Copper Overload in 6‐year‐old Twins

Abstract

6-year-old boy presented to the emergency departmentwith increasing fatigue and abdominal distention that hadworsened over several weeks. Numerous visits to immediate careclinics had resulted in various diagnoses such as pharyngitis, otitis,and viral syndrome. He was previously healthy, but was learningdisabled. He had been incorrectly labeled as autistic by a chiro-practor,whorecommendedvitaminsandacaffeinatedenergydrinkthat was purported to improve concentration and academic per-formance.On examination he was afebrile but appeared fatigued.Positive findings included abdominal distention and hepatospleno-megaly. An abdominal ultrasound confirmed an enlarged liver andspleen, and he underwent the following liver tests: alanine amino-transferase (ALT) 275 U/L, aspartate aminotransferase (AST)707 U/L, g-glutamyl transferase 155 U/L, and total bilirubin1.2 mg/dL. Albumin was low at 2.7 g/dL. He was transferred toour center for further evaluation and management.AdditionallaboratoryreportsincludedimmunoglobulinGof1600 mg/dL, anti-nuclear antibody positive, and anti-smoothmuscle antibody elevated at 45 U. His hemoglobin was low at10 g/dL but he had no hemolysis. Ceruloplasmin was normal at24 mg/dL, and urine copper was mildly elevated at 212 mg/d.A penicillamine challenge test raised the 24-hour urine copper to1600 mg/d. Liver biopsy demonstrated extensive fibrosis, andspecial staining with rhodamine was positive for copper (Fig. 1,which includes 4 stains: H and E, trichrome, reticulin, andrhodamine). A careful history for copper exposure was taken andfoundtobeunremarkable,sohisdrycopperweightof1400mg/gofliver tissue was considered diagnostic for Wilson disease (WD).He was started on chelation therapy with trientene and zinc. Within1 week he developed acute liver failure with bilirubin rising to50mg/dLandinternationalnormalizedratiorisingto6.Hereceiveda liver transplant within 72 hours from listing and has done wellpostoperatively.The patient’s 3 siblings were screened for WD with cerulo-plasmin and 24-hour urine copper. His fraternal twin brother hadmild elevation of ALT and AST, normal ceruloplasmin, andelevated 24-hour urine copper, so he underwent liver biopsy. Healso had abundant copper staining and a dry copper weight of3020 mg/g of liver tissue. His liver biopsy was negative for fibrosisor inflammation (Fig. 2, which includes 4 stains: H and E,trichrome,reticulin,andrhodamine).Hehasrespondedtochelationwith penicillamine and remained stable for 12 months.Genetic testing was obtained on the index case with sequen-cing of the entire ATP7B gene. There were no mutations found inthe region known to code for Wilson disease. A heterozygoussequence change c.2002A>G (p.M668V) was found in a regionof the gene not known to code for a functional domain (1,2).On further questioning, the mother acknowledged feedingboth of her boys 8 servings per day of AdvoCare Spark energydrink over the preceding 8 months mixed with chocolate milkalong with2 dailyFlintstones brand multivitamins. The estimatedcopper intake from these 3 sources was significantly above the440 mg recommended daily dose for copper for children thisage (3).