Wilson’s disease

1. WILSON’S DISEASE An Update… Dr.W.A.P.S.R.WEERARATHNA Registrar In Medicine Ward 10/02

2. OBJECTIVES …. WD- PATHOPHYSIOLOGY,C/F,VARIOUS PRESENTATIONS WD-DIAGNOSTIC WORK-UP TREATMENT OPTIONS/ SCREENING TOOLS PROGNOSTIC INDICATORS LATEST PRACTICAL GUIDE LINES/RECOMMENDATIONS ISSUED BY EASL & AASLD.

3. Wilson’s Disease Pathophysiology

4. Clinical Manifestations of WD

5. Lunulae ceruleae

6. KF Ring Neuropsychiatric: 99% . Hepatic : 30 to 50 % KF rings are not specific for WD. They may be found in other chronic liver disease, PBC, PSC, AIH, and familial cholestatic syndromes.

7. PSYCHIATRIC PRESENTATIONS 15-20 % of patients may present with purely psychiatric symptoms . Phobias , compulsive behaviors, aggressive and antisocial behaviors Schizophrenia Psychosis Cognitive decline

8. HEPATIC PRESENTATION Acute hepatitis, Chronic liver disease— portal HTN . Autoimmune hepatitis . Fulminant hepatic failure , with sev . coagulopathy and encephalopathy . Recurrent bouts of hemolysis may predispose to the development of gallstones . Wilson disease is rarely complicated by hepatocellular carcinoma.

9. Extrahepatic disorders Hemolytic anemia Fanconi's syndrome Nephrolithiasis Hypoparathyroidism Amenorrhea Testicular problems Infertility Arthritis, Rhabdomyolysis . Cardiomyopathy Pancreatitis

10. DIAGNOSTIC WORK-UP Biochemical Serum ceruloplasmin < 20mg/ dL (18-35) low in 90% WD 24hr Urinary Copper > 100micg/d-in symptomatics / (60-100 in pre symp .)-NR(20-50) Serum free copper >10micg/ dL Liver Copper > 250micg/g-false + in obstructive CLD Ophthalmological Slit lamp KF ring-absent in heterozygous carriers Imaging X-ray Osteoporosis Ultrasound Cirrhosis CT Scan MRI Genetics -DNA Haplotype analysis-genotype siblings only- polyorphism /specific mutation testing

11. MRI appearance in WD ‘Face of giant panda’ sign; MRSS: decreased NAA and therefore a decreased ratio with other products Bright lateral putamen or claustral sign; Pallidal hyperintensity

12. Unexplained CLD Diagnosis of WD KF Ring + CPN < 20mg / 24h.U.cu>40 KF Ring + CPN=20 24h.U.cu>40 Liver biopsy-histology &cu quantification Molecular testing KF Ring- CPN <20 24h.U.cu=>40 KF Ring – CPN<20 24h.U.cu >40 >250mcg/g 70-250mcg/g <50 mcg/g Other diagnosis

13. Neuropsychiatric +-CLD Diagnosis WD KF Ring + CPN>=20 24hU.cu>40 KF Ring + CPN>20 24hU.cu<40 Other Dx KF Ring- CPN <20 24hU.cu>40 KF Ring + CPN <20 24hU.cu>40 Liver biopsy cu quantification Molecular testing >250 70-250

14. Siblings Child>2 yr (asymptomatic ) Haplotype / Mutation analysis Diagnosis WD Identical haplotype or2 mut . Slit lamp(>4 yr) CPN LFT INR 24 h U.cu Abn.LFT CPN<20 24h U.cu >40 Liver biopsy 70-250 >250

15. Treatment Options in WD

16. Nazer prognostic index Lab measurement normal value Score Score 1 Score 2 Score 3 Score 4 Serum bilirubin 0.2-1.2 <5.8 5.8-8.8 8.9-11.7 11.8-17.5 >17.5 AST Level 10-35 <100 100-150 151-200 201-300 >300 Prolongation of PT level ( secs ) 12-14s <4s 4-8s 9-12 13-20 >20

17. DISEASE SEVERITY ASSESMENT BY NAZAR PROGNOSTIC INDEX … Scores< 7  medical theraphy >9 immediate LT 7-9 clinical judjment – Rx or LT???( trientine & Zinc acetate) With Rx-LFT usually recovers in about 1 year.. Neurologic & psychiatric mane. usually improve after 6-24 months…. Residual liver damage may persist.

18. Family Screening Biochemical Testing Children of patient: Begin at age 2 if asymptomatic, repeat once in 5 years unless reason to pursue further.   Siblings of patient: Physical examination and brief history of any liver or neurological symptoms. Liver Function Tests:  ALT, AST, Albumin, Bilirubin . Ceruloplasmin and Serum Copper. 24 hour urine copper Slit-lamp exam of the eyes for Kayser -Fleischer ring If no K-F rings, abnormal liver functions tests, and low ceruloplasmin :  liver biopsy.

19. EASL Clinical Practice Guidelines: Wilson’s disease   European Association for the Study of the Liver   Journal of Hepatology   Volume 56, Issue 3, Pages 671-685 (March 2012) DOI: 10.1016/j.jhep.2011.11.007 Copyright © 2011 European Association for the Study of the Liver Terms and Conditions

20. Wilson’s disease should be considered in any individual with liver abnormalities or neurological movement disorders of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of Wilson’s disease GRADE II-2, A, 1 AASLD Class I, Level B

21. Wilson’s disease must be considered in any patient with unexplained liver disease in combination with neurological or neuropsychiatric disorders GRADE II-2, A, 1 AASLD Class I, Level B

22. Kayser -Fleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of Kayser -Fleischer rings does not exclude the diagnosis of Wilson’s disease, even in patients with predominantly neurological disease GRADE II-2, A, 1 AASLD Class I, Level B

23. Neurologic evaluation and imaging of the brain, preferably by MR imaging , should be considered prior to treatment in all patients with neurologic Wilson’s disease and should be part of the evaluation of any patient presenting with neurological symptoms consistent with Wilson’s disease GRADE II-2, B, 1 AASLD Class I, Level C

24. A low serum ceruloplasmin level(<50mg/dl) should be taken as evidence for the diagnosis of WD. Borderline levels require further evaluation. Serum ceruloplasmin within the normal range does not necessarily exclude the diagnosis GRADE II-2, A, 1 AASLD Class I, Level B

25. Basal 24-hour urinary excretion of copper >1.6 μmol />100micg is typical in symptomatic patients. >0.6mic may indicate WD & needs Ix. Penicillamine challenge test is rec. in pt with <1.6mic In children with mild hepatic disease basal 24-hour urinary excretion of copper can only be mildly elevated or may even be in the normal range . Lowering the threshold to >0.64 μmol /24 hr may be useful for detecting asymptomatic patients but this will be less sensitive and will overlap with patients with other liver injury GRADE II-2, B, 1 AASLD Class I, Level C

26. Hepatic parenchymal copper content >4 μmol /g or >200micg dry weight provides critical diagnostic information and should be obtained in cases where the diagnosis is not straightforward and in younger patients . In untreated patients , normal hepatic copper content (<0.64-0.8 μmol /g dry weight) almost always excludes a diagnosis of Wilson’s disease GRADE III, B, 2 AASLD Class I, Level B

27. Mutation analysis with specific allelic probes or by whole-gene sequencing is currently possible and available. Specific testing for known mutations or screening of first-degree relatives of patients with haplotype analysis should be the primary mode for Wilson’s disease GRADE II-2, B, 1 AASLD Class I, Level B

28. Initial treatment for symptomatic patients with Wilson’s disease should include a chelating agent (D- penicillamine or trientine ). Trientine may be better tolerated GRADE II-1, B, 1 AASLD Class I, Level B

29. Zinc may have a role as a line therapy in neurological patients GRADE II-2, C, 2 AASLD Class II, Level C

30. Treatment of presymptomatic patients or those with neurological disease on maintenance therapy can be accomplished with a chelating agent or with zinc GRADE II-1, B, 1 AASLD Class I, Level B

31. Treatment is lifelong and should not be discontinued, unless liver transplantation is performed GRADE II-1, B, 1 AASLD Class I, Level B

32. If zinc is used, careful monitoring of transaminases is needed, with changing to chelators if these laboratory parameters are increasing GRADE C1 AASLD Class I, Level B

33. Patients should avoid intake of foods and water with high concentrations of copper, especially during the year of treatment GRADE II-3, B, 2 AASLD Class I, Level C

34. Patients with acute liver failure due to Wilson’s disease should be treated with liver transplantation when the revised King’s score is 11 or higher. GRADE II-2, B, 1 AASLD Class I, Level B [41

35. Patients with decompensated cirrhosis, unresponsive to chelation treatment, should be evaluated promptly for liver transplantation GRADE II-2, B, 1 AASLD Class I, Level B

36. Treatment for Wilson’s disease should be continued during pregnancy , but dosage reduction is advisable for D- penicillamine and trientine GRADE II-3, B, 1 AASLD Class I, Level C

37. For routine monitoring, serum copper and ceruloplasmin , liver enzymes an international normalized ratio, functional parameters, complete blood count and urine analysis as well as physical and neurologicalexaminations should be performed regularly, at least twice annually GRADE II-2, B, 1 AASLD Class I, Level C

38. The 24-hour urinary copper excretion on medication and after 2 days of cessation of therapy should be measured at least yearly. The estimated serum non- ceruloplasmin bound copper may be another useful parameter to control therapy GRADE II-3, B, 1 AASLD Class I , Level C

39. REFFERENCES - EASL Clinical Practice Guidelines: Wilson’s disease-European Association for the Study of the Liver- june 2012 AASLD PRACTICEGUIDELINES-Diagnosis and Treatment of Wilson Disease:An Update-Eve A. Roberts and Michael L. Schilsky-2012 vol 56 Harrison’s principles of Internal medicine-18 th edition

40. THANK YOU!