Cancer risk associated with alpha-1-antitrypsin deficiency: only large registries will give us the answer

Alpha-1-antitrypsin (AAT) is a serine proteinase inhibitor, the main function of which is to inhibit neutrophil elastase (NE) activity, but it also regulates several immune and inflammatory responses [1]. Deficiency of the protein (alpha-1-antitrypsin deficiency or AATD) is a well-known genetic condition associated with an increased risk of developing pulmonary emphysema and liver disease [2, 3]. It has been hypothesised that it is associated with other respiratory diseases, such as asthma or bronchiectasis [4], and it has also been linked with a potential increase of the risk of some types of cancer, although the information available is sparse [5].

In this issue of the journal, Hiller et al. [6] present the results of a longitudinal study aimed at evaluating the relative risk and risk factors for incident cancer in proteinase inhibitor (PI) *ZZ patients. For that purpose, the investigators included 1570 PI*ZZ individuals from the Swedish National AATD Registry and 5951 controls from Swedish population-based cohorts. Their results showed a significantly higher incidence of cancer in the AATD cohort, with a hazard ratio (HR) of 1.48 (95% CI 1.24 to 1.76) for any type of cancer. Interestingly, the risk of hepatic cancer was the highest (HR 20.34, 95% CI 8.83 to 46.86) and, while the risk of non-hepatic cancer considered globally was still slightly and significantly increased, no other type of cancer showed a significantly increased risk when analysed separately. After adjusting for age, sex, smoking habits and the presence of liver disease, the results did not change, and the risk of cancer was still significantly higher for any type, liver and non-hepatic cancer [6].

This is the first population-based, longitudinal study to analyse the relationship of AATD and cancer in such a large population of patients with the severe homozygous PI*ZZ AATD and the results provide strong evidence about the increased risk of liver cancer in these subjects. Nonetheless, despite the important contribution of Hiller et al. [6], the association between severe AATD and other types of cancer still remains unclear.

The relationship between AATD and liver cancer had previously been described [7], with the same Swedish authors having reported a prevalence of hepatocellular cancer of 2% in PI*ZZ individuals [8]. The pathogenesis is related to the misfolding and polymerisation of the Z variant of the AAT protein in hepatocytes, leading to its accumulation in the endoplasmic reticulum [9, 10]. This accumulation of the Z protein leads to liver damage, inducing apoptosis of the hepatocytes and a compensatory hepatocyte proliferation that eventually produces liver fibrosis and may evolve to cirrhosis or hepatocellular carcinoma [10]. The risk of developing liver disease is clearly higher for PI*ZZ individuals, but different studies have shown that in the presence of other factors, such as alcohol misuse, metabolic syndrome or non-alcoholic fatty liver disease, carriage of the Z allele, even in heterozygous form, is a strong risk factor for the development of cirrhosis [11, 12] and may also lead to faster hepatic decompensations [13].

The relationship between AATD and other types of cancer is still under debate. Due to the high incidence and mortality associated with lung cancer and the strong association between AATD and the risk of developing pulmonary emphysema, it is not surprising that most studies have been focused on analysing the possible relationship between AATD and lung cancer [5]. Although some case–control studies have found an increased risk of lung cancer of up to four-fold in AATD patients, this risk seems to be clearly higher in the presence of a diagnosis of COPD and tobacco exposure [5, 14], with some data even suggesting that it is not increased in never-smoker subjects [15]. Interestingly, Hiller et al. [6] found that the risk of lung cancer in PI*ZZ subjects was half that observed in controls (0.23 versus 0.46 cases per 1000 person-years), although the differences were not significant (p=0.09).

Data related to other types of cancer are even scarcer and limited to a few case series on breast, bladder or colorectal cancer, and include various AAT alleles [16–18]. The low incidence of these types of cancer implies that large populations must be followed for extended periods of time to achieve enough statistical power to detect a significant difference in risk, if risk really exists. The results observed by Hiller et al. [6] provide important estimates about the risk of other types of cancer in PI*ZZ individuals but cannot be considered conclusive, as no significantly increased risk was found when analysed separately, despite the small significant increased risk for non-hepatic cancers considered together.

The study reported by Hiller et al. [6] illustrates the difficulties in conducting epidemiological studies in rare diseases. Credit must be given to the authors for planning, developing and maintaining a large registry of AATD individuals that has provided relevant insight into the natural history of the disease [13, 19, 20]. Even so, larger series would be required to analyse the increased risk of some types of cancer in AATD individuals. In this respect, the new international EARCO registry has been set up by the European Respiratory Society in response to an unmet need in the research of AATD [21] and with the objective of better understanding the natural history of the disease in a large international cohort [22, 23].

In addition to the limited sample size, other limitations of the study must be considered, as indicated by the authors. The selection of the OLIN cohorts as the control group has some advantages: a large sample size, a representative sample of the general population with known smoking habits and the possibility of obtaining follow-up information. However, there were significant differences in their characteristics compared to the AATD cohort, which could lead to some sources of bias. The control individuals were selected from three population-based cohorts within the OLIN studies recruited in 1992, 1996 and 2006, respectively. Within these studies, all subjects completed a postal questionnaire survey once, with no follow-up and all additional information was collected from Swedish national registers. While the information in the registries may be robust, the scrutiny that both cohorts have received in the active search for complications has most certainly been different. We know that AATD individuals have regular medical visits and tests and are usually willing to consult if any complication occurs. On the other hand, we have no records or certainty of the kind of medical attention the control group has received. In summary, the effort invested in actively looking for cancer may have been different for the two cohorts. In addition, although the authors performed an analysis controlling for potential risk factors such as age, sex, smoking habits (smoker/never smoker) and the presence of liver disease at inclusion, other relevant risk factors for cancer, such as intensity of smoking, alcohol intake, environmental exposures, physical activity or diet, among others, were not recorded in the OLIN questionnaire.

It is well known that many types of cancer are facilitated by a sum of predisposing factors and, in this sense, AATD could partly contribute as a facilitator to the development of different types of cancers in predisposed people or those with other risk factors. The AAT protein has many regulatory biological functions beyond the inhibition of NE [1]. Therefore, besides the protease–antiprotease imbalance, the deficiency of AAT may impact other metabolic pathways that lead to immunological alterations, increased inflammation and tissue damage, which may promote carcinogenesis and tumour progression [24, 25].

The demonstration of an increased risk of non-hepatic cancers in individuals with AATD in future studies would have important implications. Firstly, AATD is the most frequent hereditary condition diagnosed in adults, but it is still highly underdiagnosed. Hence, more effort should be put into diagnosis to identify high-risk individuals to implement prevention interventions or behaviour modification [26]. Secondly, the possible beneficial effect of augmentation therapy with intravenous AAT (the only specific treatment available to date) on reducing the risk of cancer should be explored. Unfortunately, the authors were not able to investigate differences in risk of cancer between augmented and non-augmented AATD subjects because augmentation is not reimbursed in Sweden [27]. Again, a large international prospective registry would be required to investigate this important aspect [22]. Furthermore, an increased risk of cancer associated with AATD would be a strong motivation for the development and implementation of other therapies, such as gene therapy or treatments targeting AAT polymerisation. Finally, the confirmation of the significantly increased risk of liver cancer in the current study implies the responsibility of AATD reference centres to organise an adequate liver disease screening plan [11, 28], in particular in patients with advanced liver fibrosis [29]. Several of these reference centres are organised in respiratory departments, but the collaboration of liver specialists is absolutely necessary [30].

The Swedish registry constitutes an example of the importance of registries for rare diseases. Over the past decades this registry has expanded our knowledge about AATD and is now one of the founders of the new international EARCO registry that will incorporate patients from other countries in Europe and other continents.

Shareable PDF