a failure of alpha 1-antitrypsin levels to increase after myocardial infarction may be associated with a worse clinical course.     

Alpha 1-antitrypsin phenotypes in cirrhosis and hepatoma.

The phenotypic distribution of alpha-1-antitrypsin variants has been studied in 101 patients with cirrhosis and in 50 with cirrhosis plus hepatoma. 504 healthy Greeks served as controls. The ZZ and MZ phenotypes were found only once in the group of cirrhosis. The very low PiZ gene frequency suggests that the association of PiZ gene with cirrhosis is fortuitous. The FM phenotype has been observed in 14% of patients with hepatoma arised on cirrhosis and this incidence differed significantly between the two groups of patients and the controls. It is possible that cirrhotic patients phenotypically FM develop for as yet unknown reasons hepatoma in high percentage.     

Alpha1-antitrypsin replacement therapy controls fibromyalgia symptoms in 2 patients with PI ZZ alpha1-antitrypsin deficiency

Two Spanish sisters with alpha1-antitrypsin (AAT) deficiency and fibromyalgia (FM) started AAT replacement therapy with commercial alpha1-antitrypsin infusions in 1992. They both experienced a rapid, progressive, and constant control of their FM symptoms during the next 6 years (1992-98). However, in 1998, treatment of both patients was affected by the worldwide commercial shortage of AAT replacement therapy; replacement therapy infusions were halted for about 4-6 consecutive months every year for 5 years. As a result, we observed a striking recurrence of FM symptoms. Equally striking was the total disappearance of these symptoms when AAT replacement therapy infusions were resumed.