Alpha-1 Antitrypsin Deficiency

SERPINA1-related alpha-1 antitrypsin deficiency (AATD): loss-of-function lung disease, toxic gain-of-function liver disease and an allelic bleeding disorder (Pittsburgh variant).

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Alpha-1 antitrypsin deficiency has a distinctive place in medical genetics because a single plasma protein, synthesised predominantly in the liver, accounts for two diseases with opposing mechanisms. In the lung, insufficient circulating AAT reaches the alveolar interstitium, both in quantity and in activity, allowing elastase released by neutrophils to degrade the elastic matrix. In the liver, misfolded protein, particularly the Z variant, polymerises within the hepatocyte endoplasmic reticulum, fails to be secreted and injures the cell that produces it. This distinction shapes everything that follows in this article, from genotype interpretation to the reason why augmentation therapy protects the lung but not the liver [1, 6, 19].

The disease was first recognised in 1963, when Laurell and Eriksson described five patients lacking the alpha-1 band on agarose-gel serum protein electrophoresis; three had emphysema, as did nine of 14 additional patients identified by Eriksson shortly afterwards. Schultze and colleagues had isolated the protein in 1955, identifying it as the principal serum trypsin inhibitor and the predominant component (90%) of the alpha-1 fraction. Partial deficiency was soon recognised as dominantly inherited, whereas severe deficiency corresponded to homozygosity [9, 28]. In 1969, Sharp and colleagues linked the deficiency to childhood liver disease after identifying it in 14 children with liver disease, all PIZZ homozygotes; all but one developed cirrhosis [9, 29].

Fagerhol characterised protein polymorphism using starch gels and, subsequently, polyacrylamide-gel isoelectric focusing. This established the PI (protease inhibitor) nomenclature, in which letters reflect electrophoretic mobility: M denotes the normal form and Z the slowest. This terminology preceded identification of the gene and remains in clinical use alongside HGVS (Human Genome Variation Society) nomenclature [1, 9]. Swedish neonatal screening of 200,000 newborns between 1972 and 1974, published by Sveger in 1976, provided the only unbiased birth cohort. It continues to underpin estimates of childhood liver disease and, through follow-up into the fourth decade, part of our understanding of pulmonary natural history [20, 30, 31]. In 1992, Lomas and colleagues demonstrated the loop–sheet polymerisation mechanism of Z-AAT, explaining hepatocellular inclusions [32].

Augmentation therapy with plasma-purified AAT was approved in the USA in 1987 on the basis of biochemical efficacy (increased serum and pulmonary epithelial lining fluid levels). Only decades later did trials using computed tomography (CT) lung densitometry demonstrate slower progression of emphysema [14, 19, 33]. Recent research has shifted towards correcting the underlying cause through hepatic RNA interference, RNA editing and DNA base editing, as well as long-half-life recombinant proteins [34, 35]. In parallel, hepatology societies have recognised adult liver disease as a distinct entity, with a consensus definition and staging system established in 2026 [6].

2. Molecular Genetics and Pathophysiology

2.1. The SERPINA1 gene and protein

SERPINA1 is located at 14q32.13 (the designation 14q32.1 used in older sources refers to the same region), spans approximately 12.2 kb and has a 1,434 bp coding region distributed across four coding exons [1, 9]. It encodes AAT, a single-chain 52 kDa glycoprotein containing approximately 12% sialic-acid-rich carbohydrate, belonging to the serpin (serine protease inhibitor) family. The primary protein has 418 amino acids: the first 24 form the signal peptide and residues 25–418 constitute the mature protein. AAT provides more than 90% of protection against neutrophil elastase in the lower airways and is an acute-phase reactant [1, 3, 9].

The 24-residue difference explains the two numbering systems encountered throughout the literature: historical nomenclature counts from the mature protein, whereas HGVS numbering starts at the initial methionine of precursor NP_000286.3. Thus, Glu342Lys (Z) corresponds to p.(Glu366Lys), and Glu264Val (S) to p.(Glu288Val) [1, 4]. The 2025 Canadian guideline recommends adopting HGVS nomenclature in molecular reports while retaining the PI designation alongside HGVS during a transition period [10].

2.2. Alleles and variant classes

More than 100 protein variants have been described; most have normal levels [9, 20]. GeneReviews groups clinically relevant alleles as follows: PI*M, the most common normal allele in all populations, with benign subtypes M1, M2 and M3; PI*Z, the most common pathogenic allele, causing quantitative and functional deficiency; PI*S, causing mild deficiency, clinically relevant mainly in compound heterozygosity with another pathogenic allele; PI*F, quantitatively normal but with impaired elastase binding; PI*I, causing mild quantitative deficiency; and null alleles (PI*Q0), with no mRNA or no protein [1]. A review of the mutational spectrum identified more than 500 rare SERPINA1 variants detected through screening and sequencing programmes, involving loss-of-function mechanisms (null, deficient and dysfunctional variants) and gain-of-function mechanisms (polymers and altered protease affinity) [36].

The three representations of Mmalton do not denote different variants: they describe the same deletion of a phenylalanine codon in a repetitive sequence using different alignment conventions; VariantValidator 3′ normalisation shifts the deletion to c.227_229del [1, 4, 5]. This article gives historical names in parentheses whenever they are used in the cited literature.

2.3. Relationship between genotype, serum level and risk

Serum levels reflect the combined contributions of both alleles. SS homozygotes have approximately 40% lower plasma levels and ZZ homozygotes approximately 85% lower levels; synthesis of S and Z is normal, but intracellular processing and secretion are impaired [11]. The Atlas reports activity of approximately 60% of normal in PISS, 68% in PIII, 30% in PIPP and approximately 15% in PIZZ, with no detectable AAT in null genotypes [9].

Source: GeneReviews, Table 4, adapted from Brantly 1991, Stoller & Aboussouan 2005, de Serres & Blanco 2012 and Bornhorst 2013; the 2023 revision clarified that the column represents lifetime risk [1]. Serum levels alone cannot classify genotype: the MZ, SS and MS ranges overlap with MM, and the Canadian meta-analysis estimated mean differences relative to MM of −52 mg/dL for MZ, −87 mg/dL for SZ and −137 mg/dL for ZZ [10]. The prevalence columns describe genotype frequencies in genetic surveys, not disease prevalence [1].

2.4. Pulmonary mechanism: loss of function and inflammation

Circulating AAT diffuses into the pulmonary interstitium and epithelial lining fluid, where it inhibits elastase and other proteases released by neutrophils and macrophages. The protease–antiprotease hypothesis rests on observations that isolated elastase produces experimental emphysema and that tobacco smoke inactivates AAT through oxidation, explaining the gene–environment interaction [9, 19]. Smoke oxidises methionines in the Z-AAT active site and increases polymerisation [37]. The resulting injury destroys alveolar walls, with loss of architecture and enlarged airspaces, typically producing predominantly basal panlobular emphysema [1, 9].

Loss of function does not explain all variability. Z-AAT polymers formed in the lung or alveolar macrophages are chemotactic for neutrophils and may amplify injury [1, 11]. The ERS also highlights the poor concordance of FEV1 (forced expiratory volume in the first second) between siblings exposed to the same environment and the dissociation between spirometry and gas transfer, suggesting unidentified genetic and environmental modifiers [1, 20].

2.5. Hepatic mechanism: Z-AAT retention and polymerisation

In the Z variant, protein synthesis and mRNA levels are normal, but the altered conformation prevents transport out of the endoplasmic reticulum; Z-AAT isolated from the liver remains functionally active [9]. In the normal protein, glutamate 342 forms a salt bridge with lysine 290; substitution by lysine disrupts this bridge. Reintroducing glutamate at position 290 of the Z protein restored secretion, but disrupting the salt bridge alone in normal protein did not prevent secretion, indicating a broader role for tertiary structure [9]. The reactive centre loop of one molecule inserts into the A sheet of another, forming polymers; this occurs spontaneously at 37 °C and depends on temperature and concentration, making exacerbation during fever plausible [9, 32]. In ZZ homozygotes, only approximately 15% of the protein is secreted; the remainder is degraded or aggregates into insoluble inclusions [32].

The misfolded protein interacts with calnexin for prolonged periods and is directed towards endoplasmic-reticulum-associated degradation (ERAD) through the ubiquitin–proteasome pathway; the null Hong Kong variant served as a model for studying this pathway [9]. Accumulation of human Z-AAT in transgenic mice produced hepatic necrosis and inflammation [9]. GeneReviews attributes the increased risk of hepatocellular carcinoma to failure of apoptosis in cells carrying the greatest Z-AAT burden, which chronically signal regeneration to less heavily burdened hepatocytes [1]. Inclusion-forming alleles (Z, Mmalton, Siiyama) confer hepatic risk; null alleles do not, because they produce no protein, but carry the greatest pulmonary risk [1].

2.6. Inheritance and terminology

AATD is autosomal codominant: each allele contributes to circulating levels, and phenotype reflects the genotypic pair. GeneGuidance records it as autosomal recessive for consistency with OMIM and GenCC submitters, while noting that codominance is the clinically relevant principle [1, 3]. Historically, partial deficiency was described as dominant because it could be detected in heterozygotes [9]. Severe disease risk follows a recessive model (two deficient alleles), with heterozygosity modifying risk in the presence of cofactors [6, 37].

2.7. Allelic disease: AAT Pittsburgh

GeneReviews states that no allelic phenotypes are known beyond those it describes, but Orphanet and ClinVar recognise a distinct entity, the bleeding disorder caused by AAT Pittsburgh (ORPHA:178396); this information takes precedence because it is supported by the primary publication [1, 5, 8]. In 1983, Owen and colleagues studied plasma from a 14-year-old boy who died from episodic bleeding disease and identified replacement of methionine 358 (the reactive centre, serving as the elastase target) by arginine. This converted AAT into a heparin-independent thrombin inhibitor; episodes occurred because the mutant protein was an acute-phase reactant [7]. The HGVS variant is NM_000295.5:c.1145T>G, p.(Met382Arg) [4, 5]. In 2009, a Chinese family comprising a heterozygous father and daughter showed prolongation of all coagulation tests, undetectable protein C and abolished thrombin-induced platelet aggregation at 1 U/mL, with no abnormalities in seven non-carrier relatives [38]. Orphanet records four cases/families and describes spontaneous or post-traumatic haematomas and, in women, post-ovulatory ovarian haematomas [8]. The Oxford Desk Reference uses AAT as an example of a dominant mutation producing a “new protein” through altered substrate specificity [39]. This dominant gain-of-function mechanism is distinct from deficiency and is relevant to the genetic differential diagnosis of rare coagulopathies.

3. Clinical Spectrum and Manifestations by System

3.1. Overview and determinants of expression

Expression varies both between and within families. Genotype and the resulting serum level determine baseline risk; smoking is the principal accelerator of adult lung disease, while age, male sex, metabolic syndrome, alcohol and other hepatic insults modify liver disease. Non-smokers may have a normal life expectancy but can nevertheless develop pulmonary or hepatic disease [1, 6]. GeneReviews summarises the frequency of major manifestations using clinical series whose denominators are individuals already identified with severe deficiency, rather than the population of undiagnosed homozygotes [1].

Source: GeneReviews, Table 3 and text [1].

3.2. Lung

COPD, particularly emphysema and chronic bronchitis, is the most common manifestation; respiratory disease in smokers characteristically begins between 40 and 50 years, and in most observational studies the mean age of patients with lung disease falls in the fifth decade [1]. Among 1,129 participants with severe deficiency in the National Heart, Lung, and Blood Institute (NHLBI) registry, 84% reported dyspnoea, 76% wheezing with upper respiratory infections and 50% cough and sputum production [1]. The first symptom is usually exertional dyspnoea; examination may show weight loss, increased chest diameter and reduced breath sounds. Radiographs show predominantly basal hyperinflation and flattened diaphragms; advanced disease involves mild hypoxaemia exacerbated by exertion, mild pulmonary hypertension and electrocardiographic signs of right heart strain [9]. CT shows parenchymal loss and hyperlucency; emphysema is predominantly basal in two-thirds of cases, contrasting with the apical centriacinar pattern of acquired emphysema [1, 9]. The Canadian guideline notes that up to one-third of patients with severe deficiency have greater upper-region involvement and that symptoms are usually indistinguishable from other forms of COPD [10].

Lung function tests show expiratory airflow obstruction, increased lung volumes and reduced diffusing capacity; approximately 60% of patients with AATD-associated emphysema have a reversible obstructive component (a 200 mL and 12% increase in FEV1 or forced vital capacity after bronchodilator administration) [1]. Gas transfer becomes abnormal earlier than FEV1, which only begins to depart from normal in the fourth decade; emphysema may continue to progress on densitometry despite stable FEV1 [20]. The Oxford Desk Reference reports mean FEV1 declines of 35 mL/year in healthy non-smokers, 45 mL/year in ZZ non-smokers and up to 70 mL/year in ZZ smokers [11]. Smoking cessation may bring progression closer to that of never-smokers [20]. Adolescent smoking prevents attainment of maximum lung function [9].

AATD prevalence in patients with asthma does not differ from the general population, but deficiency should be investigated in adult asthma with persistent obstruction [1, 10]. Bronchiectasis is common as an anatomical finding and less common as clinical disease [1, 19]. Emphysema in children with AATD is exceptional and may reflect coexisting genetic factors; children with null alleles may have severe early emphysema [1, 9].

The Swedish cohort identified at birth provides the best source of unbiased natural history. At age 38, 41 PiZZ, 18 PiSZ and 61 PiMM controls were studied: PiZZ participants who had ever smoked already had hyperinflation and a lower carbon monoxide transfer coefficient, without between-group densitometric differences [31]. At ages 37–40, two of four current smokers had COPD [20]. Among 568 PiZZ non-smokers in the Swedish registry followed from 1991 to 2007, the overall standardised mortality ratio was 2.32 (95% CI 1.87–2.83), but it was 0.70 (0.14–2.04) in those identified through family or population screening. Emphysema and cirrhosis were the most frequent causes of death (45% and 28%), and malignant transformation occurred in 38% of cirrhosis cases [40]. These figures apply to Swedish non-smokers and should not be extrapolated to smokers or symptomatically identified patients.

The French PNDS (French National Diagnosis and Care Protocol) for pulmonary care summarises the age of expression: respiratory symptoms are exceptional in children and rare before age 25, generally appear from age 30–40 in smokers and between 50 and 60 in non-smokers, and PiZZ adults who have never smoked do not have emphysema before the fifth decade; about one third have a history of childhood asthma, wheezing or partial reversibility of obstruction, and deficiency-associated COPD has no particular features compared with COPD in smokers without deficiency, and may be associated with bronchiectasis; diagnosis is made, on average, more than 5 years after the first symptoms [24]. Regarding prognosis, the BODE index overestimates mortality in these patients compared with COPD without deficiency, and life expectancy of a PiZZ individual without respiratory or liver disease and without tobacco, alcohol or obesity is normal [24]. In the liver, the PNDS reports neonatal cholestasis in 10% of PiZZ children, usually resolving, and fibrosis, on elastography or biopsy, in 10–35% of PiZZ adults with respiratory disease, with obesity, metabolic syndrome and male sex as risk factors [24].

Table 3.2a — Disease risk by genotype and risk factors according to the French PNDS [24]

According to the PNDS, alleles M1 to M4 do not increase risk, nor do SS and MS genotypes; the MMalton allele behaves like Z (misfolding and hepatocyte retention), and null alleles (Q0), which are very rare, confer a high pulmonary risk without liver disease [24].

3.3. Pulmonary disease in heterozygotes and intermediate genotypes

In a meta-analysis of 16 studies, the COPD odds ratio for PI MZ versus PI MM was 2.31 (95% CI 1.60–3.35), higher in case–control studies and attenuated (1.61; 0.92–2.81) in smoking-adjusted studies, with no difference in mean FEV1 [41]. In a family study involving 89 MZ and 99 MM non-index individuals, MZ heterozygosity was associated with an adjusted COPD odds ratio of 5.18 overall and 10.65 in ever-smokers; the effect disappeared in never-smokers [42]. The ERS concludes that MZ never-smokers do not have increased risk, whereas MZ and SZ smokers have higher risk than MM smokers [20]. Among 70 SZ individuals compared with MM/MS relatives, SZ never-smokers had no increased risk; having smoked was associated with a 14.3-percentage-point lower FEV1, unrelated to AAT concentration [43]. GeneReviews reports that approximately 11% of SZ individuals have levels below the protective threshold and are at risk of basal emphysema and chronic bronchitis, particularly if they smoke; FF and FZ genotypes are considered at risk, and null homozygotes have the highest pulmonary risk [1, 20].

3.4. Liver disease in childhood

The most frequent childhood hepatic presentation is neonatal hepatitis syndrome with cholestasis: conjugated hyperbilirubinaemia, increased aminotransferases, hepatomegaly, sometimes splenomegaly, vomiting, faltering growth, low birth weight, dark urine and occasionally acholic stools mimicking biliary atresia [9]. The Atlas reports AATD in 14–29% of infants with neonatal hepatitis syndrome in an older English series and describes bleeding due to vitamin K deficiency [9]; the Oxford Desk Reference highlights the risk of intracranial haemorrhage through this mechanism [44]. Jaundice usually resolves by seven months [9].

In the 2024 French protocol of the reference centre for biliary atresia and genetic cholestasis, biallelic deficiency accounts for 5–10% of neonatal cholestasis. The PiZZ genotype causes the most severe form, with intense cholestasis and completely acholic stools that may mimic atresia; about 10–15% of these children progress to cirrhosis requiring liver transplantation, an estimate supported by the French paediatric DEFI-ALPHA cohort and a 2020 review [27]. The denominator is children with recognised and referred liver disease, not all PiZZ newborns: in the Swedish population screening cohort, childhood cirrhosis was 2.4% [11]. In the DEFI-ALPHA cohort itself (153 children born in France since 1989 with serum AAT below 0.8 g/L, 81.9% PiZZ and 8.1% PiSZ, followed for a mean of 4.7 years), 28 (18.3%) had severe liver disease (portal hypertension, liver failure, transplantation or death), 15 (9.8%) underwent transplantation and one died at age 3; neonatal cholestasis was associated with the severe form, and the severe cases included two PiSZ children and one Z heterozygote with a rare M variant [45]. The same protocol accepts neonatal cholestasis with other deficient genotypes, such as SZ and MZ [27]; the 2017 North American and European guideline recognises that PiSZ individuals, like PiZZ, may develop liver disease, but states that MZ, MS, SZ and SS phenotypes do not present with neonatal cholestasis without another associated cause [46]; in DEFI-ALPHA, severe cases with genotypes other than ZZ were associated with predisposing factors [45].

In Swedish screening, 14 of 120 Pi Z infants had prolonged obstructive jaundice (nine with severe clinical and laboratory abnormalities). Among 98 without clinical liver disease, liver tests were abnormal in 44 of 84 at three months and 36 of 60 at six months; infants who were small for gestational age were more frequent among those with clinical disease. None of 48 Pi SZ infants had clinical liver disease [30]. The Oxford Desk Reference summarises follow-up to eight years: among 127 ZZ newborns, almost all had elevated enzymes, 14 (11%) had prolonged neonatal jaundice and three (2.4%) developed childhood cirrhosis. Among those without jaundice or hepatomegaly, the proportion with abnormal liver tests fell from 60% at six months to approximately 15% at 12–18 years, with transient fluctuations [11]. GeneReviews reports 18% with clinically recognised hepatic abnormalities and 2.4% with cirrhosis and childhood death in the Swedish cohort [1]. Other presentations include transient acute hepatitis during infections or appendicitis from age two, hepatomegaly without previous jaundice, and cirrhosis with spider naevi from age two, portal hypertension, oesophageal varices, ascites, pruritus, hyperammonaemia and encephalopathy. Cirrhosis and early death were described in 2% of PIZZ children and 14% of those with childhood hepatic manifestations [9]. In a series of 44 children with cirrhosis or portal hypertension, outcomes ranged from liver transplantation (two) to relatively healthy survival up to 23 years after diagnosis (seven) [1].

Hepatic disease has a bimodal age distribution, with a first peak in early childhood and another around age 40; AATD is a major indication for paediatric liver transplantation, with good patient and graft survival [37]. According to the Oxford Desk Reference, it is the most frequent indication for childhood liver transplantation after biliary atresia [44]. PI*MZ and PI*SZ genotypes are not associated with childhood liver disease, although transient enzyme elevation may occur [1].

3.5. Liver disease in adults

Adult liver disease (fibrosis, cirrhosis) may develop without a neonatal history, is more frequent in men and has an estimated risk of approximately 2% between ages 20 and 40 and 4% between ages 41 and 50. Autopsy studies suggest prevalence as high as 40% in elderly never-smokers without COPD, often with subclinical disease [1]. The 2026 consensus estimates that approximately 10% of PiZZ adults develop clinically significant liver disease and that advanced fibrosis risk is approximately 20 times that in people without the variant, compared with 2 and 3 times for MZ and SZ genotypes [6].

In PI*ZZ individuals, hepatocellular carcinoma risk is several times greater than that usually associated with cirrhosis [1]; hepatomas may occur without elevated alpha-fetoprotein [9]. In a British biobank, SZ genotype was associated with approximately threefold greater fibrosis risk and almost sevenfold greater primary liver cancer risk, whereas MZ individuals do not appear to have increased liver cancer risk. MZ individuals represent up to 10% of white liver transplant candidates, and decompensation occurs more rapidly in MZ patients with cirrhosis [37]. Patients with AATD experiencing their first hepatic decompensation appear to have greater risk of further decompensation, acute-on-chronic liver failure, transplantation or death than patients with other aetiologies [6].

Biopsy shows eosinophilic, periodic acid–Schiff-positive, diastase-resistant (PAS-D) globules, predominantly periportal, present from birth and increasing with age, confirmed by anti-AAT immunofluorescence or immunoperoxidase staining and localised to the endoplasmic reticulum lumen on electron microscopy. During the infantile cholestatic phase, ductular proliferation, fibrosis, steatosis and giant cells occur [9]. Inclusions are suggestive but not pathognomonic, are not seen before 12 weeks, may be small and difficult to identify in infants, and do not reliably distinguish MZ from ZZ [1].

3.6. Other manifestations

Necrotising panniculitis (painful, migratory inflammatory nodules that may ulcerate at sites of trauma, such as the lower limbs and abdomen) occurs in approximately 1 in 1,000 individuals with AATD [1]. Another review estimates 0.1–0.9%, with true prevalence unknown, and describes extensive, potentially life-threatening wounds [37]. c-ANCA-positive vasculitis, particularly granulomatosis with polyangiitis (GPA), is associated with deficiency [1]. The Atlas describes membranous or membranoproliferative glomerulonephritis with AAT, immunoglobulin and C3 deposits, frequently found at autopsy in children who died from liver disease, and associations between Z heterozygosity and rheumatoid arthritis or anterior uveitis [9]. In cystic fibrosis, the Z allele is a risk factor for severe liver disease with cirrhosis and portal hypertension, and PI*MZ status is among the best-established genetic factors for advanced liver disease in paediatric cystic fibrosis [9, 37]. MZ individuals have an increased incidence of gallstones [37].

4. Clinical Recognition and Warning Signs

Deficiency remains underdiagnosed: only 5,000–10,000 people had been identified in the USA, the interval between first symptoms and diagnosis is 5–7 years, and delay is associated with poorer clinical status at diagnosis [1]. In a study cited by the Canadian guideline, diagnosis occurred a mean 5.3 years after initial manifestations, with mean FEV1 of 52% predicted; delay was associated with worse overall and transplant-free survival [10]. The ERS estimates that only a minority are identified and, together with the World Health Organization, recommends testing all patients with COPD or adult asthma [20]. The European EARCO registry estimates that approximately 120,000 Europeans have PiZZ genotype and that only 15–30% of severe cases are diagnosed [21].

In newborns, cholestasis with faltering growth is a prominent AATD presentation, alongside Byler disease, bile acid synthesis defects, peroxisomal disorders, Niemann–Pick disease type C and CDG; liver failure in the first month is rare but possible [49]. A firm liver in an infant or child with hepatomegaly should prompt consideration of AATD among other disorders. With isolated aminotransferase elevation, AATD is among the first conditions to exclude, together with Wilson disease after age three and cystic fibrosis [49]. The Oxford Desk Reference includes AAT measurement and phenotyping in second-line investigations for prolonged neonatal jaundice [44]. A negative family history does not exclude the diagnosis because heterozygous parents are usually asymptomatic [1, 20].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criterion

Diagnosis requires demonstration of low serum AAT together with identification of biallelic pathogenic SERPINA1 variants or detection of a functionally deficient protein by PI phenotyping [1]. Quantification is the essential first step, but quantitative deficiency must be supported by a qualitative test identifying the variant [20]. The 2026 hepatic consensus defines associated liver disease (AATD-LD) in a PiZZ adult as recurrent (possibly episodic) elevation of AST, ALT or GGT and/or significant fibrosis (stage ≥F2 on a 0–4 scale) [6].

5.2. Who should be tested: comparison of recommendations

Sources: Sandhaus 2016, recommendations 1a–1e [19]; CTS 2025, P.1.A–P.1.C [10]; ERS 2017 [20]; SBPT 2024 [22]; 2026 consensus [6]; GeneReviews Table 2 [1].

The French PNDS recommends testing for the deficiency in all patients with emphysema or COPD, regardless of age, smoking and presentation, and in all patients with chronic liver disease, and offers it to the parents, children and siblings of a patient; serum level measurement, outside an inflammatory context, is the first step, followed by isoelectric focusing or targeted S and Z genotyping if the concentration is below 1.1 g/L, and SERPINA1 sequencing if there is discordance between level and phenotype or genotype; the PNDS considers it unnecessary to add C-reactive protein systematically, because inflammation, pregnancy, oral contraceptives and cancers may normalise the level of an MZ heterozygote but never that of a PiZZ individual; in France, all these tests can be performed on dried capillary blood spots, which facilitates large-scale screening [24]. The protocol gives reference values of 0.9–2 g/L and, elsewhere, a normal value above 1.1 g/L, with a concentration below 0.5 g/L in homozygotes and between 0.5 and 1.1 g/L in MZ and SZ heterozygotes [24].

5.3. AAT measurement

Nephelometry is the most widely used method; normal values are 20–53 µmol/L, approximately 100–220 mg/dL, and patients with AATD and lung disease usually have <57 mg/dL [1]. The Atlas gives a normal range of 20–50 µmol/L and 3–6 µmol/L for Z genotype, and historically recommended phenotyping below 40% of normal [9]. The historical protective threshold is 11 µmol/L, approximately 0.57 g/L depending on the assay [10]. In the ERS meta-analysis, the optimal threshold for distinguishing PI*MM from genotypes with at least one S or Z allele was 24.4 µmol/L (1.1 g/L), with 73.4% sensitivity and 88.5% specificity [20]. The CTS considers that ≥23 µmol/L (≥1.2 g/L) excludes severe deficiency in moderately suspicious cases, except for rare dysfunctional variants. Some authors propose higher thresholds because deficient patients can reach 1.4 g/L during acute inflammation [10]. In the Brazilian COPD study, serum levels below 113 mg/dL prompted genotyping, and the SBPT retains this threshold in its algorithm [22, 50].

AAT is an acute-phase reactant: levels increase with inflammation and pregnancy and vary in children; measurement should occur during clinical stability, ideally with simultaneous C-reactive protein measurement [19, 20, 22]. Test–retest reproducibility is poor [10]. Quantification alone should therefore not exclude diagnosis or determine carrier status, since heterozygote levels overlap with normal values [1]. Dried blood spot collection has facilitated centralised testing but has greater variability [20, 51].

5.4. Qualitative and molecular tests

The proportion of variants detectable by a method is not its clinical sensitivity: S/Z genotyping detects 95% of disease alleles but misses patients with rare alleles. The Canadian guideline estimates more than 300 such variants, and the 2026 clinical case reports that they account for up to 10% of pathogenic alleles [1, 10, 52]. MZ-Pratt is benign and should not be confused with MZ [52]. For symptomatic diagnosis, the Alpha-1 Foundation recommends genotyping at least S and Z, confirmation by an independent method (phenotyping, level and/or extended genotyping), and consideration of null alleles whenever level and genotype disagree, a situation that may reveal questions of paternity [19]. The CTS proposes coding-region sequencing (exons 2–5) as the reference standard: initially with high suspicion and following a level <23 µmol/L with moderate suspicion [10]. The ERS reserves sequencing for suspected null alleles or deficient variants other than S and Z [20].

A European external quality assessment programme involving seven laboratories (2019–2021), published in July 2026, found almost perfect agreement for M, S (p.E288V) and Z (p.E366K) (Fleiss kappa 0.85–1.00, zero error), but inconsistent detection of rare variants such as Mprocida (p.L65P), Mheerlen (p.P393L) and Mwurzburg (p.P393S), with allelic error rates of 0.14–0.29. Sequencing outperformed phenotyping and basic genotyping, and report nomenclature varied widely [51].

Molecular reports should specify the gene, versioned transcript (NM_000295.5, MANE Select), HGVS c. and p. nomenclature alongside the PI designation, zygosity, ACMG/AMP classification, method (targeted or sequencing, with or without deletion analysis) and limitations [1, 4, 10]. Novel rare variants should be referred to a specialist centre capable of functional characterisation [10]. A variant of uncertain significance cannot be reclassified on serum levels alone or clinical response.

5.5. Practical algorithm

1. Clinical suspicion (section 4) → AAT measurement (nephelometry) with C-reactive protein during clinical stability [20, 22].
2. High suspicion or low level → S/Z genotyping (with I and F when available) or SERPINA1 sequencing, according to access and the adopted guideline [10, 19].
3. Discordant level and genotype/phenotype, or suspected non-S/Z variant → complete sequencing and deletion analysis; test parents if a null allele is suspected [1, 20].
4. Relatives → genotyping initially, because levels do not define risk [19, 22].
5. Confirmed diagnosis → assessment of disease extent (post-bronchodilator spirometry, volumes, diffusion, oxygenation, chest CT; hepatic assessment with laboratory and non-invasive methods; skin examination; genetic consultation) [1, 6, 19].

The hepatic consensus proposes non-invasive staging in PiZZ adults: FIB-4 <1.3 and APRI <0.5 identify low risk (49–77% of patients in a European cohort, with limited sensitivity). Vibration-controlled transient elastography (VCTE) is preferred, with <8 kPa indicating low risk, 8–15 kPa intermediate risk and ≥15 kPa high risk (probable cirrhosis). Magnetic resonance elastography (approximately 3 kPa) and shear-wave elastography are alternatives without disease-specific validation; biopsy is unnecessary for diagnosis and reserved for excluding other causes [6]. In a longitudinal cohort of more than 700 adults, VCTE predicted major hepatic outcomes at five years with AUC 0.95, APRI with 0.92 and FIB-4 with 0.90 [6, 37].

5.6. Actionability

The ClinGen Actionability Working Group (report AC093, released 20 December 2024) scored adult augmentation therapy for pulmonary morbidity and mortality (8DA), avoidance of tobacco smoke and other exposures (9DC), and specialist surveillance with consideration of transplantation for liver disease (8AA); in the paediatric context it scored specialist hepatic surveillance (9AB) [53].

6. Differential Diagnosis

6.1. Lung disease

The differential includes other causes of COPD, emphysema, chronic bronchitis and bronchiectasis [1]. Clinical distinction is limited because AATD-related COPD is usually indistinguishable from conventional COPD, and the basal pattern is not invariably present [10, 20]. A French-Canadian family with autosomal dominant predisposition to predominantly basal emphysema beginning in the fourth–fifth decade was associated with PTPN6; unlike AATD, inheritance is dominant [1].

6.2. Neonatal cholestasis and liver disease

The differential for neonatal cholestasis includes biliary atresia, gestational alloimmune liver disease (previously termed neonatal haemochromatosis), several metabolic disorders and acquired causes; in adults, it includes chronic viral hepatitis, alcohol-related and metabolic dysfunction-associated liver disease, sclerosing cholangitis and primary biliary cholangitis [1]. Biliary atresia is the most urgent diagnosis, and coexistence with AATD has been described; identifying PiZZ does not remove the need to exclude atresia by scintigraphy and, if necessary, cholangiography [52]. For prolonged neonatal jaundice, the Oxford Desk Reference also lists Alagille syndrome, galactosaemia, Zellweger syndrome, Smith–Lemli–Opitz syndrome, bile acid synthesis defects, progressive familial intrahepatic cholestasis and Gilbert syndrome [44]. Saudubray includes AATD in recurrent childhood liver failure precipitated by fever and infections (Table 1.13) and in the diagnostic evaluation of firm hepatomegaly and isolated aminotransferase elevation [49].

The French PNDS for biliary atresia organises this differential by urgency. Any jaundice persisting beyond the 10th day of life should be investigated, and in the newborn a conjugated bilirubin above 17 µmol/L suggests cholestasis [27]. The PNDS adds a proportional criterion, set at 10% of total bilirubin in the summary and 20% in the diagnosis chapter [27]; the 2017 NASPGHAN/ESPGHAN guideline considers any direct or conjugated bilirubin above 1.0 mg/dL (17 µmol/L) abnormal, whatever the total bilirubin, and abandoned the 20% criterion as physiologically and clinically difficult to apply [46]. Causes requiring urgent treatment (biliary atresia, urinary tract infection or sepsis, cortisol deficiency, obstruction of the common bile duct) and those that are easy to detect (Alagille syndrome, choledochal cyst, cystic fibrosis and AATD) are sought first. Initial evaluation includes fasting ultrasound, to exclude dilatation of the extrahepatic bile ducts, full blood count with platelets and reticulocytes, prothrombin time before and after vitamin K, factor V, aminotransferases, GGT, total and conjugated bilirubin, total bile acids, cholesterol, blood glucose, vitamins A, D and E, immunoreactive trypsinogen from newborn screening or a sweat test, cultures when there are signs of infection, and quantitative serum AAT measurement, which the document includes in the initial evaluation of any neonatal cholestasis, in line with the ESPGHAN proposal [27]. Normalisation of the prothrombin time after vitamin K, with normal factor V, points to cholestasis; failure to correct with low factor V points to hepatocellular failure [27].

A low AAT level is complemented by isoelectric focusing (phenotype) and/or genotyping, without this step delaying the identification of atresia. The success of Kasai portoenterostomy declines from the 30th day of life, so the aim is to establish or exclude atresia before one month of age, by cholangiography in a specialised centre whenever suspicion persists. According to the PNDS, an SZ or MZ phenotype is not sufficient to stop the search for atresia; the reported coexistence of the two diseases leads to the same reasoning in a PiZZ infant [27, 52]. In the same framework, Alagille syndrome accounts for 10–15% of neonatal cholestasis and 10–20% of atresias have a syndromic form [27]. These PNDS proportions come from reference centres; in a systematic review of 17 consecutive series (1,692 infants with conjugated hyperbilirubinaemia), AAT deficiency accounted for 4.1%, Alagille syndrome for 1.0% and extrahepatic biliary atresia for 25.9% [54].

Source: GeneReviews, Table 5 [1]. The original table spells the gene “ATPB1”; the corresponding gene is ATP8B1, as in the Oxford Desk Reference [44].

6.3. Skin, vessels and haemostasis

AATD panniculitis belongs in the differential diagnosis of neutrophilic panniculitides, and the association with GPA warrants testing in patients with c-ANCA vasculitis [1, 19]. In AAT Pittsburgh bleeding disease, the laboratory pattern (prolongation of all coagulation tests, undetectable protein C, inhibition of thrombin-induced aggregation) and episodic course, exacerbated by the acute-phase response, distinguish it from factor deficiencies and acquired inhibitors [7, 38].

7. Treatments and Risk Management Strategies

7.1. General measures and conventional treatment of lung disease

Complete, permanent avoidance of active and passive tobacco smoke has the greatest impact: the Alpha-1 Foundation gives this a strong recommendation supported by high-quality evidence. AATD diagnosis is associated with less smoking initiation when made at birth and greater cessation success when made in adulthood [19]. GeneReviews also recommends avoiding occupational exposure to agricultural pollutants, mineral dust, gases and fumes, and excessive alcohol consumption; the Canadian guideline includes vaping and inhaled cannabis [1, 10]. COPD is treated according to conventional guidance with long-acting bronchodilators (beta-2 agonists and antimuscarinics), inhaled corticosteroids when indicated, pulmonary rehabilitation, oxygen and influenza and pneumococcal vaccination, because no evidence demonstrates a different treatment response in COPD with versus without deficiency [1, 19, 21]. In a small randomised trial, adding an inhaled corticosteroid to a long-acting agonist reduced dynamic hyperinflation and improved FEV1, walking distance and dyspnoea [1]; a 2026 review reports slower FEV1 decline with inhaled corticosteroids in PiZZ patients with eosinophils >0.2 × 10⁹/L [35]. The Alpha-1 Foundation emphasises that COPD and liver disease drugs are used in AATD by extrapolation, since virtually all approval trials excluded these patients, and describes this use within the AATD community as “off-label” [19].

The European Delphi panel agreed that each visit should record exacerbations treated with antibiotics or systemic corticosteroids, pneumonia, emergency department visits or admissions, changes in smoking and environmental exposures [21]. Hepatitis A and B vaccination is recommended by GeneReviews for liver disease and by the European summary of product characteristics (SmPC) for patients repeatedly receiving plasma-derived products [1, 13].

The French PNDS treats deficiency-associated COPD like any COPD, according to the recommendations of the Société de Pneumologie de Langue Française (smoking cessation, vaccines, inhaled bronchodilators, exacerbations, nutrition, rehabilitation), and stresses that the functional decline of former smokers becomes equal to that of non-smokers, partly in proportion to the duration of abstinence; lung volume reduction techniques appear as effective as without deficiency, and lung transplantation has results similar to those of other indications, but timing is delicate because, with the same BODE score, survival with deficiency is better than in COPD without deficiency [24]. Homozygous or heterozygous carriers of the Z allele should not smoke, should not drink alcohol and should avoid excess weight, and should ensure adequate respiratory protection in occupational exposures to gases, irritants or inhaled toxicants, although current data do not allow advice on choice of occupation; in a Swedish cohort identified at birth, 21% of ZZ or SZ carriers smoked or had smoked, compared with 32% of controls, but knowing oneself to be a Z heterozygote did not reduce smoking [24]. In France, the patient usually qualifies for long-term condition (affection de longue durée) no. 14 (severe chronic respiratory failure due to COPD) and, more rarely, no. 17 (hereditary metabolic diseases), and should avoid hepatotoxic drugs [24].

7.2. Augmentation therapy: products and labels

Augmentation therapy involves regular intravenous infusion of human AAT purified from donor plasma. It raises antigenic and functional serum levels (anti-elastase capacity) and epithelial lining fluid levels; with 60 mg/kg/week, levels remain above the historical threshold of 11 µmol/L, but according to the US labels the clinical benefit of raising levels has not been established [12, 55]. All products have the same labelled dose, 60 mg/kg body weight once weekly, intravenously, without dose-finding studies using efficacy outcomes [12, 13, 55–58]. The authorised indication is in adults; safety and efficacy below age 18 have not been established, and in patients aged 65 or over they have not been studied in specific trials [12, 13]. The labels define no maximum dose; in the European SmPC, single doses of 120 mg/kg were administered to 137 patients, and the Alpha-1 Foundation guideline does not recommend weekly doses above 60 mg/kg [13, 19].

Shared contraindications are IgA deficiency with anti-IgA antibodies, owing to severe hypersensitivity risk, and a history of anaphylaxis or severe systemic reactions to AAT products [12, 13, 55, 58]. Hypersensitivity can occur despite previously tolerated infusions; if a reaction occurs, slow or stop the infusion and resume at a tolerated rate if symptoms resolve. Anaphylaxis requires emergency treatment [12, 13]. The European SmPC lists dizziness, headache, dyspnoea and nausea as common (≥1/100 to <1/10); hypersensitivity, paraesthesia, flushing, urticaria, rash, asthenia and infusion-site reactions as uncommon; and anaphylactic reactions as very rare [13]. Plasma-derived products carry a residual infectious transmission risk, reduced by donor selection, testing, and viral inactivation and removal steps [13, 57]. The SBPT recommends measuring total IgA before initiation and reports 13 years without anaphylaxis at a Brasília hospital treating 8–12 patients weekly [22].

No label establishes paediatric safety or efficacy, and efficacy in older adults has not been established in dedicated trials [12, 13, 55, 57]. Reproductive studies are unavailable; because AAT is an endogenous human protein, fetal harm at recommended doses is considered unlikely, but use during pregnancy requires caution. Excretion into breast milk is unknown [12, 13].

7.3. Comparison of regulatory status

Panniculitis, liver disease and MZ genotypes are absent from all labelled indications; AAT treatment for panniculitis is therefore off-label in both the USA and EU [12, 13, 20].

In France, three plasma-derived products are available, Alfalastin® (LFB Biomédicaments), Respreeza® (CSL Behring) and Prolastin® (Grifols), at a dose of 60 mg/kg per week intravenously, the same as in the labels; they are dispensed only by hospital pharmacies (rétrocession), even for outpatient use; the first infusion takes place in hospital and subsequent ones at home, with rare adverse effects, mainly headache; patients must be informed about the infectious risk of blood-derived medicinal products, and strict batch traceability is required [24]. The PNDS acknowledges the effect on the decline in lung density in the randomised trial and the signals of longer survival in cohorts, but without a demonstrated effect on exertional dyspnoea, quality of life or exacerbations [24].

7.4. Who should be treated: differences between guidelines

Sources: [10, 19–22, 24]. The Alpha-1 Foundation does not recommend augmentation for COPD with MZ genotype (strong), bronchiectasis without obstruction (weak), liver disease (strong), or after successful liver transplantation (strong; high evidence, because the graft produces normal AAT) [19]. The European Delphi panel agreed that augmentation should not be initiated after successful lung transplantation [21]. Differences reflect evolving evidence (RAPID was published during drafting of the US guideline) and outcome selection: the CTS relies on densitometry, supporting FEV1 <80%, whereas the SBPT and Portuguese consensus rely on functional decline [10, 19, 22].

7.5. Evidence of efficacy

CT densitometry is the most sensitive marker of emphysema progression, and the Food and Drug Administration (FDA) accepted it as a clinically relevant outcome in 2009 [20]. Based on trials, the ERS concludes that augmentation reduces densitometrically measured emphysema progression, but that evidence is lacking for SZ, MZ and smokers, and that individualising doses by trough levels still requires validation [20]. RAPID extrapolation estimated six additional years before death or transplantation if treatment continued; modelling showed an association between trough levels and protection without a plateau, prompting the double-dose trial [10, 13].

Interpretation requires caution. RAPID did not meet its primary outcome; significance was confined to density at total lung capacity, analysed as a separate outcome. The 34% reduction reported in the SmPC derives from a one-sided analysis (p=0.017) [13, 33]. No controlled trial demonstrated effects on FEV1, quality of life or exacerbations, and US labels retain this limitation [20, 55]. Favourable survival data derive mainly from observational registries, with potential bias [19, 20]. Trials predominantly enrolled PiZZ patients; the CTS disputes regulatory extension to SZ [10]. Product comparisons rest on pharmacokinetic and bioequivalence studies rather than clinical outcomes [56, 57]. Inhaled AAT results were negative for primary outcomes; the CTS reports higher FEV1 with inhaled treatment in a one-year trial, of uncertain relevance [10, 25].

7.6. Practical aspects of augmentation therapy

The Alpha-1 Foundation does not recommend weekly doses above 60 mg/kg (weak; low), although an occasional double dose before a two-week absence may be convenient; 120 mg/kg/week appears safe and approaches physiological levels, without proven clinical efficacy [19]. It does not recommend trough-level monitoring (strong; moderate), unlike the European Delphi panel, which agreed on measurement after dose or interval changes and considered extended intervals, such as fortnightly dosing, acceptable [19, 21]. The SBPT considers evidence insufficient for fortnightly or monthly administration and does not recommend routine level monitoring [22]. Abrupt withdrawal has been associated with increased admissions and exacerbations [1]. The European SmPC permits home self-administration following training and at the treating physician's discretion [13].

7.7. Lung volume reduction and lung transplantation

The Alpha-1 Foundation does not recommend lung volume reduction surgery (weak; low) because benefit is shorter and mortality greater in basal panlobular emphysema [19]. The ERS allows surgical reduction and endobronchial valves in patients selected by an experienced multidisciplinary team, noting that specialist centres no longer exclude AATD patients from valve therapy, although dedicated studies are lacking [20].

Lung transplantation is an option in end-stage disease (FEV1 <30%) [1]. AATD emphysema accounted for 5.4% of lung transplants between 1995 and 2014 [20] and 4.9% between 1995 and June 2017, affecting 7–13% of patients with severe deficiency [37]. In a matched Swedish study, transplantation increased survival from 5 to 11 years; a British study additionally matched for quality of life and gas transfer showed improved quality of life but no survival gain. The ERS concludes that survival benefit is uncertain and that quality of life is the principal indication [20]. Hepatic assessment is critical in candidates; combined lung–liver transplantation is available at only a few centres [20, 37].

7.8. Liver disease

No pharmacological therapy is authorised for liver disease; management follows that for other chronic liver disorders [6, 19]. In children with cholestasis, the Atlas describes vitamin K and D supplementation, cholestyramine for pruritus and, historically, portocaval or splenorenal shunts for varices [9]. For affected siblings of an AATD proband, the Oxford Desk Reference recommends intramuscular vitamin K at birth and active treatment of intercurrent infections to minimise fever and acute-phase inflammation, on theoretical grounds [11]. Intravenous augmentation is not indicated for liver disease because hepatic injury results from protein retention rather than circulating deficiency; clinical experience suggests that augmentation neither improves nor worsens liver disease [19]. Observational data associate augmentation with better surrogate markers of liver injury, but do not support a recommendation [37].

The guidelines consulted on AATD do not define a vitamin regimen for the cholestatic infant; the French PNDS for biliary atresia defines one for infant cholestasis in general, and it is applied here by declared extrapolation. As soon as cholestasis is diagnosed, vitamin K 10 mg is given intravenously or intramuscularly, whatever the weight, to prevent intracranial haemorrhage. If cholestatic jaundice persists with total bilirubin above 60 µmol/L, the regimen is: vitamin D 200,000 IU IM every 3 months; vitamin A 50,000 IU IM once a month; vitamin K as a mixed-micelle solution, 10 mg IM or IV, or alternating 20 mg orally and 10 mg IM over 15-day periods, or 20 mg orally every 15 days, or 10 mg orally per week; and oral tocofersolan (Vedrop®, 50 mg/mL) 0.35 mL/kg/day (about 17.5 mg/kg/day), adjusted to the serum vitamin E/(cholesterol + triglycerides) ratio, with no fixed maximum dose because adjustment follows the serum level. With total bilirubin below 60 µmol/L, an oral preparation of vitamins A, D, E and C (Uvestérol vitamine A.D.E.C®, 1–2 mL/day, a French product) is combined with oral vitamin K 20 mg every 15 days. Vitamin A, D and E levels and the prothrombin time are measured regularly to adapt the regimen [27]. The European SmPC for tocofersolan sets 0.34 mL/kg/day (17 mg/kg/day) in congenital or hereditary chronic cholestasis, from term newborns to 18 years, with adjustment to the plasma vitamin E level and no defined maximum, and contraindicates it in preterm infants [63]. For pruritus, the same PNDS proposes oral rifampicin 5 mg/kg/day, increased stepwise to a maximum of 20 mg/kg/day [27]; use for pruritus is off-label, and the US label, which authorises 10–20 mg/kg/day in paediatric tuberculosis, adds an absolute ceiling of 600 mg/day [64]. The PNDS accepts ursodeoxycholic acid 600 mg/m²/day in two doses when there is bile flow, acknowledging that it has not demonstrated efficacy in atresia [27]; the sources consulted on AATD provide no efficacy data for these drugs, and the Atlas mentions colestyramine [9].

The PNDS diverges from the other sources on four points. The estimate of 10–15% cirrhosis with transplantation refers to children with neonatal cholestasis and is not directly comparable with the 2.4% childhood cirrhosis in the Swedish screening cohort [11, 27]. The PNDS accepts neonatal cholestasis in SZ and MZ genotypes, whereas GeneReviews does not associate them with childhood liver disease beyond transient enzyme elevations, and the NASPGHAN/ESPGHAN guideline accepts liver disease in PiSZ individuals but excludes neonatal cholestasis in MZ, MS, SZ and SS without another cause; the guideline serves as the reference [1, 27, 45, 46]. The PNDS proportional threshold for conjugated bilirubin (10% or 20% of total, depending on the section) does not appear in the NASPGHAN/ESPGHAN guideline, which uses only the absolute value of 17 µmol/L [27, 46]. Regarding vitamin K, the Oxford Desk Reference recommends it intramuscularly at birth in affected siblings and the PNDS 10 mg at diagnosis of any cholestasis, which are complementary recommendations; the PNDS tocofersolan dose (0.35 mL/kg/day) is slightly higher than that of the SmPC (0.34 mL/kg/day), and the guideline serves as the reference [11, 27, 63].

The 2026 consensus recommends complete, permanent alcohol abstinence in treatment candidates, obesity management, hepatocellular carcinoma surveillance and portal hypertension management according to guidance for cirrhosis of any aetiology, with early transplantation referral from the first decompensation (ascites, variceal bleeding or encephalopathy) to a centre experienced in transplant hepatology and AATD [6]. Liver transplantation definitively treats severe disease and normalises circulating AAT, which acquires the donor phenotype [1, 11]. The European hepatology guideline, cited in a review, permits PiMZ organs only for living donation when no alternative exists and there is no evidence of injury, and excludes PiZZ livers as donor organs [37].

7.9. Panniculitis

GeneReviews recommends dapsone or doxycycline and high-dose intravenous augmentation for refractory cases [1]; the Alpha-1 Foundation recommends augmentation for necrotising panniculitis (strong; low evidence, based on case reports), allowing doses above those approved for lung disease [19]. Consulted sources do not provide dapsone or doxycycline doses or specify high-dose AAT, so these are not presented; this is off-label use [1, 19].

7.10. Research and recent developments (October 2025 to October 2026)

Fazirsiran (TAK-999, ARO-AAT). A subcutaneously administered N-acetylgalactosamine-conjugated RNA interference agent that degrades hepatocyte SERPINA1 mRNA and reduces Z-AAT synthesis; it does not increase circulating AAT and therefore is not intended for lung disease [34, 65]. In an open-label phase 2 study of 16 PiZZ adults with fibrosis (200 mg or 100 mg on day 1, at week 4 and then every 12 weeks), median hepatic Z-AAT fell 83%, serum Z-AAT approximately 90% at nadir, and globule burden from 7.4 to 2.3 (0–9 scale); fibrosis regressed in 7 of 15 and progressed in 2 of 15, and four serious adverse events resolved [66]. In placebo-controlled phase 2 SEQUOIA (40 patients), serum Z-AAT fell 61%, 83% and 94% with 25, 100 and 200 mg at week 16; median hepatic Z-AAT fell 93% versus a 26% increase with placebo. Portal inflammation improved in 5 of 12 vs 0 of 8, METAVIR stage improved in 7 of 14 vs 3 of 8, and lung function remained stable [65]. Fazirsiran has FDA Breakthrough Therapy and Fast Track designations [67]. Ongoing studies include the placebo-controlled phase 3 trial in METAVIR F2–F4 fibrosis (NCT05677971; estimated 160 patients; 200 mg on day 1, week 4 and every 12 weeks until week 196; primary outcome: ≥1-stage improvement at week 106 in F2–F3; expected primary completion January 2029), the phase 3 F1 trial (NCT06165341; safety and lung densitometry outcomes; August 2028), and an open-label extension (NCT05899673) [15]. Takeda's half-year report (November 2025) describes fazirsiran as on track to become the first indicated treatment for associated liver disease [68]; this is a sponsor statement, without phase 3 results. The 2026 consensus adopted ≥1-stage fibrosis improvement over two years as the phase 3 primary outcome and warned of the substantial placebo histological response in a phase 2b trial [6].

Efdoralprin alfa (SAR447537, formerly INBRX-101). A recombinant AAT–IgG4 Fc fusion protein with prolonged half-life. In phase 1 (31 adults), 120 mg/kg every three weeks maintained functional AAT >21 µmol/L until four weeks after the last dose [69]. In phase 2 ElevAATe (99 patients; dosing every 3 or 4 weeks vs Zemaira 60 mg/kg/week; primary outcome: steady-state functional AAT at week 32), the sponsor reported superiority over the plasma product across all primary and key secondary outcomes. The EMA granted orphan designation in December 2025, the FDA had already granted orphan and fast-track designations, and Sanofi anticipated US submission in the second half of 2026 [16, 62]. The data were not published in a peer-reviewed journal in the consulted sources.

SPARTA (Grifols). A randomised phase 3 trial with 345 patients (60 mg/kg, 120 mg/kg or placebo weekly for 156 weeks; outcome: PD15 lung density). The last patient's final visit was expected in August 2026 and topline results by the end of the fourth quarter of 2026; Grifols also initiated a phase 3 trial of 15% subcutaneous AAT in June 2026 [62, 70].

Genetic editing. BEAM-302, a liver-directed lipid-nanoparticle base editor, corrects the Z variant; more than 25 patients received treatment during dose exploration, with increased total and functional AAT, reduced Z-AAT and production of corrected M-AAT. The company selected 60 mg as the optimal biological dose, reached alignment with the FDA regarding potential accelerated approval based on 12-month AAT biomarkers, and treated the first patient in the pivotal cohort (approximately 50 patients) in July 2026 [17, 71]. The title of a 2026 preprint, not yet peer-reviewed, reports liver-biopsy confirmation of SERPINA1 correction in one patient after in vivo base editing [72]. For WVE-006, a subcutaneous GalNAc-conjugated RNA-editing oligonucleotide, a May 2026 announcement reported M-AAT comprising 64% of total AAT, a 71% reduction in Z-AAT and total AAT of 11.9 µmol/L with 200 mg fortnightly (13.6 µmol/L with 400 mg monthly), with an FDA meeting regarding accelerated approval expected in late summer 2026 [18]. KRRO-110 (nanoparticle RNA editing) was discontinued after failing to achieve projected levels following a single dose; the sponsor redirected the programme towards GalNAc conjugates [71, 73]. AIR-001 (RNA editing), TSRA-196 (gene writing) and CTX460 (guide-RNA editing, not yet recruiting) are in phase 1/2, and BMN 349 (a small-molecule stabiliser) is in phase 1 [34, 71].

Discontinued or negative programmes. Oral correctors VX-814 and VX-864 were discontinued (VX-864 because of cutaneous and subcutaneous events) [35, 71]; belcesiran (RNAi) and NTLA-3001 were stopped or withdrawn [71]. The carbamazepine trial, testing autophagy induction, was terminated without available results [34, 71]; intramuscular rAAV1 gene therapy did not achieve therapeutic levels [34]. The oral neutrophil elastase inhibitor alvelestat completed two phase 2 trials, with results described as promising in a review [35, 62]. A 2025 regulatory analysis identified 20 substances with FDA orphan designation (one approved) and nine with European orphan designation (none approved) [14].

These programme figures derive from small populations and surrogate outcomes (AAT levels, hepatic Z-AAT, histology); indirect comparisons should not be used to rank them, and none has yet demonstrated benefit on clinical outcomes [6, 34].

7.11. French PNDS for pulmonary care: divergences

Table 7.11 — Divergences between the French PNDS (2022) and the other guidance cited [10, 13, 19, 20, 22, 24]

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

AATD follows autosomal codominant inheritance. Most probands' parents are heterozygotes (e.g. PI*MZ or PI*SZ), although a parent may themselves be PI*ZZ; parental molecular testing is recommended to establish status and recurrence risk [1]. The Oxford Desk Reference notes that apparently healthy parents of a ZZ or SZ child may be ZZ or SZ [11]. With two MZ parents, each sibling has a 25% probability of being ZZ, 50% of being MZ and 25% of being MM; with one ZZ and one MZ parent, probabilities are 50% ZZ and 50% MZ. Children of an affected individual are obligate heterozygotes unless the other parent also carries a deficient allele, which is more likely in populations with high carrier frequency or consanguinity. Offspring risk can therefore be defined only after partner testing [1, 20]. Siblings of heterozygous parents have a 50% probability of being carriers [1].

8.2. Risk of severe liver disease in siblings

Age at onset, severity and course cannot be predicted from genotype. Based on Cox (2004), GeneReviews estimates that, if heterozygous parents have not had a child with severe liver disease, the risk of a child being affected and developing severe childhood liver disease is below 1% (0.64%). If an affected child died from childhood liver disease, the risk for each sibling is 10% (25% × 40%); if the affected child had no severe disease or it regressed, the risk is 3.3% (25% × 13%) [1]. The Oxford Desk Reference states that Psacharopoulos's 78% estimate (1983) is almost certainly an overestimate and that current estimates are approximately 20–30% for significant liver disease in a ZZ sibling, corresponding to 5–7% per pregnancy [11]. These values differ in outcome definition (severe versus significant disease) and should be presented with that qualification.

8.3. Prenatal and preimplantation diagnosis

Once familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are technically possible [1]. Historically, prenatal diagnosis required fetal blood sampling; subsequently, oligonucleotide probes were applied to amniocyte DNA (two cases at risk of ZZ, both MZ), followed by exon 5 amplification with specific probes. Prior parental typing is essential to exclude null or rare alleles [9]. The Oxford Desk Reference describes diagnosis through chorionic villus genotyping after parental phenotyping and genotyping in a specialist laboratory [11]. The ATS/ERS statement and most guidelines do not recommend fetal testing because of variable expressivity and the possibility of a normal life, particularly in never-smokers. Testing may be relevant to couples who previously had a child with severe liver disease, and the decision is personal [1]. Risk clarification and discussion of these options are ideally undertaken before pregnancy; DNA banking should be considered when molecular diagnosis has not been confirmed [1].

8.4. Testing relatives and minors

The Alpha-1 Foundation recommends counselling and testing adult siblings (strong) and parents, children, minor siblings and extended family (weak). Testing children without clinical indications is unsupported and may be replaced by parental testing. Family testing should use genotyping, be offered at each visit until all interested relatives have undergone testing, and provide confidentiality options [19]. In the USA, the 2008 Genetic Information Nondiscrimination Act protects health insurance and employment, but not life insurance [19]. The ERS considers early detection good practice in children of couples who both carry a deficient allele, provided there is no legal restriction, and extends testing beyond first-degree relatives according to family history or when one parent is PiZZ. Pre- and post-test genetic counselling and informed consent are essential [20]. The SBPT recommends testing first-degree relatives and partners, meeting with the family to explain results, avoiding stigmatisation and explaining genetics to children when they are old enough to understand [22]. In contrast, from a 2017 British clinical genetics perspective, the Oxford Desk Reference considered whole-family cascade screening rarely appropriate because of high carrier frequency and rare severe neonatal liver disease, emphasising smoking avoidance as the principal message [11]. This divergence reflects different aims: pulmonary prevention and surveillance in respiratory guidelines versus prevention of childhood liver disease in the paediatric perspective.

Serum levels cannot determine carrier status because heterozygote levels overlap with normal values and increase during the acute phase [1, 19]. Subsequent siblings of a proband should receive intramuscular vitamin K at birth [11].

In France, the PNDS points out that examination of genetic characteristics (genotyping or SERPINA1 sequencing) requires written consent after information by the prescriber or a genetic counsellor, with return of the result by the same professionals and explanation of the risk associated with the genotype, and that it is prohibited in asymptomatic minors without immediate benefit, which applies to AAT deficiency; carriers of the Z allele, whether homozygous or heterozygous, have a legal obligation to inform their parents, children, grandchildren and siblings of the predisposition, of the possibility of a genetics clinic consultation or screening, and of preventive measures (smoking, alcohol, weight) [24].

8.5. Pregnancy

Pregnancy management follows conventional principles, with or without liver disease; emphysema is not expected during reproductive years, particularly in non-smokers [1]. Plasma AAT labels lack controlled pregnancy data and recommend caution [12, 13].

8.6. Neonatal screening

The 1972–1974 Swedish programme screened 200,000 newborns and identified 127 PIZ and 48 PISZ; its principal aim was to reduce tobacco exposure [20]. It was discontinued because of psychological effects on parents, who interpreted deficiency as an immediate threat and retained negative feelings for 5–7 years [9]; 20 years later, mothers had greater anxiety than control mothers [20]. At ages 18–20, identified individuals smoked less (6% vs 17%) and were more frequently never-smokers (88% vs 65%); an Oregon programme found smoking initiation of 27.3% vs 56.9% [20]. The ERS concludes that neonatal screening reduces youth smoking and that psychological effects may be mitigated by counselling at specialist centres [20]. The SBPT and other guidelines do not recommend screening the general population, adolescents or newborns [22]; AATD is not included in the US recommended uniform newborn screening panel [52].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and European gradient

AATD is among the most frequent genetic diseases in people of Northern European ancestry: approximately 1/5,000–7,000 in North America and 1/1,500–3,000 in Scandinavia, with lower frequencies in all other groups [1]. Swedish screening found approximately 1/1,500 PIZZ births and a Z allele frequency of 0.026; for the USA, the Atlas reports 1/6,000, with allele frequencies of 0.01 for Z, 0.03 for S and approximately 0.95 for M [9]. The Oxford Desk Reference estimates 1/1,600–1,800, with 10% of Europeans carrying S or Z (Z in 4% of Northern Europeans, 1/25; S in 6%, 1/17) [11, 74]. The Alpha-1 Foundation estimates 1/2,500–1/5,000 PI*ZZ individuals in the USA and Europe [19]. Orphanet gives point prevalence of 47.5/100,000 in Ireland, 25/100,000 in Germany and 20/100,000 in Europe (EMA 2016 estimate), and birth prevalence of 17/100,000 in the USA and 63.5/100,000 in Sweden [2]. The S allele is more frequent in people of Iberian ancestry [1]. EARCO estimates approximately 120,000 PiZZ individuals in Europe and AATD in approximately 1 in 800 COPD patients [21]; the Canadian guideline cites 2% of severe COPD patients and identified 4 PiZZ individuals among 1,359 CanCOLD participants [10].

Source: Oxford Desk Reference, Table A8, reproducing Lazarin et al. (Genet Med 2013) [74]. The table measures carrier frequency in a US laboratory panel with self-reported ancestry, not disease prevalence. The Alpha-1 Foundation recommends testing African American and Asian patients with compatible presentations despite lower prevalence [19].

In Ireland, the national targeted detection programme (3,000 individuals) identified 42 ZZ, 44 SZ, 14 SS, 430 MZ and 263 MS individuals; a random sample of 1,100 people included 113 MS, 46 MZ, 2 SS and 2 SZ individuals, with Z and S frequencies among the world's highest [75].

By modelling the European allele frequency and recent British data, the French PNDS estimates that France has about 10,000 PiZZ homozygotes, 100,000 SZ heterozygotes and 1,500,000 MZ heterozygotes, and that the PiZZ genotype is present in 1 to 2 per 1000 patients with COPD; these figures are modelling estimates, not counts of diagnosed patients [24].

9.2. Portugal

In Madeira, genotyping 200 unrelated individuals showed PI*S frequency of 18% and PI*Z frequency of 2.5%, with an estimated frequency of deficient genotypes (ZZ, SS, SZ) of 41 per 1,000, considered by the authors to be the world's highest; this was a small sample from an island population [76]. A series of 1,684 people tested between 2006 and 2015 in a Portuguese genetic diagnostic laboratory database, covering almost all regions, found MZ in 25.4%, MS in 15.5%, SZ in 11.2%, ZZ in 9.4% and SS in 5.6%; 9.5% carried at least one rare deleterious allele, including PGaia, Q0Oliveira do Douro, Q0Vila Real and a novel SGaia variant; 24.7% had severe or very severe deficiency [77]. As a referred testing series, this demonstrates Portuguese allelic diversity but not population prevalence. Portuguese centres (Funchal, Lisbon, Porto, Braga, Coimbra) participated in the European PiZZ hepatic fibrosis cohort [26]. According to the ERS, in January 2017 Portugal had centres throughout the country, unrestricted augmentation access, 118 patients receiving treatment and 100% public reimbursement [20]. The national Sociedade Portuguesa de Pneumologia consensus (2018) aimed to reduce inter-hospital heterogeneity in diagnosis and treatment decisions [23].

9.3. Brazil and Latin America

In a cross-sectional study of 926 COPD patients from five Brazilian states, overall AATD prevalence was 2.8% and PI*ZZ prevalence 0.8%, using dried blood spot screening, serum measurement (<113 mg/dL) and genotyping [50]. The SBPT reports 0.83% in Argentina and, among 30,827 people with suspected deficiency tested by buccal swab or dried blood spot between 2018 and 2022 in six countries (Argentina, Brazil, Chile, Colombia, Spain and Turkey), 12.7% MS, 7.4% MZ, 3.0% ZZ, 1.6% SZ and 0.8% SS. A buccal swab test identifying 14 variants has been used in Brazil since 2018, but few Brazilian laboratories analyse dried blood spots [22]. The SBPT describes difficulties accessing rare disease care through the Sistema Único de Saúde despite the legal right to healthcare, and advocates specialist centre treatment [22]. Product registration and adoption status at ANVISA and CONITEC were not verified in consulted sources.

9.4. Special populations

Lung disease is exceptional in children, and pulmonary monitoring is generally unnecessary unless asthma or symptoms occur. The 2026 consensus suggests baseline adult pulmonary assessment at age 18 and regular hepatic follow-up using non-invasive methods, noting that no hepatic treatment trial accepts participants below 18 [6]. MZ heterozygotes are not intrinsically ill but form a risk population whose risk depends on smoking and hepatic cofactors (steatosis, alcohol, cystic fibrosis) [20, 37, 48].

9.5. European networks, registries and patient organisations

The ERS recommends follow-up supervised by national or regional reference centres, with European Reference Networks serving as knowledge centres [20]. Pulmonary disease falls within ERN-LUNG and hepatic disease within ERN RARE-LIVER, which includes a coordinating centre for AATD liver disease and the EASL “Alpha1-Liver” registry group [25, 26, 66]. EARCO, an ERS initiative, maintains the international AATD registry, with data from 24 European countries and Argentina, Colombia, Costa Rica and Canada [21, 22]. Patient resources cited in the sources include the Alpha-1 Foundation (USA), Alpha-1 Canada, Alpha-1 Advocacy Alliance, Alpha-1 Research Registry, Alpha-1 Canadian Registry, Alpha-1 Awareness UK, Children’s Liver Disease Foundation, American Liver Foundation, ChiLDReN network and Liver UK [1, 11, 44]; the European Lung Foundation coordinated national patient organisations' participation in the ERS statement [20]. In France, the reference centre for biliary atresia and genetic cholestasis, coordinated at Bicêtre Hospital (AP-HP) with a network of competence centres, belongs to the FILFOIE health network (rare liver diseases in adults and children) and is the author of the PNDS that includes AATD in the differential diagnosis of neonatal cholestasis; active chronic liver disease and cirrhosis give access to the long-term condition scheme ALD 6, and organ transplantation to ALD 28 [27]. The sources consulted do not identify Portuguese or Brazilian patient organisations; this does not demonstrate their absence.

In France, pulmonary care is coordinated by the OrphaLung reference centre for rare lung diseases (coordinated at the Hospices Civils de Lyon), with constituent and regional competence centres, within the RespiFIL network; the patient association ADAAT Alpha1-France, founded in 2007, promotes information, screening and research, and there are similar associations in Belgium, Switzerland and Canada; the PNDS refers hepatic follow-up to the recommendations of the Association Française pour l'Étude du Foie (2020) [24].

10. Illustrative Clinical Case

10.1. Early neonatal cholestasis with PiZZ genotype (James et al., 2026)

A term male newborn (38 weeks), small for gestational age (2,150 g, below the 3rd percentile, with intrauterine growth restriction), born to a mother colonised with group B streptococcus and treated during delivery, received prophylactic vitamin K and erythromycin. On the fourth day of life he presented to the emergency department with hypothermia (94.4 °F, as reported in the original), a weak cry, lethargy and poor feeding. He had jaundice without hepatomegaly, splenomegaly or dysmorphism; glucose was 49 mg/dL, AST 83 U/L, ALT 34 U/L, alkaline phosphatase 398 U/L, GGT 632 U/L, albumin 2.4 g/dL, total bilirubin 23.7 mg/dL and direct bilirubin 2.4 mg/dL; prothrombin time was 14.2 s (INR 1.3). He was treated for presumed sepsis with ampicillin, ceftazidime and aciclovir and triple phototherapy; cultures and herpes PCR were negative and antimicrobials discontinued. Cholestasis became evident between days three and five (maximum direct bilirubin 2.6 mg/dL; GGT 632 U/L). AAT was <20 mg/dL and PiZZ phenotype was confirmed on day eight [52].

Investigations excluded cytomegalovirus infection, cystic fibrosis (normal immunoreactive trypsinogen and sweat test 12 mEq/L) and Alagille syndrome (no posterior embryotoxon, butterfly vertebrae or cardiac disease); serum bile acids were elevated (156 µmol/L). The non-consanguineous parents, of mixed European ancestry, had no hepatic or pulmonary disease history; the mother was PI*MZ and the father declined testing during admission. The child was discharged on day nine; the authors started ursodeoxycholic acid at 15 mg/kg/day, and direct bilirubin was 2.1 mg/dL at four weeks. A post-discharge hepatobiliary iminodiacetic acid (HIDA) scan showed intestinal excretion, making biliary atresia less likely (Figure 1 and Figure 2, sequential scintigraphic series) [52].

The case demonstrates that AATD cholestasis may present in a context suggesting sepsis, that negative family history is usual when parents are heterozygotes, and that identifying PiZZ does not remove the need to exclude biliary atresia [1, 52]. The authors acknowledge the limitation of only four weeks' follow-up. Ursodeoxycholic acid was the team's decision and is not recommended in the consulted guidelines; some explanations proposed for absent family history (de novo mutations, uniparental disomy) are rare possibilities that do not change the usual approach of testing both parents [1, 52].

10.2. Basal emphysema in a PiZZ adult with neonatal jaundice (Olivares Rivera et al., 2025)

A 55-year-old woman assessed at a German centre in 2023 had GOLD II COPD and PiZZ genotype without augmentation therapy. She had neonatal jaundice and psoriasis from childhood, asthma diagnosed at 20 without identified allergies, and a non-ST-elevation myocardial infarction during her first pregnancy (2009). She had smoked for 15 years (approximately 8 pack-years) and stopped 25 years earlier; COPD was diagnosed at 40 and AATD in 2010, at 41. AAT was 0.1 g/L (2022) and 0.3 g/L (2024); FEV1 was 1.96 L (56% predicted at initial assessment), with FEV1/FVC <0.7, and DLCO 50% predicted. High-resolution CT showed severe basal panlobular emphysema, with an overall emphysema index of 23% and up to 41% in basal segments, lingula, middle lobe and lower lobes, and early bronchiectasis (Figure 1 — high-resolution CT; Figure 2 — automated lobar quantification). Liver stiffness on transient elastography was normal (5.8 kPa) [78].

Laboratory investigation of the patient's protein showed fewer circulating polymers, reduced anti-elastase activity and altered N-glycosylation compared with other untreated PiZZ patients. The authors linked these properties to pulmonary predominance and early psoriasis [78]. This interpretation is a single-case research hypothesis, not a clinical criterion. The case demonstrates the association between neonatal jaundice and adult lung disease, typical basal predominance, coexisting asthma and bronchiectasis, and dissociation between lung injury and an unfibrotic liver. Under Alpha-1 Foundation criteria (FEV1 30–65%) and CTS criteria (FEV1 <80% with emphysema and AAT <11 µmol/L), she would be eligible for augmentation; the article does not discuss why she was not receiving it [10, 19, 78].

10.3. Childhood cirrhosis (Atlas case)

The Atlas describes a 7-year-old girl (J.P.) presenting with haematemesis. At age 2 she had hepatomegaly and biopsy-proven cirrhosis. Examination showed two spider naevi on her arms, a surgical scar over the liver, palpable 3 cm below the costal margin, and a spleen palpable 8 cm below; endoscopy showed oesophageal varices (Figure 107.1, p. 808) [9]. This case represents the minority of PIZZ children progressing to cirrhosis and portal hypertension, for whom early transplantation assessment applies [9, 11].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends on genotype, smoking and route to diagnosis. PiZZ never-smokers identified through screening did not have higher mortality than the Swedish population, whereas those identified through respiratory symptoms had a standardised mortality ratio of 2.55 [40]. The ERS reports near-normal life expectancy in never-smokers and suggests that perhaps half retain normal spirometry into older age [20]. Densitometry and gas transfer detect progression before FEV1 [20]. The 2026 consensus notes that lung disease mortality increases significantly particularly when FEV1 falls below 50% predicted, and that historical median FEV1 in US-diagnosed patients is approximately 50% [6]. For liver disease, elastography and APRI and FIB-4 indices predict decompensation, transplantation and liver-related death; many adults die from hepatic causes at ages compatible with transplantation, possibly because of pulmonary comorbidity or rapid decompensation [37]. Most childhood neonatal cholestasis resolves; a minority develop cirrhosis, and biochemical abnormalities may fluctuate until adolescence [9, 11].

11.2. Surveillance

Annual liver ultrasound in the 2016 US guideline and elastographic staging in the 2026 consensus are compatible: the former addresses all individuals with AATD, whereas the latter stratifies PiZZ adult risk and defines intervals [6, 19]. In clinical trials, FEV1 or KCO reduction is considered significant only if ≥20% and confirmed on two consecutive tests, because of test variability (daily FEV1 variation 4–7%) [6].

11.3. Transition and organisation of care

Transition from paediatric hepatology to adult care should include baseline respiratory assessment, tobacco and alcohol education, and family testing [6, 19]. The ERS recommends reference-centre follow-up with activity recording and participation in national and international registries, and proposes multidisciplinary coordination of initial assessment, augmentation decisions and follow-up [20].

12. Summary and Final Considerations

Alpha-1 antitrypsin deficiency results from SERPINA1 variants with codominant effects. The Z allele, c.1096G>A p.(Glu366Lys), historically Glu342Lys, is the most important; dual numbering requires reports to specify transcript NM_000295.5 and HGVS nomenclature alongside the PI designation [1, 4, 10]. Pulmonary injury reflects loss of function, modified predominantly by smoking; hepatic injury reflects toxic Z-AAT polymer accumulation independent of smoking. Null alleles spare the liver but worsen pulmonary disease; the Pittsburgh variant causes a distinct allelic bleeding disorder [1, 7, 32].

Diagnosis combines quantification with variant identification. Guidelines converge on testing all patients with COPD, adult asthma with persistent obstruction, unexplained bronchiectasis, unexplained chronic liver disease, necrotising panniculitis or GPA, and relatives of carriers; they differ on initial methods, between S/Z genotyping and SERPINA1 sequencing [10, 19, 20]. A 2026 European external assessment showed excellent S and Z performance but failures for rare variants, reinforcing sequencing at reference laboratories [51].

Augmentation with 60 mg/kg/week plasma AAT slows lung density loss in patients with severe deficiency and emphysema, without demonstrated effects on FEV1, exacerbations or quality of life in controlled trials, and does not treat liver disease; initiation criteria vary across jurisdictions [10, 19, 20, 33]. Adult PiZZ liver disease is frequent and often silent, with significant fibrosis in 20–36% by non-invasive methods; the 2026 consensus introduced a definition, elastographic staging and trial outcomes [6, 26]. Fazirsiran, in phase 3, is the first therapy targeting the hepatic cause with phase 2 histological data; long-half-life recombinant proteins and RNA and DNA editing are in early or pivotal phases, with evidence still mainly from sponsors [15–18, 65]. Core genetic responsibilities remain correct genotype interpretation, smoking counselling and cascade testing, and coordination between respiratory medicine, hepatology and reference centres [19, 20].

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