Alpha1-antitrypsin phenotypes in patients with cryptogenic fibrosing alveolitis: a case-control study

Cryptogenic fibrosing alveolitis (CFA) is an interstitial lung disease, which by definition is of unknown aetiology. Recent evidence has suggested that smoking and occupational exposure to dusts may be environmental risk factors for the disease, but there has been little research into potential host risk factors. One previous study has suggested that the prevalence of abnormal alpha1-antitrypsin phenotypes may be increased in patients with CFA. Since alpha1-antitrypsin is important in regulating inflammation within the lung in response to environmental exposures, such abnormalities may be of aetiological importance in this disease. We have compared the alpha1-antitrypsin phenotypes of 189 patients with CFA with 189 age-, sex-, and community-matched controls. This sample size was sufficient to provide more than 95% power to detect an odds ratio (OR) of 2.5. Alpha1-antitrypsin phenotype was established by isoelectric focusing, and the prevalence of abnormal phenotypes in cases and controls was compared by conditional logistic regression. Personal smoking histories were obtained by postal questionnaire. The prevalence of abnormal alpha1-antitrypsin phenotypes was similar in cases and controls (12.7 versus 15.3%; OR 0.88; 95% confidence interval 0.49-1.57; p=0.66). No interaction was found between the presence of abnormal alpha1-antitrypsin phenotypes and a history of smoking. We conclude that cryptogenic fibrosing alveolitis is not associated with abnormal alpha1-antitrypsin phenotypes.     

Alpha-1-antitrypsin phenotypes among patients with intracranial aneurysms

A deficiency of alpha 1-antitrypsin has been implicated in the development of arterial aneurysms, including intracranial aneurysms. The authors determined the prevalence of alpha 1-antitrypsin deficiency of different phenotypes in 100 consecutive patients with intracranial aneurysms and compared the distribution of alpha 1-antitrypsin phenotypes to that in the general population (904 people). The study population consisted of 44 men and 56 women with a mean age of 52 years (range 15-81 years). The heterozygous alpha 1-antitrypsin deficiency states (PiMS and PiMZ) were more common in patients (16%) than in the general population (7%), providing an odds ratio of 2.56 (95% confidence interval (CI) 1.32-4.75; p = 0.005). In addition, one patient (1%) was homozygous for the deficient allele (PiZZ) compared to an expected number of 0.015, providing an odds ratio of 67.0 (95% CI 2.0-363.3; p = 0.015). These findings lead the authors to suggest that the heterozygous and homozygous alpha 1-antitrypsin deficiency states are genetic risk factors for the development of intracranial aneurysms.     

Transfer of the human Alpha1-antitrypsin gene into pulmonary macrophages in vivo

Issues related to psychological recovery following coronary bypass surgeries (CABG) have emerged in recent years. Other research has shown the effects of spiritual or religious activities on health and aging. However, little is known about the relationship of spiritual coping, including religious coping, to post-CABG adjustment. This study addressed multifactorial determinants of postoperative psychological recovery and the effects of private prayer, a form of spiritual coping, on the recovery of 151 older patients. Results show that most patients pray about their postoperative problems and that private prayer appears to significantly decrease depression and general distress one year post-CABG.     

Alpha 1-antitrypsin deficiency and asthma. The continuing search for the relationship

Patients with alpha 1-antitrypsin (AAT) deficiency, like those with asthma and chronic obstructive pulmonary disease, usually present with dyspnea, wheeze, and cough. The similarity in presentation and unfamiliarity among clinicians with AAT deficiency account for much of the delay in diagnosis. Normally, AAT inhibits serine proteases, which cause alveolar destruction, and alters the function of cells that release mediators of inflammation. Diagnostic findings suggesting deficiency include irreversible airflow obstruction, a decreased diffusing capacity of the lung for carbon monoxide, bibasilar bullous disease on chest films, and a low serum level of AAT. Asthma is usually diagnosed on the basis of clinical findings and response to inhaled beta agonists. The presence of inflammation is believed to be necessary for development of clinically significant asthma. Inflammation added to a deficiency of antiprotease inhibitor activity significantly worsens bronchial hyperreactivity. This is only one mechanism by which AAT deficiency may potentiate allergic and bronchospastic responses. The prevalence of bronchial asthma in patients with AAT deficiency is unknown. Studies by the National Institutes of Health regarding the natural history of AAT deficiency and its response to therapy are under way. Perhaps more will be discovered about the relationship between the disorder and bronchial asthma.     

Frequency and significance of phenotypes for alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis

To evaluate the frequency and significance of alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis, 181 Caucasian patients were assessed for variant phenotypes. Three hundred three Caucasian patients with various other chronic liver diseases were similarly evaluated. Twenty-one of the 181 patients (12%) had heterozygous deficiencies, including the MS (6%) and MZ (6%) phenotypes. These patients were indistinguishable from those with normal phenotypes. Immediate outcomes after corticosteroid therapy were also similar in both groups. Variant phenotypes were present in 34 of the 303 patients with other chronic liver diseases (11%). Patients with nonalcoholic steatohepatitis had a significantly greater frequency of deficiency phenotypes than patients with chronic hepatitis C (20% vs 7%, P = 0.03). In conclusion, deficiency phenotypes are common in type 1 autoimmune hepatitis and they have no clinical or prognostic importance. In certain liver diseases, such as nonalcoholic steatohepatitis, variant phenotypes may be comorbid factors.     

Extended major histocompatibility complex haplotypes in celiac patients in the west of Ireland

The highest reported prevalence of celiac disease (gluten-sensitive enteropathy) is found in the West of Ireland. Recent genetic data have suggested that major histocompatibility complex-linked loci may have a dominant genetic effect for disease susceptibility in this population compared with a recessive effect in other groups. To further understand the role of the MHC in celiac disease in the West of Ireland, we analyzed markers for 22 MHC haplotypes from celiac patients and compared them with 18 nontransmitted haplotypes found in the parents of celiac children, and with reported haplotypes from other populations. An extended MHC haplotype including [HLA-B8, DR3, DQw2, Bf*S, C4A*Q0, and C4B*1] accounted for 50% of celiac haplotypes but only 27% of nontransmitted parental haplotypes. Compared with other reported haplotypes in celiacs, patients from the West of Ireland show a higher prevalence of HLA-A1 as a component of this extended haplotype, suggesting that although the core haplotype is similar between Irish patients and others, the celiac population in the West of Ireland differs at other HLA loci. We did not observe any other common haplotypes among our patients unlike the situation in other populations. These differences may underlie the possible dominant effect of HLA-linked loci and the unusually high prevalence of celiac disease in the Irish population. We also found that the serum levels of complement components C3c, C4, and factor B were significantly lower among celiac patients than nonceliacs. The lower serum level of C4 appears to be related to the presence of deletions and null alleles at the C4A and C4B loci in celiacs.     

Alleles of the alpha-1-antitrypsin phenotype in patients with aortic aneurysms

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurodevelopmental disorders with interrelated genetic mechanisms because genomic imprinting within the chromosome 15q11-13 region affects both the PWS and the AS locus. Methylation analysis is one method of distinguishing between the maternally and paternally inherited chromosome 15. Here we present clinical and molecular data on a large series of 258 referred patients, evaluated with methylation analysis: 115 with suspected PWS and 143 with suspected AS. In these patients, the clinical phenotype was graded into three groups: classical (group 1); not classical but possible (group 2); not classical and unlikely (group 3). For PWS, a fourth group consisted of hypotonic babies. DNA methylation analysis confirmed the diagnosis of PWS in 30 patients (26%) and AS in 28 patients (20%). For 21 PWS patients the mechanism was established: 15 had deletions, 4 had uniparental disomy (UPD) and 2 a presumed imprinting defect. Clinically all those with an abnormal methylation pattern had the classical phenotype and none of those with a normal methylation pattern had classical PWS. For 23 AS patients in whom a mechanism was established, 17 had a deletion, 3 had UPD and 3 had a presumed imprinting defect. There was greater clinical overlap in AS, with 26 classical AS patients having a normal methylation pattern while an abnormal methylation pattern was seen in one patient from group 2. In addition, there were a further 40 patients with a normal methylation pattern in whom AS was still a possible diagnosis. Our conclusion is that methylation analysis provides an excellent screening test for both syndromes, providing approximately 99% diagnosis for PWS and for AS, a 75% diagnostic rate, supplemented for the remaining 25% with an essential basic starting point to further investigations.     

Fecal excretion and the clearance of alpha 1-antitrypsin in patients with Crohn's disease

In previous work we defined the normal values of faecal alpha-1 antitrypsin (A1ATF) and their plasmatic clearance (CLAT) in 25 healthy patients. The aim of the present study is to compare these previous results with new results obtained when we applied this test to 30 patients with Crohn's disease (CD). We also show the good performance of the mentioned tests as indicators of the intestinal inflammatory activity. We compare the values of A1ATF and CLAT of healthy patients with those of CD patients. We also compare the Crohn's Disease Activity Index (CDAI) and Simple Index between active and inactive CD patients. Our results show significant differences between A1ATF excretion and CLAT as measured in healthy and CD patients. The relationship between those parameters could be explained by the equation CLAT = 0.325 x A1ATF. Active and inactive CD patients only differ significantly with respect to their leucocytes and C reactive protein values. In our group the A1ATF excretion is larger in CD patients with colonic disease.     

Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease

The functional integrity of the small bowel is impaired in coeliac disease. Intestinal permeability, as measured by the sugar absorption test probably reflects this phenomenon. In the sugar absorption test a solution of lactulose and mannitol was given to the fasting patient and the lactulose/mannitol ratio measured in urine collected over a period of five hours. The sugar absorption test was performed in nine patients with coeliac disease with an abnormal jejunum on histological examination, 10 relatives of patients with coeliac disease with aspecific symptoms but no villous atrophy, six patients with aspecific gastrointestinal symptoms but no villous atrophy, and 22 healthy controls to determine whether functional integrity is different in these groups. The lactulose/mannitol ratio (mean (SEM) is significantly higher in both coeliac disease (0.243 (0.034), p < 0.0001)) and relatives of patients with coeliac disease (0.158 (0.040), p < 0.005)) v both healthy controls (0.043 (0.006)) and patients with aspecific gastrointestinal symptoms (0.040 (0.011)). The lactulose/mannitol ratio in relatives of coeliac disease patients was significantly lower than in the coeliac disease patient group (p = 0.04). The lactulose/mannitol ratio was the same in healthy controls and patients with aspecific gastrointestinal symptoms. It is concluded that the sugar absorption test is a sensitive test that distinguishes between patients with coeliac disease and healthy controls. The explanation for the increased permeability in relatives of patients with coeliac disease is uncertain. Increased intestinal permeability may be related to constitutional factors in people susceptible to coeliac disease and may detect latent coeliac disease. The sugar absorption test may therefore be helpful in family studies of coeliac disease.     

Anticonnective tissue and other antitissue 'antibodies' in the sera of patients with coeliac disease compared with the findings in a mixed hospital population

Serum IgG specificities directed against various components of basement membrane and reticulin have been described, and their incidence in 138 patients with coeliac disease has been compared with that in 110 hospital inpatients, 100 normal blood donors, and 1441 other patients. A wide variety of antitissue specificities were observed but only a few appeared to be of any significance. The 'antireticulin' specificities have been subdivided into different groups according to their distinctive histological staining patterns. Specificity directed primarily against endothelial basement membrane was found most frequently in the sera of patients with hiatus hernia (35%) or coeliac disease (22%). The same specificity was also observed in patients with myasthenia gravis and to a lesser extent in Crohn's disease and in a mixed group of patients with unspecified organic gastrointestinal disease. An epithelial basement membrane reactivity was found in patients with rheumatoid arthritis but only rarely in other conditions. Staining of perivascular connective tissue represented a third type of 'antireticulin' specificity. It was found only rarely, although in coeliac disease this reactivity was found more frequently in combination with other connective tissue specificities.     

Sexual behaviour in untreated and treated coeliac patients

BACKGROUND: Sexual behaviour is often altered in chronic illness. AIM: To evaluate sexual behaviour in coeliac patients before and after treatment with a gluten-free diet. PATIENTS: Fifty-five adults with coeliac disease and 51 age- and sex-matched healthy controls. METHODS: Routine clinical and laboratory work-up was used for diagnosis of coeliac disease. Age of first sexual intercourse, prevalence of individuals who were sexually active, frequency of intercourse, reduction in sexual desire, difficulty in attaining orgasm, pain during intercourse, and prevalence of individuals defining themselves as satisfied with their sexual life were investigated by an anonymous, self-administered questionnaire administered before and after one year's treatment with a gluten-free diet in coeliac patients, and only once in controls. Analyses included clinical conditions, demographic and socio-economic data. RESULTS: Compared with controls, untreated coeliac patients had a significantly lower frequency of intercourse and a lower prevalence of individuals satisfied with their sexual life. Patients with overt and subclinical coeliac disease did not show significant differences for any indices of sexual behaviour. Compared with untreated conditions, coeliac patients after one year of treatment had improved values for all indices of sexual behaviour: differences were significant for frequency of intercourse and prevalence of individuals satisfied with their sexual life. CONCLUSION: Untreated coeliac disease, even in its subclinical presentation, is associated with disorders in sexual behaviour which are improved by the dietary treatment.     

Pathophysiology and treatment of alpha 1-antitrypsin deficiency

The pathophysiology of alpha 1-antitrypsin (AAT) deficiency and the use of alpha 1-proteinase inhibitor therapy in the management of emphysema caused by AAT deficiency are described. AAT deficiency is the most common genetic cause of liver disease in children and emphysema in adults. However, not all patients with AAT deficiency develop hepatic or pulmonary involvement. Changes in the composition of the AAT molecule have been associated with AAT dysfunction in liver disease, whereas lung disease occurs when AAT concentrations are reduced. A definitive diagnosis can be made through serum AAT phenotype determination. Therapy for liver disease induced by AAT deficiency consists of supportive measures. Therapy for pulmonary disease due to AAT deficiency includes AAT augmentation therapy along with supportive measures. The available product, alpha 1-proteinase inhibitor, is derived from fractionated plasma and has similar biological activity to native serum AAT. Clinical trials have demonstrated a positive effect on serum and lung concentrations of AAT with few adverse events. Two recombinant forms of AAT have also been developed; however, few trials have been published evaluating their safety and efficacy in AAT-deficient patients. Many questions remain unanswered concerning AAT deficiency and replacement therapy. AAT augmentation therapy appears to reduce the progression of emphysema in some AAT-deficient patients.     

Fibromuscular dysplasia of the internal carotid artery in a child with alpha-1-antitrypsin deficiency

Fibromuscular dysplasia (FMD) is a non-inflammatory segmental arteriopathy of unknown origin. Most often the renal arteries are affected, however, also mesenteric, lumbar, vertebral, or carotid arteries may be involved. FMD has frequently been reported as a cause of stroke in adults, but very rarely in children. We report the case of an 11-year-old boy who presented with an ischaemic infarction in the anterior part of the territory of the left middle cerebral artery. Angiography demonstrated a 'string of beads' lesion suggestive of FMD causing occlusion at the origin of the middle artery. Laboratory analyses revealed the protease inhibitor (Pi) phenotype SZ (PiSZ) of alpha-1-antitrypsin deficiency as well as decreased antioxidants and signs of enhanced lipid peroxidation. Such an imbalance may be associated with diminished resistance to oxidation, possibly causing direct cellular and tissue injury. Whether alpha-1-antitrypsin deficiency and an impaired status of antioxidants, as seen in our patient, might play a role in the pathogenesis of FMD is presently unclear.     

Apparent total alpha1-antitrypsin deficiency: report of a case

A 29-year-old female, with chronic renal failure and chronic bilateral emphysema, was admitted with severe uremia and septicemia secondary to multiple abscesses in the right kidney. Her condition improved after right nephrectomy. Pulmonary function studies showed marked obstructive and restrictive lung disease consistent witht the diagnosis of primary emphysema. On biochemical and histological examination, the liver was found to be normal. Alpha1-antitrypsin could not be demonstrated in the patient's serum at normal pH by any of the known techniques, but protein molecules with alpha1-antitrypsin antigencity were found at pH 4.8; this suggests a pH-dependent structural difference in alpha1-antitrypsin protein. Starch gel electrophoresis gave a multibanding pattern not previously described. A new form of apparent total alpha-1-antitrypsin deficiency is postulated.     

Alpha-1-antitrypsin PLowell: a normally functioning variant present in low concentration

BACKGROUND: Alpha-1-antitrypsin deficiency is associated with a high risk for the development of emphysema, particularly for phenotype Pi ZZ, which is both deficient and an abnormal inhibitor of the powerful proteolytic enzyme, human neutrophil elastase. The rare variant PLowell is also expressed at abnormally low levels, but its anti-elastase activity has not been described. AIM: To study the anti-elastase activity of alpha-1-antitrypsin PLowell and compare it to the common M, S and Z proteins. METHOD: Alpha-1-antitrypsin from a female patient aged 75 years with the rare genotype PLowell NullBellingham was studied for its ability to inhibit human neutrophil elastase in a time dependent manner. RESULTS: PLowell has near normal function as an inhibitor of human neutrophil elastase with an association rate constant of 7.4 x 10(6) M-1 S-1 at 25 degrees C, similar to that of M and S. CONCLUSION: Alpha-1-antitrypsin PLowell is associated with a severe deficiency of alpha-1-antitrypsin similar to Z, but unlike that protein it has near normal function as an anti-elastase.     

Alpha 1-antichymotrypsin is present in and synthesized by the cornea

The proteinase inhibitor alpha 1-antichymotrypsin is present in the epithelial, stromal and endothelial layers of the human cornea. This was determined by immunolocalization in corneal sections and by Western blot analysis of extracts from the three separated layers. The inhibitor was quantified in the extracts by immunodot blot analysis. The levels observed were 1.3 +/- 0.3 microgram/cornea for the epithelial layer, 22.8 +/- 3.8 micrograms/cornea for the stromal layer and an average of 0.17 micrograms/cornea for the endothelial layer. alpha 1-Antichymotrypsin is being synthesized by the cornea. Metabolically labeled inhibitor was immunoprecipitated from the three layers following organ culture of the intact cornea. Two major forms were detected. These were the native, mature 64 kDa form and a 50 kDa form which is either a degradation product or an incompletely glycosylated form. These results indicate that the cornea has the ability to locally control degradation through synthesis of this inhibitor. Local synthesis of this inhibitor releases the cornea from total dependance upon the vascular system for its supply of alpha 1-antichymotrypsin.