Abstract
Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).
Highlights
Endoplasmic reticulum storage diseases (ERSD) are genetic disorders affecting secretory proteins
In addition to these features, we have observed thedeveloping intraluminal deficiency significantly increases the riskthat of the hepatocellular usually appears as amorphous fluffy material detached from the membranes, can carcinoma (HCC) [66]
The disease has drawn the interest of pathologists and hepatologists, while hematologists have accepted with skepticism the new entity for two reasons: (i) it was the first time that hypofibrinogenemia resulted from hepatic storage, (ii) it was hardly believable that a severe hypofibrinogenemia could exist in a patient without overt coagulation problems or impairment of the main functions of fibrinogen [15]
Summary
Endoplasmic reticulum storage diseases (ERSD) are genetic disorders affecting secretory proteins. The three storing variants are characterized by aggregation of the mutant AAT in the ER of hepatocytes and by liver disease; (ii) absence of gene expression and of circulating protein (Pi Null); (iii) molecular lability and intracellular degradation (Pi S that is the second most frequent variant, representing around 7–10% in the general population) [6]. The identification of the first mutation in the fibrinogen gamma chain gene [12] and the demonstration that the hereditary hypofibrinogenemia, in analogy with AATD, was due to the intrahepatic retention of the mutant protein [13,14,15], have led to the discovery of a new disease, hereditary hypofibrinogenemia with hepatic storage (HHHS), and to the concept of ERSD [1,15,16]. AAT and fibrinogen in normal conditions and in ERSD, in view of their potential towards future strategies finalized to the treatment of ERSD
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