Hereditary hypofibrinogenemia with fibrinogen storage in the liver

Abstract

A family with hereditary autosomal dominant hypofibrinogenemia is described. The outstanding feature is massive deposition of fibrinogen/fibrin within hepatocytes, faintly visible in routine microscopic sections, but clearly demonstrable by immunohistologic techniques. Circulating fibrinogen shows normal electrophoretic mobility of A alpha-, B beta-, and gamma-chains. We assume that the hereditary defect in this family interferes with fibrinogen release from hepatocytes. Clinically there are fluctuating slight elevations of serum transaminase levels. Hemostasis and wound healing are undisturbed.

Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins

“…As a potential example among hemostatic proteins, fibrinogen has the polypeptide composition (␣␤␥) 2 , and autosomal dominant forms of hypofibrinogenemia could include additional instances of this mechanism, particularly among patients with missense mutations that impair subunit synthesis 38,39 or cause intracellular fibrinogen to accumulate. 39,40 The same mechanism might enable heterozygous collagen mutations to reduce the secretion of triple-helical collagen, thereby contributing to the pathophysiology associated with missense mutations in collagen ␣ 1(I) or collagen ␣ 1(II), which cause dominant osteogenesis imperfecta 41 or hypochondrogenesis, 42 respectively. As in the case of VWF, testing this mechanism for other proteins will require methods to distinguish mutant and normal subunits so that their intracellular association can be detected.…”

Fibrinogen storage disease without hypofibrinogenaemia associated with acute infection

“…Type I inclusions are mostly encountered in cases of familiar fibrinogen storage disease. In the cases reported concerning German families 2,3 and a family from Brescia, 5 fibrinogen accumulates due to its altered molecular structure. This retention is permanent and involves mainly the rough endoplasmic reticulum.…”

“…The most common example of the latter condition is α 1 ‐antitrypsin deficiency 1 . Recently, congenital retention of fibrinogen has been described 1–5 . In these patients fibrinogen retained by hepatocytes was present histologically as eosinophilic cytoplasmic inclusions, which gave the appearance of ground glass hepatocytes.…”

Molecular Genetics of Quantitative Fibrinogen Disorders

“…Although fibrinogen deficiencies are considered only as coagulation disorders, some hypofibrinogenemic patients suffer from chronic hepatitis/cirrhosis due to intra-hepatic fibrinogen storage [19,[29][30][31][32]. Moreover, mutations affecting a small portion of the C-terminal region of the A chain have been described as the cause of renal amyloidosis (MIM+134820).…”