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Wilson Disease: Never Too Late . . .

      To the Editor:
      A 43-year-old man presented with a 4-month history of abdominal bloating, loss of appetite and 5 kg weight loss. He was previously fit and well, with no history of alcohol or drug ingestion, and no prior blood transfusion. Clinical examination revealed pigmentation around the cornea of both eyes, consistent with Kayser-Fleischer (KF) rings (Figure A), but there were no other clinical features of chronic liver disease. On abdominal examination there was no organomegaly. He had no neurological deficits.
      Figure
      Figure(A) Kayser-Fleischer ring within right cornea. (B) Copper deposition in Descemet membrane on ocular slit lamp examination. (C) Liver biopsy (hemolysin and eosin [H&E] stain; magnification × 40) showing cirrhotic changes with fatty metamorphosis, ballooning degeneration, acidophilic body (arrow), neutrophilic infiltrate and focal cholestasis. (D) Marked peri-portal deposition of copper (red granules, arrow; magnification × 40; Rhodanine stain).
      Ultrasound and computed tomography (CT) scans of the abdomen demonstrated a shrunken liver with features of cirrhosis, portal hypertension, minimal ascites, and splenomegaly. Initial laboratory results were unremarkable, with normal full blood count, electrolytes and renal function, liver function, and prothrombin time. Serum ferritin, alpha-fetoprotein, viral serology, and an autoimmune liver screen were also unremarkable.
      Further laboratory evaluation showed a low serum ceruloplasmin level (<9.3 mg/dL; reference range [RR] 20-60), low serum copper (23.66 µg/dL; RR 70-140), and elevated 24-h urinary copper excretion (88 µg/d; RR 3-50). An ocular slit-lamp examination confirmed the presence of copper deposition in Descemet membrane (Figure B). A liver biopsy was performed, which revealed fibrosis (Figure C) with copper deposition (Figure D), confirming the diagnosis of Wilson disease. Magnetic resonance imaging of the brain was unremarkable. Genetic analysis of the ATP7B gene identified a known pathogenic homozygous missense variant in exon 13, c.3053c>T (p.Ala1018Val) and another homozygous missense variant of uncertain significance in exon 6, c.1883A>G (p.His628Arg). The patient was treated with 1000 mg/d of copper chelating therapy with penicillamine and zinc, with subsequent marked clinical improvement (including complete resolution of ascites) over the next months.
      Wilson disease is an autosomal recessive disorder of copper metabolism due to loss-of-function-mutations in the ATP7B gene that encodes a transmembrane copper-transporting ATPase, thereby resulting in defective copper excretion, and accumulation in the liver, brain, and other organs.
      • Członkowska A
      • Litwin T
      • Dusek P
      • et al.
      Wilson disease.
      ,
      • Bandmann O
      • Weiss KH
      • Kaler SG.
      Wilson's disease and other neurological copper disorders.
      A younger age at presentation is typical of Wilson disease,
      • Bandmann O
      • Weiss KH
      • Kaler SG.
      Wilson's disease and other neurological copper disorders.
      with large studies (1,223 subjects) reporting that only 3.8% of people are diagnosed at >40 years of age, as occurred here.
      • Ferenci P
      • Członkowska A
      • Merle U
      • et al.
      Late-onset Wilson's disease.
      Interestingly, our patient exhibited no clinical or radiological features of central nervous system involvement. KF rings are reported in 50% of individuals with hepatic manifestations of Wilson disease, as observed in this case.
      European Association for Study of Liver (EASL)
      EASL Clinical Practice Guidelines: Wilson's disease.
      However the absence of a KF ring does not exclude the diagnosis of Wilson disease.
      • Bandmann O
      • Weiss KH
      • Kaler SG.
      Wilson's disease and other neurological copper disorders.
      The prognosis for treated Wilson disease is excellent, including in those with more advanced liver disease and, hence, the importance of considering the diagnosis even in older patients.
      • Członkowska A
      • Litwin T
      • Dusek P
      • et al.
      Wilson disease.
      The finding of more than 1 mutation in ATP7B is also consistent with a study, which had highlighted the importance of comprehensive gene analyses in suspected cases.
      • Coffey AJ
      • Durkie M
      • Hague S
      • et al.
      A genetic study of Wilson's disease in the United Kingdom.

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        Wilson's disease and other neurological copper disorders.
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        Late-onset Wilson's disease.
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        • et al.
        A genetic study of Wilson's disease in the United Kingdom.
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