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Long‐term Outcome of Liver Disease–related Fibrinogen Aguadilla Storage Disease in a Child

2011; Lippincott Williams & Wilkins; Volume: 53; Issue: 6 Linguagem: Inglês

10.1097/mpg.0b013e318232c477

1536-4801

Giuseppe Maggiore, Silvia Nastasio, Marco Sciveres,

Iron Metabolism and Disorders

To the Editor: Sogo et al (1) reported in this journal a case of aguadilla hepatic fibrinogen storage disease (HFSD) with considerable liver disease. Severe liver disease with early liver fibrosis was also present at diagnosis in a child with HFSD presenting with persisting abnormalities of liver enzymes, described by us in 2006 (2). HFSD, in fact, results in a wide range of liver injuries, from mild liver damage to severe hepatic fibrosis in children (3) and leads to decompensated cirrhosis in adults (4). No follow-up data on natural history for these patients or suggestions for any possible treatment of this disorder are available. HFSD belongs to the endoplasmic reticulum storage diseases, a group of inborn errors of metabolism affecting secretory proteins and resulting in hepatocytic storage and plasma deficiency of the corresponding protein (5). Hepatocellular storage is the result of a genetically determined molecular abnormality hindering the translocation of the abnormal protein from the rough to the smooth endoplasmic reticulum. The storage of the mutant protein predisposes to the development of chronic liver damage. Endoplasmic reticulum storage diseases include α1-antitrypsin (AAT) deficiency, one of the most common genetic disorders causing liver disease in childhood. As in HFSD, the Z deficiency allele (PI*Z) of SERPINA1, which encodes the serine protease inhibitor AAP, results in storage of the mutant protein in endoplasmic reticulum and leads to a wide range of liver injuries, from minimal damage to cirrhosis and to end-stage liver disease. The genetic and environmental factors that predispose some individuals with AAT deficiency to liver disease while sparing others are unknown. Similarly, the susceptibility of each patient with HFSD to progression of liver damage may be determined by several factors. Even though a specific therapy is not available for children with AAT deficiency and liver damage, ursodeoxycholic acid has been shown to significantly improve clinical status and liver test results in some children with moderate liver disease (6). Moreover, oxidative free radicals have been suggested to play a role in promoting liver damage in AAT deficiency (7). We thus decided to treat our patient with aguadilla HFSD with ursodeoxycholic acid 20 mg · kg−1 · day−1, and α-tocopherol 14 mg · kg−1 · day−1. When we started this treatment, he was 3 years 11 months old, in good general condition, although with a liver palpable below the costal edge that presented an increased consistency; aspartate aminotransferase (AST) was 3 times the upper limit of normal (N) and alanine aminotransferase (ALT) 4 × N. Treatment was well tolerated without adverse effects. He was reviewed after 12 months: clinical examination was normal, liver was not palpable, and there were no clinical signs of chronic liver disease. Biochemical evaluation showed reduction of aspartate aminotransferase to 1.2 × N and of ALT to 1.6 × N. Treatment was continued and the patient was reviewed after a total of 24 months of treatment. Again, the clinical examination was normal; aspartate aminotransferase and ALT activity and total serum bile acids were normal. After 6 months of treatment, the child underwent yearly follow-up for a total of 89 months, showing normal clinical examination and liver enzymes. At the last clinical examination, at age 11 years 4 months, a liver stiffness measurement using transient elastography showed results (3.7 kPa) compatible with the absence of fibrosis. It is suggestive but difficult to demonstrate that the treatment we proposed has been responsible for this progressive and stable normalization of clinical and biochemical parameters. Possible mechanisms explaining a favorable effect of the treatment may be related to some specific antioxidant effects of the drugs used. An inhibition of endoplasmic reticulum stress secondary to the accumulation of misfolded proteins and apoptotic signaling had been demonstrated for ursodeoxycholic acid in Z AAT deficiency (8). Moreover, in Z AAT deficiency, autophagy, which contributes to macromolecular turnover and rejuvenation of cellular organelles, is specifically activated by the oxidative stress from the accumulation of mutant Z AAT and plays a key role in the intracellular degradation of this mutant protein (9). Autophagy also participates in the degradation of aggregated mutant fibrinogen that accumulates in the endoplasmic reticulum in HFSD (10), and vitamin E has been demonstrated to enhance autophagy in rat hepatocytes (11). An alternative but also interesting option could be that HFSD may spontaneously progress toward normalization of liver damage and reduction of liver fibrosis. Because controlled studies are not feasible in such rare disorders and considering the safety of the above treatment, we suggest that this treatment may be proposed in children with HFSD and evidence of liver damage.