Wilson disease: Diagnostic tests
- Michael L Schilsky, MD, FAASLD
Michael L Schilsky, MD, FAASLD
- Medical Director, Adult Liver Transplant
- Yale-New Haven Transplantation Center
- Associate Professor of Medicine and Surgery, Digestive Diseases and Transplantation and Immunology
- Yale University Medical Center
- Section Editors
- Elizabeth B Rand, MD
Elizabeth B Rand, MD
- Section Editor — Pediatric Hepatology
- Professor of Pediatrics
- University of Pennsylvania School of Medicine
- Bruce A Runyon, MD
Bruce A Runyon, MD
- Section Editor — Cirrhosis and Its Complications
- Clinical Professor of Medicine
- University of New Mexico, Division of Gastroenterology and Hepatology
- Special Hepatology Consultant to the Indian Health Service
- Northern Navajo Medical Center, Shiprock, New Mexico
- Michael J Aminoff, MD, DSc
Michael J Aminoff, MD, DSc
- Editor-in-Chief — Neurology
- Section Editor — Medical Neurology
- Professor of Neurology
- University of California, San Francisco School of Medicine
Wilson disease (hepatolenticular degeneration) is an autosomal recessive defect in cellular copper transport. It is found worldwide, with a prevalence of approximately 1 case in 30,000 live births in most populations. Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually becomes cirrhotic and fails. In addition, patients may develop neurologic complications, which can be severe and progressive. Establishing a diagnosis of Wilson disease is crucial since early detection and treatment may prevent disease progression and even reverse damage in some patients.
Wilson disease should be considered in any patient with unexplained liver, neurologic, or psychiatric abnormalities. In addition, first-degree relatives of patients with Wilson disease should be screened for Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'When to consider Wilson disease' and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Screening family members'.)
This topic will review the specific diagnostic tests used in the evaluation of patients with suspected Wilson disease. The epidemiology, pathogenesis, clinical manifestations, approach to diagnosis, and treatment of Wilson disease are discussed separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Clinical manifestations, diagnosis, and natural history" and "Wilson disease: Treatment and prognosis".)
In patients with clinical features suggestive of Wilson disease (eg, abnormal liver tests combined with neurologic symptoms), we start by obtaining liver biochemical tests, a complete blood count, serum ceruloplasmin and copper levels, an ocular slit-lamp examination, and a 24-hour urinary copper excretion. The results of these tests may be sufficient to make a diagnosis of Wilson disease (or to exclude it), but patients with indeterminate results will require additional testing, such as a liver biopsy with copper quantitation or molecular testing for ATP7B mutations.
The general approach to diagnosing Wilson disease, including when to obtain additional testing, is discussed separately. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnosis'.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (Baltimore) 1992; 71:139.
- Stremmel W, Meyerrose KW, Niederau C, et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med 1991; 115:720.
- Gibbs K, Walshe JM. A study of the caeruloplasmin concentrations found in 75 patients with Wilson's disease, their kinships and various control groups. Q J Med 1979; 48:447.
- Steindl P, Ferenci P, Dienes HP, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113:212.
- Gow PJ, Smallwood RA, Angus PW, et al. Diagnosis of Wilson's disease: an experience over three decades. Gut 2000; 46:415.
- Cauza E, Maier-Dobersberger T, Polli C, et al. Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin. J Hepatol 1997; 27:358.
- Sánchez-Albisua I, Garde T, Hierro L, et al. A high index of suspicion: the key to an early diagnosis of Wilson's disease in childhood. J Pediatr Gastroenterol Nutr 1999; 28:186.
- Perman JA, Werlin SL, Grand RJ, Watkins JB. Laboratory measures of copper metabolism in the differentiation of chronic active hepatitis and Wilson disease in children. J Pediatr 1979; 94:564.
- Martins da Costa C, Baldwin D, Portmann B, et al. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease. Hepatology 1992; 15:609.
- European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56:671.
- Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol 1999; 3:147.
- Edwards CQ, Williams DM, Cartwright GE. Hereditary hypoceruloplasminemia. Clin Genet 1979; 15:311.
- Griffith DP, Liff DA, Ziegler TR, et al. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity (Silver Spring) 2009; 17:827.
- Kumar N, McEvoy KM, Ahlskog JE. Myelopathy due to copper deficiency following gastrointestinal surgery. Arch Neurol 2003; 60:1782.
- Greenberg SA, Briemberg HR. A neurological and hematological syndrome associated with zinc excess and copper deficiency. J Neurol 2004; 251:111.
- Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004; 63:33.
- Dufour JF, Kaplan MM. Muddying the water: Wilson's disease challenges will not soon disappear. Gastroenterology 1997; 113:348.
- Merle U, Eisenbach C, Weiss KH, et al. Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson's disease. J Hepatol 2009; 51:925.
- Roberts EA, Cox DW. Wilson disease. Baillieres Clin Gastroenterol 1998; 12:237.
- Roberts EA, Schilsky ML, Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guideline on Wilson disease. Hepatology 2003; 37:1475.
- Frommer DJ. Direct measurement of serum non-caeruloplasmin copper in liver disease. Clin Chim Acta 1976; 68:303.
- Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47:2089.
- McMillin GA, Travis JJ, Hunt JW. Direct measurement of free copper in serum or plasma ultrafiltrate. Am J Clin Pathol 2009; 131:160.
- Venelinov TI, Davies IM, Beattie JH. Dialysis-Chelex method for determination of exchangeable copper in human plasma. Anal Bioanal Chem 2004; 379:777.
- El Balkhi S, Trocello JM, Poupon J, et al. Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis. Clin Chim Acta 2011; 412:2254.
- LaRusso NF, Summerskill WH, McCall JT. Abnormalities of chemical tests for copper metabolism in chronic active liver disease: differentiation from Wilson's disease. Gastroenterology 1976; 70:653.
- Emre S, Atillasoy EO, Ozdemir S, et al. Orthotopic liver transplantation for Wilson's disease: a single-center experience. Transplantation 2001; 72:1232.
- Demirkiran M, Jankovic J, Lewis RA, Cox DW. Neurologic presentation of Wilson disease without Kayser-Fleischer rings. Neurology 1996; 46:1040.
- Dunn LL, Annable WL, Kliegman RM. Pigmented corneal rings in neonates with liver disease. J Pediatr 1987; 110:771.
- Goyal V, Tripathi M. Sunflower cataract in Wilson's disease. J Neurol Neurosurg Psychiatry 2000; 69:133.
- Stevens AC, Glaser J. Image of the month. Sunflower cataract. Gastroenterology 1997; 112:6, 317.
- Giacchino R, Marazzi MG, Barabino A, et al. Syndromic variability of Wilson's disease in children. Clinical study of 44 cases. Ital J Gastroenterol Hepatol 1997; 29:155.
- Frommer DJ. Urinary copper excretion and hepatic copper concentrations in liver disease. Digestion 1981; 21:169.
- Nicastro E, Ranucci G, Vajro P, et al. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology 2010; 52:1948.
- Kim EK, Yoo OJ, Song KY, et al. Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease. Hum Mutat 1998; 11:275.
- Müller T, Koppikar S, Taylor RM, et al. Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson's disease in children. J Hepatol 2007; 47:270.
- Schilsky ML. Non-invasive testing for Wilson disease: revisiting the d-penicillamine challenge test. J Hepatol 2007; 47:172.
- Smallwood RA, Williams HA, Rosenoer VM, Sherlock S. Liver-copper levels in liver disease: studies using neutron activation analysis. Lancet 1968; 2:1310.
- Ferenci P, Steindl-Munda P, Vogel W, et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease. Clin Gastroenterol Hepatol 2005; 3:811.
- Yang X, Tang XP, Zhang YH, et al. Prospective evaluation of the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample. Hepatology 2015; 62:1731.
- Faa G, Nurchi V, Demelia L, et al. Uneven hepatic copper distribution in Wilson's disease. J Hepatol 1995; 22:303.
- McDonald JA, Snitch P, Painter D, et al. Striking variability of hepatic copper levels in fulminant hepatic failure. J Gastroenterol Hepatol 1992; 7:396.
- Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008; 48:1167.
- Maier-Dobersberger T, Ferenci P, Polli C, et al. Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction. Ann Intern Med 1997; 127:21.
- Wu ZY, Wang N, Lin MT, et al. Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. Arch Neurol 2001; 58:971.
- Loudianos G, Dessi V, Lovicu M, et al. Molecular characterization of wilson disease in the Sardinian population--evidence of a founder effect. Hum Mutat 1999; 14:294.
- Thomas GR, Jensson O, Gudmundsson G, et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet 1995; 56:1140.
- García-Villarreal L, Daniels S, Shaw SH, et al. High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology 2000; 32:1329.
- Schilsky ML, Ala A. Genetic testing for Wilson disease: availability and utility. Curr Gastroenterol Rep 2010; 12:57.
- Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003; 23:139.
- DIAGNOSTIC APPROACH
- SERUM CERULOPLASMIN CONCENTRATION
- Limitations of serum ceruloplasmin
- SERUM COPPER CONCENTRATION
- OCULAR SLIT-LAMP EXAMINATION
- Kayser-Fleischer rings
- Sunflower cataracts
- URINARY COPPER EXCRETION
- Penicillamine challenge
- ADDITIONAL TESTING
- Liver biopsy
- - Hepatic copper concentration
- - Liver histology
- Genetic testing
- Brain imaging
- Scoring system for establishing a diagnosis of Wilson disease
- SUMMARY AND RECOMMENDATIONS