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Fibrinogen Storage Disease Caused by Aguadilla Mutation Presenting With Hypobeta‐lipoproteinemia and Considerable Liver Disease

2009; Lippincott Williams & Wilkins; Volume: 49; Issue: 1 Linguagem: Inglês

10.1097/mpg.0b013e31817ed7ea

1536-4801

Tsuyoshi Sogo, Hironori Nagasaka, Haruki Komatsu, Ayano Inui, Takashi Miida, Francesco Callea, Paola Francalanci, Ken‐ichi Hirano, Hajime Kitamura, Toru Yorifuji, Tomoo Fujisawa,

Hemoglobinopathies and Related Disorders

Fibrinogen storage disease (FSD), a form of hepatic endoplasmic reticulum (ER) storage disease, is characterized by the retention of fibrinogen in the hepatic ER. The number of patients with diagnoses of FSD has been increasing in Europe and in the Unites States but not in Asian countries, including Japan (1–8). Certain mutations in the fibrinogen γ-chain gene have been confirmed in European and US patients, but no such genetic abnormalities have been identified in most Asian and Japanese patients (3,5,6,8). We report here a case of FSD presenting as hypobeta-lipoproteinemia along with substantial liver damage in a young Japanese boy. To our knowledge this is the first such case to be reported. We also discuss the possible contribution of FSD to hypobeta-lipoproteinemia. CASE REPORT A 2-year-old Japanese boy was born to healthy parents with no consanguinity at 38 gestational weeks, weighing 3332 g. There was no family history of liver or hematologic diseases. At age 2 months, the boy was taken to a local hospital because of bloody stool and was found to have mild liver dysfunction, hypocholesterolemia, and hypofibrinogenemia. Thereafter, the bloody stool remitted but the mild liver dysfunction, hypocholesterolemia, and hypofibrinogenemia continued. At age 2, the patient was referred to our hospital for evaluation of liver dysfunction and accompanying hypocholesterolemia and hypofibrinogenemia. The liver was palpable at 4 cm below the right costal margin; the spleen was not palpable. Abdominal ultrasonography showed mild hepatomegaly. Laboratory tests revealed hypocholesterolemia (total cholesterol, 76 mg/dL [normal range for children 2–5 years old 107–190 mg/dL]) and elevated aspartate aminotransferase (190 IU/L), alanine aminotransferase (200 IU/L), and γ-glutamyl transpeptidase (72 IU/L). High levels of serum ceruloplasmin (99.0 mg/dL [normal range, 20–50 mg/dL]) and α-1 antitrypsin (185 mg/dL [normal range 94–150 mg/dL]) were seen with a PiMM phenotype. Hematologic tests revealed profound hypofibrinogenemia (fibrinogen 37.6 mg/dL [normal range 150–400 mg/dL]) and mildly impaired coagulation (prothrombin time 61.1% [normal range 70–140%], activated partial thromboplastin time, 32 seconds [normal range 25–35 s], and hepaplastin test 66.7% [normal range >70%]). However, markers of liver protein synthesis, including total protein (7.0 g/dL), albumin (4.0 g/dL), and choline esterase (385 IU/L), were within normal range. Serological markers of known hepatotrophic viruses (hepatitis A, B, and C, the group of herpesviruses, and adenovirus) and diagnostic markers of autoimmune liver disease (various autoimmune antibodies) were negative. Analyses of amino acids and organic acids revealed no findings suggestive of a diagnosis. Lipid and lipoprotein analysis showed that serum levels of total cholesterol, low-density lipoprotein (LDL) and apolipoprotein B (apo B), a major apolipoprotein on LDL, were extremely low (LDL cholesterol 32 mg/dL [age-matched normal range 68–115 mg/dL] and apo B 32 mg/dL [age-matched normal range 56–105 mg/dL]), whereas those of other lipids and apolipoproteins, including high-density lipoprotein (HDL)-cholesterol, triglycerides, and apolipoprotein A-I (apo A-I), were normal (HDL-cholesterol 40 mg/dL [normal range 35–80 mg/dL], triglycerides 46 mg/dL [normal range 35–135 mg/dL], apo A-I 115 mg/dL [normal range 110–159 mg/dL]). Agarose-gel electrophoresis displayed a weak beta band (data not shown). These findings were consistent with those of hypobeta-lipoproteinemia. Mutations in the microsome transfer protein gene and the apo B gene have been known as causes of hypobeta-lipoproteinemia and abeta-lipoproteinemia (9–11); however, gene analyses covering all exons and exon-intron boundaries following previously described procedures (12,13) showed no such mutations in this patient. Histological examination of a percutaneous liver biopsy specimen showed moderate to severe portal fibrosis with mild inflammation. The lobular architecture was partially collapsed, with thin fibrous septa linking portal tracts to central veins (Fig. 1A). Hepatocytes contained multiple, irregularly rounded, deeply eosinophilic globules (Fig. 1B) that failed to stain with periodic acid-Schiff. Intracytoplasmic material in the hepatocytes reacted strongly with antifibrinogen antisera (Fig. 1C). Electron microscopy of the liver showed that the dilated rough ER with the lumen was engorged with densely packed tubular structures arranged in curved bundles, similar to a fingerprint pattern (Fig. 1D). These findings were compatible with FSD type I. The diagnosis was confirmed by gene analysis, which revealed the Aguadilla mutation (Arg375Trp) in the fibrinogen γ-chain, described as one of the most common mutations among patients with FSD (3,6,8) (Fig. 2).FIG. 1: Liver histology of patient. A, Fibrous septa linking the portal tract to central vein (Azan stain, original magnification ×200). B, Hepatocytes contain multiple, irregularly rounded, deeply eosinophilic globules, which fail to stain with periodic acid-Schiff (hematoxylin and eosin, original magnification ×1000). C, Intracytoplasmic material of hepatocytes reacts strongly with antifibrinogen antisera (immunoperoxidase staining with fibrinogen antibody, original magnification ×1000). D, Electron microscopy shows dilated rough endoplasmic reticulum including densely packed tubular structures, presenting a fingerprint pattern (uranyl acetate and lead citrate stain, original magnification ×23,000).FIG. 2: DNA sequence from exon 9 of the fibrinogen γ-chain gene. DNA analysis shows heterozygous CGG→TGG mutation (arrow) at codon 375 of the γ-chain gene in this patient and his father.Familial analyses for the fibrinogen γ-chain gene revealed that the patient's father also had the Aguadilla mutation, and his mother and younger sister did not. In addition, his father was found to have hypofibrinogenemia (93.3 mg/dL), suggesting an autosomal dominant mode of inheritance. The father's total cholesterol and LDL-cholesterol levels 3 to 4 hours after breakfast were near the lower limits of the normal ranges (total cholesterol 169 mg/dL [age-matched normal range 168–227 mg/dL] and LDL-cholesterol 78 mg/dL [age-matched normal range 75–138 mg/dL]), but HDL-cholesterol and triglycerides were normal (HDL-cholesterol 71 mg/dL, triglycerides 105 mg/dL). The mother did not show hypobeta-lipoproteinemia (total cholesterol 210 mg/dL, LDL-cholesterol 119 mg/dL, apo B 104 mg/dL, HDL-cholesterol 67 mg/dL). These results implied a similar lipoprotein metabolism in the father and patient. Unlike his son, however, the father showed normal levels of aspartate aminotransferase and alanine aminotransferase. The patient had shown normal growth and development until this writing. DISCUSSION To our knowledge, this is the first report of a Japanese pedigree with the fibrinogen gamma Arg375Trp mutation (fibrinogen Aguadilla). In α-1 antitrypsin deficiency, one of the hepatic ER storage diseases, the gene frequency for the Z-type is high in whites (14) but rare in Asians. It is possible that the gene mutation for FSD may differ between whites and Asians as well. To date, there have been no reports in the literature describing Asian patients with the fibrinogen γ-chain Aguadilla mutation (Arg375Trp). Although advanced liver disease in adults with FSD type I caused by the Brescia mutation (Gly284Arg) and Aguadilla mutation (Arg375Trp) in the fibrinogen γ-chain gene have been described (3,6), we are unaware of any children with FSD type I who experienced considerable liver damage. However, Francalanci et al (8) recently described a patient with FSD with de novo Aguadilla mutation who experienced moderate to severe liver disease from early childhood. It has been suggested that the clinical picture of FSD differs in individuals but is not affected by the gene mutation (6). This hypothesis is supported by our observation that our patient with the Aguadilla mutation showed considerable liver damage from early life, whereas his father with same mutation showed normal liver function. The susceptibility of each patient with FSD to liver disease may be determined by several factors, including an abnormality in the ER degradation pathway and α1-antitrypsin deficiency, which causes storage of abnormal α1-antitrypsin in the hepatic ER and takes a diverse clinical course. Because the clinical manifestations of FSD, liver dysfunction, and hypofibrinogenemia without otherwise severe coagulopathy are known (1–8), it is unexpected to find hypobeta-lipoproteinemia in a patient with FSD. To our best knowledge, no previous reports have described dyslipidemia associated with FSD. In this case, hypobeta-lipoproteinemia cannot be explained as a consequence of liver damage. Abnormal lipoprotein profiles are often detected in liver diseases, and they show a wide diversity depending on the underlying disease or severity (15–17). In general, severe liver damage leading to profound impairment in liver synthetic function is associated with hypocholesterolemia together with hypobeta-lipoproteinemia, and it is always accompanied by hypoalpha-lipoproteinemia. Compared to patients with liver disease who have hypocholesterolemia, the liver damage in our patient was mild, and the hypobeta-lipoproteinemia was not accompanied by hypoalpha-lipoproteinemia. In the present case, hypobeta-lipoproteinemia cannot be explained by the mutations in the microsome transfer protein and apo B genes that are known to account for most congenital hypobeta-lipoproteinemia, because our patient lacked such mutations (9–11). In addition, unlike hypobeta- or abeta-lipoproteinemia caused by mutations in the microsome transfer protein and apoB genes, the patient never showed the clinical presentations associated with these mutations, such as impaired intestinal fat absorption, retinitis pigmentosa, or acanthocytosis (9–11). Xia and Redman reported that cholesterol production and apo B secretion in HepG2 cells were increased by the promotion of fibrinogen gene expression (18,19). The results of frequent lipoprotein analyses after the diagnosis of FSD in our patient showed that serum total cholesterol levels were positively correlated with plasma fibrinogen levels (Spearman correlation test, n = 6, rs = 0.9429, P = 0.0048; detailed data not shown). Moreover, the patient's father with FSD due to the same mutation also presented with mild hypobeta-lipoproteinemia. Together, these findings suggest a close relation between hypobeta-lipoproteinemia and FSD. In addition to hypofibrinogenemia, the patient showed high serum levels of ceruloplasmin and α-1 antitrypsin, which are secreted from the hepatic ER, as is fibrinogen, suggesting diverse abnormalities in the functions of the hepatic ER (20). In this context, it is plausible that impairment in the process of assembly of apo B and lipids within the hepatic ER (20), or in their subsequent secretion, may contribute to the hypobeta-lipoproteinemia. A 2-year-old Japanese boy is reported having as the first case, to our knowledge, of FSD with hypobeta-lipoproteinemia. Further investigation is required to understand the detailed clinical picture of FSD, including dyslipidemia.