Bartlett, Mark G.; Erickson, Nissa I.
Division of Pediatric Gastroenterology, University of Minnesota, Minneapolis, MN.
Address correspondence and reprint requests to Mark G. Bartlett, MD, Division of Pediatric Gastroenterology, University of Minnesota, 6th Floor, East Building, 2450 Riverside Ave, Minneapolis, MN 55454 (e-mail: Bartl204@umn.edu).
Received 19 January, 2011
Accepted 14 July, 2011
The authors report no conflicts of interest.
A 6-year-old boy presented to the emergency department with increasing fatigue and abdominal distention that had worsened over several weeks. Numerous visits to immediate care clinics had resulted in various diagnoses such as pharyngitis, otitis, and viral syndrome. He was previously healthy, but was learning disabled. He had been incorrectly labeled as autistic by a chiropractor, who recommended vitamins and a caffeinated energy drink that was purported to improve concentration and academic performance.
On examination he was afebrile but appeared fatigued. Positive findings included abdominal distention and hepatosplenomegaly. An abdominal ultrasound confirmed an enlarged liver and spleen, and he underwent the following liver tests: alanine aminotransferase (ALT) 275 U/L, aspartate aminotransferase (AST) 707 U/L, γ-glutamyl transferase 155 U/L, and total bilirubin 1.2 mg/dL. Albumin was low at 2.7 g/dL. He was transferred to our center for further evaluation and management.
Additional laboratory reports included immunoglobulin G of 1600 mg/dL, anti-nuclear antibody positive, and anti-smooth muscle antibody elevated at 45 U. His hemoglobin was low at 10 g/dL but he had no hemolysis. Ceruloplasmin was normal at 24 mg/dL, and urine copper was mildly elevated at 212 μg/d. A penicillamine challenge test raised the 24-hour urine copper to 1600 μg/d. Liver biopsy demonstrated extensive fibrosis, and special staining with rhodamine was positive for copper (Fig. 1, which includes 4 stains: H and E, trichrome, reticulin, and rhodamine). A careful history for copper exposure was taken and found to be unremarkable, so his dry copper weight of 1400 μg/g of liver tissue was considered diagnostic for Wilson disease (WD). He was started on chelation therapy with trientene and zinc. Within 1 week he developed acute liver failure with bilirubin rising to 50 mg/dL and international normalized ratio rising to 6. He received a liver transplant within 72 hours from listing and has done well postoperatively.
The patient's 3 siblings were screened for WD with ceruloplasmin and 24-hour urine copper. His fraternal twin brother had mild elevation of ALT and AST, normal ceruloplasmin, and elevated 24-hour urine copper, so he underwent liver biopsy. He also had abundant copper staining and a dry copper weight of 3020 μg/g of liver tissue. His liver biopsy was negative for fibrosis or inflammation (Fig. 2, which includes 4 stains: H and E, trichrome, reticulin, and rhodamine). He has responded to chelation with penicillamine and remained stable for 12 months.
Genetic testing was obtained on the index case with sequencing of the entire ATP7B gene. There were no mutations found in the region known to code for Wilson disease. A heterozygous sequence change c.2002A>G (p.M668V) was found in a region of the gene not known to code for a functional domain (1,2).
On further questioning, the mother acknowledged feeding both of her boys 8 servings per day of AdvoCare Spark energy drink over the preceding 8 months mixed with chocolate milk along with 2 daily Flintstones brand multivitamins. The estimated copper intake from these 3 sources was significantly above the 440 μg recommended daily dose for copper for children this age (3).
DISCUSSION AND CONCLUSIONS
After genetic testing failed to show a known Wilson mutation and the dietary history was better elucidated, we consider these cases to be an Indian childhood cirrhosis—like injury from copper overload (4–6). The heterozygous sequence change in the ATP7B gene is not previously described as being associated with WD. Perhaps it could be responsible for this child's increased vulnerability to copper overload.
The liver failure in the index case even at a lower copper load (half that of his twin) could also be because of concurrent injury from underlying liver disease (eg, autoimmune hepatitis), or perhaps a second basic defect of copper metabolism that has yet to be found in this patient (7). The graph Figure 3 helps demonstrate the variation in how much copper humans can tolerate. Above a certain level, Copper is toxic for all humans; however, some have a lower threshold for developing liver damage when exposed to copper. Others, such as those with WD, are vulnerable even at the recommended daily allowance (RDA) for copper.
The sources of copper in these 6-year-old twins’ diet in addition to any obtained through meals were as follows: Spark energy drink 200 μg/8 oz (1600 μg in the daily amount consumed), chocolate milk 436 μg/8 oz (3488 μg in the daily amount consumed), and Flinstones vitamins 2000 μg/tablet (4000 μg/d in the amount consumed). These boys were therefore each consuming a total of 9088 μg/d of copper, approximately 21 times the RDA for their age.
This case illustrates the risk of unchecked use of vitamin supplements in children. Although the amount of copper in Flintstones vitamins (9) is advertised as 100% of RDA in a single tablet, this is actually twice the adult RDA of 1000 μg and is >4 times the RDA for a 6-year-old. The AdvoCare (10) Spark energy drink has 22% of the adult RDA for copper, but this is 45% of a 6-year-old's RDA (11). The directions are to mix with the “beverage of your choice” 1 to 3 times daily and to consult a health care professional before using in children. This family was vulnerable because they had no consistent medical caregiver, were suspicious of allopathic medicine (ie, had foregone vaccinations and well-child examinations), and had trusted the counsel of a chiropracter who they believed provided more natural therapies. Although the diagnosis of autism was later proven to be incorrect in this case, the fear of this diagnosis led the parents to resort to untested therapies recommended by a provider unschooled in their dangers.
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. Accessed April 21, 2011.
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. Accessed October 26, 2012.
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. Accessed October 26, 2012.