There has been much literature devoted to alpha-1 antitrypsin deficiency (AATD) and lung cancer, albeit separately, thus complicating efforts to combine the 2 disciplines and compare the 2 diseases objectively. AATD is an exceedingly rare disease, while lung cancer is more common. As physicians, we know that the most common cause of lung cancer is smoking. If we are honest with ourselves, there are many times we may feel exceedingly frustrated when a patient with chronic obstructive pulmonary disease (COPD), wheezing away on high-flow oxygen, refuses to even contemplate that their heavy smoking habit had anything to do with the disease.
Looking beyond issues of patient compliance, it is in the interest of the medical world to identify associations between different diseases, simply because it helps us to make better clinical decisions. This is certainly true regarding rare diseases, such as AATD. We understand that they damage the lungs and the liver; however, to what extent do they cause malignancies such as lung cancer? The possibility of developing lung malignancies should certainly sharpen our focus when it comes to patient monitoring and the questions we ask during routine follow-ups. We cannot afford for a late diagnosis to be made if scientific literature tells us that a link is plausible.
Read more about AATD etiology
Researchers set out to conduct a literature review regarding this issue and published their findings in Translational Oncology. Let us look at their research in detail.
Literature Review Study Design
According to the researchers of this study, “To obtain the necessary information, we implemented a predefined search strategy based on a combination of keywords (alpha-1 antitrypsin and lung cancer), using both English and Spanish as search languages.” The researchers also had a very broad study period, covering almost 35 years from January 1, 1975, to April 30, 2020.
Their inclusion criteria for the research papers they reviewed were as follows:
- The study type must be case-control or cohort studies or systematic reviews only
- Patients must be aged 18 and above and belong to the general population
- The sample size must be 50 or more cases of lung cancer, and the total sample size must be 100 patients or more
- Patients must have an alpha-1 antitrypsin (AAT) plasma level and corresponding phenotype/genotype
- Patients must have a pathological diagnosis of lung cancer without a previous history of cancer
- The quality of the study must be 5 points or greater (based on a special scale that the researchers devised, with the maximum score being 10) .
Out of 282 research papers, only 6 met the stringent inclusion and exclusion criteria. We will now summarize some of their key findings.
A Strong Link
A study investigated 260 patients with lung cancer for AAT-deficient phenotypes. They found that 12.3% of the patients were carriers of the deficient phenotype, with 11.1% being smokers and 20.6% having never smoked. Researchers also found that the number of patients displaying the AAT-deficient phenotype increased when diagnosed with both COPD and lung cancer.
The same study found that carriers of AAT-deficient phenotypes were statistically more likely to develop lung cancer than the controls. This finding alone establishes a strong link between AATD and lung cancer, which should prompt physicians to be more aware of the risk of developing such a disease in their patients and to initiate appropriate investigations the moment signs and symptoms of lung cancer arise.
Read more about AATD prognosis
With regards to the histological type of lung cancer, researchers discovered that AATD increases the risk of developing adenocarcinomas, which was associated with 2 lung cancer histological types, bronchoalveolar carcinoma, and squamous cell carcinoma.
Among the studies chosen for this literature review, a study looked at the survival rates of patients with non-small cell lung cancer (NSCLS) that was associated with AATD. The study shows, unsurprisingly, that the PI*MS and PI*MZ genotypes were among the most common. In AATD carriers, the survival rate was 2.9 years; among non-AATD carriers, the survival rate was very similar at 2.7 years. This suggests that further research into the association between AATD and lung cancer is warranted for us to further understand how these diseases are related.
Proposed Mechanisms of This Association
Let’s get to the heart of the matter – how does AATD cause lung cancer? Several mechanisms have been proposed. The first is that the protease/antiprotease imbalance caused by AATD increases proteolytic activity of the various serine proteases, with neutrophil elastase being the prime example, resulting in a cellular microenvironment favorable for carcinogenesis and tumor progression.
Another study showed that in examining 2000 patients with lung cancer, a higher incidence of AATD (12.3%) was observed compared to the general population (7%). The researchers also discovered that patients with AATD had a significantly higher risk of developing lung cancer than the controls.
It is particularly important that we remember the profoundly protective role of the AAT enzyme on lung health. AAT levels increase in the plasma when systemic inflammation arises, which is common in many neoplasms. It has known anti-inflammatory and antimicrobial properties. Deficiency in this enzyme renders its function ineffective, inviting a range of opportunistic infections to take root.
It is always useful for physicians to know how a disease is associated with other diseases. This allows for more detailed observations during follow-ups and a greater awareness that more serious diseases may develop over time. As physicians, especially those of us working in general practice, we need to get better at identifying malignancies in their early stages, yet be able to reassure our patients when the probability of such an occurrence is low. It is a fine balancing act, but isn’t that what medicine is all about?
Tubío-Pérez RA, Torres-Durán M, Fernández-Villar A, Ruano-Raviña A. Alpha-1 antitrypsin deficiency and risk of lung cancer: a systematic review. Transl Oncol. 2021;14(1):100914. doi:10.1016/j.tranon.2020.100914
Sinden NJ, Baker MJ, Smith DJ, Kreft JU, Dafforn TR, Stockley RA. α-1-antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2015;308(2):L179-L190. doi:10.1152/ajplung.00179.2014