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Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting
Insights
Alpha 1-Antitrypsin (AAT) deficiency is a genetic disorder often underdiagnosed, primarily causing COPD and liver disease. Early detection and awareness are crucial for managing this prevalent condition.
Area of Science:
- Genetics
- Pulmonology
- Hepatology
Background:
- Alpha 1-Antitrypsin (AAT) deficiency is an inherited disorder caused by genetic mutations in the AAT gene.
- It is characterized by low levels of AAT, a protein that protects the lungs and liver from damage.
- The most common deficiency allele is PI*Z, with individuals having the PI type ZZ genotype most severely affected.
Purpose of the Study:
- To review existing knowledge on AAT deficiency.
- To develop strategies for increasing awareness among healthcare providers and the public.
- To explore new methods for case-finding and disease prevention.
Main Methods:
- A WHO meeting convened experts to discuss AAT deficiency.
- Discussions focused on current knowledge, diagnostic challenges, and therapeutic options.
- Recommendations were formulated for enhancing awareness and improving case detection.
Main Results:
- AAT deficiency is a prevalent genetic disorder, comparable in frequency to cystic fibrosis.
- Chronic obstructive pulmonary disease (COPD), particularly panacinar emphysema, is the most common clinical manifestation.
- Liver disease is another significant manifestation, with chronic liver disease and associated complications occurring in adults.
Conclusions:
- AAT deficiency is widely underdiagnosed, with a small fraction of affected individuals identified.
- Increased awareness and improved diagnostic strategies are essential for timely intervention.
- Further research and public health initiatives are needed to address this prevalent genetic disorder.
Abstract:
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.