Wilson Disease. Maggie Benson Virginia Commonwealth University Department of Physical Therapy

Transcription

1 Wilson Disease Maggie Benson Virginia Commonwealth University Department of Physical Therapy

2 What is Wilson Disease? Wilson Disease (WD)= hepatolenticular degeneration Hereditary disorder Autosomal recessive mutation Abnormal copper transportation Accumulation of copper in liver, brain, eye and other vital organs

3 Wilson Disease ATP7B gene is mutated This gene produces membrane protein for regulation of copper transportation out of cells Mutation of ATP7B results in inefficient copper exportation

4 Role of ceruloplasmin Mutation leads to reduced binding of copper to the protein ceruloplasmin Ceruloplasmin is produced in the liver Normal: ceruloplasmin binds to copper in liver à circulates through bloodà delivers copper to distant cells Abnormal: decreased binding of copper to ceruloplasmin and disruption of copper excretion from biliary Accumulation of copper = damaged liver cells

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6 Prevalence 30 affected individuals per million population Symptoms usually appear within 2 nd and 3 rd decade of life Equally affects men and women

7 Characteristics First attacks the liver, CNS, or both Progressive degeneration of basal ganglia Gradual replacement of liver cells with fibrous tissue

8 Characteristics Kayser- Fleischer rings: most unique characteristic of Wilson disease Due to buildup of copper in eye Rusty-brown ring around edge of iris and rim of cornea

9 Clinical Features Hepatic Acute liver failure, cirrhosis, acute hepatitis, fatty liver Neurological Movement disorders (tremor, involuntary movements), dysarthria, rigid dystonia, migraine headaches, insomnia, seizures Psychiatric Depression, neurotic behaviors, personality changes, psychosis

10 Clinical Features Other systems Ocular: Kayser-Fleischer rings, sunflower cataracts Cutaneous: lunulae ceruleae Renal abnormalities: aminoaciduria and nephrolithiasis Skeletal: premature osteoporosis and arthritis Cardiomyopathy Pancreatitis Hypoparathyroidism Menstrual irregularities, infertility, repeated miscarriages

11 Diagnosis Levels of copper in blood Level of ceruloplasmin (< 50 mg/l or <5 mg/dl) Biopsy of liver Genetic testing Slit lamp to detect Kayser-Fleischer rings MRI may detect structural abnormalities in basal ganglia for individuals with neurological symptoms

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13 Screening Unexplained liver disease or neurological symptoms Family history Abnormal liver tests Early diagnosis and treatment may reverse effects and prevent damage to brain and liver Usually a lifelong treatment

14 Medical Therapy Chelating substances: penicillamine or trientine hydrochloride Releases copper into bloodstream for urine excretion Drugs may worsen neurological symptoms Penicillamine Not uncommon for individual to excrete 5-10 mg copper/ day Side effects include bone marrow suppression, proteinuria, autoimmune diseases, wrinkling of skin) Trientine Urine excretion typically mg/day Side effects similar to penicillamine but at lower frequency

15 Medical Therapy Zinc Induces intestinal cell metallothionein and inhibits copper absorption Very safe Tetrathiomolybdate (TM) Form a tripartite complex with protein, copper and itself Given with meals to render any food with copper as unabsorbable

16 Initial Medical Therapy Brewer et al.

17 Maintenance Therapy Begin when further acute copper toxicity is eliminated (usually 2-4 months) Can be initiated if patient is asymptomatic First choice: Zinc, second choice: Trientine Required good compliance Life long therapy Important to follow-up every 2 years and assess compliance

18 Medical Management Maintain low copper levels (high-protein, lowcopper diet) Tube feedings restricted to less than 1.5 mg copper/ day Do not use water with over 0.1 ppm of copper

19 Prognosis Improvement noted 5-6 months after initiation of anti-copper therapy for patients with neurological symptoms Continue to improve over 18 months Any residual abnormalities over 24 months usually permanent Greater initial severity= more likely significant disability will be permanent

20 Prognosis Psychiatric and behavioral symptoms usually improve in conjunction with improved neurological symptoms (1-2 years) Suggested that most patients resume normal life A case report of 282 subjects with WD determined a mean duration of illness at time of diagnosis of 28 ± 36 months

21 Long Term Risks If have portal hypertension, risk bleeding from esophageal or gastric varices Risk generally decreases with length of anti-copper therapy Dysphagia and aspiration Generally 1-2 years post treatment dysphagia improves to point of aspiration not occurring Risk of falls if significant incoordination Suicidal if psychiatric and behavioral symptoms

22 Therapy Physical Therapy Maintain ROM and physical fitness Physiological positioning if dystonia present Speech Therapy If difficulty communicating, use of alphabet boards or electronic devices Occupational Therapy Getting back into work (near 2 year point) Possible surgeries for contractures

23 Deep Brain Stimulation (DBS) Treatment Tremor is present in 22-55% of patients with WD Common types are action tremor and wing-beating tremor First line therapy agent: primidone and propranolol Targeting thalamic ventral intermediate (Vim) shown to be effective for treating tremors for patients with MS or BI Dystonia is present in 10-65% of patients Can be focal, segmental, or multifocal Caused by lesions in basal ganglia Symptomatic therapy includes chemodennervation using botulinum A or B toxin Stimulation of globus pallidus pars interna (Gpi) proven to provide symptom relief

24 DBS Treatment Single case report demonstrated bilateral Gpi stimulation to improve severity of dystonia by only 14% Improvements of 50% for overall measures of quality of life and caregiver burden Stimulation of ventralis oralis anterior and posterior nuclei that receive pallidal projections may be more appropriate for individuals with dystonic tremors Conclusion Consider alternative approach for tremors for patients with WD may be stimulating the Vim If patient has hyperkinetic dystonia, targeting Gpi may be beneficial

25 Summary WD caused by accumulation of copper affecting liver, eyes and brain Important to diagnose early and begin medical therapy to reverse effects and prevent further damage PT, SLP, and OT to address impairments common in patients with WD Patients with WD have potential to return to normal life but medical treatment is lifelong

26 References 1. Brewer, G. J. and Askari, F. K Wilson s disease: Clinical management and therapy. Journal of Hepatology, Hedera, P Treatment of Wilson s disease motor complications with deep brain stimulation, Annals of the New York Academy of Sciences, Medici, L., Rossaro, L., and Sturniolo, G. C Wilson disease: A practical approach to diagnosis, treatment and followup. Digestive and Liver Disease, National Digestive Diseases Information Clearninghouse Wilson disease. NDDIC, Roberts, E. A. and Schilsky, M. L A practice guideline on Wilson disease. Hepatology, Roberts, E. A. and Schilsky, M. L Diagnosis and treatment of Wilson disease: An update. Hepatology, Taly, A.B Wilson Disease: Description of 282 patients evaluated over 3 decades. Medicine, Weiss, K. H Zinc monotherapy is not as effective as chelating agents in treatment with Wilson disease. Gastrienterology, "Wilson disease." Encyclopaedia Britannica. Britannica Academic. Encyclopædia Britannica Inc., Web. 28 Jan <