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If you have low levels of AAT but normal liver and lung function tests, you may not need treatment; however, you will be monitored with repeat testing over time. All patients with genetic variants that can cause severe liver disease should also receive specialized hepatology care. The data supporting the clinical efficacy of intravenous AAT replacement are robust and include randomized trials that evaluated outcomes such as serum AAT concentrations, lung function, and lung density on chest CT.3,9,105,106, In Europe and the United States, various studies have emphasized the need for careful diagnosis and access to intravenous AAT replacement therapy in patients with severe AATD. It is essential to monitor patients with AATD for the appearance of pulmonary emphysema and liver disease.
Most patients will have predominant basal emphysema, and a small proportion, simultaneously or not, has upper zone emphysema. Emphysema and COPD are the main clinical features of AATD; severity depends on genotypes and health behaviors (discussed above). A limitation of this approach is that a negative result (absence of Z protein in blood) may lead to underdiagnosis of non-Z AATD genotypes.
The PiZZ genotype is the most common severe deficiency genotype and so tends to result in the worst clinical presentation, hence it has been the major focus of research. Clinical heterogeneity has been demonstrated in alpha-1 antitrypsin deficiency (AATD), such that clinical suspicion plays an important role in its diagnosis. The underlying pathophysiology for SHBG changes in liver disease remains subject to speculation. Elevated SHBG is well documented in a variety of other liver disorders such as alcoholic liver disease, haemochromatosis, while low SHBG is documented in non-alcoholic fatty liver disease.19
Desmosine and isodesmosine (lung elastin degradation products usually elevated in COPD patients but also in AATD patients) were reduced after long-term intravenous AT and possibly with nebulized therapy52. Use of CT densitometry in disease monitoring has been vital in proving an effect of AT in emphysema10, and lower CT density has also been related to mortality in AATD patients with basal emphysema, while FEV1 and DLCO alone have a weaker relationship11. Although these are rare associations, they are plausible, since AAT is anti-inflammatory and immunomodulatory47,49; thus, in AATD, enhanced risk of inflammatory and autoimmune diseases could occur. CB, as part of the spectrum of neutrophilic inflammation in the lungs, might be one of the clinical features that should draw attention to AATD diagnosis2. AATD lung disease is characterized by basal pan-lobular emphysema at an early age, though a range of other phenotypes have been recognized (Figure 2).
Confirmatory testing, through phenotyping and genotyping, are strongly recommended to identify normal, deficient, or non-functioning alleles, or even rarer AAT alleles, which otherwise would go unrecognized14,27,28. Nevertheless, a faster rate of decline in lung function has been observed in both genotypes, which indicates that tobacco cessation must be a priority25,26. Since these types of emphysema may be driven by different mechanisms2, we can speculate that the pathophysiology of emphysema differs between PiSZ and PiZZ genotypes such that therapy applicable to PiZZ cannot be assumed to be effective in PiSZ. The major clinical risk in PiSZ is the development of COPD, which is three times higher compared with PiMM9, less so in never-smoking patients10. AAT, alpha-1 antitrypsin; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity of lung for carbon monoxide; FEV1, forced expiratory volume in 1 second On the other hand, alcohol stimulates AAT production in hepatocytes, which may aggravate liver function in carriers of a single abnormal allele, in particular in carriers of the more pathogenic Z allele4.
It is conceivable that targeting pro-inflammatory pathways with inhaled corticosteroids (ICS) would be more beneficial in AATD patients, since exacerbation rates are higher and longer than in usual COPD56, but this remains unproven. It is important to initiate and maintain bronchodilator therapy, with a good inhaler technique, such as long-acting β-adrenergic receptor agonists (LABA) and long-acting muscarinic receptor agonists (LAMA)25. The role of C3d in AATD is still unknown; however, a potential role for the complement system is emerging in the pathogenesis of emphysema55. More recently, complement component C3d was proposed, since it correlates with both radiographic emphysema and severity of the emphysema in AATD, but not in usual COPD; also, in PiZZ AATD after intravenous AT, AAT disrupts C3 activation, thereby decreasing C3d plasma levels. At present, they are a more important pathogenic theme in usual COPD, but contribution to immune activation within the disease process in AATD is not excluded54.

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