AATD clinical session

Pneumonology Service University Hospital of Malaga

Francisco Casas, coordinator of the Andalusian Alpha-1 Center of Granada, participates in a clinical session on alpha-1 antitrypsin deficiency (DAAT) of the Pneumology Service of the Regional University Hospital of Malaga.

The session has been developed in 2 thematic blocks to address:

Where we come from?
Where we go?

Alpha-1 Antitrypsin Deficiency Clinical Session: Block 1

Review of clinical aspects

Alpha-1 antitrypsin (AAT) is a water-soluble and tissue-diffusible circulating serpin, of medium size (molecular weight of 52 kDa) and a half-life in blood of 4.5 days.

Diagnosis, Spanish Registry of Patients with AATD (REDAAT) and treatment of AATD

AAT is synthesized and secreted mainly by hepatocytes (≥ 80%).

The main function of AAT is to inhibit neutrophil elastase to prevent excessive proteolytic degradation of connective tissue in the lungs.

In other words, it is the most abundant protease inhibitor in human serum and its target is neutrophil elastase, although it also has antioxidant capacity, anti-inflammatory, antimicrobial, tissue repair and immunomodulatory properties.

DAAT is a genetic disease

The gene encoding AAT is expressed primarily in hepatocytes.

Human AAT is encoded by the SerpinA1 gene, which occupies the distal end of chromosome 14, and has two alleles that are transmitted by Mendelian recessive, autosomal, and codominant inheritance.

DAAT characteristics

In its severe forms, it predisposes to the development of chronic obstructive pulmonary disease (COPD), emphysema or liver disease.

AATD is characterized by abnormally low concentrations of alpha-1 antitrypsin (AAT) in plasma and is one of the most well-known and frequent genetic causes.

In addition, it is estimated that in Spain there may be around 14,000 individuals with severe homozygous Pi*ZZ deficiency.

Despite this known relationship, COPD secondary to DAAT continues to be a challenge as it is a disease with a high degree of underdiagnosis due to its low clinical suspicion.

On the other hand, there are more challenges, such as improving knowledge of this disease from a basic point of view (etiopathogenesis and epidemiology), as well as its treatment.

Smoking aggravates the disease

Smoking is the best known factor that modifies the natural history of subjects with DAAT.

FEV1 loss and mortality are directly influenced by the amount of tobacco consumed.

The diagnosis of DAAT happens in the following way:

Determination of the serum concentration of alpha-1 antitrypsin in the population at risk, and 2) Confirmation of the disease by phenotyping/genotyping.

Its status as a minority respiratory disease makes it necessary to concentrate the cases detected in centers of excellence in AATD, with the aim of generating knowledge about the disease and developing lines of research.

AATD patient registries are fundamental tools for biomedical and clinical research.

Studies in patients help to better understand the natural history, diagnosis and treatment of this disease.

The advancement of knowledge in DAAT

In 1986 Wewers and Cols initiated the first experiences of treatment with iv AAT from donor plasma.

A year later, the Food and Drug Administration (FDA-USA) approved the use of AAT for intravenous administration (60 mg/kg/7 days) in pulmonary emphysema due to severe AATD.

In search of the cure

The goal of IV AAT treatment is to preserve lung function, stop the progression of emphysema, reduce the rate of exacerbations, and reduce mortality.

Its efficacy is defined based on biochemical and clinical criteria, and has been demonstrated in randomized, double-blind, placebo-controlled studies, with the analysis of the fall in lung density as the main measurement parameter. In addition, therapy with periodic IV infusion of AAT is the only specific treatment that exists to slow down the progression of emphysema associated with DAAT, a rare orphan respiratory disease.

Alpha-1 Antitrypsin Deficiency Clinical Session: Block 2

A new tool has been developed for the diagnosis of AATD using PROGENIKA’s A1AT genotyping test technology, Alphakit® (dried blood drop) and AlphaID® (oral smear).

Previously, the implantation and development of diagnostic circuits were discussed.

The importance of patient registries was also discussed and the Pan-European AATD Registry EARCO (European Alpha-1 Research Collaboration) was presented, a collaboration that provides real-world longitudinal data for AATD patients.

On the other hand, EARCO currently has more than 1,300 patients registered in 46 centers in 16 countries.

Spain has already registered almost 600 patients.

Resource: Centro Andaluz Alfa 1

We move towards a better future

Finally, we discuss future therapeutic prospects

The objectives of the new therapies are aimed at:

Reduce lung inflammation: Antioxidants
Promote alveolar regeneration
Block neutrophil nuclear polymorph elastase
Increase AAT levels: Endogenous and exogenous.

New therapies

Therapies aimed at reducing pulmonary inflammation with antioxidants or promoting alveolar regeneration have not been shown to be effective.

Strategies to endogenously increase AAT levels can be achieved with liver transplantation, inhibiting ΑAT polymerization, or through gene therapy and pluripotent stem cell autotransplantation.

The action on the polymerization of ΑAT has a double advantage, since it increases serum levels of AAT and reduces liver damage caused by the accumulation of polymerized AAT within the hepatocyte.

Regarding strategies to increase AAT levels exogenously, therapies with AAT by inhaled and subcutaneous routes are being developed, and there are clinical trials with higher doses of AAT (120 mg/kg of weight/week).

On the other hand, oral elastase inhibitors show great promise and have been shown to reverse liver fibrosis.