First author, year [ref.] | Patient population | Type of complication | Patients affected % | Risk factors for morbidity (value estimate) | Main outcomes |
Pulmonary morbidity | |||||
Herrera, 2021 [43] | Severe AATD (n=711) | COPD | 75.8 | Not evaluated | Patients with severe AATD-related PM requiring hospitalisation are substantially burdened by more frequent events and a more severe clinical course. |
Nonsevere AATD (n=1963) | COPD | 56.9 | |||
Severe AATD (n=711) | Emphysema | 33.8 | |||
Nonsevere AATD (n=1963) | Emphysema | 23.8 | |||
Tanash, 2019 [25] | Severe AATD (n=1595) | COPD | 53 | The proportion of subjects with COPD was higher among individuals with than those without liver disease. | |
Hiller, 2019 [26] | Severe AATD (n=1132) | COPD | 52 | Smoking# 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) | 75.6 | Not evaluated | PiSZ 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) | Bronchiectasis | 3.8 | Not evaluated | Patients 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) | Emphysema | 21.2 | |||
Cortese, 2016 [45] | AATD (n=475) | Bronchiectasis | 12 | Patients with bronchiectasis had more comorbidities (p=0.008) and were more frequently affected by pneumonia (p=0.024) than those without bronchiectasis | The 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) | Bronchiectasis | 24 | PiZZ# | PiZZ individuals were significantly more likely to have severe bronchiectasis versus those with other alleles. |
AATD with bronchiectasis (n=26) | Emphysema | 53.8 | |||
Kawkgi, 2013 [47] | AATD (PiSZ) with smoking history (n=29) | Emphysema | 36 | Smoking# | 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) | Bronchiectasis | 54 | |||
Ferrarotti, 2012 [48] | Severe AATD (n=312) | Overall (not specified) | 79 | Smoking 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) | COPD | 73 | Smoking# Dust exposure# | AATD led to significant morbidity in affected subjects. |
Subramanian, 2010 [40] | AATD PiMZ (n=497) | Lung nodule | 26.8 | hs-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 cancer | PiMM 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) | Emphysema | Patients 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 obstruction¶ | 47.3 45.9 74.6 | Smoking | Patients 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) | COPD | Not stated | Not stated | PiSZ 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) | Bronchiectasis | 27 (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) | 88 | Not evaluated | This 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) | 10 | Not evaluated | This 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) | 29 | AST (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 fibrosis | 3 | Not evaluated | Patients 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 fibrosis | 23 | |||
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 fibrosis | 18 | Not evaluated | PiMZ 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 fibrosis | 21 | Not evaluated | AATD 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 steatosis | 37 | |||
AATD (n=19) | Cirrhosis | 11 | |||
Hamesch, 2019 [38] | AATD with homozygous PiZZ (n=403) | Liver fibrosis (LSM) | 23.6 | Age >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) | Cirrhosis | 7 | Male 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 carcinoma | 2 | |||
Stone, 2014 [37] | AATD (n=651) | Cirrhosis | 4 | Not evaluated | |
Clark, 2018 [27] | AATD (n=94) | Liver fibrosis | 35.1 | Sex (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 disease | Stage 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 1 | Liver fibrosis/cirrhosis | Liver 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 1 | Liver primary cancer | PiSZ 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 2 | Liver fibrosis/cirrhosis | 24 | |||
AATD PiSZ (n=239): cohort 2 | 13 | ||||
Controls (noncarriers n= 279): cohort 2 | 5 | ||||
AATD PiMZ (n=419): cohort 1 | Liver fibrosis | 10 | |||
Schneider, 2020 [55] | AATD PiZZ (n=309): cohort 1 | LSM >7.1 kPa | 25 | Obesity and diabetes were the most important factors associated with LSM ≥7.1 kPa in subjects with the PiMZ genotype. | |
Control (noncarriers n=284): cohort 1 | 4 | ||||
AATD PiMZ (n=84): cohort 2 | Liver steatosis | Stage 1 40.5 Stage 2 28.5 Stage 3 15.5 | |||
AATD PiZZ (n=35): cohort 2 | Stage 1 34.3 Stage 2 37.1 Stage 3 2.9 | ||||
AATD PiMZ (n=84): cohort 2 | Liver fibrosis | Stage 1 13.1 Stage 2 28.6 Stage 3 28.6 Stage 4 16.7 | |||
AATD PiZZ (n=35): cohort 2 | Stage 1 5.7 Stage 2 20.0 Stage 3 42.9 Stage 4 28.6 | ||||
AATD PiMZ (n=84): cohort 3 | Perisinusoidal fibrosis | 69.1 | |||
AATD PiZZ (n=35): cohort 3 | 97.1 | ||||
Hakim, 2021 [56] | SERPINA 1 Z allele (n=299 939) | Cirrhosis | 0.5 | The 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 | <1 | Four out of 1595 patients with a PiZZ genotype | No patients with panniculitis developed liver disease. |
Stone, 2014 [37] | AATD (n=651) | Panniculitis | 0.9 | The 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 polyangiitis | 0.8 | ||||
Inflammatory bowel disease (UC and Crohn disease) | 1.5 | ||||
Hypothyroidism | 4 | ||||
Choate, 2019 [44] | AATD PiZZ (n=3031) | High blood pressure | 38.4 | A statistically significant greater proportion of PiSZ in our cohort were diagnosed with the six most prevalent comorbidities. | |
Reflux | 33.9 | ||||
Sinus disease | 15.4 | ||||
Heart rhythm problems | 12.0 | ||||
Tumour/cancer | 11.2 | ||||
Diabetes | 7.3 | ||||
Skin problems (including panniculitis) | 8.6 | ||||
Pulmonary hypertension | 6.3 | ||||
PVD | 6.3 | ||||
CTD | 6.0 | ||||
AATD (PiSZ=504) | High blood pressure | 52.0 | |||
Reflux | 40.4 | ||||
Sinus disease | 20.4 | ||||
Heart rhythm problems | 18.6 | ||||
Tumour/cancer | 16.2 | ||||
Diabetes | 17.0 | ||||
Skin problems (including panniculitis) | 7.0 | ||||
Pulmonary hypertension | 8.1 | ||||
PVD | 7.0 | ||||
CTD | 7.4 | ||||
Basil, 2021 [30] | Severe AATD | VTE | 7 | Unadjusted 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. |
Controls | 1 | ||||
Tanash, 2020 [41] | AATD (PiZZ) (n=1545) | Ischaemic heart disease | 8 | HR 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) | Cancer | 12 | Adjusted 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) | Periodontitis | 88 | Periodontitis 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.