Authors: Mark A. Colantonio, Sanjana Aggarwal, Himanshu Deshwal
Categories: Case Report, Alpha 1 anti-trypsin, Pulmonary artery aneurysm, Pulmonary hypertension, Dilated pulmonary artery, Pulmonary vascular disease
Source: Respiratory Medicine Case Reports
Authors: Mark A. Colantonio, Sanjana Aggarwal, Himanshu Deshwal
Alpha-1 antitrypsin is a relatively well-known genetic disease known to primarily affect the lungs and liver. Extrapulmonary manifestations of this disease have been reported, including vascular aneurysms. To date, few cases have reported vascular manifestations of this disease affecting the pulmonary vasculature. Here, we present a rare manifestation of alpha-1 antitrypsin deficiency leading to a saccular pulmonary artery aneurysm.
Alpha-1 antitrypsin (AAT) deficiency is an autosomal, co-dominantly transmitted mutation coding the SERPINA gene, affecting roughly one in three thousand individuals in the United States [1,2]. To date, the most common allelic variants described in the literature include the S and Z variants, each producing differing quantities of protein [1]. Alleles I and M also exist; however, these are rarely described in the literature [3]. Individuals carrying the S variant will have decreased levels of AAT protein, whereas those with the Z variant will have significantly deficient levels of AAT [1]. In its native form, AAT functions as a protease inhibitor, preventing lung and liver insults secondary to neutrophil elastase [1]. However, protein misfolding leads to polymerization of dysfunctional units, most commonly in the liver and lungs [3]. Exposures, including cigarette smoke and hazardous occupational chemicals, are thought to worsen the severity of protein dysfunction [1].
Interestingly, those with SZ allelic variations were found to have a three times higher risk for the development of emphysema compared to the general population. In contrast, those with the MS variation are at no higher risk for the development of emphysema/chronic obstructive pulmonary disease (COPD) when controlled for smoking [4]. Early diagnosis is essential, as diagnostic delay is associated with worse clinical outcomes [4].
The lungs and liver are the most commonly affected organs secondary to AAT deficiency, accounting for roughly 5 % of cases of COPD in the United States [2]. However, many individuals go undiagnosed, and it is estimated that only 5 % of this population has been identified [2]. Unexpected extrapulmonary manifestations may play a role in this unidentified population. AAT deficiency is thought to play a role in vascular pathology secondary to enzymatic protease activity on the vascular wall [5]. Dako et al. investigated the relationship between AAT deficiency and ascending aortic aneurysm in a retrospective cohort, single-center study, finding a significant association between AAT deficiency and aortic aneurysmal size [6]. Further studies have shown that AAT allelic variants may play a role in aneurysmal location, such as abdominal vascular aneurysms in heterozygous S allelic variants [6]. However, pulmonary artery aneurysms are rare, found in roughly one in fourteen thousand individuals [7]. Pizarro et al. previously described pulmonic artery rupture in an individual with a homozygous AAT deficiency [8]. Otherwise, very little literature has described this association. Here, we present a rare case of pulmonic artery aneurysm secondary to AAT deficiency.
A 73-year-old female was referred to our pulmonary hypertension (PH) clinic for evaluation of dyspnea on exertion and an incidental finding of a dilated pulmonary artery on computed tomography (CT) of the chest. She has a past medical history of obesity (Body Mass Index- 46 kg/m^2^), type 2 diabetes mellitus, hypertension, hyperthyroidism, coronary artery disease, heart failure with preserved ejection fraction (HFpEF), lifelong non-smoker and AAT deficiency (SZ heterozygous phenotype). The patient initially presented to the emergency department in September 2021 after sustaining a fall at home. Her presenting chief complaint was hip and right-sided chest pain with tenderness. As a part of clinical evaluation, she underwent a CT chest with intravenous contrast that incidentally demonstrated saccular dilation of the main pulmonary artery measuring 5.5 cm in size (Fig. 1A). No evidence of emphysema was noted and no other fractures or traumatic injuries were identified. She was referred to cardiothoracic surgery for evaluation of pulmonary artery aneurysm. However, due to significant cardiopulmonary comorbidities and deconditioning, surgical repair of the aneurysm was deemed high risk, and evaluation for secondary causes of pulmonary artery dilation was considered, prompting referral to our pulmonary hypertension clinic. On subsequent evaluation, she endorsed dyspnea on exertion with a modified Medical Research Council Scale (mMRC) of 3, leg swelling, and orthopnea.Fig. 1Sequential CT imaging depicting stable, saccular, central pulmonary aneurysm from 2021 (A) to 2024 (B).Fig. 1
Further evaluation was negative for underlying connective tissue disorders, Behcet's syndrome, infectious etiology (including Syphilis), and thromboembolic disease. Serum AAT testing demonstrated an SZ heterozygous phenotype with a reduced AAT level of 74 mg/dl, similar to prior levels. Pulmonary function tests revealed an forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio of 80 %, an FEV1 of 1.77 L, FVC of 2.21 L, total lung capacity (TLC) of 4.94 L and residual volume (RV) to TLC ratio of 52 %, consistent with a normal spirometry without a significant bronchodilator response.
An echocardiogram was performed, and it demonstrated normal left ventricular systolic function with an ejection fraction of 60 % and indeterminate diastolic function. Right ventricular morphology could not be assessed properly due to suboptimal windows and body habitus. Subsequently, she underwent a cardiac magnetic resonance imaging (MRI), which revealed mild, mid-myocardial delayed enhancement at the right ventricular inferior septal insertion that was nonspecific, but could be related to chronic right ventricular strain seen in pulmonary hypertension. Redemonstration of aneurysmal dilation of the main pulmonary artery measuring 5.8 cm was also observed, as well as dilation of the right pulmonary artery branch measuring 3.1 cm and the left main pulmonary artery measuring 2.7 cm (Fig. 2 A,B,C).Fig. 2A. Cardiac MRI demonstrating fusiform aneurysm of pulmonary artery. B. Coronal section demonstrating pulmonary artery dilation relative to the aorta. C. Cardiac MRI with a sagittal view of the right ventricular outflow tract demonstrating pulmonary artery dilation.Fig. 2
A diagnostic right heart catheterization was also performed to rule out pulmonary hypertension and revealed isolated postcapillary pulmonary hypertension with elevated biventricular filling pressures (right atrial pressure of 12 mm Hg, mean pulmonary artery pressure of 29 mm Hg, pulmonary artery occlusion pressure of 17 mm Hg, pulmonary vascular resistance of 2 Wood units) and preserved cardiac index of 2.4 L/min/m2. No intracardiac shunt was identified , with pulmonary artery O2 saturation of 68 %. These findings were overall consistent with 'history of HFpEF and were deemed unrelated to the pulmonary artery aneurysm.
Subsequently, after a multidisciplinary discussion and shared decision-making with the patient, a conservative approach of annual monitoring with chest imaging was considered over surgical correction given the patient's significant comorbidities, deconditioning, and relative stability of the aneurysm size over the past three years. A decision was made to consider monitoring AAT levels and consideration for replacement therapy if there was a progression of the aneurysm.
Alpha-1 antitrypsin deficiency is frequently described in literature affecting the lungs and liver [1,3]. Phenotypic expression is dependent on genotypic variations of the AAT protein [9]. The most common AAT variant is the MM allelic variant, whereas the least common is the ZZ protein variant, occurring in 0.003 % of the population worldwide [9]. The Z allele is the most common pathogenic variant, and those homozygous for this trait have severe deficiency of AAT and are at high risk for the development of liver and lung disease [9]. A less severe variant, the S allele, can present with reduced levels of AAT, but are only clinically significant when paired with other pathogenic variants [9]. This is similar to the I allele, which presents with a mild deficiency [9]. First approved in 1987, first-line treatment includes intravenous, purified AAT replacement therapy, which has been shown to reduce loss of lung density [10]. Treatment guidelines vary by society recommendations. Per the Global Initiative for Chronic Obstructive Pulmonary Disease, treatment is recommended for those with a severe AAT deficiency, categorized as <11 μM, and an FEV1 between 35 and 65 % [11]. As replacement therapy is not without risks, a multidisciplinary approach should be taken when considering replacement therapy.
Extrapulmonary pathology, including aneurysmal vascular changes, should not be ignored and can be a rare manifestation of the disease. Common vascular pathology described in literature includes ascending aortic aneurysm thought to be secondary to vascular wall degradation by overactive proteases [5]. In addition to aortic aneurysms, several case reports have described aneurysmal rupture of other vessels. Mitchell et al. described the rupture of a middle colic artery in an individual with AAT deficiency [12]. Later, Schievink et al. described four cases of hemorrhagic stroke secondary to ruptured intracranial aneurysm and cervical artery dissection in those with known AAT deficiency [13]. More recently, Liang et al. described a case of coronary artery dissection in a patient with AAT deficiency [14]. Pini et al. explored the relationship between AAT and abdominal aortic aneurysm formation [15]. When controlling for hypertension, diabetes, and smoking, 22 out of a 138-patient cohort with aortic aneurysmal dilation were found to have AAT deficiency [15]. Compared to the general population, this difference was found to be statistically significant (p < 0.01) [15]. These cases highlight the potential extrapulmonary complications of this genetic disease. Aneurysm pathophysiology is important to understanding pulmonary artery involvement in AAT deficient. Aneurysms are known to form due to the degradation of arterial wall proteins, including elastin and collagen [16]. Eventually, this degradation leads to thinning of the arterial wall and aneurysm formation [16]. In relation to AAT deficiency, there is likely an imbalance between active trypsin and anti-trypsin leading to further degradation of pulmonary arterial wall proteins, whereas in other conditions predisposing to aneurysm formation, such as PH, increased shear vascular wall stress increases risk of aneurysm formation [13,17]. We suspect aneurysmal formation secondary to AAT deficiency and subsequent protease imbalance would lead to focal, rather than diffuse, aneurysmal formation. Schachner et al. presented a similar case describing this hypothesis, finding a relationship between reduction of AAT levels in ruptured abdominal aortic tissue compared to helathy controls, suggesting an imbalance may lead to proteolytic damage of vasulature on the molecular level [18]. Our case presentation further supports this hypothesis. As few cases of pulmonary artery involvement in AAT deficiency have been described, the pathophysiology behind aneurysm formation further highlights this rare manifestation.
Pulmonary artery aneurysms in patients with AAT deficiency are extremely rare with only a few case reports described in medical literature. Our patient underwent a comprehensive evaluation with no other identifiable etiology to explain the presence of a saccular PA aneurysm other than AAT deficiency. Interestingly, our patient did not have any evidence of emphysema and was a lifetime non-smoker. The absence of emphysema is not an uncommon finding in those with an SZ phenotype, such as our patient, as there is a 20–50 % lifetime risk of emphysema development in this population [9]. Pulmonary artery aneurysm is a known complication of pulmonary hypertension (PH), most commonly affecting the main pulmonary arterial vasculature and, less frequently, the branching system [17]. PH is thought to contribute to pulmonary aneurysmal dilation due to increased hemodynamic pressure leading to increased wall stress [17]. However, PA dilation in PH is uniform, unlike our patient, who had a focal saccular aneurysm and an absence of precapillary PH [19]. In addition, an intracardiac shunt or congenital heart disease, including patent ductus arteriosus, atrial septal defect, and tetralogy of Fallot, should be considered in patients with pulmonary artery aneurysm, all of which were unrevealing on echocardiography and cardiac MRI [19]. Other common causes of pulmonary artery dilation and aneurysm are listed below in Table 1. Chronic pulmonary emboli is one of the more common etiologies of PH associated aneurysmal formation and commonly presents with calcified/organized thrombi [19]. These findings were absent in our patient.Table 1Common causes of pulmonary artery dilation and aneurysm.Table 1CongenitalAcquired•Truncus arteriosus [20,21]•Septal defects (atrial septal defect, ventral septal defect) [20,21]•Marfan's syndrome [20,21]•Valvular anomalies (ex: stenotic, absent, bicuspid or quadricuspid) [20,21]-Primary pulmonary hypertension [20,21]-Mitral valve stenosis [20,21]-Pulmonary embolism [20,21]-Trauma [20,21]-Rupture of aortic aneurysm [20,21]-Syphilis [22]-Tuberculosis [22]-Behcet's disease [22]-Vasculitis [22]-Systemic sarcoidosis [23]
As discussed above, Pizarro et al. described one of the few cases of pulmonary arterial aneurysm in an individual with AAT deficiency [8]. In this case, a 57-year-old female categorized with COPD GOLD D initially presented with endorsements of dyspnea and chest pain [8]. Further imaging with CT scan revealed left pulmonary aneurysm and ultimate hemorrhage [8]. Unlike characteristic aneurysms associated with PH, imaging revealed a segmental aneurysm [17]. Further chart review revealed our patient had the presence of the pulmonary artery aneurysm years prior in the absence of PH, suggesting AAT deficiency contributed to initial aneurysmal dilation. We present one of the few cases described in the literature highlighting this association, highlighting the importance of considering AAT deficiency evaluation in patients with otherwise idiopathic segmental PA aneurysm. Further research should focus on specific AAT phenotypes predisposing individuals to formation of pulmonary arterial aneurysms.
AAT deficiency is a relatively well-known genetic pathology associated with decreased levels of AAT [1,2]. Phenotypic variations are known and present with differing levels of protein. Infrequently discussed, AAT also has extrapulmonary vascular manifestations, including large vessel aneurysms [1,5]. We present a case of an elderly female with known AAT deficiency who presented with a saccular pulmonary artery aneurysm as a primary manifestation of the disease. Future research should explore this rare association to further highlight vascular pathologies associated with this disease.
Mark A. Colantonio: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Sanjana Aggarwal: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Data curation, Conceptualization. Himanshu Deshwal: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
Informed consent was obtained from the patient.
Data sharing does not apply to this article as no new data was created.
None.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.