5-year-old boy • behavioral issues • elevated ALT and AST levels • Dx?

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Case Reports

5-year-old boy • behavioral issues • elevated ALT and AST levels • Dx?

J Fam Pract. 2020 March;69(2):97-100

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References

1. Wu F, Wang J, Pu C, et al. Wilson’s disease: a comprehensive review of the molecular mechanisms. Int J Mol Sci. 2015;16:6419-6431.

2. Merle U, Stremmel W, Gessner R. Influence of homozygosity for methionine at codon 129 of the human prion gene on the onset of neurological and hepatic symptoms in Wilson disease. Arch Neurol. 2006;63:982-985.

3. Compston A. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver, by S. A. Kinnier Wilson, (From the National Hospital, and the Laboratory of the National Hospital, Queen Square, London) Brain 1912: 34; 295-509. Brain. 2009;132(pt 8):1997-2001.

4. Thomas R, Sanders S, Doust J, et al. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135:e994-e1001.

5. Kang K. Abnormality on liver function test. Pediatr Gastroenterol Hepatol Nutr. 2013;16:225-232.

6. Lorincz M. Neurologic Wilson’s disease. Ann NY Acad Sci. 2010;1184:173-187.

7. Dening TR, Berrios GE, Walshe JM. Wilson’s disease and epilepsy. Brain. 1988;111(pt 5):1139-1155.

8. Socha P, Janczyk W, Dhawan A, et al. Wilson’s disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutrit. 2018;66:334-344.

9. Bull PC, Thomas GR, Rommens JM, et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5:327-337.

10. Ala A, Schilsky ML. Wilson disease: pathophysiology, diagnosis, treatment and screening. Clin Liver Dis. 2004;8:787-805, viii.

11. Thomas GR, Forbes JR, Roberts EA, et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995;9:210-217.

12. Pfeiffer RF. Wilson’s disease. Semin Neurol. 2007;27:123-132.

13. Das SK, Ray K. Wilson’s disease: an update. Nat Clin Pract Neurol. 2006;2:482-493.

14. Morgan HG, Stewart WK, Lowe KG, et al. Wilson’s disease and the Fanconi syndrome. Q J Med. 1962;31:361-384.

15. Wiebers DO, Hollenhorst RW, Goldstein NP. The ophthalmologic manifestations of Wilson’s disease. Mayo Clin Proc. 1977;52:409-416.

16. Jackson GH, Meyer A, Lippmann S. Wilson’s disease: psychiatric manifestations may be the clinical presentation. Postgrad Med. 1994;95:135-138.

17. O’Conner JA, Sokol RJ. Copper metabolism and copper storage disorders. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press; 2007:626-660.

18. Dening TR, Berrios GE. Wilson’s disease: a longitudinal study of psychiatric symptoms. Biol Psychiatry. 1990;28:255-265.

Hepatic and neurocognitive effects. Excess copper in hepatocytes causes oxidative damage and release of copper into the circulation, with accumulation in susceptible organs (eg, brain, kidneys). Hepatocyte apoptosis is accelerated by copper’s negative effect on inhibitor of apoptosis protein.^12,13 Renal tubular damage leads to Fanconi syndrome,¹⁴ in which substances such as glucose, phosphates, and potassium are excreted in urine rather than absorbed into the bloodstream by the kidneys. Excess copper deposition in the Descemet membrane may lead to Kayser-Fleisher ring formation.¹⁵ In the brain, copper deposition may occur in the lenticular nuclei,³as well as in the thalamus, subthalamus, brainstem, and frontal cortex—resulting in extrapyramidal, cerebral, and mild cerebellar symptoms.⁶

Cognitive impairment, which may be subtle, includes increased impulsivity, impaired judgment, apathy, poor decision making, decreased attention, increased lability, slowed thinking, and memory loss.⁶ Behavioral manifestations include changes in school or work performance and outbursts mimicking ADHD^12,16,17 as well as paranoia, depression, and bizarre behaviors.^16,18 Neuropsychiatric abnormalities include personality changes, pseudoparkinsonism, dyskinesia/dysarthria, and ataxia/tremor. Younger patients with psychiatric symptoms may be labelled with depression, anxiety, obsessive-compulsive disorder, bipolar disorder, or antisocial disorder.^6,16,18

Hepatic disease manifestations range from asymptomatic elevations in AST/ALT to acute hepatitis, mimicking infectious processes. Cirrhosis is the end result of untreated Wilson disease, with liver transplantation required if end-stage liver disease results. Rarely, patients present in fulminant hepatic failure, with death occurring if emergent liver transplantation is not performed.^6,8,10

In this case, routine screening saved the day.

Of note, before age 10, > 80% of patients with Wilson disease present with hepatic symptoms; those ages 10 to 18 often manifest psychiatric changes.¹⁷ Kayser-Fleisher rings are common in patients with neurologic manifestations but less so in those who have hepatic presentations or are presymptomatic.^6,15

Effective disease-mitigating treatment is indicated and available for both symptomatic and asymptomatic individuals and includes the copper chelators D-penicillamine (starting dose, 150-300 mg/d with a gradual weekly increase to 20 mg/kg/d) and trientine hydrochloride (a heavy metal chelating compound; starting dose, 20 mg/kg/d to a maximum of 1000 mg/d in young adults). Adverse effects of D-penicillamine include cutaneous eruptions, neutropenia, thrombocytopenia, proteinuria, and a lupus-like syndrome; therefore, trientine is increasingly being used as first-line therapy.⁸

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