α1-antitrypsin deficiency, liver ICD-10: E88.0
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Frau, 45 J., schweres Lungenemphysem, Dyspnoe, stirbt an Rechtsherzversagen.
Autopsiepräparat
- Portalfelder bindegewebig verbreitert
und lymphohistiozytär infiltriert
- PAS-positive, kugelförmige, intrazytoplasmatische Einschlüsse
(bis Kerngrösse) in Leberepithelien, besonders periportal, in
Kuzifer'schen Sternzellen und Gallengangsepithelien. Lokalisation
(in abnehmender Reihenfolge): Periportal/Zonen I/II/III
- Natur der Granula: Glykoproteine, Sekretionsstop im endoplasmatischen
Retikulum
α-1-Antitrypsin kann immunzytochemisch
spezifisch in der Leber lokalisiert werden
Autosomale, kodominante Vererbung: piZZ Homozygote (normaler Phänotyp:
piMM) haben nur ca. 10% der normalen α-1-AT-Funktion, piSS haben
ca. 50%. Es resultiert eine mRNA mit einer Mutation, das Protein zeigt
die Substitution einer Aminosäure, Proteinase Inhibitor Lokus
(Pi) auf Chromosom 14. Dies führt zum Sekretionsstop im endoplasmatischen
Retikulum der Hepatozyten und Makrophagen. Es sind viele verschiedene
Phänotypen bekannt.
45-year-old female suffered from dyspnea due to severe emphysema. She succumbed to
right ventricular failure (specimen from autopsy).
- A section of the liver is shown. At low magnification, a distinct nodular
architecture is observed. Fibrosis of portal tracts and bridging fibrous septae in between portal tracts are prominent.
Portal tracts exhibit an inflammatory infiltrate consisting of lymphocytes and histiocytes; periportal necroinflammatory
activity is also present. In addition, a marked proliferation of bile ductules can be seen.
- Periportal hepatocytes (Portalfelder) contain spherical eosinophilic intracytoplasmic inclusions which stain positive for PAS and are diastase
resistant. Cells exhibiting inclusion bodies are most frequently localized in zone 1 followed by zone 2 and 3.
Genetics: α-1-antitrypsin (AAT) deficiency, one of the most common serious
hereditary disorders, is inherited by an autosomal-recessive mode. The AAT gene is located on chromosome 14 and a high number
of allelic variants have been described. The Z and S deficiency variants are both caused by single base-pair substitutions
and account for the majority of deleterious variants found in patients with AAT deficiency. The homozygous ZZ variant causes
the most severe phenotype. Patients with this variant only have approximately 15% of the normal amount of AAT. The SS variant
may also be associated with severe lung disease. Patients with this genotype express around 60% of the normally observed amounts
of AAT. Both point mutations lead to the substitution of a single amino-acid which prevents proper folding of the protein and as
a consequence its retention in the endoplasmatic reticulum of the liver.
AAT-1 can be detected in the liver by immunohistochemistry.