Alpha 1 Antitrypsin deficiency: Pathogenesis. Ethiology. Clinical symptoms (2023)


Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. 2006 Oct 27 [Updated 2020 May 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from:
National Center for Biotechnology Information (US). Genes and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Alpha-1-antitrypsin deficiency. [Updated 2011 Jan 31]. Available from:
Meseeha M, Attia M. Alpha 1 Antitrypsin Deficiency. [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from:

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With any inflammation in the lung tissue, the amount of neutrophils, greatly increase and activated neutrophils in the area of inflammation, begin to secrete proteolytic enzymes, like neutrophil elastase, that destroy elastin fibers and there by cause severe damage to alveoli.

Just recall that the walls of alveoli are composed of connective tissue, primarily of collagen and elastin, and also the basal membrane that sepparates the gas inside the alveoli from the blood in the blood vessel is also composed of collagen and elastin.


When neutrophils release Elastase in the lung tissue it’s like a fire meet gasoline.

This proteolytic enzyme rapidly destroy elastin fibers there by it cause severe damage to the walls of alveoli and also to the basal membrane.


This condition called Emphysema.


One of the major risk factors of emphysema is cigarette.


Becouse smoking provoke additional inflammation in the lung tissue, there by it.

Aggrevates emphysema.

To control.

This very aggressive enzyme in liver tissue hepatocytes in endoplasmic reticulum produce specific protein called Alpha.

1 antitrypsin.This protein is delivered to all tissues, but the major site is the lung tissue.

This protein inhibits proteolytic enzymes, like trypsin and elastase, and by this it controls inflammation and prevents damage to alveoli.


We also have to know is that Alpha 1 antitrypsin is encoded by SERPINA1 gene, that is located on long arm of chromosome 14.

And normal version of that gene callled M, allele., So, M allele results in normal production of Alpha 1 antitrypsin, protein.


We know that mutations can alter nucleotide sequence of a particular gene and by this they create the other version of this gene.

And recall that the versions of gene called alleles.

And different alleles result in different production of alpha 1 antirypsin.


Apart of the M allele, there are S allele, that encodes moderately low antitrypsin production.

Z allele, that encodes very low antitrypsin production.

And Null allele, that encodes no antitrypsin production at all.


We know person has 1 allele from each parents.So.

Healthy individual has two M alleles, and this results in totally normal antitrypsin production And by the way it’s.

The most common combination.

People, with MS and MZ varients, have slightly decreased antrypsin, production, SS and SZ combinations results in low antrypsin production, important that there is still enough amount of antitypsin to protect lung tissue.


This category of patients are at high risk of lung injury, especially with smoking.

And, now very high yield.


People, who have ZZ variant, are at very high risk of lung injury and liver, injury., With, lung injury.

Everything is simple–, ZZ varient cause very low production of Alpha 1 antitrypsin, that can’t sufficiently inhibit activity of proteolytic enzymes, and this results in alveoli, damage., With, liver damage, it’s, not that simple.

The concept is ZZ variant, produce not only small amount of antitrypsin proteins.

This proteins also have slightly different structure.

That makes some of them prone to polymerization.


This polymerization occurs right after the protein is synthesized in the endoplasmic reticulum.

And in polymerized state.

This proteins can not be secreted.

And becouse of that ZZ variant also called unsecreted variant of Alpha 1 antitrypsin protein.


The specific feature that this polymerized antitrypsin proteins are strong chemotactic agents for neutrophils, that comes into liver tissue and begin to rapidly produce proteolytic enzymes that cause inflammation in the liver tissue that result in severe liver, damage.


What we have to understand, is that becouse Alpha 1 antitrypsin production begins right after birth, this progressive accumulation of polymers cause severe liver, inflammatory damage since neonatal period, (and becouse of that this condition called neonatal hepatitis).


Where is inflammation, there is fibrosis that, with time progress to cirrhosis.

And cirrhosis markedly increase the risk of hepatocellular carcinoma.

So patients with ZZ allele can have cirrhosis or hepatocellular carcinoma in very young age.

Another posibility is Null phenotype – it’s, the most rare variant that results in no antitrypsin protein production at all.

There by patients who have this variant are in huge risk of the most severe lung injury.

But becouse.

There is no production of antitrypsin protein at all.

There is no risk of polymerization and there by no possibility of liver, injury., So, liver injury, it’s, a unique feature of ZZ variant.


There are a few characteristic features of A1AT deficiency.

First of all becouse Alpha 1 antitrypsin deficiency cause emphysema, which is the form of chronic obstructive pulmonary disease, patients usually present with typical COPD symptoms as chronic shortness of breath and productive cough.

And very important that they have this symptoms in a relatively young age, for example, smokers present in their 30s, whereas nonsmokers present in their 40s.

And when emphysema develops in a 40 years old person without any smoking history it’s quite a suspicious clinical situation.


In such case, we always have to keep in mind the possibility that this person maybe has very low antitrypsin production.

The characteristical feature of alpha-1 antitrypsin deficiency is panacinar ( or so called panlobular) emphysema – basicly it’s, a destruction predominantly of the lower lung lobes in the basal regions of the lung.

Becouse, for example, smoking-induced emphysema involves predominantly upper lobes and called centriacinar ( or so called centrilobular) emphysema.

So it’s help in differantial diagnosis And also keep in mind that with ZZ allele patients can have hepatitis, cirrhosis or even hepatocellular carcinoma in a very young age.


What is the pathogenesis of alpha-1 antitrypsin deficiency? ›

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by low serum levels of alpha-1 antitrypsin (AAT). Loss of AAT disrupts the protease-antiprotease balance in the lungs, allowing proteases, specifically neutrophil elastase, to act uninhibited and destroy lung matrix and alveolar structures.

What are the clinical manifestations of alpha-1 antitrypsin? ›

What Are the Symptoms of AAT Deficiency?
  • Shortness of breath.
  • Excessive cough with phlegm/sputum production.
  • Wheezing.
  • Decrease in exercise capacity and a persistent low energy state or tiredness.
  • Chest pain that increases when breathing in.
Nov 17, 2022

What is the clinical presentation of alpha-1 antitrypsin deficiency? ›

The initial symptoms of alpha1-antitrypsin deficiency include cough, sputum production, and wheezing. Symptoms are initially intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma.

What diseases are associated with alpha-1 antitrypsin deficiency? ›

Alpha-1 antitrypsin deficiency (AATD) is an inherited disease that causes an increased risk of having chronic obstructive pulmonary disease (COPD), liver disease, skin problems (panniculitis), and inflammation of the blood vessels (vasculitis).

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