Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency

Franciosi, Alessandro N; Hobbs, Brian D.; McElvaney, Oliver J; Molloy, Kevin; Hersh, Craig P.; Clarke, Louise C.; Gunaratnam, Cedric; Silverman, Edwin K.; Carroll, Tomás P.; McElvaney, Noel G.

doi:10.1164/rccm.202002-0262oc

Cited by 33 publications

(30 citation statements)

References 41 publications

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“…Consequently, MZ AATD smokers represent a common, high-risk subgroup, with a genetically predetermined course toward greater morbidity. Similar findings have been demonstrated in SZ individuals who smoke [8][9][10].…”

Section: Introductionsupporting

confidence: 86%

“…In spite of this, the evidence suggests that AATD remains underdiagnosed [21,22]. The increased risk of COPD in heterozygote smokers has only been demonstrated in recent years [5,6,8,23] and this risk may not yet be sufficiently recognized among clinicians. Lower perception of risk has previously been associated with reduced smoking cessation [24] and our data suggests that severity of deficiency correlates with awareness of diagnosis and formersmoker (vs current-smoker) status.…”

Section: Discussionmentioning

confidence: 99%

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Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population

Franciosi

Alkhunaizi

Woodsmith

et al. 2021

COPD: Journal of Chronic Obstructive Pulmonary Disease

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The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is strongly associated with COPD, even in never-smokers. Moderate AATD genotypes (MZ and SZ) have been shown to increase the severity of COPD in smokers. In this comparative study, we examine the association between AATD, genotypes, and smoking cessation. Two hundred and ninety-three Irish people with AATD [MZ (n ¼ 91), SZ (n ¼ 72), and ZZ/rare (n ¼ 130)] completed a custom questionnaire assessing their social and smoking histories. The primary outcomes analyzed were the predictors of ever-smoking and effect of genotype on awareness of AATD and maintained smoking cessation, using logistic regression analyses. Parental smoking exposure was associated with ever-smoking status (OR 1.84 vs. no parental smoking, p ¼ 0.018), higher cumulative tobacco consumption (23.47 vs. 14.87 packyears, p ¼ 0.005) and more quit attempts required to achieve cessation among former-smokers (2.97 vs. 5.60, p ¼ 0.007). Awareness of genotype was 67.7% versus 56.3% versus 33% for ZZ, SZ, and MZ, respectively (p < 0.001). Among ever-smokers, current-smoking was uncommon (2.5% vs. 17% vs. 16% for ZZ, SZ, and MZ, respectively, p ¼ 0.009) with ZZs significantly less likely to be current-smokers (OR 0.15 relative to MZ, p ¼ 0.025). These results suggest that the genetic risk of COPD in AATD families is compounded by transmission of social risk factors (via parental smoking). Increasing severity of genotype is associated with lower current-smoking rates among eversmokers. Whether this is attributable to greater awareness of risk is an area of interest. Achieving a change in smoking habits may also result in positive health behavior in subsequent generations.

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Section: Introductionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population

Franciosi

Alkhunaizi

Woodsmith

et al. 2021

COPD: Journal of Chronic Obstructive Pulmonary Disease

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“…8 Both mutations result in misfolding of the protein, with the S variant resulting in a proportion of the AAT protein (~40%) being retained within hepatocytes, which reduces plasma levels but may not affect susceptibility to either liver or lung disease. [9][10][11] The Z mutation occurs in over 95% of diagnosed AATD patients and causes greater misfolding and polymerisation of the protein. These polymers have no anti-neutrophil elastase activity and accumulate in the endoplasmic reticulum (ER) of cells.…”

Section: Introductionmentioning

confidence: 99%

<p>Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency</p>

Belchamber¹,

Walker²,

Stockley³

et al. 2020

COPD

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Alpha-1 antitrypsin deficiency (AATD) is a genetic condition characterised by low circulating levels of alpha-1 antitrypsin (AAT), a serine proteinase inhibitor. The most common deficiency variants are the S and Z mutations, which cause the accumulation of misfolded AAT in hepatocytes resulting in endoplasmic reticular stress and insufficient release of AAT into the circulation (<11μmol/L). This leads to liver disease, as well as an increased risk of emphysema due to unopposed proteolytic activity of neutrophil-derived serine proteinases in the lungs. AATD has been traditionally viewed as an inflammatory disorder caused directly by a proteinase-antiproteinase imbalance in the lung, but increasing evidence suggests that low AAT levels may affect other cellular functions. Recently, AAT polymers have been identified in both monocytes and macrophages from AATD patients and evidence is building that these cells may also play a role in the development of AATD lung disease. Alveolar macrophages are phagocytic cells that are important in the lung immune response but are also implicated in driving inflammation. This review explores the potential implications of monocyte and macrophage involvement in non-liver AAT synthesis and the pathophysiology of AATD lung disease.

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“…7 Increasing evidence suggests that the SZ variant may also only lead to significant disease in the presence of such exposures. 8,9 Those who are homozygous for PiZZ can also present with liver disease. This is because the Z allele leads to severe misfolding of the protein, and as AAT is secreted from hepatocytes the misfolded protein polymerizes causing hepatocyte damage.…”

Section: Introductionmentioning

confidence: 99%

“… 7 Increasing evidence suggests that the SZ variant may also only lead to significant disease in the presence of such exposures. 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

<p>Obstacles to Early Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency: Current Perspectives</p>

Quinn¹,

Ellis²,

Pye³

et al. 2020

TCRM

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This review summarizes the current research and outlooks regarding the obstacles to diagnosing and treating early alpha-1-antitrypsin deficiency (AATD). It draws on prior systematic reviews and expert surveys to discover precisely what difficulties exist in early diagnosis and treatment of AATD and elucidate potential solutions to ease these difficulties. The perceived rarity of AATD may translate to a condition poorly understood by primary care physicians, and even many respiratory physicians, which results in opportunities for diagnosis being missed, especially in mild or asymptomatic patients. There are diagnostic techniques involving biomarkers and home testing methods which could improve the rate of early diagnosis. With respect to treatment, AATD involves treating two separate pathologies, lung disease and liver disease. The only specific AATD treatment, augmentation therapy, has proven ability in treating lung disease but not liver disease. Alpha-1-antitrypsin (AAT) synthesized in the liver can form damaging polymers that also result in reduced circulating AAT levels and, whilst liver transplantation is used to effectively treat AATD, it is inappropriate in early disease. Novel therapeutic areas such as gene editing and increasing autophagy are therefore being researched as future treatments. Ultimately, diagnosis and treatment are intrinsically linked in AATD, with earlier diagnosis leading to better treatment options and thus better patient outcomes.

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Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency

Cited by 33 publications

References 41 publications

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population

<p>Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency</p>

<p>Obstacles to Early Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency: Current Perspectives</p>

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