Alpha1-antitrypsin deficiencyE88.0

Autosomal recessive inherited metabolic disorder that leads to a disruption in the synthesis, secretion or function of the body's most important antiprotease, alpha-1-antitrypsin (alpha-1-AT = AAT). A general reduced or missing function of the proteinase inhibitor leads to increased proteolysis with consecutive lung and liver changes.

Alpha1-Antitrypsin (syn: Alpha-1-Proteinase Inhibitor, Alpha1-PI) is a complex glycoprotein consisting of 394 amino acids that is almost exclusively produced in the liver. The glycoprotein belongs to the "acute phase proteins" and is one of the most important proteinase inhibitors in serum. Alpha-1-antitrypsin inhibits, among other things, the proteinases trypsin, the "neutrophil elastase - NE formed by the neutrophil granulocytes and various collagenases.

The disease is one of the most common congenital metabolic diseases. The most common PiZ mutation is found in 1:1600/1800 newborns.

The gene coding for alpha1-antitrypsin is located on chromosome 14 (in close proximity to the genes for the heavy chains of immunoglobulins). Currently, 75 allele variants (Z-,S-,O-,M-special forms) are known to be affected by different mutations. These variants of alpha-1-antitrypsin differ in their migration during isoelectric focusing. They are designated by capital letters (M,0,Z,S).

• Normal allele variants: normal concentration and function of alpha-1-antitrypsin detectable (PiM -Pi proteinase inhibitor)
• zero variants (Pi0): no alpha-1-antitrypsin detectable
• Variants of deficiency: reduced concentration and function of alpha-1-antitrypsin. In Europe, the most common variant is PiZ; the PiS variant is less common.
• Dysfunctional variant: loss of function of alpha-1-antitrypsin as an antiprotease, but instead acts as a thrombin inhibitor.

The mutations lead to a structural change of the encoded proteins. The consequence is a disturbed secretion and faulty function. There is aggregation and accumulation in the endoplasmic reticulum (ER) of the hepatocytes and furthermore a deficiency in the cytoplasm of the cells (values mostly < 40% of the norm). The result: reduced proteinase inhibitor activity and increased proteolysis.

Lung: Non-inhibited leukocyte elastase leads to proteolytic destruction of the lung scaffold with development of progressive emphysema, possibly with chronic obstructive pulmonary disease (J44.99), chronic obstructive bronchitis (J42), bronchiectasis (J47), consecutive respiratory failure, right heart failure and cor pulmonale. The pulmonary changes mainly affect the constellations PiZZ, PiZ0, PiSZ and Pi00; they usually occur after the age of 30.

Liver: Hepatic changes (chronic hepatitis) become apparent in most patients (especially genotype PiZZ) already in childhood. The accumulation of alpha1-antitrypsin (the protein cannot be secreted due to its structural changes) in the hepatocytes leads to cell damage and subsequently to fibrosis and liver cirrhosis. In later life, up to 40% of those affected develop liver cirrhosis and about 15% hepatocellular carcinoma. In heterozygotes with the allele types PiMZ, PiSZ the risk of developing cirrhosis or hepatoma is much lower. Note: the hepatic changes are not due to the actual alpha1-antitrypsin deficiency but to an additional disturbance of certain proteins in the endoplasmic reticulum(chaperones), which check and correct the folding structure of newly formed proteins. It is also possible that degradation processes of the proteins retained in the endoplasmic reticulum are disturbed. In addition, disturbances of the innate immunity may also play a role in the realization of the disease symptoms.

Vessels: Rarer are: necrotizing vasculitis, granulomatosis with polyangiitis

Kidney: Glomerulonephritis,

Pankras: Pancreatitis and pancreatic fibrosis.

Skin (very rare: 60 cases known): neutrophilic panniculitis with ulcer formation on the lower legs (see panniculitis alpha-1-antitrypsin deficiency associated)

• Alpha1-antitrypsin in serum: < 0,9 g/l
• Determination of the phenotype of alpha1-antitrypsin
• Detection of the gene mutation (PiZZ, PiMZ and PiSZ)
• Histology: PAS-positive, proteaseresistant hepatocellular inclusion bodies (= antitrypsin deposits)

In addition to the substitution required in some cases, the secondary diseases are treated first and foremost, especially chronic obstructive bronchitis.

Absolute abstinence from smoking is absolutely necessary (the oxidants contained in smoke can inactivate alpha-1-antitrypsin).

Prophylactic: vaccinations recommended (flu, pneumococcus).

For severe emphysema, a substitution therapy of alpha-1-antitrypsin (Prolastin®, Respreeza®) is recommended.

Organ transplantation: In advanced stages, a lung or liver transplantation may be necessary. Liver transplantation is curative because alpha1-antitrypsin is only produced in small amounts in extrahepatic tissue.

Serum concentration: 0,97-1,68 g/l. Given at < 0.6 g/l. Alpha1-antitrypsin deficiency. Determination of the phenotype of alpha-1-antitrypsin given (method of choice is isoelectric focusing of the plasma protein fraction).

1. Baraldo S et al (2015) Immune activation in α1-antitrypsin-deficiency emphysema. Beyond the protease-antiprotease paradigm. At J Respir Crit Care Med 191:40 -409.
2. Ferrarotti I et al (2015) How Can We Improve the Detection of Alpha1-Antitrypsin Deficiency? PLoS One 10:e0135316.
3. Greene CM et al. (2016) α1-Antitrypsin Deficiency. Nat Rev Dis Primers 2:16051.
4. Hatipoglu U et al. (2016) α1-Antitrypsin Deficiency. Clin Chest Med 37:487-504.
5. Henao MP et al (2016) Recent advances in understanding and treating COPD related to α(1)-antitrypsin deficiency. Expert Rev Respir Med 10:1281-1294.
6. Mohammad A et al (2014) Primary systemic vasculitis with severe α1-antitrypsin deficiency revisited. Scand J Rheumatol 43:242-255.
7. O'Reilly LP et al. (2014) α1-antitrypsin deficiency and the hepatocytes - an elegans solution to drug discovery. Int J Biochem Cell Biol 47:109-112.
8. Suh-Lailam BB et al. (2014) Challenging identification of a novel PiISF and the rare PiMmaltonZ α1-antitrypsin deficiency variants in two patients. At J Clin Pathol 141:742-746.