Effect of one year of a gluten-free diet on the clinical evolution of irritable bowel syndrome plus fibromyalgia in patients with associated lymphocytic enteritis: a case-control study.

INTRODUCTION: Irritable bowel syndrome (IBS), lymphocytic enteritis (LE) and fibromyalgia syndrome (FMS) are three common disorders. Since a gluten-free diet (GFD) has been shown to be helpful in LE, we aimed to assess its effect in a series of LE patients also diagnosed with IBS and FMS. METHODS: The study sample comprised 97 IBS plus FMS adult females, of whom 58 had LE (Marsh stage 1), and 39 had a normal duodenal biopsy (Marsh stage 0). All patients fulfilled the Rome III and American College of Rheumatology 1990 criteria. All participants followed a GFD, the effectiveness of which was assessed by changes in the results of several tests, including those of the Fibromyalgia Impact Questionnaire (FIQ), the Health Assessment Questionnaire (HAQ), tender points (TPs), the Short Form Health Survey (SF-36), and the Visual Analogue Scales (VAS) for gastrointestinal complaints, pain and fatigue. RESULTS: At baseline, all patients had a poor quality of life (QoL) and high VAS scores. After one year on a GFD, all outcome measures were somewhat better in the Marsh stage 1 group, with a mean decrease of 26 to 29% in the TPs, FIQ, HAQ and VAS scales, accompanied by an increase of 27% in the SF-36 physical and mental component scores. However, in the IBS plus FMS/Marsh stage 0 group, the GFD had almost no effect. CONCLUSIONS: This pilot study shows that a GFD in the LE-related IBS/FMS subgroup of patients can produce a slight but significant improvement in all symptoms. Our findings suggest that further studies of this subject are warranted.

Clinical impact of a gluten-free diet on health-related quality of life in seven fibromyalgia syndrome patients with associated celiac disease.

BACKGROUND: Celiac disease (CD) is an autoimmune disorder, characterized by the presence of gastrointestinal and multisystem symptoms, which occasionally mimic those of Irritable Bowel Syndrome (IBS) and Fibromyalgia Syndrome (FMS). To assess the effectiveness of a Gluten-Free Diet (GFD) in seven adult female screening-detected CD subjects, categorized as severe IBS and FMS patients. METHODS: All subjects showed villous atrophy in duodenal biopsies, were HLA-DQ2/DQ8-positive, and fulfilled the Rome III and ACR 1990 criteria respectively for IBS and FMS classification. GFD effectiveness was assessed at baseline and after 1 year, examining the score changes in the Tender Points (TPs) test, Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ), Short Form Health Survey (SF-36), Visual Analogue Scales (VAS) for gastrointestinal complaints, pain and tiredness, drug prescriptions and tissue-Trans-Glutaminase (tTG) serum levels. RESULTS: At baseline, all patients had poor Quality of Life and VAS scores, a high number of TPs and drug prescriptions, and increased tTG levels. After 1 year of GFD, all outcome measures significantly improved, with a decrease of 51-60% in TPs, FIQ, HAQ, and VAS scales, and in the number of prescribed drugs, accompanied by an increase of 48-60% in SF-36 Physical and Mental Component Summary scores, and a decrease of tTG to normal values. CONCLUSION: Results of this pilot study show that the adherence to a GFD by CD-related IBS/FMS patients can simultaneously improve CD and IBS/FMS symptoms, and indicate the merit of further research on a larger cohort.

Remarkable prevalence of coeliac disease in patients with irritable bowel syndrome plus fibromyalgia in comparison with those with isolated irritable bowel syndrome: a case-finding study.

INTRODUCTION: Irritable bowel syndrome (IBS) and fibromyalgia syndrome (FMS) are two common central sensitization disorders frequently associated in the same patient, and some of these patients with IBS plus FMS (IBS/FMS) could actually be undiagnosed of coeliac disease (CD). The present study was an active case finding for CD in two IBS cohorts, one constituted by IBS/FMS subjects and the other by people with isolated IBS. METHODS: A total of 104 patients (89.4% females) fulfilling the 1990 ACR criteria for FMS and the Rome III criteria for IBS classification and 125 unrelated age- and sex-matched IBS patients without FMS underwent the following studies: haematological, coagulation and biochemistry tests, serological and genetic markers for CD (i.e., tissue transglutaminase 2 (tTG-2) and major histocompatibility complex HLA-DQ2/HLA-DQ8), multiple gastric and duodenal biopsies, FMS tender points (TPs), Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ), 36-Item Short Form Health Survey (SF-36) and Visual Analogue Scales (VASs) for tiredness and gastrointestinal complaints. RESULTS: As a whole, IBS/FMS patients scored much worse in quality of life and VAS scores than those with isolated IBS (P < 0.001). Seven subjects (6.7%) from the IBS/FMS group displayed HLA-DQ2/HLA-DQ8 positivity, high tTG-2 serum levels and duodenal villous atrophy, concordant with CD. Interestingly enough, these seven patients were started on a gluten-free diet (GFD), showing a remarkable improvement in their digestive and systemic symptoms on follow-up. CONCLUSIONS: The findings of this screening indicate that a non-negligible percentage of IBS/FMS patients are CD patients, whose symptoms can improve and in whom long-term CD-related complications might possibly be prevented with a strict lifelong GFD.

Alpha-1 Antitrypsin Deficiency PI*Z and PI*S Gene Frequency Distribution Using on Maps of the World by an Inverse Distance Weighting (IDW) Multivariate Interpolation Method.

UNLABELLED: . BACKGROUND: Currently, there is a remarkable lack of genetic epidemiological studies on alpha 1-antitrypsin (AAT) deficiency in about half of the 193 countries of the World. This fact impedes the establishment of a true prevalence pattern of this deleterious hereditary disorder in extensive regions of human population. 2. OBJECTIVES: The aim of the present study was to generate detailed maps of the frequency distribution of the two most frequent AAT deficiency alleles (i.e., PI*S and PI*Z) in all areas of the World. 3. MATERIALS AND METHODS: Available data provided by epidemiological studies performed in 94 of 193 countries worldwide was used to develop detailed maps of these two alleles, We employed an informatics mathematical approach, namely: the ArcMap [a component of ESRI's ArcGIS Geographical Information System (GIS), for Microsoft Windows], based on the inverse distance weighting (IDW) multivariate interpolation method, which creates new numerical points from known data, using a simple logarithm based in the distance existing between them 4. RESULTS: In this method, PI*S and PI*Z frequencies were represented by colored scales, where qualitative colors were converted into quantitative data, providing information on their distribution in all parts of the world. This approach not only confirmed our previous data, but also provided digital images of the remaining regions of all continents. 5. CONCLUSIONS: By using this approach, striking differences were found among regions, and unsuspected significant values of the PI*S and PI*Z alleles frequencies were obtained for several geographic regions where have not been studied yet. In fact, some of these regions might be considered as priority targets for further screening studies on AAT deficiency, in order to identify, and properly manage, individuals at risk for the diverse adverse health effects associated with AAT deficiency.

Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review.

Genetic epidemiological studies on the prevalence and numbers of individuals with α1-antitrypsin deficiency in each of 97 countries worldwide were used to estimate the numbers in each of the five following phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ. These 97 countries were then grouped into 10 major geographic regions to make it possible to compare the numbers in each of these five phenotypic classes in immediately adjacent countries. Such groupings also make it possible to review the spread of the PI*S and PI*Z alleles from one major geographic grouping to another in the world as well as the spread of these two deficiency alleles within a major geographic region. The data in the 10 tables on the numbers in each of the five phenotypic classes in the countries in the same geographic region as well as the prevalence of the PI*S and PI*Z alleles in countries in the same geographic region provide a novel database for the identification of large numbers of individuals in a given phenotypic class. The database also provides useful information for the identification of countries with high numbers of PI*ZZ individuals for augmentation therapy within a given geographic region.

Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema.

Up to now alpha 1-antitrypsin (AAT) augmentation therapy has been approved only for commercial use in selected adults with severe AAT deficiency-related pulmonary emphysema (i.e. PI*ZZ genotypes as well as combinations of Z, rare and null alleles expressing AAT serum concentrations <11 µmol/L). However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma. Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection. These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema. The aim of the present study is to compile and analyze both clinical and histological features of the aforementioned published case studies and reports where AAT augmentation therapy was used for conditions other than pulmonary emphysema. Particularly, our research refers to ten case reports and two clinical trials on AAT augmentation therapy in patients with both AAT deficiency and, at least, one of the following diseases: fibromyalgia, vasculitis, panniculitis and bronchial asthma. In all the cases, AAT was successfully applied whereas previous maximal conventional therapies had failed. In conclusion, laboratory studies in animals and humans as well as larger clinical trials should be, thus, performed in order to determine both the strong clinical efficacy and security of AAT in the treatment of conditions other than pulmonary emphysema.

Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America.

BACKGROUND: Our earlier publications have demonstrated that alpha-1 antitrypsin (AAT) deficiency is not a rare disorder in the United States with at least 33,728 PI*ZZ homozygote individuals at risk. METHOD: Using data on the prevalences of the two most common deficiency alleles PI*S and PI*Z in the five major individual ethnic subgroups in the United States, the numbers of heterozygotes for PI*MS and PI*MZ, and compound heterozygotes/homozygotes for PI*SS, PI*SZ and PI*ZZ have been determined for each ethnic subgroup. RESULTS: When the data for the prevalence of AAT deficiency in individual cohorts are displayed as a function of ethnic subgroup, striking differences are found in the numbers in each of the five phenotypic classes of PI*S and PI*Z. This type of analysis has demonstrated striking differences in the risk for AAT deficiency in each of these five ethnic subgroups. This analysis as a function of ethnic subgroup also has demonstrated that there are higher numbers of each of the five PI*S and PI*Z deficiency classes, namely PI*MS, PI*SS, PI*MZ, PI*SZ and PI*ZZ. CONCLUSIONS: This analysis has demonstrated that the highest risk for AAT deficiency is found in Whites, followed by Hispanics and Blacks with the lowest prevalence among Mexican Americans and no risk among Asians. The numbers for those at risk for AAT deficiency in the United States are well documented and in the present analysis there are, for example, a total of 48,904 PI*ZZ homozygotes at risk. The critical question for our healthcare professionals is 'When will the medical community acknowledge that AAT deficiency is a prevalent and well-documented human genetic disorder and develop appropriate mechanisms for early diagnosis, medical follow-up and treatment both in the United States and worldwide?'

Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients.

Formalin-fixed, paraffin-embedded skin tissue sections were collected from a matched cohort of 63 fibromyalgia syndrome (FMS) patients and 49 volunteers from the general population with both alpha1-antitrypsin (AAT) normal and deficiency variants. These tissues were examined for the expression of the broad-spectrum inhibitor AAT, the serine proteinases elastase and tryptase, the proinflammatory cytokines MCP-1 and TNFα, the endothelium biomarker VEGF, and the inflammation/nociception-related receptor PAR(2). The most relevant finding of the study was a significantly increased number of mast cells (MCs) in the papillary dermis of all FMS patients (greater than or equal to five to 14 per microscopic high power field) compared to zero to one in controls (p < 0.001). MCs strongly stained with tryptase, AAT and PAR(2) antibodies, exhibited a spindle-like shape and were uniformly distributed around blood vessels and appendages. MCP-1 and VEGF expressed weak/moderate positivity in most samples, with a higher expression in controls than in FMS patients (p < 0.001 and 0.051, respectively). No differences in elastase and TNFα were found between both groups. Moreover, no histological differences were found between samples from AAT deficiency and normal AAT phenotypes. Our results indicate that FMS is a MC-associated condition. MCs are present in skin and mucosal surfaces throughout the human body, and are easily stimulated by a number of physical, psychological, and chemical triggers to degranulate, releasing several proinflammatory products which are able to generate nervous peripheral stimuli causing CNS hypersensitivity, local, and systemic symptoms. Our findings open new avenues of research on FMS mechanisms and will benefit the diagnosis of patients and the development of therapeutics.

Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia.

Abnormalities in blood inflammatory markers have been associated with clinical manifestations and the pathogenesis of the fibromyalgia syndrome (FMS); a relationship between inherited alpha1-antitrypsin deficiency (AATD) and FMS has also been recently raised. In this study, plasma levels of inflammatory markers in FMS patients with and without AATD have been investigated. Blood samples from 138 age-matched females (79 FMS) and 59 general population (GP), with normal MM [n = 82 (59.4%)] and with MS, MZ, SZ, and ZZ AATD genotypes [n = 56 (40.6%)], were analyzed by ELISA for monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha), soluble TNFalpha receptors I and II, interleukin-8, and vascular endothelial growth factor (VEGF). Plasma levels of MCP-1, VEGF, and TNFalpha were significantly lower in FMS and GP subjects with AATD compared with those with normal MM-AAT genotypes. Moreover, plasma levels of MCP-1, VEGF, and TNFalpha were lower in AATD subjects with FMS than in those without FMS (P = 0.000, 0.000, and 0.046, respectively). No statistical differences were found for the other substances measured. Furthermore, a logistic regression model based on plasma MCP-1 cutoff value of

Estimating the risk for alpha-1 antitrypsin deficiency among COPD patients: evidence supporting targeted screening.

Alpha-1 antitrypsin deficiency is known as a significant genetic risk factor for COPD for carriers of phenotype PIMZ, and for phenotypes PIZZ and PISZ. Genetic epidemiological studies for alpha-1 antitrypsin deficiency conducted by others on both COPD patients and concurrent non-COPD controls were used to estimate the risk factors for all six phenotypic classes (namely, the normal phenotype PIMM, and the 5 deficiency allele phenotypes: PIMS, PIMZ, PISS, PISZ, and PIZZ). Studies on alpha-1 antitrypsin deficiency in white (Caucasian) COPD and non-COPD populations in 6 countries were combined to obtain estimates of the prevalence of the PIS and PIZ deficiency alleles in the combined COPD and non-COPD cohorts. The odds ratios for each of the six phenotypic classes of alpha-1 antitrypsin deficiency were calculated for a hypothetical population of 19.3 million white COPD patients in the United States of America. This approach demonstrated that 1,829,673 alpha-1 antitrypsin deficiency patients would be detected by testing 19.3 million white COPD patients and 536,033 in white non-COPD concurrent controls. The odds ratios for each of the phenotypic classes among white COPD patients demonstrate highly significant decreases in the normal phenotype PIMM, no significant change in the PIMS and PISS deficiency phenotypes, but highly significant increases in the prevalences of the PIMZ, PISZ, and PIZZ deficiency phenotypes. The result of the present study supports the concept of targeted screening for alpha-1 antitrypsin deficiency in countries with large populations of white (Caucasian) COPD patients.

High prevalence of alpha 1 antitrypsin phenotypes in viral hepatitis B infected patients in Iran.

OBJECTIVE: Hepatitis B virus (HBV) infection is a major global public health problem. Approximately 2 billion people are infected worldwide and more than 350 million of these individuals are chronic carriers of HBV. Approximately 15-40% of infected patients will develop cirrhosis, liver failure, or hepatocellular carcinoma (HCC). Alpha 1 antitrypsin (AAT) deficiency is one of many factors that may be involved in abnormalities such as liver and lung disease, inflammatory joint diseases, and inflammatory eye diseases. In the present study, the role played by AAT in HBV infected individuals is analyzed. METHODS: AAT phenotyping and trypsin inhibitory capacity (TIC) experiments were performed on 281 HBV infected patients who were referred to Tehran and Zahedan Hepatitis Center for a period of 3 years from June 2001 to September 2003. The same tests were performed on 257 individuals who did not suffer from any systemic diseases (control group). The case group was subdivided into three groups: carrier (36.7%), chronic (50.5%), and cirrhotic (12.8%). RESULTS: The results showed that AAT phenotypes, MS, MZ, M(1)Z, and M(1)S, were significantly higher in the HBV group (p<0.01). In addition, there was a significant difference in AAT phenotypes (MS, MZ, and M(1)Z) among inactive carriers and individuals in the chronic and cirrhotic group (p<0.001). CONCLUSIONS: There is a high prevalence of moderate AAT (MS, M(1)S, and MV) and severely deficient (MZ and M(1)Z) phenotypes in Iranian HBV individuals. In addition, AAT deficiency might be a risk factor for infected HBV individuals progressing from the carrier stage to chronic and cirrhotic stages.

Alpha-1-antitrypsin phenotypes and HLA-B27 typing in uveitis patients in southeast Iran.

OBJECTIVES: Uveitis is an eye disease that affects humans worldwide. Inflammation of the uveal tract is termed uveitis. Alpha-1-antitrypsin (AAT) deficiency is one of many factors that may be involved in abnormalities such as liver and lung disease, inflammatory joint diseases, and inflammatory eye diseases. In this study, the role of AAT in uveitis is analyzed. DESIGN AND METHODS: AAT phenotyping and serum-trypsin inhibitory capacity (S-TIC) experiments were performed on 103 patients who were referred to the ALZAHRA eye center in Zahedan (southeast of Iran). The same experiments were performed on 167 people who did not suffer from any eye or systemic diseases and served as a control group. RESULTS: The results revealed that the frequency of M1S, M2S, M1Z, and MV phenotypes were significantly higher in uveitis patients (P < 0.001). There was no difference in AAT phenotype frequencies between various types of uveitis (P = 0.1). CONCLUSION: AAT deficiency appears to be a risk factor for uveitis in southeast Iran. More investigation is needed to establish potential benefits of AAT phenotyping tests and AAT therapy in the diagnosis and treatment of uveitis cases with unclear etiology.

Health implications of alpha1-antitrypsin deficiency in Sub-Sahara African countries and their emigrants in Europe and the New World.

PURPOSE: To determine the frequencies of the protease inhibitor (PI) deficiency alleles of alpha1-antitrypsin deficiency (AAT Deficiency) in indigenous populations in 12 countries in Sub-Sahara Africa because of their potential impact on the health in these populations with regard to the high risk for development of liver and lung disease. In addition, to discuss the unique susceptibility of these populations and emigrants to Europe and the New World to the adverse health effects associated with exposure to environmental microbes, chemicals, and particulates. METHODS: Detailed statistical analysis of the 24 control cohort databases from genetic epidemiological studies by others were used to estimate the allele frequencies and prevalence for the two most common deficiency alleles PIS and PIZ and to estimate the numbers at risk in each of the local Sub-Sahara populations as well as those who have emigrated from these countries to Europe and the New World. RESULTS: The present study has provided evidence for the presence of both PIS and PIZ in the general populations of Nigeria, Republic of South Africa, and Somalia, the PIS allele in Angola, Botswana, Cameroon, Mozambique, Namibia, and the Republic of Congo, and only the PIZ allele in Mali. CONCLUSION: AAT Deficiency is found in both the Black and "Colored" populations in many of the Sub-Sahara countries in Africa, providing evidence for the presence of AAT Deficiency in such populations in Europe and in the New World. Such populations should be screened for AAT Deficiency and made aware of their unique susceptibility to exposure to chemical and particulate agents in the environment.

alpha1-Antitrypsin and fibromyalgia: new data in favour of the inflammatory hypothesis of fibromyalgia.

alpha1-Antitrypsin (AAT) circulates in high serum concentrations, and impregnates most body tissues. AAT has a broad anti-inflammatory spectrum, and modulates most inflammatory reactions occurring in human body. Recently, a possible relationship between AAT deficiency (AAT-D) and fibromyalgia (FM) has been raised, with the finding that intravenous infusions of purified human AAT efficiently controlled FM symptoms in two patients with severe hereditary AAT-D. On the other hand, functional magnetic resonance imaging has detected a significant greater activity in pain sensitive areas of the brain in patients with FM, in response to cutaneous stimuli, providing further evidence for a physiological explanation for FM pain. In recent studies abnormal profiles of inflammation markers in serum and biopsies have been found in FM patients. Since most of these inflammation mediators can be inhibited by AAT, these observations would suggest that at least a subset of the FM syndrome could be related to an inflammatory process, possibly due to an imbalance between inflammatory and anti-inflammatory substances, in the soft body tissues. Future directions of research would be: (1) to develop epidemiological studies to determine the gene frequency of AAT deficiency alleles in FM patients; (2) implementation of a double-blind placebo-controlled clinical trial to determine the specific role of AAT augmentation therapy in AAT-D patients with FM; (3) identification of specific laboratory markers for diagnostic and clinical evaluation purposes in FM; (4) application of the newest medical imaging techniques for diagnosis; and (5) identification of genetic, familial, and environmental risk factors suspected to participate in the FM syndrome development.

[PI*S and PI*Z alpha 1-antitrypsin deficiency: estimated prevalence and number of deficient subjects in Spain]. / Déficit de alfa-1-antitripsina en España (variantes deficientes PI*S y PI*Z): prevalencia estimada y número de sujetos calculados para cada fenotipo.

BACKGROUND AND OBJECTIVE: Alpha-1-antitrypsin deficiency (AATD) is an hereditary disorder with increased risk of pulmonary emphysema and chronic liver diseases in children and adults. Since it is possible currently in Spain to apply alpha-1-antitrypsin replacement therapy to AATD patients, the objective of this study was to calculate the total number of subjects affected by PIS and PIZ AATD, and its phenotypic distribution. SUBJECTS, MATERIAL AND METHOD: Selection of published studies on allelic frequencies PIS and PIZ according to the following criteria: a) alpha-1-antitrypsin phenotyping performed by isoelectrofocusing; b) rejection of "screening studies"; c) statistic precision factor score of 5, and d) samples representative of the Spanish general population. RESULTS: Four out 34 cohorts were selected. Mean gene frequencies (per 1,000) were: 104 (95% confidence interval [CI], 96-113) for PI*S and 17 (95% CI, 14-21) for PI*Z. These data indicated that it would exist in Spain 9,173,181 AATD subjects (95% CI, 9,167,966-9,178,398), with the following phenotypic distribution: 7,358,263 (95% CI, 6,696,222-8, 072,328) for PIMS; 1,222,041 (95% CI, 972,767-1,539,805) for PIMZ; 436,023 (95% CI, 369,057-514,244) for PISS; 144,827 (95% CI, 107,227-195,038) for PISZ; and 12,026 (95% CI, 7,788-18,493) for PIZZ. The global prevalence was 1 out of 4.4 individuals, with the following distribution: PIMS 1/5; PIMZ 1/33; PISS 1/92; PISZ 1/278; and PIZZ 1/3,344. CONCLUSIONS: AATD is a frequent but underdiagnosed disease in Spain.

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.

Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed.

Articles in the literature on alpha-1 antitrypsin (AAT) deficiency have been interpreted as indicating that AAT deficiency is a rare disease that affects mainly Caucasians (whites) from northern Europe. In a recent publication on the worldwide racial and ethnic distribution of AAT deficiency, new data were presented demonstrating that it is also found in various populations of African blacks; Arabs and Jews in the Middle East; and Central, Far East, and Southeast Asians, as well as whites in Australia, Europe, New Zealand, and North America. The new data on the prevalence of AAT deficiency in other major racial groups worldwide will affect the standards for the diagnosis of AAT deficiency by the medical community, with the realization that is not a rare disease of whites in northern Europe and immigrants from these countries in the New World. In a total population of 4.4 billion in the 58 countries surveyed, there are at least 116 million carriers (those with Pi phenotypes PiMS and PiMZ) and 3.4 million with deficiency allele combinations (phenotypes PiSS, PiSZ, and PiZZ) for the two most prevalent deficiency alleles PiS and PiZ; therefore, the new data suggest that AAT deficiency may be one of the most common serious single-locus genetic diseases in the world. Particularly important is the unique susceptibility of AAT-deficient individuals to exposure to chemical and particulate environmental agents. Such exposures are known to result in both lung and liver disease as well as other adverse health effects.

Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) deficiency is an inherited genetic disorder currently diagnosed in approximately 5,000 people in the United States. Although some individuals with AAT deficiency are asymptomatic, the condition often leads to deterioration of lung function in adults and is associated with emphysema, asthma, chronic obstructive pulmonary disease, and other respiratory diseases. In children, AAT deficiency can result in severe liver disease, including fatal cirrhosis in newborn infants. Although much is known about the clinical pathology of AAT deficiency, researchers are just beginning to characterize environmental, occupational, and genetic modifiers affecting the onset and progression of diseases related to AAT deficiency. On 19 August 2002, a group of basic scientists, clinicians, environmental health researchers, and public interest groups gathered at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, to discuss ongoing research on these topics. The goals of this workshop were to a) assess the present state of knowledge regarding environmental and occupational risk factors contributing to AAT deficiency morbidity and mortality, b) define future research needs in this area, and c) explore collaborative opportunities to advance understanding of risk factors affecting the progression of AAT deficiency-related disease. Participants agreed that new research initiatives in these areas represent an opportunity to benefit both basic science, through enhanced understanding of gene-environment interaction, and the AAT deficiency patient community, through innovative new approaches to disease management and treatment.

Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys.

STUDY OBJECTIVES: Alpha1-antitrypsin (AAT) deficiency is a genetic disease that is widely known in Europe as a disease of white individuals, who, along with their descendants in other parts of the world, are at the highest risk for liver and/or lung disease. There is a limited database of individuals affected by this disease worldwide. It has been estimated, for example, that there are 70,000 to 100,00 individuals affected in the United States, with comparable numbers in Europe. STUDY DESIGN: Genetic epidemiologic studies in the peer-reviewed literature have been used in an exploratory study to estimate the number of carriers and the number of those individuals who are homozygous or heterozygous for the two most common defective alleles for AAT deficiency in 58 individual countries. The total country database of 373 control cohorts has been combined to estimate the numbers of carriers and deficiency allele combinations for PiS and PiZ in 11 geographic regions and worldwide. The study was designed to be illustrative rather than comprehensive, and more detailed publication of the enormous database developed in this exploratory study is planned. CONCLUSIONS: The database presented indicates that in a total population of 4.4 billion in the countries surveyed worldwide, there are at least 116 million carriers (PiMS and PiMZ) and 3.4 million deficiency allele combinations (PiSS, PiSZ, and PiZZ). Furthermore, this database demonstrates that AAT deficiency is found in various populations of African blacks, Arabs and Jews in the Middle East, whites in Australia/New Zealand, Europe, and North America, central Asians, far east Asians, and southeast Asians. These data demonstrate that AAT deficiency is not just a disease of whites in Europe, but that it affects individuals in all racial subgroups worldwide. In addition, AAT deficiency may be one of the most common serious hereditary disorders in the world.