Alpha-1 Antitrypsin Deficiency AATD

Transcription

1 Alpha-1 Antitrypsin Deficiency AATD Hamad Yaseen, PhD MLS Department, FAHS, HSC Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin deficiency is an inherited disorder that may cause sever lung and liver diseases. It occurs worldwide, but its prevalence varies by population. It affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. 1

2 What is Alpha-1 Antitrypsin? Alpha-1 Antitrypsin (AAT) is a serine protease inhibitor. Synthesized in the liver Travels to lung by passive diffusion. Glossary: Protease inhibitors are molecules that inhibit the function of proteases. Protease refers to a group of enzymes whose catalytic function is to hydrolyze (breakdown) peptide bonds of proteins. AAT is Secreted by the Liver Liver AAT Blood vessel To all tissues Hepatocytes Blood vessel 2

3 What is Alpha-1 Antitrypsin? Its main function is to protect the lung against proteolytic damage from neutrophil elastase, which is secreted by neutrophils and macrophages during inflammation. Glossary: Neutrophil elastase is a serine proteinase secreted by neutrophils and macrophages during inflammation, it destroys bacteria and host tissue. What is Alpha-1 Antitrypsin? Despite its name, AAT reacts with neutrophil elastase much more avidly than with Trypsin. 3

4 Alpha-1 Antitrypsin Deficiency The liver doesn t produce enough functional AAT, and neutrophil elastase gets out of control. AAT serum level Consenquence mm Normal 3-7 mm AATD 11mM Protective thershold 4

5 Reaction results in destruction of both AAT and NE Reactive loop NE AAT AAT flings the tethered NE to the opposite end of the AAT molecule This distorts the NE active site and alters its structure so it can be destroyed 5

6 6

7 7

8 8

9 9

10 10

11 Clinical features Patients usually develop the first signs and symptoms of lung disease between ages 20 and 50. Severity varies depending on mutations. 11

12 Symptoms The earliest symptoms are: Shortness of breath following mild activity, Reduced ability to exercise Wheezing. Other signs and symptoms can include: Unintentional weight loss, Recurring respiratory infections, Fatigue, Rapid heartbeat upon standing, and Vision abnormalities Clinical Features Advanced lung disease leads to emphysema, in which small air sacs in the lungs (alveoli) are damaged. Characteristic features of emphysema include: Difficulty breathing, Hacking cough, and Barrel-shaped chest. 12

13 Clinical Features Panniculitis In rare cases, people with AATD develop a skin condition called panniculitis, which is characterized by hardened skin with painful lumps or patches. 1 O Riordan K. Transplantation. 1997;53: Smith KC. J Am Acad Dermatol. 1989;21:

14 AATD often Misdiagnosed as Chronic obstructive pulmonary disease COPD Misdiagnosed as: COPD due to smoking/environmental/ occupational exposure Asthma Allergies Bronchitis Clinical recognition confounded by symptoms typical in patients with COPD Clinician must differentiate AAT deficiency from other causes of lung disease 1 Brantly ML. Am Rev Respir Dis. 1988;138: McElvaney NG. Chest. 1997;111:394. Pulmonary Signs and Symptoms COPD Only Onset > 50 years Airflow obstruction reversible with treatment Centriacinar or paraseptal emphysema COPD & AAT Deficiency Chronic cough Shortness of breath with activity Wheezing Increased sputum production Increased lower respiratory infections AAT Deficiency Only Panacinar emphysema Early onset (< 50 years) of symptoms in patients with smoking history Airflow obstruction not reversible with treatment Family history of COPD Definitive diagnosis is simple via a blood test 14

15 The Genetics of AATD Genetics of AATD This condition is inherited in an autosomal codominant pattern. In which two alleles of a gene pair in a heterozygote both have full phenotypic expression. Do not mix it up with incomplete dominance pattern!!! 15

16 Co-dominance vs. Incomplete dominance Co-dominance Co-dominance occurs when the contributions of both alleles are visible in the phenotype. Incomplete dominance occurs when the phenotype of the heterozygous genotype is distinct from and often intermediate to the phenotypes of the homozygous genotypes. Genetics of AATD Mutations in the SERPINA1 gene cause AATD The official name of this gene is Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1. Located on the long (q) arm of chromosome 14 at position (14q32.1) 16

17 SERPINA1 It provides instructions for making a protein called alpha-1 antitrypsin. Mutations in the gene can lead to a shortage (deficiency) of alpha-1 antitrypsin or an abnormal form of the protein that cannot control neutrophil elastase causing AATD. SERPINA1 mutations 17

18 SERPINA1 Alleles There are more than 100 distinct AAT alleles, with varying clinical significance Deficiency alleles encode abnormal protein that is not secreted normally, resulting in decreased circulating levels of AAT Most common alleles PI*M (normal) PI*S (moderately deficient) PI*Z (severely deficient) The null allele (rare), which produces no protein, results in the most severe deficiency SERPINA1 Alleles The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. 18

19 SERPINA1 Alleles Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. the S allele produces moderately low levels of this protein, Z allele produces very little alpha-1 antitrypsin. Allele Type of mutation Cellular Defect Disease association Normal Alleles M None Normal Deficiency Allelels S Glu264Val IC Degradation Lung Z Glu342Lys IC Accumulation Lung, liver* *Polymerization results in retention of aggregates of AAT in hepatocytes, leading to liver cirrhosis. 19

20 Range of Serum Levels by Phenotype Adapted from The Alpha-1 Foundation slide set. Courtesy of H. Ari Jaffe, MD Range of Serum Levels by Phenotype Bottom normal level Adapted from The Alpha-1 Foundation slide set. Courtesy of H. Ari Jaffe, MD 20

21 Range of Serum Levels by Phenotype Bottom normal level Protective threshold The green line denotes the bottom normal level of AAT. The red line denotes the protective threshold for AAT deficiency (individuals with serum AAT levels below this are considered AAT deficient). The protective threshold evolved from the observation that patients with heterozygote phenotypes whose levels exceeded this level were usually free from emphysema Third Generation Inheritance Prior to Clinical Disease F1 F2 F2 F3 21

22 Genetic testing Pay attention!!!!!!!!!!!!! 22