TABLE 1

Clinical burden review: morbidity associated with alpha-1 antitrypsin deficiency (AATD)

First author, year [ref.]Patient populationType of complicationPatients affected %Risk factors for morbidity (value estimate)Main outcomes
Pulmonary morbidity
 Herrera, 2021 [43]Severe AATD (n=711)COPD75.8Not evaluatedPatients with severe AATD-related PM requiring hospitalisation are substantially burdened by more frequent events and a more severe clinical course.
Nonsevere AATD (n=1963)COPD56.9
Severe AATD (n=711)Emphysema33.8
Nonsevere AATD (n=1963)Emphysema23.8
 Tanash, 2019 [25]Severe AATD (n=1595)COPD53The proportion of subjects with COPD was higher among individuals with than those without liver disease.
 Hiller, 2019 [26]Severe AATD (n=1132)COPD52Smoking#
Middle age#
Frequent exacerbation#
Respiratory symptoms#
Active smoking, age, respiratory symptoms at baseline and repeated severe exacerbations of COPD were associated with accelerated decline of lung function in severe AATD.
 Choate, 2019 [44]AATD (PiZZ n=3031)Exacerbation over the past year (lung condition not specified)75.6Not evaluatedPiSZ patients reported more frequent exacerbations than PiZZ patients, even after adjusting for age, sex, current smoking status and CCI score.
AATD (PiSZ n=504)78.3
 Costa, 2017 [29]AATD (PiSS and PiMS n=32; PiMZ n=64; PiSZ n=8)Bronchiectasis3.8Not evaluatedPatients with intermediate AATD were often symptomatic and some had mild obstruction and emphysema. Exposure to risk factors seemed to be more important than AATD serum level in determining lung function.
AATD (PiSS and PiMS n=32; PiMZ n=64; PiSZ n=8)Emphysema21.2
 Cortese, 2016 [45]AATD (n=475)Bronchiectasis12Patients with bronchiectasis had more comorbidities (p=0.008) and were more frequently affected by pneumonia (p=0.024) than those without bronchiectasisThe presence or absence of bronchiectasis should be ascertained in patients affected by severe AATD because of its clinical consequences.
 Araújo, 2015 [46]AATD (n=110)Bronchiectasis24PiZZ#PiZZ individuals were significantly more likely to have severe bronchiectasis versus those with other alleles.
AATD with bronchiectasis (n=26)Emphysema53.8
 Kawkgi, 2013 [47]AATD (PiSZ) with smoking history (n=29)Emphysema36Smoking#Individuals with the SZ phenotype were at risk of developing emphysema if they smoked; however, the rate of bronchiectasis in this population was high, regardless of smoking history.
AATD (PiSZ) with smoking history (n=29)Bronchiectasis54
 Ferrarotti,  2012 [48]Severe AATD (n=312)Overall (not specified)79Smoking and possession of rare deficient allele other than S or Z#This database enabled a detailed characterisation of the natural course of the disease and the status of patient care.
 Guttmann,  2011 [49]Severe AATD (n=713)COPD73Smoking#
Dust exposure#
AATD led to significant morbidity in affected subjects.
 Subramanian,  2010 [40]AATD PiMZ (n=497)Lung nodule26.8hs-CRP due to lung nodule (p<0.005)An association between the presence of lung nodules (accompanied by a significant increase in hs-CRP) and the subsequent development of COPD was suggested.
 Torres-Durán,  2015 [36]AATD (n=212)Lung cancerPiMM 70
PiMS 21.1
PiMZ 3.8
PiSZ 1.4
PiSS 3.3
There was a significant four-fold increase in lung cancer risk in never-smokers with PiSS compared with PiMM genotypes (OR 4.64; 95% CI 1.08–19.92).
 Gupta, 2020 [32]No deficiency (n=1149)
Mild deficiency (n=147)
Intermediate deficiency (n=59)
Severe deficiency (AATD) (n=4)
EmphysemaPatients with severe AATD (ZZ, SZ and SDonostiZ) had lower diffusion capacity and greater CT-based emphysema versus patients without AATD.
 Franciosi,  2021 [50]AATD PiMZ (n=91)
AATD PiSZ (n=72)
AATD PiZZ/rare (n=130)
Lung disease, airflow obstruction47.3
45.9
74.6
SmokingPatients with AATD and a PiZZ genotype were more likely to have been diagnosed with AATD due to lung disease, demonstrated by worse airflow obstruction.
 Franciosi,  2020 [33]AATD PiSZ (n=70)
AATD PiMM/MS (controls) (n=46)
COPDNot statedNot statedPiSZ never-smokers demonstrated no increased risk of COPD, regardless of AAT concentration.
 Esquinas,  2018 [35]AATD PiZZ (n=122)Emphysema
Chronic bronchitis
Bronchiectasis
Asthma
83.1
44.6
42.3
20
Tobacco consumption (p=0.001)
Previous pneumonia (p=0.026)
Higher baseline FEV1 % (p=0.010)
Tobacco consumption, previous pneumonia and better lung function at baseline were related to a faster decline in FEV1.
 Parr, 2007 [51]AATD PiMZ (n=74)Bronchiectasis27 (clinically significant)Emphysema was the predominant component of COPD in AATD, but the prevalence and impact of airway disease was expected to be greater than is currently recognised.
 Piras, 2013 [34]AATD PiZZ (n=547)Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD
26
63.1
11
19
78.4
PiZZ patients had more severe respiratory disease than those with PiSZ, despite lower smoking levels.
AATD PiSZ (n=124)Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD
22.6
33.9
17.7
12.9
43.5
AATD Spain (n=416)Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD
36.1
66.6
15.9
27.2
76.2
AATD Italy (n=329)Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD
9.4
45.9
5.5
4
67.8
Hepatic morbidity
 Teckman,  2019 [52]AATD with liver disease (n=93)Liver fibrosis (Ishak score 0–1)88Not evaluatedThis study documented a highly variable range of findings with fibrosis.
AATD with liver disease (n=93)Liver fibrosis (Ishak score 2)2
AATD with liver disease (n=93)Liver fibrosis (Ishak score 3)2
AATD with liver disease (n=93)Liver fibrosis (Ishak score 4–6)8
 Ferrarotti,  2012 [48]Severe AATD (n=312)Overall (not specified)10Not evaluatedThis database enabled a detailed characterisation of the natural course of the disease and the status of patient care.
 Chakraborty,  2016 [28]AATD (n=212)Overall (not specified)29AST (p=0.001)
BMI (p=0.04)
Platelet reduction (OR 0.97, 95% CI 0.96–0.98)
Liver disease in this AATD cohort was high, with obese individuals at greatest risk.
 Mandorfer,  2017 [53]Severe AATD with PM (n=31)Advanced liver fibrosis3Not evaluatedPatients with severe pulmonary manifestation AATD rarely developed advanced liver fibrosis during adulthood. Autopsy reports, which observed cirrhosis in about one-third of PiZZ patients, may have overestimated the risk of end-stage liver disease.
Severe AATD with PM (n=31)Liver fibrosis23
Severe AATD with PM (n=31)Liver steatosis<Stage 1 65
<Stage 2 52
 Strnad, 2017 [39]AATD with PiMZ without known liver disease (n=115)Liver fibrosis18Not evaluatedPiMZ heterozygotes had higher serum ALT, AST and GGT levels than controls. Alcohol misusers carrying the PiZ variant were more prone to develop cirrhosis.
Matched controls without AAT mutations (n=100)6
 Arslanow,  2017 [23]AATD (n=19)Advanced liver fibrosis21Not evaluatedAATD presented with both impaired body composition and liver function tests. A third of the patients displayed abnormal TE measurements, indicating steatosis or advanced fibrosis.
AATD (n=19)Liver steatosis37
AATD (n=19)Cirrhosis11
 Hamesch,  2019 [38]AATD with homozygous PiZZ (n=403)Liver fibrosis (LSM)23.6Age >50 years
Male sex
Elevated ALT/AST/GGT
Reduced platelet count
Lung function PiZ carrier (OR 19.8, 95% CI 4.6–84.1)
Male sex, age >50 years, increased levels of ALT/AST/GGT and low numbers of platelets were associated with a higher liver fibrosis burden. No evidence for a relationship between lung function and liver fibrosis was found.
AATD without PiZ mutation (n=234)Liver fibrosis (LSM)6.4
AATD with homozygous PiZZ (n=403)Advanced liver fibrosis (LSM)13.6
AATD without PiZ mutation (n=234)Advanced liver fibrosis (LSM)1.3
AATD with homozygous PiZZ (n=403)Liver fibrosis (APRI)19.6
AATD without PiZ mutation (n=234)Liver fibrosis (APRI)5.4
AATD with homozygous PiZZ (n=403)Advanced liver fibrosis (APRI)4.5
AATD without PiZ mutation (n=234)Advanced liver fibrosis (APRI)0.5
AATD with homozygous PiZZ (n=403)Liver fibrosis (HepaScore)36.3
AATD without PiZ mutation (n=234)Liver fibrosis (HepaScore)13.5
AATD with homozygous PiZZ (n=403)Advanced liver fibrosis (HepaScore)25.6
AATD without PiZ mutation (n=234)Advanced liver fibrosis (HepaScore)4.1
AATD with homozygous PiZZ (n=403)Liver steatosis (mild)61.1
AATD without PiZ mutation (n=234)Liver steatosis (mild)48.2
AATD with homozygous PiZZ (n=403)Liver steatosis (severe)38.7
AATD without PiZ mutation (n=234)Liver steatosis (severe)28.4
 Tanash, 2019 [25]PiZZ AATD (n=1595)Cirrhosis7Male gender (risk ratio 1.45, 95% CI 1.15–2.14; p=0.03)
Age >50 years (risk ratio 2.02, 95% CI 1.30–3.16; p=0.002)
Ever-smokers (risk ratio 0.85, 95% CI 0.56–1.30; p=0.46)
Repeated elevated LFTs (risk ratio 7.66, 95% CI 5.10–11.73)
Hepatitis infection (risk ratio 3.12, 95% CI 1.21–8.08; p=0.02)
COPD (risk ratio 2.20, 95% CI 1.32–3.70; p=0.003)
Diabetes (risk ratio 3.87, 95% CI 2.18–6.87)
Hypertension (risk ratio 0.91, 95% CI 0.50–1.66; p=0.76)
In this large study, the prevalence of liver disease in PiZZ individuals was 10%. Age >50 years, male gender, repeated elevated liver enzymes, hepatitis and the presence of diabetes mellitus and COPD were risk factors for developing liver disease.
PiZZ AATD (n=1595)Hepatocellular carcinoma2
 Stone, 2014 [37]AATD (n=651)Cirrhosis4Not evaluated
 Clark, 2018 [27]AATD (n=94)Liver fibrosis35.1Sex (p=0.04)
Diabetes (p=0.002)
Impaired fasting glucose (p=0.003)
Obesity (p=0.01)
Metabolic syndrome (p<0.001)
Individuals with large amounts of AAT on biopsy may be at risk of liver injury and fibrosis. Metabolic syndrome was associated with a greater degree of liver injury.
 Black, 2020 [54]Heterozygous AATD (chronic liver disease + AAT globules) (n=23)Liver diseaseStage 1 13.0
Stage 2 8.7
Stage 3 26.1
Stage 4 52.2
Stage 4 (p=0.017)Heterozygous AATD may potentiate the progression of concurrent liver diseases.
Controls (chronic liver disease, no AAT globules) (n=120)Stage 1 30.8
Stage 2 23.3
Stage 3 24.2
Stage 4 21.7
 Fromme, 2022 [24]AATD PiMZ (n=17 006): cohort 1Liver fibrosis/cirrhosisLiver fibrosis/cirrhosis was 20 times more common in PiZZ versus noncarriers (adjusted OR 21.7, 95% CI 8.8–53.7; p<0.0001), but also markedly enriched in Pi*SZ subjects (adjusted OR 3.1, 95% CI 1.1–8.2; p=0.027) and moderately in Pi*MZ participants (adjusted OR 1.7, 95% CI 1.2–2.2; p=0.001)The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.
AATD PiSS (n=1014): cohort 1Liver primary cancerPiSZ and PiZZ increased the risk of primary liver cancer (adjusted OR 6.6, 95% CI 1.6–26.9 and adjusted OR 44.5, 95% CI 10.8–183.6) versus noncarriers
AATD PiSZ (n=864): cohort 1
AATD PiZZ (n=138): cohort 1
Controls (noncarriers n=422 506): cohort 1
AATD PiZZ (n= 586): cohort 2Liver fibrosis/cirrhosis24
AATD PiSZ (n=239): cohort 213
Controls (noncarriers n= 279): cohort 25
AATD PiMZ (n=419): cohort 1Liver fibrosis10
 Schneider,  2020 [55]AATD PiZZ (n=309): cohort 1LSM >7.1 kPa25Obesity and diabetes were the most important factors associated with LSM ≥7.1 kPa in subjects with the PiMZ genotype.
Control (noncarriers n=284): cohort 14
AATD PiMZ (n=84): cohort 2Liver steatosisStage 1 40.5
Stage 2 28.5
Stage 3 15.5
AATD PiZZ (n=35): cohort 2Stage 1 34.3
Stage 2 37.1
Stage 3 2.9
AATD PiMZ (n=84): cohort 2Liver fibrosisStage 1 13.1
Stage 2 28.6
Stage 3 28.6
Stage 4 16.7
AATD PiZZ (n=35): cohort 2Stage 1 5.7
Stage 2 20.0
Stage 3 42.9
Stage 4 28.6
AATD PiMZ (n=84): cohort 3Perisinusoidal fibrosis69.1
AATD PiZZ (n=35): cohort 397.1
 Hakim, 2021 [56]SERPINA 1 Z allele (n=299 939)Cirrhosis0.5The SERPINA1 Z allele was associated with cirrhosis in an allele dose-dependent manner (OR 1.69; p=2.3×10−07)
The SERPINA1 Z allele was associated with higher odds of cirrhosis in both heterozygotes versus noncarriers (OR 1.53; p=1.1×10−04) and homozygotes versus noncarriers (OR 11.8; p=1.8×10−09)
SERPINA1 Z allele heterozygosity was an important risk factor for liver disease.
SERPINA 1 PiMZ (n=12 603)0.7
SERPINA 1 PiZZ (n=129)4.7
 Abu Rmilah,  2021 [57]AATD PiMM with cirrhosis (n=1094)Cryptogenic cirrhosis
NASH
ALD
Autoimmune
Viral hepatitis
PSC/PBC
Others
76.9
67.3
70.6
87.5
87.5
88.8
89.3
Rates of pre-operative and post-operative pulmonary complications were found to be higher for PiMZ than PiMM. The MZ phenotype was significantly enriched in NASH, ALD and cryptogenic cirrhosis.
AATD PiMZ with cirrhosis (n=130)Cryptogenic cirrhosis
NASH
ALD
Autoimmune
Viral hepatitis
PSC/PBC
Others
23.0
22.0
20.0
10.0
5.6
3.2
10.7
Other morbidity
 Tanash, 2019 [25]Severe AATD (n=1595)Panniculitis<1Four out of 1595 patients with a PiZZ genotypeNo patients with panniculitis developed liver disease.
 Stone, 2014 [37]AATD (n=651)Panniculitis0.9The prevalence of inflammatory bowel disease and hypothyroidism was higher than that predicted in the UK, supporting a potential link between AATD and these conditions.
Granulomatosis with polyangiitis0.8
Inflammatory bowel disease (UC and Crohn disease)1.5
Hypothyroidism4
 Choate, 2019 [44]AATD PiZZ (n=3031)High blood pressure38.4A statistically significant greater proportion of PiSZ in our cohort were diagnosed with the six most prevalent comorbidities.
Reflux33.9
Sinus disease15.4
Heart rhythm problems12.0
Tumour/cancer11.2
Diabetes7.3
Skin problems (including panniculitis)8.6
Pulmonary hypertension6.3
PVD6.3
CTD6.0
AATD (PiSZ=504)High blood pressure52.0
Reflux40.4
Sinus disease20.4
Heart rhythm problems18.6
Tumour/cancer16.2
Diabetes17.0
Skin problems (including panniculitis)7.0
Pulmonary hypertension8.1
PVD7.0
CTD7.4
 Basil, 2021 [30]Severe AATDVTE7Unadjusted HR 6.5, 95% CI 4.9–8.6
Adjusting for risk factors: male, age, COPD, cancer and liver disease HR 5.2, 95% CI 3.7–7.4
Subjects with severe AATD had considerably increased risk of developing VTE versus the general population, even after accounting for risk factors.
Controls1
 Tanash, 2020 [41]AATD (PiZZ) (n=1545)Ischaemic heart disease8HR 1.8, 95% CI 1.4–2.3
Ever-smokers HR 2.1, 95% CI 1.5–2.9
Never-smokers HR 1.5, 95% CI 1.1–2.2
PiZZ individuals had a lower risk of developing incident ischaemic heart disease than controls with known smoking habits.
Controls (n=5883)12
 Hiller, 2020 [42]AATD (PiZZ) (n=1585)Cancer12Adjusted HR 1.6, 95% CI 1.3–1.9
Ever-smokers HR 1.5, 95% CI 1.2–1.8
Never-smokers HR 1.7, 95% CI 1.3–2.2
PiZZ individuals had a lower risk of developing incident cancer than the general population adjusting for age and sex, both in ever- and never-smokers.
Controls (n=5999)10
 Sapey, 2020 [58]AATD (n=68)Periodontitis88Periodontitis severity associated with lung disease severity (AATD, periodontitis versus no periodontitis; FEV1 56% versus 99% predicted; TLCO 59% versus 81% predicted; p<0.0001 for both)The results supported shared pathophysiology between periodontitis and COPD, especially when associated with AATD.
COPD (n=88)95
 Mandich,  2011 [59]AATD (n=33)Bipolar disorder
Schizophrenia
Depression
Anxiety
3.0
0
18.2
15.2
The incidence of psychiatric disorders was higher than the national incidence.

PM: pulmonary manifestation; PiMM/MZ/SZ/ZZ: Pi (or SERPINA1 gene) MM, MZ, SZ and ZZ alleles; CCI: Charlson Comorbidity Index; hs-CRP: high-sensitivity C-reactive protein; CT: computed tomography; AAT: alpha-1 antitrypsin; FEV1: forced expiratory volume in 1 s; AST: aspartate aminotransferase; BMI: body mass index; ALT: alanine aminotransferase; GGT: γ-glutamyl transferase; TE: transient elastography; LSM: liver stiffness measurement; APRI: AST-to-platelet ratio index; LFT: liver function test; NASH: nonalcoholic steatohepatitis; ALD: alcoholic liver disease; PSC: primary sclerosing cholangitis; PBC: primary biliary cirrhosis; UC: ulcerative colitis; PVD: peripheral vascular disease; CTD: connective tissue disease; VTE: venous thromboembolism; HR: hazard ratio; TLCO: transfer factor of the lung for carbon monoxide. #: no estimated value was presented, although a qualitative statement establishing a relationship between variable and complication was reported (the majority were conference abstracts); : Global Initiative for Chronic Obstructive Lung Disease classification 1–4 representing airflow obstruction with an FEV1 80–100% pred, 50–79% pred, 30–49% pred and <30% pred, respectively.