An Italian family suffering from a novel hereditary disease, i.e. hypofihrinogenemia connected with hepatic storage of fibrinogen, has been identified. A similar disorder has previously been described in two German families. The discovery originated from the finding of a massive hepatic storage of fibrinogen in a liver biopsy specimen from a 65 years old female who during a laparotomy unexpectedly turned out to display cirrhosis. Identification of the stored material as fibrinogen was carried out by specific immunostaining applied on both light and electron-microscopic level. The stored fibrinogen appeared in the form of eosinophilic, pale, irregularly shaped inclusions within the cytoplasm of the hepatocytes. E.M. showed that the inclusions correspond to dilated cisternae of the RER filled by densely packed, curved, tubular structures arranged in a fingerprint-like fashion. Similar features of fibrinogen storage were not detected in any of 500 consecutive liver biopsy specimens examined for this purpose by appropriate techniques. Plasma fibrinogen (thrombin clottable fibrinogen) was found to be 35 mg/dl (n.v. 100-300 mg/dl), and remained persistently very low (20-1-0 mg/dl) over a follow-up period of two years. The immunoreactive fibrinogen was found to be two-three times as high as the clottable. The patient showed no clinical defect of hemostasis or impaired wound healing. Eight out of 19 family members also had persistently low plasma fibrinogen levels (U5-80 mg/dl) over the same follow-up period. Hypofibrinogenemia with hepatic storage of fibrinogen seems to represent a further endoplasmic reticulum storage disease in addition to a-1-antitrypsin deficiency, the plasma deficiency being due to defective secretion of the protein from the hepatocytes. A genetically determined molecular abnormality may be responsible for the defective intracellular transport and subsequent storage at the primary site of protein synthesis, the RER. Hepatic storage of fibrinogen is likely to predispose to development of liver cirrhosis, but neither to defective hemostasis nor impaired wound healing.

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