Clinical Consequences of Alpha-1

Antitrypsin Deficiency

Oana Cristina Arghir

School of Medicine Ovidius University of Constanta

Background
 The roots of a1ATD
Underdiagnosed disease?

• Kuzemko, 1994; Kubba & Young, 1998-

Speculation:

Poland's greatest composer, Frederic Chopin, died on October

17, 1849, at age 38, suffered from AATD with his physician
failing to confirm pulmonary TB instead discovering "a disease
not previously encountered" on autopsy;
 History of COPD - Emphysema
• Emphysema is one of the pathologic features of the COPD;

• A part of the normal aging process (Lynne M. Reid, 1967);

• William Briscoe “an accelerated ageing process,” although the

mechanism was obscure.

• The fact that COPD ran in families suggested a clear genetic

component.

• However, despite extensive genetic screening studies, little has

emerged (perhaps reflecting the heterogeneity of the COPD
syndrome) that outranks the chance of AATD discovery.
 The chance
of AATD
Discovery
2013 marking the 50th anniversary of the discovery of Alpha-1 antitrypsin
deficiency
 The electrophoretic a1-globulin pattern of
serum in a1-antitrypsin deficiency
Male, age 35. Left pneumothorax, diffuse vescicular emphysema. Left
Patient No.1 lobectomy : severe emphysema and bronchiectasis.

Male, aged 38. Two siblings with asthma and emphysema. Admitted
Patient No.2 for pneumonia. Chest X-ray : typical for emphysema, with flattened
diaphragm.

Male, aged 43. Admitted for pneumonia. Frequent exacerbations in

Patient No.3 wintertime. Chest X-ray : sings of emphysema. Broncography:
presence of diffuse bronchiectasis

Female, aged 76. Chronically treated with oral corticosteroids for RA.
Patient No. 4 Admitted for multiple vertebral fractures. Repeated chest-X rays : no
signs of lung disease. No respiratory symptoms.

Patient No.5 Female, aged 31. Admitted for abdominal pain. Chest-X ray showed
no abnormalities.

Hence, the cardinal clinical features of AATD were established: absence of a protein in the
alpha1 region of the SPEP, emphysema with early onset, and a genetic predisposition.
What is the minimum Level of AAT
necessary for lung protection?

11 umol/L or 80 mg/dL
(NV: 20-53 umol/L or 150 300 mg/dL)

Based on population studies

 Emphysema
• Hereditary Pulmonary Emphysema “alpha1 antitrypsin
deficiency”
• Accounts for about 2% of emphysema cases
• The classic pulmonary presentation of lung disease in
AATD:
– Severe
– Early onset
– Panacinar emphysema with a basilar predominance
in adults

(Gishen et al, 1982)

 Pattern of Emphysema Distribution

The classical AATD patients have emphysema mainly at the lung bases

Top (Apex) Bottom (Base)

Parr et al AJRCCM: 2004 ;170 :1172-1178

 Polarised emphysema distribution and
FEV1/Kco abnormalities

• Parr et al showed:

– isolated FEV1 abnormality linked with a more basal

emphysema distribution

– isolated Kco abnormality with a more apical distribution.

 ZZ Phenotype
• Is a major risk factor for COPD;

• The classic severe respiratory deficiency AAT is

associated with the Pi Z genotype.

• Relationship between PiZ genotype and COPD in

older persons (˃65 yr-old) who have been exposed
throughout their lives to smoking, and other
environmental exposures (QUID R Cohort 2,104).
 SZ Phenotype
• Increased susceptibility to COPD related smoking

• Less emphysema in the lower lobes on CT scan

• Less abnormal spirometry test results;

• Cigarette smoking correlates more strongly with

airflow obstruction in SZ than in ZZ subjects;

• Equivalent health status impairment compared to

matched ZZ subjects (Holme and Stockley, 2009)
 MZ Phenotype
• Moderately reduced serum levels of AAT

• Controversy – the increased risk of COPD

• 100 studies in the last 40 yrs:

– Metaanalysis Hersh et al, 2004 elevated OR (2.31; 95%CI 1.60 to 3.35)

MZ vs MM;

– MZ individuals exhibit accelerated decline in diffusing capacity of the

lung for carbon monoxide (DLCO) in a large prospective population-
based study (n=1,057)- Silva et al, 2008;

– Good motivation for tobacco smoking cessation (Carpenter et al, 2007)

 AATD a genetic risk for COPD

• ZZ higher risk of developping COPD

• MZ and SZ are at risk, too

• There is little information regarding MZ and SZ

 Spirometric and Gas Transfer Discordance in α1-
Antitrypsin Deficiency03B11-Antitrypsin
Deficiency and COPD Progression: Patient
Characteristics and Progression
Lung function begins to decline at some later point. FEV1 decreases in adult PiZZ
patients at 51-317 mL per year (estimated decline in healthy patients is 30 mL/y).

PiZZ

Definition of the physiologic groups and number of subjects in each.

Kco = carbon monoxide transfer coefficient.
Antitrypsin Deficiency Assessment and Program for Treatment (ADAPT) project; 2008-2011
Chest. 2014;145(6):1316-1324. doi:10.1378/chest.13-1886
Survival in AATD according to FEV1

0,6
0,5
0,4
Mortality rate 0,3
0,2
0,1
0
15 20 25 30 35 60
% of predicted FEV 1

2 year Mortality

Seersholm N et al. Eur Respir J 1994;7:1985

 COPD
• COPD is largely underdiagnosed (Mannino and
Braman, 2007) particularly in its early phases
(Mannino et al, 2000)

• AATD = A genetic risk factor for COPD;

• Cigarette smoking is by far the single most important

risk factor for the development of COPD
– Jannot and Carp,1977;
– Seersholm and Kok-Jensen, 1995;
– Mayer et al., 2006
 COPD related smoking
• Smoking reduces the life expectancy of a ZZ patient by up to 25 yrs
(The AATD Registry Study Group, 1998)

• Based on a large clinical population study, Bornhorst et al suggested

that:
– early diagnosis of AATD is sporadic and
– average age of diagnosis is 45.5 ± 9.5 years

• Exposure to second hand tobacco smoking in childhood can

accelerate the onset of symptoms in ZZ AATD individuals
(Mayer et al, 2006);
 COPD in non smokers
• Swedish registry study group (Piitulainen, Tornling,
and Eriksson, 1997) demonstrated that non-smoking
ZZ individuals:
– may not develop COPD until later in life but
– display a decline in lung function (FEV1) with age
especially after 50 ;

• 1 yr Follow-up study revealed agricultural exposure

associated with decreased lung function (Piitulainen,
Tornling, and Eriksson, 1998);
 Inherited COPD
• ZZ phenotype is a genetic risk factor for COPD:
1-3% of cases (Brantly, 2003);

• Among 965 COPD patients (Lieberman, Winter, Sastre,

1986, USA):
– 1.9% ZZ
– 8% MZ

• 10% if includes ZZ, SZ and MZ phenotypes (Carroll, 2011)

Clinical features that suggest the possibility
of AATD with lung involvement
• Emphysema
– at an early age (age 45 y or younger),
– in the absence of a recognized risk factor like smoking or occupational dust
exposure,
– of the lower lungs,

• Asthma with persistent airflow obstruction after treatment,

• Bronchiectasis without a clear etiology,

• A family history of emphysema, bronchiectasis, liver disease, or

panniculitis.
 Clinical consequences that may suggest the
possibility of AATD with lung involvement
• AATD Carriers are more vulnerable to carcinogen containing tobacco
smoke (Ping Yang et al, 2008);
– High risk of developping lung cancer (2.2 fold risk vs noncarriers);
– Higher risk if having a history of heavy smoking and COPD;
– Associated with adenocarcinoma and squamous cell carcinoma;
– It remains ill defined.

• Because AAT is normally inactivating some pro-inflammatory molecules in

the airways and alveoli, AATD may have Asthma like clinical picture with
bronchodilator responsiveness
– The average age 52 yrs with a delay of 10 yrs in diagnosing AATD.

Ping Yang et al Alpha-1 Antitrypsin Deficiency Carriers, Tobacco Smoke, COPD, and Lung cancer Risk.
Arch Intern Med 168(10), 2008: 1097-1102
 AATD
• Hereditary autosomal recessive and a codominant
disorder with a remarkable variability in its clinical
presentation: pulmonary and/or extrapulmonary.

• An affected individual has 2 abnormal deficiency

alleles (homozygotes).

• Heterozygotes (carriers) are often asymptomatic

but may have mildly deficient a1AT levels

• More than 1/3 of the carriers can stay symptomless

their entire life

• Underdiagnosed medical condition.

 DISTRIBUTION OF DIFFERENT CLINICAL
RESPIRATORY PHENOTYPES ACCORDING TO
GENOTYPES
100%
90%
80%
70%
60% bronchiectasis
50% asthma
40% emphysema
30% chronic bronchitis
20% other lung diseases
10%
0%

Ers-education.org
* R denotes non-Z and non-S deficiency variants
 LIFE CYCLE OF AATD ASSOCIATED CONDITIONS

Neonatal Liver
disease
Lung Disease Chronic Liver Disease

1 30 50 Age
70 (yrs)

Ers-education.org
 Frequency of lung and/or liver disease
at diagnosis

%
Lung disease 59.62
Lung and liver
disease 19.28
Liver disease 6,25
Healthy 14,85
Ers-education.org
 Conclusions:

1. Unrecognized disease with delay of diagnosing lung AATD related diseases

2. Severe AATD is the only defined genetic risk factor for COPD;

3. Respiratory phenotypes vs Usual presentation;

4. Cigarette smoking markedly increases the risk of COPD and even lung cancer;

5. The risk of developping COPD in heterozygotes, the association of asthma and

bronchiectasis with AATD are still controversial.

6. Smoking cessation and the avoidance of occupational and environmental

exposures ( particulate matter, chemical vapours and agricultural dusts) is
paramount in AATD patient education (ATS/ERS Guidelines, 2003)
Thank you!