Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder of codominant inheritance, caused by a mutation in the SERPINA1 gene [1]. It leads to low levels of alpha-1 antitrypsin (AAT), resulting in low anti-elastase activity [2]. More than 1000 variants of this gene have been identified, being the proteinase inhibitor (PI)*S and Z the most common of all [3]. PI*S is highly prevalent in the northwest of the Iberian Peninsula and PI*Z has its origins in Northern Europe [4]. The highest risk for the development of emphysema corresponds to the PI*ZZ genotype, with AAT levels of approximately 15% in blood [5], and the PI*SZ genotype, with around 40% protein serum levels, is the next most frequent severe deficient genotype. Some studies suggest an increased susceptibility to developing COPD in smokers with PI*SZ genotype, and an elevated risk of liver disease [6,7]; however, information about this genotype is scarce.

There is great variability in the clinical presentation and severity of lung and liver disease in patients with AATD [8]. Therefore, it is important to identify markers and biomarkers that can predict respiratory involvement, both in terms of clinical phenotypes and severity. Recently, biomarkers such as proinflammatory interleukins, desmosine and isodesmosine, and circulating AAT polymers have been found to be associated with prognosis of lung disease [9–11]. Nevertheless, the use of these biomarkers remains largely confined to research settings and they are rarely incorporated into routine clinical practice. In this context, a recent study reported that certain serum biomarkers—including higher hematocrit levels, gamma-glutamyl transferase (GGT), and the platelet-to-lymphocyte ratio (PLR)—were associated with more severe forms of emphysema in patients with the PI*ZZ genotype, although the prognostic accuracy of these markers was low.

This study aimed to compare routine serum biomarkers between PI*SZ individuals with and without emphysema, and assess their correlations with lung disease severity across the entire PI*SZ population.

This multicentre cross-sectional study included patients from the European Alpha-1 Antitrypsin Deficiency Research Collaboration (EARCO) international registry database who had confirmed AATD and PI*SZ genotype [13]. Patients on augmentation therapy were excluded. Demographic data, smoking history, comorbidities, respiratory symptoms, presence of lung and/or liver disease, medical history of respiratory exacerbations within the past 12 months and lung function tests (forced expiratory volume in the first second [FEV1] and the carbon monoxide transfer coefficient [KCO]) were collected. Routine serum biomarkers were obtained and the neutrophil-to-lymphocyte ratio (NLR), eosinophil-to-lymphocyte ratio (ELR) and PLR were calculated. Normally distributed variables were compared using the Student t test, whereas non-normally distributed variables were analyzed with the Mann–Whitney U test. Categorical variables were analyzed using the chi-square or Fisher exact test, as appropriate, and correlations were assessed using Pearson or Spearman correlation coefficients according to data distribution.

The EARCO registry (ID: NCT04180319) was approved by Hospital Universitari Vall d’Hebron Ethics Committee and written informed consent was obtained from all participants prior to their inclusion in the study.

Of the 2419 patients included in the EARCO Registry as of October 2024, 571 (23.6%) had the Pi*SZ genotype and were not receiving augmentation therapy. Among them, 51% were men, with a mean age of 51.8 years (SD, 16.3) and 46.7% had never been smokers. Mean FEV1 (%) was 92.3% (SD, 25.9%), mean KCO (%) was 89% (SD, 22.2%), and emphysema was reported in 118 (20.7%). Overall, 12.3% of patients were current smokers, 41.0% were former smokers, and 46.7% had never smoked. Emphysema was present in 22 (31.4%) current smokers, 85 (36.5%) former smokers and 11 (4.2%) never smokers.

Individuals with emphysema were older, with a higher proportion of men, greater smoking history, and worse lung function vs individuals without emphysema. Biomarker analysis in emphysema patients showed significantly elevated levels of AAT, aspartate aminotransferase (AST), GGT, fibrosis-4 index (FIB-4), hemoglobin, leukocytes, neutrophils, and the NLR (Table 1). In addition, among all PI*SZ patients, weak but significant negative correlations were observed between FEV1(%) and serum levels of AAT, GGT, FIB-4 index, hemoglobin, leukocytes, lymphocytes, neutrophils, and the NLR. Similarly, for KCO(%), weak but significant negative correlations were found with AAT, FIB-4 index, leukocytes, neutrophils, platelets, and the NLR, while a positive correlation was observed with ALT (Fig. 1).

Fig. 1.

Correlations between routine serum biomarkers and FEV1% and KCO%.

Only a limited number of studies have investigated the role of blood biomarkers in AATD, and almost all have focused on patients with the PI*ZZ genotype [9–12]. Therefore, our study addresses an important gap in the literature by evaluating routine blood biomarkers in a large, well-characterised PI*SZ population. In addition to contributing novel genotype-specific data, these findings complement and extend previous work from the same EARCO registry in PI*ZZ individuals, allowing for comparisons across genotypes and providing a valuable resource for future research in AATD [14].

Clinical trials have suggested that individuals with the PISZ genotype exhibit respiratory features more similar to those observed in PIMZ than in PI*ZZ, and that the emphysema pattern may resemble smoking-related COPD [15]. Consequently, and as expected, our patients with PI*SZ genotype and emphysema were older, with a higher smoking exposure and worse lung function vs those without emphysema. Data on the comparison of biomarkers in Pi*SZ individuals with or without lung disease are scarce. We found that PI*SZ patients with emphysema displayed a distinct biomarker profile vs those without the disease, indicating increased systemic inflammation, liver changes, and potential metabolic changes. These findings are mostly aligned with previous observations in PI*ZZ individuals from the EARCO registry, where patients with established lung disease also showed higher levels of hemoglobin, GGT, NLR, PLR, and ELR, with weak but significant negative correlations with spirometric parameters [12]. Of note, the distinction is limited by differences in disease definition (emphysema vs COPD), yet the overlap in biomarker patterns suggests possible genotype-specific differences in systemic inflammatory responses, thus reinforcing that routine blood biomarkers alone have limited ability to predict the severity of lung disease in PI*SZ individuals.

Regarding the associations between biomarkers and lung disease severity, former studies have suggested that markers, such as GGT or fibrinogen cleavage product Aα-Val360 may be associated with lung function in AATD [16,17]. In our cohort, although some correlations reached statistical significance, they were consistently weak, reflecting the marked heterogeneity of pulmonary involvement in this population. Factors such as the distribution and extent of emphysema, presence of comorbidities, and smoking exposure may contribute to this variability. These findings underscore that, while serum biomarkers can offer valuable insights into systemic inflammation or metabolic alterations, they should be interpreted with caution when assessing pulmonary disease severity in any given individual.

Limitations of our study include its cross-sectional design, which excludes any possibility of deducing causality between biomarker levels and the presence or severity of lung disease. Additionally, neither can determine the value of these biomarkers in predicting disease and clinical progression. Therefore, prospective follow up studies in PI*SZ individuals are needed to validate the prognostic value of blood biomarkers. Furthermore, lung phenotypes were based on physician-reported diagnoses without standardized imaging or centralized validation, which may be a source of misclassification or diagnostic variability. In addition, the study was limited to routine blood biomarkers and did not include disease-specific markers, such as circulating AAT polymers, desmosine or pro-inflammatory cytokines, which may be source of pathophysiological insight. Furthermore, the number of C-reactive protein (CRP) measurements in our cohort were too low to be included in the analysis.

In conclusion, AAT PI*SZ deficiency with emphysema was associated with a distinct biomarker profile, reflecting systemic inflammation, liver changes, and potential metabolic changes. Moreover, although some correlations between serum biomarkers and lung disease severity reached statistical significance, they were consistently weak, illustrating the heterogeneity of pulmonary involvement and suggesting caution when using serum biomarkers to assess disease severity in this population.