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Wilson's disease
Parkinsonism and Related Disorders 15S3 (2009) S126–S129
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Wilson’s disease Neziha Gouider-Khouja* National Institute of Neurology, Tunis, Tunisia
article info Keywords: Wilson’s disease Inborn errors of metabolism Review
1. Introduction
3. Molecular biology
Wilson’s disease (WD), also called progressive hepatolenticular degeneration, is a rare autosomal recessive inborn error of metabolism, first described by S.A.K. Wilson in 1912 [1]. The consequences of this disorder, related to copper deposition in various tissues, are treatable and preventable. From this point of view, even if rare, WD should be searched for in any patient with early onset movement disorder and/or hepatic manifestations as it typically associates liver and neurological signs and symptoms and often presents with a movement disorder [2,3]. If untreated, WD results in severe neurological and hepatic complications leading to death [4]. The confirmation of the role of copper and the discovery of the implication of the ATP7B gene gave new insights into WD pathogenesis and into the role of copper in liver and nervous system lesions. Several clinical and biochemical markers are available that allow diagnosis and, treatment with chelating agents and zinc salts may stabilize or reverse the disease. Liver transplantation corrects the underlying pathophysiology and can be lifesaving [4]. Prevention of copper accumulation is mandatory in asymptomatic family members. However, as genetic testing is expensive and complicated by the great variability of the genetic background of WD, diagnosis of affected asymptomatic members still relies upon probability arguments and preventive treatment is based on a benefit–risk decision. This article reviews pathogenesis, recent molecular biology advances, clinical picture, diagnosis and treatment options in WD.
WD is linked to mutations of the ATP7B gene (chromosome 13) [6– 9]. This gene is highly expressed in liver, kidney and placenta. More than 300 different mutations have been described. A few mutations predominate depending on the ethnic group. The H1069Q mutation accounts for 37 to 63% of WD in Caucasian. In Chinese patients, this mutation was not found, but the R778L accounted for 34 to 38% of WD. Both H1069Q and R778L mutations were not found in Indian patients. A 4193del mutation of the ATP7B gene with a founder effect was reported in Saudi Arabian patients. In Tunisian patients, over 64 cases and 48 families, the H1069Q was not found and, interestingly various new mutations were found and no founder effect was observed. In addition to this genetic heterogeneity, WD patients are often compound heterozygotes for ATP7B gene mutations. Despite these advances, the genetic heterogeneity of WD makes it difficult to rely solely on genetic testing for diagnosis. Clinical, neuro-radiological, biochemical and liver biopsy data, gathered into diagnostic recommendations, remain very useful in daily practice.
2. Epidemiology The estimated prevalence of WD is between 1/30,000 and 1/100,000 individuals. It affects equally both genders. The usual age of onset is within the second decade of life, however much earlier (3 years) and later onset cases have been reported (up to the seventh decade of life) [5]). * Correspondence: Neziha Gouider-Khouja, National Institute of Neurology, Department of Child and Adolescent Neurology, Tunis, Tunisia. E-mail address: [email protected] (N. Gouider-Khouja). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
4. Physiopathology 25 to 50% of dietary copper is absorbed in the stomach and duodenum and transported via the portal vein to the liver. Copper is taken up into the hepatocyte via copper transporter 1 ATP7A [10]. A specific copper chaperone, ATOX1, delivers copper to the copper transporter ATP7B. It has been shown that ATP7B is present in liver, nervous system and kidney and that he amount of intrahepatic copper regulates intracellular ATP7B [11]. ATP7B located in the Golgi apparatus, incorporates copper in apoceruloplasmin (holocaeruloplasmin). Under conditions of copper loading, ATP7B migrates to the cytoplasm compartment and the formation of vesicles results in export of copper into bile [4]. Defective ATP7B function results in hepatic copper accumulation leading to the hepatic and neurological features of Wilson’s disease. The addition of copper results in the redistribution of ATP7B to vesicles and then to vacuoles [12]. When excess copper in present,
N. Gouider-Khouja / Parkinsonism and Related Disorders 15S3 (2009) S126–S129
the protein moves towards the canalicular aspect of the hepatocyte, where it takes on an excretory role in promoting biliary copper excretion. Mutation of the protein ATP7B can interrupt its normal cellular processing. Excess copper accumulates in liver, linked to the metalloprotein (storage protein) and as free copper. It is no longer incorporated in apoceruloplasmin leading to reduction of serum ceruloplasmin and holoceruloplasmin concentrations [4]. Copper accumulation may last several years before the appearance of the first clinical symptoms, involving usually the liver. Later on, deposition of copper in extra-hepatic organs accounts for neurological and other symptoms. 5. Histopathology 5.1. Liver abnormalities In early stages of the disease, diffuse cytoplasmic copper accumulation is associated with macrosteatosis, microsteatosis, and glycogenated nuclei [2]. The ultrastructural abnormalities range from enlargement and separation of the mitochondrial inner and outer membranes, with widening of the intercristal spaces, to increases in the density and granularity of the matrix, or the occurrence of large vacuoles [13]. The intermediate stage is characterised by periportal inflammation, mononuclear cellular infiltrates, erosion of the limiting plate, lobular necrosis, and bridging fibrosis, and these features are indistinguishable from those of autoimmune hepatitis [14,15]. Mallory bodies can be seen in up to 50% of biopsy specimens [16]. Later on, cirrhosis, with either a micronodular or a mixed macronodular-micronodular histological pattern appears [17]. In patients with fulminant hepatic failure, parenchymal apoptosis, necrosis, and collapse might predominate, often with a background of cirrhosis. 5.2. Central nervous system abnormalities These abnormalities predominate in the basal ganglia. There is an increase in astrocytes, associated with swollen glia, liquefaction, and spongiform degeneration. Neuronal loss is often accompanied by gliosis and active glial fibrillary protein. The characteristic astrocytes are Alzheimer type 1 and 2 cells. Opalski cells, thought to originate from degenerating astrocytes, with fine granular cytoplasm and slightly abnormal nuclei, are distinctive for WD [18]. 6. Clinical aspects and diagnosis WD is classified into 3 main forms: the presymptomatic form, usually discovered fortuitously in the frame of a family study or a routine biology for liver function; the hepatic form; and the extrahepatic forms especially the neurological form. 6.1. Hepatic manifestations These may consist in a persistently elevated serum aminotransferases; or present acutely with liver failure (coagulopathy, encephalopathy), haemolysis, or both; or more chronically with chronic heptatitis or cirrhosis (decompensated or compensated) [19]. Mean age of onset of hepatic symptoms is 15 years. Hepatocellular carcinoma has been described in 11 cases of WD [4]. 6.2. Neurological and/or psychiatric signs Neurological and/or psychiatric signs are presenting features in 40–50% of patients with WD. They tend to appear later than hepatic
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signs, at a mean age of 20 years [20,21], however, most patients with neurological signs do not have symptomatic liver disease at the time of the neurological presentation. Movement disorders are the most characteristic neurological presentation of WD: tremor (pseudosclerosis tremor), choreiform movements, parkinsonism or akinetic rigid syndrome, and rigid dystonia. Other neurological manifestations include: gait disturbances, drooling, dysarthria, pseudobulbar palsy, seizures, headaches and insomnia. Neurological signs may be accompanied by psychiatric disturbances ranging from personality and behavior changes to psychosis, depression and neuroses [4]. Cerebral MRI shows high-T2 and low-T1 signal intensity lesions in the putamen, globus pallidus, caudate, thalamus, midbrain, pons, and cerebellum; cortical atrophy and white matter changes [22,23]. These lesions tend to be more severe in patients with the neurological form of WD than in patients with only hepatic involvement [24]. 6.3. Ophthalmic findings These include mainly Kayser–Fleischer (KF) rings and sunflower cataracts and less commonly night blindness, exotropic strabismus, optic neuritis [25]. KF rings are caused by the granular deposition of copper on the inner surface of the cornea in Descemet’s membrane. They may be visible to the naked eye as golden brown rings at the periphery of the cornea, however slit lamp examination is necessary to confirm their presence or absence. Sunflower cataracts do not impair vision and are visible only by slit-lamp examination [26,27]. Both KF rings and sunflower cataracts are reversible with medical therapy. 6.4. Other signs Other signs are rare, even though some of them may be evocative (such as thrombocytopenia or brown pigmentation on the anterior surface of the lower limbs). They include: renal abnormalities (aminoaciduria and nephrolithiasis) bone and joint changes (osteomalacia, osteoporosis, spontaneous fractures, osteoarthritis, osteochondritis dissecans, chondrocalcinosis, subchondral cyst formation and azure lunulae of the fingernails); cardiomyopathy and arrhythmias, hypoparathyroidism, infertility, and repeated miscarriages [4,28]. 6.5. Diagnosis WD should be considered in the setting of any liver abnormalities of uncertain cause or any new onset movement disorder in a young individual [3,28], especially in countries where consanguinity is high in the general population. Diagnosis work-up should include history, physical examination, liver function tests, full blood count, cerebral MRI, serum copper caeruloplasmin, 24-h urinary copper excretion and ophthalmologic examination. Molecular analysis of ATP7B mutations (if available), can potentially be diagnostic. Family screening of first-degree relatives must be undertaken in order to detect and treat presymptomatic cases. Neuro-imaging abnormalities in the basal ganglia, KF rings, caeruloplasmin <0.2 g/l and, 24-h urinary copper excretion >100 ug/24 h24 h are consistent with WD [4]. Liver biopsy with copper concentrations >250 mg/g dry weight remains the best biochemical evidence for WD. While this represents the typical clinical picture, many patients present with intermediate clinical and biological picture rendering the definite diagnosis of WD difficult to establish. Some authors proposed guidelines and scores in order to increase diagnosis accuracy [29,30].
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7. Treatment Treatment of WD is based on several chelating agents and zinc salts for medical therapy. Liver transplantation (LT) corrects the underlying pathophysiology and can be lifesaving. Prevention of copper accumulation is mandatory in asymptomatic family members. First-degree relatives should be screened for WD (liver function tests, serum copper and caeruloplasmin concentration and ophthalmologic examination). 24-h urinary copper might be difficult to interpret in WD heterozygotes and some individuals (with low caeruloplasmin concentration and without KF rings) might need a liver biopsy to eliminate the diagnosis [4]. However, as genetic testing is expensive and complicated by the great variability of the genetic background of WD, diagnosis of affected asymptomatic members still relies upon probability arguments. Preventive treatment of asymptomatic carriers is based on a benefit-risk decision and the matter is complicated by the absence of a consensus on the best therapeutic approach. 7.1. Copper-chelation – Penicillamine is a copper-chelator, it enhances urinary copper excretion. The initial dose of penicillamine is 1000–1500 mg per day in two to four divided doses [4], accompanied by vitamin B6, as penicillamine can affect pyridoxine metabolism, especially in children, pregnant women and patients with malnutrition or an intercurrent illness [31]. Adverse effects (AE) may occur in 10–20% of patients and monitoring of full blood count and urinary protein is recommended. Some of these AE such as sensitivity reactions occur in the early phase of treatment and should lead to stopping penicillamine and using an alternative drug; other AE such as nephrotoxicity, bone marrow suppression and skin abnormalities may appear later. It has been reported that 20–50% of penicillamine-treated WD patients develop worsening of neurological manifestations [32, 33]. Such worsening should prompt consideration of alternative drug therapy. However, improvement of hepatic signs and symptoms is proven and gradual improvement of neurological manifestations is likely in an important proportion of cases. – Trientine, also a copper-chelator, should be started a dose of 1200–1800 mg per day in two to three divided doses, and gradually increased until a dose of 900–1200 mg per day is reached [4]. It has few AE as compared to penicillamine and is has proven to be effective as a first-line treatment of WD with less important initial neurological deterioration [33,34]. This observation has prompted some authors to recommend the use of trientine rather than penicillamine as a first-line treatment [4]. 7.2. Prevention of copper intestinal absorption – Ammonium tetrathiomolybdate acts as a drug preventing intestinal copper absorption [35]. It also has few and transitory dose-related AE (bone marrow suppression and increase in hepatic enzymzes) [36]. – Zinc, also a drug preventing intestinal copper absorption, additionally reduces the damaging effects of free copper by inducing copper-binding metallothionein in hepatocytes. Used as elementary zinc or as sulphate, acetate, or gluconate, the required dose is 150 mg per day divided in three doses. It is used as preventing treatment in asymptomatic or presymptomatic individuals or in patients predominantly with neurological disease, as well as a maintenance therapy after an initial treatment with trientine and zinc [37,38] 7.3. Liver transplantation LT is indicated for WD patients with acute fulminant hepatic failure or in case of failure of medical therapy to stabilise and prevent
progressive hepatic insufficiency [39]. LT is an effective cure in these cases [40], however it seems of no use in patients with predominant neurological and psychiatric involvement. 7.4. Treatment strategies Penicillamin or trientine are the first line treatment. For asymptomatic patients, zinc alone, or a combination of zinc and trientine is used by some authors [41]. For maintenance therapy of patients who are initially symptomatic and have responded to chelator treatment, the dose of the chelator can be reduced or replaced with zinc. Compliance of the patient to treatment is mandatory because of the relentless course of the disease if untreated. Clinical followup and monitoring of copper concentrations and excretion are crucial and in these conditions treatment results in stabilisation or improvement of hepatic and – often at a lesser degree – neurological manifestations in most patients [4]. Unfortunately, some patients will continue deteriorating and LT, if possible, could help for predominating hepatic disease. 8. Conclusion WD is a challenging disease in many of its aspects: growing data on molecular biology could help better understanding of pathogenesis and management of pre-symptomatic cases; better knowledge of long-term treatment effects and AE is now available that allows a more accurate approach to therapy. It is also an example of what could be done in treatable inborn errors of metabolism, a crucial issue for orphan diseases. Acknowledgements The author wishes to thank Dr Narjess Fraj for her help in manuscript preparation. Conflict of interests None declared. References 1. Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912;34:295–509. 2. Saudubray JM, Sedel F, Walter JH. Clinical approach to treatable inborn metabolic diseases: an introduction. Metab Dis 2006;29:261–74. 3. Sedel F, Saudubray JM, Roze E, Agid Y, Vidailhet M. Movement disorders and inborn errors of metabolism in adults: A diagnostic approach. J Inherit Metab Disord 2008;31:308–3. 4. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. J Neurol Neurosurg Psychiatry 1999;67:195–8. 5. Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology 2005;41:668–70. 6. Frydman M, Bonne-Tamir B, Farrer LA, et al. Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus. Proc Natl Acad Sci USA 1985;82:1819–21. 7. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 1993;5:327–37. 8. Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344–50. 9. Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochem Biophys Res Commun 1993;197:271–7. 10. Safaei R, Howell SB. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol 2005;3:13–23. 11. van Dongen EM, Klomp LW, Merkx M. Copper-dependent protein–protein interactions studied by yeast two-hybrid analysis. Biochem Biophys Res Commun 2004;323:789–95. 12. Roelofsen H, Wolters H, Van Luyn MJ, Miura N, Kuipers F, Vonk RJ. Copperinduced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology 2000;119:782–93.
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13. Alt E, Sternlieb I, Goldfischer S. The cytopathology of metal overload. Int Rev Exp Pathol 1990;31:165–88. 14. Sternlieb I. Mitochondrial and fatty changes in hepatocytes of patients with Wilson’s disease. Gastroenterology 1968;55:354–67. 15. Schilsky ML, Scheinberg IH, Sternlieb I. Prognosis of Wilsonian chronic active hepatitis. Gastroenterology 1991;100:762–7. 16. Muller T, Langner C, Fuchsbichler A, et al. Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis. Hepatology 2004;39:963–9. 17. Strand S, Hofmann WJ, Grambihler A, et al. Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95 (APO-1/Fas) mediated apoptosis. Nat Med 1998;4:588–93. 18. Opalski A. Type special de cellules neurologiques dans la degenerescence lenticulaire progressive. Z Ges Neurol Psychiatrie 1930;124:420. 19. Pietrangelo A. Inherited metabolic diseases of the liver. Curr Opin Gastroenterol 2009;25:209–14. 20. Medici V, Mirante VG, Fassati LR, et al. Monotematica AISF 2000 OLT Study Group. Liver transplantation for Wilson’s disease: The burden of neurological and psychiatric disorders. Liver Transpl 2005;11:1056–63. 21. Santos RG, Alissa F, Reyes J, Teot L, Ameen N. Fulminant hepatic failure: Wilson’s disease or autoimmune hepatitis? Implications for transplantation. Pediatr Transplant 2005;9:112–16. 22. King AD, Walshe JM, Kendall BE, et al. Cranial MR imaging in Wilson’s disease. AJR Am J Roentgenol 1996;167:1579–84. 23. Sinha S, Taly AB, Ravishankar S, et al. Wilson’s disease: cranial MRI observations and clinical correlation. Neuroradiology 2006;48:613–21. 24. Kozic D, Svetel M, Petrovic B, Dragasevic N, Semnic R, Kostic VS. MR imaging of the brain in patients with hepatic form of Wilson’s disease. Eur J Neurol 2003;10:587–92. 25. Richard JM, Friendly DS. Ocular findings in pediatric systemic disease. Pediatr Clin North Am 1983;30:1123–44. 26. Williams HP, Walshe JM. “Sunflower cataract” in Wilson’s disease. BMJ 1969;3: 95–96. 27. Wiebers DO, Hollenhorst RW, Goldstein NP. The ophthalmologic manifestations of Wilson’s disease. Mayo Clin Proc 1977;52:409–16.
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28. Mark CM, Lam CW. Diagnosis of Wilson’s disease. Crit Rev Clin Lab Sci 2008;45: 263–90. 29. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139–42. 30. Roberts EA, Schilsky ML. A practice guideline on Wilson disease. Hepatology 2003;37:1475–92. 31. Gibbs KR, Walshe JM. Penicillamine and pyridoxine requirements in man. Lancet 1966;309:175–9. 32. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol 1987;44:490–3. 33. Schilsky MN. Treatment of Wilson’s disease: what are the relative roles of penicillamine, trientine, and zinc supplementation? Curr Gastroenterol Rep 2001;3:54–9. 34. Ferenci P. Review article: diagnosis and current therapy of Wilson’s disease. Aliment Pharmacol Ther 2004;19:157–65. 35. Brewer GJ. Neurologically presenting Wilson’s disease: epidemiology, pathophysiology and treatment. CNS Drugs 2005;19:185–92. 36. Brewer GJ, Askari F, Lorincz MT, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate. IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006;. 37. Brewer GJ. The use of copper lowering therapy with tetrathiomolybdate in medicine. Expert Opin Invest Drugs 2009;18:89–97. 38. Askari FK, Greenson, Dick RD, Johnson VD, Brewer GJ. Treatment of Wilson’s disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc. J Lab Clin Med 2003;142:385–90. 39. Brewer GJ, Hedera P, Kluin KJ, et al. Treatment of Wilson’s disease with ammonium tetrathiomolybdate. III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 2003;60:379–85. 40. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson’s disease: indications and outcome. Hepatology 1994;19:583–87. 41. Brewer GJ, Dick RD, Johnson V, et al. Treatment of Wilson’s disease with zinc: XV. Long-term follow-up studies. J Lab Clin Med 1998;132:264–78.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Wilson’s disease Neziha Gouider-Khouja* National Institute of Neurology, Tunis, Tunisia
article info Keywords: Wilson’s disease Inborn errors of metabolism Review
1. Introduction
3. Molecular biology
Wilson’s disease (WD), also called progressive hepatolenticular degeneration, is a rare autosomal recessive inborn error of metabolism, first described by S.A.K. Wilson in 1912 [1]. The consequences of this disorder, related to copper deposition in various tissues, are treatable and preventable. From this point of view, even if rare, WD should be searched for in any patient with early onset movement disorder and/or hepatic manifestations as it typically associates liver and neurological signs and symptoms and often presents with a movement disorder [2,3]. If untreated, WD results in severe neurological and hepatic complications leading to death [4]. The confirmation of the role of copper and the discovery of the implication of the ATP7B gene gave new insights into WD pathogenesis and into the role of copper in liver and nervous system lesions. Several clinical and biochemical markers are available that allow diagnosis and, treatment with chelating agents and zinc salts may stabilize or reverse the disease. Liver transplantation corrects the underlying pathophysiology and can be lifesaving [4]. Prevention of copper accumulation is mandatory in asymptomatic family members. However, as genetic testing is expensive and complicated by the great variability of the genetic background of WD, diagnosis of affected asymptomatic members still relies upon probability arguments and preventive treatment is based on a benefit–risk decision. This article reviews pathogenesis, recent molecular biology advances, clinical picture, diagnosis and treatment options in WD.
WD is linked to mutations of the ATP7B gene (chromosome 13) [6– 9]. This gene is highly expressed in liver, kidney and placenta. More than 300 different mutations have been described. A few mutations predominate depending on the ethnic group. The H1069Q mutation accounts for 37 to 63% of WD in Caucasian. In Chinese patients, this mutation was not found, but the R778L accounted for 34 to 38% of WD. Both H1069Q and R778L mutations were not found in Indian patients. A 4193del mutation of the ATP7B gene with a founder effect was reported in Saudi Arabian patients. In Tunisian patients, over 64 cases and 48 families, the H1069Q was not found and, interestingly various new mutations were found and no founder effect was observed. In addition to this genetic heterogeneity, WD patients are often compound heterozygotes for ATP7B gene mutations. Despite these advances, the genetic heterogeneity of WD makes it difficult to rely solely on genetic testing for diagnosis. Clinical, neuro-radiological, biochemical and liver biopsy data, gathered into diagnostic recommendations, remain very useful in daily practice.
2. Epidemiology The estimated prevalence of WD is between 1/30,000 and 1/100,000 individuals. It affects equally both genders. The usual age of onset is within the second decade of life, however much earlier (3 years) and later onset cases have been reported (up to the seventh decade of life) [5]). * Correspondence: Neziha Gouider-Khouja, National Institute of Neurology, Department of Child and Adolescent Neurology, Tunis, Tunisia. E-mail address: [email protected] (N. Gouider-Khouja). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
4. Physiopathology 25 to 50% of dietary copper is absorbed in the stomach and duodenum and transported via the portal vein to the liver. Copper is taken up into the hepatocyte via copper transporter 1 ATP7A [10]. A specific copper chaperone, ATOX1, delivers copper to the copper transporter ATP7B. It has been shown that ATP7B is present in liver, nervous system and kidney and that he amount of intrahepatic copper regulates intracellular ATP7B [11]. ATP7B located in the Golgi apparatus, incorporates copper in apoceruloplasmin (holocaeruloplasmin). Under conditions of copper loading, ATP7B migrates to the cytoplasm compartment and the formation of vesicles results in export of copper into bile [4]. Defective ATP7B function results in hepatic copper accumulation leading to the hepatic and neurological features of Wilson’s disease. The addition of copper results in the redistribution of ATP7B to vesicles and then to vacuoles [12]. When excess copper in present,
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the protein moves towards the canalicular aspect of the hepatocyte, where it takes on an excretory role in promoting biliary copper excretion. Mutation of the protein ATP7B can interrupt its normal cellular processing. Excess copper accumulates in liver, linked to the metalloprotein (storage protein) and as free copper. It is no longer incorporated in apoceruloplasmin leading to reduction of serum ceruloplasmin and holoceruloplasmin concentrations [4]. Copper accumulation may last several years before the appearance of the first clinical symptoms, involving usually the liver. Later on, deposition of copper in extra-hepatic organs accounts for neurological and other symptoms. 5. Histopathology 5.1. Liver abnormalities In early stages of the disease, diffuse cytoplasmic copper accumulation is associated with macrosteatosis, microsteatosis, and glycogenated nuclei [2]. The ultrastructural abnormalities range from enlargement and separation of the mitochondrial inner and outer membranes, with widening of the intercristal spaces, to increases in the density and granularity of the matrix, or the occurrence of large vacuoles [13]. The intermediate stage is characterised by periportal inflammation, mononuclear cellular infiltrates, erosion of the limiting plate, lobular necrosis, and bridging fibrosis, and these features are indistinguishable from those of autoimmune hepatitis [14,15]. Mallory bodies can be seen in up to 50% of biopsy specimens [16]. Later on, cirrhosis, with either a micronodular or a mixed macronodular-micronodular histological pattern appears [17]. In patients with fulminant hepatic failure, parenchymal apoptosis, necrosis, and collapse might predominate, often with a background of cirrhosis. 5.2. Central nervous system abnormalities These abnormalities predominate in the basal ganglia. There is an increase in astrocytes, associated with swollen glia, liquefaction, and spongiform degeneration. Neuronal loss is often accompanied by gliosis and active glial fibrillary protein. The characteristic astrocytes are Alzheimer type 1 and 2 cells. Opalski cells, thought to originate from degenerating astrocytes, with fine granular cytoplasm and slightly abnormal nuclei, are distinctive for WD [18]. 6. Clinical aspects and diagnosis WD is classified into 3 main forms: the presymptomatic form, usually discovered fortuitously in the frame of a family study or a routine biology for liver function; the hepatic form; and the extrahepatic forms especially the neurological form. 6.1. Hepatic manifestations These may consist in a persistently elevated serum aminotransferases; or present acutely with liver failure (coagulopathy, encephalopathy), haemolysis, or both; or more chronically with chronic heptatitis or cirrhosis (decompensated or compensated) [19]. Mean age of onset of hepatic symptoms is 15 years. Hepatocellular carcinoma has been described in 11 cases of WD [4]. 6.2. Neurological and/or psychiatric signs Neurological and/or psychiatric signs are presenting features in 40–50% of patients with WD. They tend to appear later than hepatic
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signs, at a mean age of 20 years [20,21], however, most patients with neurological signs do not have symptomatic liver disease at the time of the neurological presentation. Movement disorders are the most characteristic neurological presentation of WD: tremor (pseudosclerosis tremor), choreiform movements, parkinsonism or akinetic rigid syndrome, and rigid dystonia. Other neurological manifestations include: gait disturbances, drooling, dysarthria, pseudobulbar palsy, seizures, headaches and insomnia. Neurological signs may be accompanied by psychiatric disturbances ranging from personality and behavior changes to psychosis, depression and neuroses [4]. Cerebral MRI shows high-T2 and low-T1 signal intensity lesions in the putamen, globus pallidus, caudate, thalamus, midbrain, pons, and cerebellum; cortical atrophy and white matter changes [22,23]. These lesions tend to be more severe in patients with the neurological form of WD than in patients with only hepatic involvement [24]. 6.3. Ophthalmic findings These include mainly Kayser–Fleischer (KF) rings and sunflower cataracts and less commonly night blindness, exotropic strabismus, optic neuritis [25]. KF rings are caused by the granular deposition of copper on the inner surface of the cornea in Descemet’s membrane. They may be visible to the naked eye as golden brown rings at the periphery of the cornea, however slit lamp examination is necessary to confirm their presence or absence. Sunflower cataracts do not impair vision and are visible only by slit-lamp examination [26,27]. Both KF rings and sunflower cataracts are reversible with medical therapy. 6.4. Other signs Other signs are rare, even though some of them may be evocative (such as thrombocytopenia or brown pigmentation on the anterior surface of the lower limbs). They include: renal abnormalities (aminoaciduria and nephrolithiasis) bone and joint changes (osteomalacia, osteoporosis, spontaneous fractures, osteoarthritis, osteochondritis dissecans, chondrocalcinosis, subchondral cyst formation and azure lunulae of the fingernails); cardiomyopathy and arrhythmias, hypoparathyroidism, infertility, and repeated miscarriages [4,28]. 6.5. Diagnosis WD should be considered in the setting of any liver abnormalities of uncertain cause or any new onset movement disorder in a young individual [3,28], especially in countries where consanguinity is high in the general population. Diagnosis work-up should include history, physical examination, liver function tests, full blood count, cerebral MRI, serum copper caeruloplasmin, 24-h urinary copper excretion and ophthalmologic examination. Molecular analysis of ATP7B mutations (if available), can potentially be diagnostic. Family screening of first-degree relatives must be undertaken in order to detect and treat presymptomatic cases. Neuro-imaging abnormalities in the basal ganglia, KF rings, caeruloplasmin <0.2 g/l and, 24-h urinary copper excretion >100 ug/24 h24 h are consistent with WD [4]. Liver biopsy with copper concentrations >250 mg/g dry weight remains the best biochemical evidence for WD. While this represents the typical clinical picture, many patients present with intermediate clinical and biological picture rendering the definite diagnosis of WD difficult to establish. Some authors proposed guidelines and scores in order to increase diagnosis accuracy [29,30].
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7. Treatment Treatment of WD is based on several chelating agents and zinc salts for medical therapy. Liver transplantation (LT) corrects the underlying pathophysiology and can be lifesaving. Prevention of copper accumulation is mandatory in asymptomatic family members. First-degree relatives should be screened for WD (liver function tests, serum copper and caeruloplasmin concentration and ophthalmologic examination). 24-h urinary copper might be difficult to interpret in WD heterozygotes and some individuals (with low caeruloplasmin concentration and without KF rings) might need a liver biopsy to eliminate the diagnosis [4]. However, as genetic testing is expensive and complicated by the great variability of the genetic background of WD, diagnosis of affected asymptomatic members still relies upon probability arguments. Preventive treatment of asymptomatic carriers is based on a benefit-risk decision and the matter is complicated by the absence of a consensus on the best therapeutic approach. 7.1. Copper-chelation – Penicillamine is a copper-chelator, it enhances urinary copper excretion. The initial dose of penicillamine is 1000–1500 mg per day in two to four divided doses [4], accompanied by vitamin B6, as penicillamine can affect pyridoxine metabolism, especially in children, pregnant women and patients with malnutrition or an intercurrent illness [31]. Adverse effects (AE) may occur in 10–20% of patients and monitoring of full blood count and urinary protein is recommended. Some of these AE such as sensitivity reactions occur in the early phase of treatment and should lead to stopping penicillamine and using an alternative drug; other AE such as nephrotoxicity, bone marrow suppression and skin abnormalities may appear later. It has been reported that 20–50% of penicillamine-treated WD patients develop worsening of neurological manifestations [32, 33]. Such worsening should prompt consideration of alternative drug therapy. However, improvement of hepatic signs and symptoms is proven and gradual improvement of neurological manifestations is likely in an important proportion of cases. – Trientine, also a copper-chelator, should be started a dose of 1200–1800 mg per day in two to three divided doses, and gradually increased until a dose of 900–1200 mg per day is reached [4]. It has few AE as compared to penicillamine and is has proven to be effective as a first-line treatment of WD with less important initial neurological deterioration [33,34]. This observation has prompted some authors to recommend the use of trientine rather than penicillamine as a first-line treatment [4]. 7.2. Prevention of copper intestinal absorption – Ammonium tetrathiomolybdate acts as a drug preventing intestinal copper absorption [35]. It also has few and transitory dose-related AE (bone marrow suppression and increase in hepatic enzymzes) [36]. – Zinc, also a drug preventing intestinal copper absorption, additionally reduces the damaging effects of free copper by inducing copper-binding metallothionein in hepatocytes. Used as elementary zinc or as sulphate, acetate, or gluconate, the required dose is 150 mg per day divided in three doses. It is used as preventing treatment in asymptomatic or presymptomatic individuals or in patients predominantly with neurological disease, as well as a maintenance therapy after an initial treatment with trientine and zinc [37,38] 7.3. Liver transplantation LT is indicated for WD patients with acute fulminant hepatic failure or in case of failure of medical therapy to stabilise and prevent
progressive hepatic insufficiency [39]. LT is an effective cure in these cases [40], however it seems of no use in patients with predominant neurological and psychiatric involvement. 7.4. Treatment strategies Penicillamin or trientine are the first line treatment. For asymptomatic patients, zinc alone, or a combination of zinc and trientine is used by some authors [41]. For maintenance therapy of patients who are initially symptomatic and have responded to chelator treatment, the dose of the chelator can be reduced or replaced with zinc. Compliance of the patient to treatment is mandatory because of the relentless course of the disease if untreated. Clinical followup and monitoring of copper concentrations and excretion are crucial and in these conditions treatment results in stabilisation or improvement of hepatic and – often at a lesser degree – neurological manifestations in most patients [4]. Unfortunately, some patients will continue deteriorating and LT, if possible, could help for predominating hepatic disease. 8. Conclusion WD is a challenging disease in many of its aspects: growing data on molecular biology could help better understanding of pathogenesis and management of pre-symptomatic cases; better knowledge of long-term treatment effects and AE is now available that allows a more accurate approach to therapy. It is also an example of what could be done in treatable inborn errors of metabolism, a crucial issue for orphan diseases. Acknowledgements The author wishes to thank Dr Narjess Fraj for her help in manuscript preparation. Conflict of interests None declared. References 1. Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912;34:295–509. 2. Saudubray JM, Sedel F, Walter JH. Clinical approach to treatable inborn metabolic diseases: an introduction. Metab Dis 2006;29:261–74. 3. Sedel F, Saudubray JM, Roze E, Agid Y, Vidailhet M. Movement disorders and inborn errors of metabolism in adults: A diagnostic approach. J Inherit Metab Disord 2008;31:308–3. 4. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. J Neurol Neurosurg Psychiatry 1999;67:195–8. 5. Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology 2005;41:668–70. 6. Frydman M, Bonne-Tamir B, Farrer LA, et al. Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus. Proc Natl Acad Sci USA 1985;82:1819–21. 7. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 1993;5:327–37. 8. Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344–50. 9. Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochem Biophys Res Commun 1993;197:271–7. 10. Safaei R, Howell SB. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol 2005;3:13–23. 11. van Dongen EM, Klomp LW, Merkx M. Copper-dependent protein–protein interactions studied by yeast two-hybrid analysis. Biochem Biophys Res Commun 2004;323:789–95. 12. Roelofsen H, Wolters H, Van Luyn MJ, Miura N, Kuipers F, Vonk RJ. Copperinduced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology 2000;119:782–93.
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