Cancer risk in severe alpha-1-antitrypsin deficiency

Abstract

BackgroundSevere alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is a risk factor for pulmonary emphysema and liver disease, but its effect on cancer risk is unknown. Our aim was to evaluate the risk and the risk factors for incident cancer in PiZZ individuals compared with the general population with known smoking habits.MethodsA longitudinal study of PiZZ individuals (n=1595) from the Swedish National AATD Register, and controls (n=5999) from Swedish population-based cohorts. Data on cancer and mortality were obtained by cross-linkage with national registers. Individuals who had undergone lung transplantation (n=10) and those with a cancer diagnosis within 5 years prior to inclusion (n=63) were excluded. The risk factors for developing cancer were analyzed using proportional hazards and Fine-Gray regression models, adjusting for age, sex, smoking habits and the presence of liver disease.ResultsThe median follow-up time was 17 years (IQR 11) for the whole study population. The incidence rate of hepatic and non-hepatic cancer per 1000 person-years was 1.6 (95% CI 1.1–2.3) and 8.5 (95% CI 7.2–10.0) for the PiZZ individuals, and 0.1 (95% CI 0.04–0.2) and 6.6 (95% CI 6.0–7.1) for the controls, respectively. The adjusted hazard ratios (HR) for hepatic and for non-hepatic cancer were 23.4 (95% CI 9.9–55.4) and 1.3 (95% CI 1.1–1.5) respectively, in the PiZZ individuals compared with the controls.ConclusionThese results suggest that individuals with severe alpha-1-antitrypsin deficiency may have an increased risk of developing both hepatic and non-hepatic cancer, compared with the general population.

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

“…Another major caveat are the lacking data about the development of hepatocellular carcinoma (HCC). While the absolute risk seems to be 20-50x elevated in Pi*ZZ subjects [45,54], the current data suggest that it develops primarily in subjects with advanced liver fibrosis [55],…”

“…Another major caveat is the lacking data about the development of hepatocellular carcinoma (HCC). While the absolute risk seems to be 20 to 50 times elevated in Pi à ZZ subjects, 45,54 the current data suggest that it develops primarily in subjects with advanced liver fibrosis, 55 who should receive ultrasound-/imagingbased HCC screening every 6 months. Given that liver cirrhosis constitutes an increased risk for HCC, we advocate for HCC screening for all AATD patients with cirrhosis, irrespectively of their genotype.…”

The impact of alpha-1 antitrypsin deficiency alleles on lung cancer survival

“…This leads us to believe that the problem may stem from AAT activity. Its dysfunction would cause an imbalance between protease-antiprotease, not in quantity but rather functionality, where despite normal or even elevated AAT levels, said protein has little or no anti-elastase activity ( 4 , 15 , 16 ).…”

Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease

“…Our data clearly indicated that miR-425-5p expression was significantly decreased in AATD individuals. Given that AATD individuals may have an increased risk of developing hepatocellular carcinoma (86) decreased levels of plasma EV-associated miR-425-5p may suggest a defense mechanism to prevent cancer in this patient's population.…”