Pathology Teach and Tell: Fibrinogen Storage Disease in a Child With Hypofibrinogenemia and Decreased Ceruloplasmin

Abstract

The authors present a clinical case of a patient with mild liver disease and coagulopathy. The diagnosis was reached through careful histologic examination of liver biopsy. Electron microscopy played an important role in confirming the diagnosis.

γ375W fibrinogen-synthesizing CHO cells indicate the accumulation of variant fibrinogen within endoplasmic reticulum

“…These results demonstrated that assembled and non-secreted 375W fibrinogen was accumulated in the dilated ER and aggregated variant fibrinogen was seen as regularly structured fibular material, being similar to the fingerprint-like pattern observed at inclusion bodies in patients' hepatocytes affected with HERSD [10][11][12][13][14]. In addition to R375W mutation, G284R [8], T314P [9], and deletion of G346-Q350 [15], all mutations residing in the globular D domain, have been reported as HERSD with hypofibrinogenemia, and all also demonstrated the presence of hepatocellular cytoplasmic inclusion bodies filled with anti-fibrinogen antibody-reacting materials and were also observed as tubular materials with a 16 fingerprint-like pattern by electron microscopy [8,9,15].…”

“…5C, F), the width of the ER was expanded slightly, 176.6 ± 34.7 nm (n = 22) and, moreover, the ER lumen was filled with regularly structured fibular materials. These appeared to have a fingerprint-like pattern, as shown in hepatocytic inclusion bodies of HERSD patients by transmission electron microscopy [10][11][12][13][14].…”

“…On the other hand, HERSD-induced variant known as fibrinogen Aguadilla; R375W, was reported as heterozygous hypofibrinogenemia; namely, the plasma fibrinogen concentration determined by the thrombin time method and immunological method was 0.6 g/L by both [10]. Another four identical variant fibrinogens also reported lower levels of plasma fibrinogen and were diagnosed as hypofibrinogenemia [11][12][13][14]. Overall, 15 considering the excretion pattern of 375W we conclude that our recombinant fibrinogen-producing system using CHO cells gives results similar to patients with hypofibrinogenemia.…”

“…Genetic abnormalities in patients with these diseases have been found in all three genes and identified as missense, nonsense, or frameshift mutations; splice-site abnormalities; or large deletions, as listed in the fibrinogen variant database [updated on 26/01/2012, http://site.geht.org/site/Pratiques-Professionnelles/Base-de-donnees-Fibrinogene/Base-d e-donnees/Base-de-donnees-des-variants-du-Fibrinogene_40_.html]. Some patients with only four variant types of hypofibrinogenemia, substitution of G284R [8], T314P [9], and R375W mutation [10][11][12][13][14], and deletion of G346-Q350 [15] (all numbered as mature protein without signal peptide) have been reported to show onset of liver disease in so-called hepatic ER storage disease (HERSD) [16] or fibrinogen storage disease, being in the same category as genetic deficiency of -1-antitrypsin (A1AT) (G342K, Z-mutation) [17].…”

“…In addition, these cells showed elevated levels of cytoplasmic fibrinogen. Namely, some single In this study, to analyze the variant fibrinogen-producing Chinese hamster ovary (CHO) cells causing HERSD, we established CHO cells synthesizing γ375W, γ375G, or γ375E fibrinogen, and compared the synthesis of fibrinogen and morphological characteristics because the variant fibrinogen, R375W, was found in HERSD patients with heterozygous hypofibrinogenemia [10][11][12][13][14] and fibrinogen Osaka V, R375G, was reported as heterozygous dysfibrinogenemia [20]. Immunofluorescence using anti-fibrinogen antibody showed that only 375W, not γ375G or γ375E fibrinogen-synthesizing CHO cells, formed cytoplasmic inclusion bodies.…”