Hepatic fibrinogen storage disease and hypofibrinogenemia caused by fibrinogen Aguadilla mutation: a case report

Abstract

Hepatic fibrinogen storage disease is a rare autosomal dominant genetic disorder characterized by hypofibrinogenemia, as well as the retention of variant fibrinogen within the hepatocellular endoplasmic reticulum. Here, we describe an asymptomatic 4-year-old boy with abnormal liver function test results and unexpected hypofibrinogenemia. Liver biopsy showed circular eosinophil inclusion bodies in the hepato-cytoplasm. Immunostaining results of eosinophil inclusion bodies were positive for fibrinogen. Following pretreatment with diastase, the inclusion bodies failed to stain with the periodic acid–Schiff technique; moreover, immunostaining results were positive for fibrinogen, but negative for alpha-1-antitrypsin. Genetic analysis identified a heterozygous missense mutation c.1201C > T (p. Arg401Trp) within the fibrinogen γ-chain ( FGG) gene and an additional single nucleotide polymorphism c.-58 A > G within the 5′-untranslated region of the fibrinogen Aα-chain ( FGA) gene. Thus, the patient was diagnosed with hepatic fibrinogen storage disease. Our results indicate that, for patients who exhibit chronic liver disease with unexpected hypofibrinogenemia, hepatic fibrinogen storage disease should be considered in the differential diagnosis. Moreover, our findings emphasize the importance of molecular diagnosis in patients with cryptogenic liver disease.

Protein Aggregation in the ER: Calm behind the Storm

“…HFSD is characterized by the ER retention and aggregation of mutant and wild type fibrinogens, leading to liver damage, hypofibrinogenemia, and excessive bleeding [ 174 , 227 , 228 ]. Fibrinogen, secreted by hepatocytes, is essential for hemostasis, blood clotting, wound healing, inflammation, angiogenesis, and many other processes [ 229 , 230 , 231 ].…”

Hereditary Hypofibrinogenemia with Hepatic Storage

“…To date, only 21 index cases characterized at the molecular level, all with a diagnosis of HHHS based on immunohistochemistry and electron microscopy findings, have been described in the English literature. Table 1 lists their main clinical features [ 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

Hypertransaminasemia and liver fibrosis associated with haptoglobin retention and anhaptoglobinemia in a paediatric patient

“…13,15 In contrast, in FSD-patients lack of fibrinogen is not known to cause severe bleeding tendency and does not affect patients in their daily lives. 16 Population data show that the variant was detected with an allele frequency of 0.0001282, making it very rare among the studied population. Since our patient is, according to gnomAD data, the first described individual with a homozygous presentation of the mutation, the condition is likely extremely rare.…”

“…Most affected individuals develop pulmonary emphysema 13,15 . In contrast, in FSD‐patients lack of fibrinogen is not known to cause severe bleeding tendency and does not affect patients in their daily lives 16 . However, affected persons develop liver‐disease of varying severity, ranging from unaffected mutation carriers to severe cirrhosis 12 because of accumulation of misfolded protein.…”