CASE REPORT

Un caz rar de boală de stocaj a fibrinogenului hepatic la un copil – prezentare de caz

 A rare case of pediatric hepatic fibrinogen storage disease – case report

First published: 31 octombrie 2022

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Pedi.67.3.2022.7238

Abstract

Hepatic fibrinogen storage disease is a rare autosomal do­mi­nant genetic disorder characterized by the retention of fibrinogen in the hepatocellular endoplasmic reticulum. We describe the case of an asymptomatic 3-year-old boy with abnormal liver function test results and with unexpected hypofibrinogenemia. Liver biopsy showed normal hepatic lobule structure, with microvesicular steatosis, and the im­mu­no­staining results were positive for fibrinogen, changes consistent with the diagnosis of hepatic fibrinogen storage disease. The genetic analysis was not performed.
 

Keywords
metabolic disease, liver storage disease, child

Rezumat

Boala hepatică de stocare a fibrinogenului este o afecţiune ge­ne­ti­că rară, cu transmitere autozomal dominantă, caracterizată de acumularea de fibrinogen în reticulul endoplasmatic he­pa­to­ce­lu­lar. Prezentăm cazul unui băiat în vârstă de 3 ani, asimp­to­ma­tic, care s-a internat în clinica noastră pentru un sindrom de he­pa­to­ci­to­li­ză moderat şi hipofibrinogenemie. Puncţia-biopsie he­pa­ti­că, cu examen histopatologic din prelevatele biopsice, a evidenţiat ficat cu structură normală a lobulului hepatic, cu steatoză microveziculară, cu teste de imunohistochimie po­zi­ti­ve, modificări care susţin o boală hepatică de stocare a fi­bri­no­ge­nu­lui. Nu s-a efectuat testare genetică.
 

Introduction

In the last decade, a novel subgroup of fibrinogen disorders has emerged, being characterized by fibrinogen g chain gene mutations (FGG), and causing hypofibrinogenemia(1).

Fibrinogen is a high molecular weight plasma protein synthesized exclusively in the liver, playing an important role in hemostatic cascade and fibrinolysis.

Hepatic fibrinogen storage disease is a rare autosomal dominant genetic disorder characterized by hypofibrinogenemia and by the accumulation of fibrinogen in hepatocytes, that induce liver injury with a variable severity(2).

The number of patients with the diagnosis of hepatic fibrinogen storage disease has been increasing in Europe and in the Unites States of America, but not in Asian countries, including Japan.

Case report

We report the case of a 3-year-old boy who was admitted to our hospital for abnormal liver function during the hospitalization for acute pneumonia. The familial medical history was unremarkable. The patient’s personal medical history showed no particular previous medical history. The physical examination revealed relatively good general condition, underweight (BMI=13.5 kg/m2, wasting, growth for age Z score = -2 DS), with no fever, without jaundice, with pale teguments, cardiovascular and respiratory balanced, with capricious appetite, normal stools; his liver was palpable 2 cm below the right costal margin, without splenomegaly. The laboratory investigations revealed a normal complete blood count, without inflammatory syndrome, with elevated serum alanine aminotransferase (141 U/L) and aspartate aminotransferase (243 U/L). Other biochemical tests (total bilirubin, g glutamyl-transpeptidase, albumin, ammonia) were within the normal ranges. Viral hepatitis screens (HAV IgM, HBs Ag, HCV IgG, Epstein-Barr virus, cytomegalovirus) were all negative. The levels of immunoglobulins IgG, IgA, IgM and ceruloplasmin were normal. The diagnostic markers of autoimmune liver disease (the serum anti-smooth muscle antibody [SMA], serum anti-nuclear antibody [ANA] and anti-liver kidney microsomal antibody [LKM-1]) were negative. Extensive laboratory evaluations excluded metabolic and endocrine diseases (normal plasma amino acids, normal glucoce­re­bro­sidase enzyme activity, and normal levels of thyroid hormones). The serum a-1-antitrypsin level was normal (125 mg/dL). The abdominal ultrasonography revealed mild hepatomegaly, without splenomegaly or ascites. The coagulation tests showed abnormal results: prothrombin time (14 seconds), moderate hypofibrinogenemia (47.4 mg/dl) and elevated D-dimer level. The patient underwent liver biopsy, following by the administration of Haemocomplettan® 1 g for two days.

The histopathological exam revealed normal hepatic lobule structure, with microvesicular steatosis, and the immunostaining results were positive for fibrinogen. A genetic analysis was not performed.

Familial analyses for fibrinogen for his father, his mother and his younger sister were recommended.

Discussion

Congenital fibrinogen disorders are a heterogenous group of rare inherited abnormalities of blood coagulation and can be classified as type I and type II disorders. Quantitative deficiencies include afibrinogenemia and severe hypofibrinogenemia, whereas qualitative deficiencies comprise dysfibrinogenemia and hypodysfibrinogenemia. According to the European Network of Rare Bleeding Disorders, quantitative fibrinogen deficiency may be classified into mild hypofibrinogenemia (fibrinogen level below 1 g/L), moderate hypofibrinoge­nemia (fibrinogen level between 0.5 and 0.9 g/L), severe hypofibrinogenemia (fibrinogen level between 0.1 and 0.5 g/L), and afibrinogenemia (fibrinogen level below 0.1 g/L)(3). The prevalence of hepatic fibrinogen storage disease in unknown. The storage of fibrinogen in liver cells at light microscopy and electron microscopy levels was first observed in German families. The fibrinogen g chain gene mutations (FGG) is responsible for the inclusion of fibrinogen in the liver and for hypofibrinogenemia. The second mutation, fibrinogen Aguadilla (g375ArgTrp), has subsequently been found in additional cases reported from Switzerland, Japan and Italy(4,5). The afflicted patients may be asymptomatic, have moderate to severe hepatitis, or may have liver cirrhosis. The reported treatments include ursodeoxycholic acid, vitamin E and carbamazepine, which provide a potential autophagy-enhancing therapy based on the understanding of disease mechanism(6).

Conclusions

Hepatic fibrinogen storage disease is a rare genetic metabolic disease and manifests clinically as abnormal liver function with hypofibrinogenemia. We described a patient with hepatic fibrinogen storage disease characterized by classical pathological changes(7). However, the diagnosis of hepatic fibrinogen storage disease cannot be completely ruled out if the relevant mutations are not detected.  

 

Conflict of interests: The authors declare no con­flict of interests.

Bibliografie

  1. Pfeifer U, Ormanns W, Klinge O. Hepatocellular fibrinogen storage in familial hypo­fibrinogenemia. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;36(2-3):247-255.

  2. Wehinger H, Klinge O, Alexandrakis E, et al. Hereditary hypofibrinogenemia with fibrinogen storage in the liver. Eur J Pediatr. 1983;141:109–112.

  3. Casini A, Undas A, Palla R, Thachil J, de Moerloose P; Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(9):1887-1890.

  4. Simurda T, Brunclikova M, Asselta R, et al. Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype. Int J Mol Sci. 2020;21(13):4616.

  5. Medicina D, Fabbretti G, Brennan SO, et al. Genetic and immunological characterization of fibrinogen inclusion bodies in patients with hepatic fibrinogen storage and liver disease. Ann N Y Acad Sci. 2001;936:522–525.

  6. Puls F, Goldschmidt I, Bantel H, et al. Autophagy-enhancing drug carbama­ze­pine diminishes hepatocellular death in fibrinogen storage disease. J Hepatol. 2013;59(3):626-630.

  7. Lee MJ, Venick R, Bhuta S, Li X, Wang HL. Hepatic Fibrinogen Storage Disease in a Patient with Hypofibrinogenemia: Report of a Case with a Missense Mutation of the FGA Gene. Semin Liver Dis. 2015;35(4):439-443. 

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