AATD and pulmonary emphysema

AATD (severe alpha-1-antitrypsin deficiency), PiZZ phenotype, is a risk factor for pulmonary emphysema and liver disease, but its effect on cancer risk is unknown.

Incidental Cancer Risk Factors

Purpose of the research

The aim stated by the authors in this study, published in the prestigious European Respiratory Journal, was to assess the relative risk and risk factors for incidental cancer in the large cohort of PiZZ individuals included in the Swedish AATD Registry compared to a random sample from the general population with known smoking habits, and to assess survival after cancer diagnosis.

AATD in adults presents clinically with pulmonary and hepatic manifestations, including early-onset chronic obstructive pulmonary disease (COPD) and a risk of developing chronic liver disease and liver carcinoma.

Alpha-1-antitrypsin (AAT) is an antiprotease that neutralizes proteases, especially neutrophil elastase, and thus inhibits lung parenchymal degradation.

Is there a possibility of developing cancer?

It is well known that people with severe AATD, PiZZ phenotype, are at increased risk of developing liver cancer.

However, the risk of non-hepatic cancer and other types of cancer is less well known.

Cancer is a global public health problem and in 2020 it is estimated that there have been more than 10 million cancer-related deaths worldwide.

Risk factors for developing cancer include smoking, alcohol consumption, and air pollution, but also genetic factors.

Several mechanisms have been proposed for the development of cancer in AAT, including an excess of neutrophil elastase that cannot be neutralized by a low concentration of AAT, which facilitates tissue damage and the appearance of neoplasms.

How was this study carried out?

This was a national longitudinal study of registry-based PiZZ individuals and a random sample of the general population with known smoking habits.

All information was collected using personal identity numbers, crossing data between the Swedish National AATD Registry, the Swedish National Patient Registry (SNPR), the Swedish Cancer Registry, and the Swedish Cause of Death Registry.

Sampling and data collection

The PiZZ individuals included in the present study were included in the Swedish National DAAT Registry.

The registry began in 1991 and the inclusion criteria are: subjects aged 18 years or older, diagnosed with severe AATD (PiZZ, PiZNull or PiNullNull phenotypes, verified by isoelectric focusing) and written informed consent to participate.

Where was the study carried out?

The results of the individual’s clinical examination, as well as laboratory (liver function) and pulmonary function tests, are performed at the local hospital or home clinic every 2 years.

These are reported by the responsible physician to the Swedish AATD Registry by means of a questionnaire.

General criteria

The three groups of patients were recruited in 1992, 1996, and 2006, respectively.

They constituted three population samples, randomly selected from the general population, between 20 and 69 years of age.

In addition, they were invited to complete a postal survey that included questions about respiratory symptoms and diseases, and smoking habits.

Smoking status was classified as non-smoker, ex-smoker, and current smoker.

An ex-smoker is an individual who has stopped smoking 12 months before her inclusion in the AATD registry (for PiZZ individuals) or before answering the survey (for controls).

Former smokers and current smokers were also classified as smokers.

A total of 1,570 PiZZ individuals and 5,951 controls were included in the analyses.

Data were obtained from the Swedish National Register of Causes of Death on vital status and causes of death, up to 1 January 2015, for all people included in the study.

Data on diagnoses of COPD, liver disease, and cancer were obtained from the SNPR and the National Cancer Registry, and coded according to revisions 7, 9, and 10 of the World Health Organization International Classification of Diseases system.

AATD and pulmonary emphysema: discussion

The main finding of this study is that people with severe AATD may be at increased risk of developing cancer compared to the general population.

The risk of liver and non-liver cancer was increased after controlling factors such as age, sex, smoking, and the presence of liver disease at enrollment.

This was significantly higher among PiZZ individuals who ever and never smoked than the corresponding general population controls.

A systematic review suggested that AATD may increase the risk of developing lung cancer, particularly squamous cell and adenocarcinoma types.

The risk increases with exposure to tobacco and a previous diagnosis of COPD

In 260 patients with lung cancer, they found a significantly higher incidence of lung cancer among individuals with AATD compared with the general population (12% vs. 7%).

Elevated levels of neutrophil elastase have been observed in various types of cancer, such as:

  • Gallbladder cancer
  • Bladder cancer
  • Lung cancer
  • Malignant lymphoma

In fact, they have been negatively associated with the stage and grade of the cancer and survival.

In AATD, the excess neutrophil elastase cannot be neutralized by the low concentration of AAT.

Several mechanisms have been suggested justifying the role of an imbalance between neutrophil elastase and AAT in the development and progression of cancer.

Furthermore, neutrophil elastase is supposed to inhibit cell apoptosis and promote tumor progression, invasion, and metastasis.

Additional Risks

As expected, an elevated risk of liver cancer was found in this study among PiZZ individuals.

A previous study from the Swedish AATD registry found a 2% prevalence of hepatocellular cancer in PiZZ adults.

Survival time after diagnosis of any type of cancer was significantly shorter in PiZZ individuals compared to controls, but was not significant after diagnosis of non-hepatic cancer.

Survival time after a diagnosis of liver cancer has been reduced to less than 2 years.

These findings show the importance of periodic monitoring of PiZZ individuals using imaging techniques that improve early detection of liver cancer and, therefore, its prognosis.


There is an increased risk of developing liver and non-liver cancer

In conclusion, these results suggest that PiZZ individuals may be at increased risk of developing liver and non-liver cancer.

Risk remains elevated after adjusting for risk factors:

  • Age
  • Sex
  • smoking habit
  • Presence of liver disease at the time of inclusion

Further studies are needed to investigate the role of DAAT in the pathogenesis of cancer.

The authors of the study want to emphasize the importance of early identification of individuals with severe AATD, in order to follow up, thus reducing the cancer burden.

Source Puv Med Eur Respir J

Cancer risk in severe alpha-1-antitrypsin deficiency

Adriana-Maria Hiller1, Magnus Ekström2, Eeva Piitulainen1, Anne Lindberg3, Eva Rönmark And Hanan Tanash1

1 Dept of Respiratory Medicine and Allergology, Lund University, Skåne University Hospital, Malmö, Sweden.

2 Lund University, Faculty of Medicine, Dept of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund, Sweden.

3 Dept of Public Health and Clinical Medicine, Section of Medicine, the OLIN unit, Umeå University, Umeå, Sweden.

4 Dept of Public Health and Clinical Medicine, Section of Sustainable Health, the OLIN unit, Umeå University, Umeå, Sweden.

Eur Respir J. 2022 Oct 27;60(4):2103200. doi: 10.1183/13993003.03200-2021. PMID: 35361631.

Centro Andaluz Alfa-1