Wilson's disease (wilson)

AR inherited disorder of impaired copper excretion characterized by excessive deposition of copper in many tissues and organs, principally the liver, brain, and eye. • Discovered by Samuel Alexander kinnier Wilson. Liver fails to excrete sufficient Cu via the bile, and the ability to incorporate Cu into CP is diminished Due to loss of function mutations of the ATP7B gene on chromosome 13, which encodes a copper-transporting ATPase (ATP7B). Most common presentations are with liver disease or neuro- psychiatric disturbances. Kayser–Fleischer ring is the clinical hallmark of WD. caused by deposition of copper in Desçemet’s membrane of cornea. Penicillamine is the of choice.

1. Wilson's disease Insp Dr Mahadev Deuja Tuesday, December 18, 2018

2. Outlines INTRODUCTION​ EPIDEMIOLOGY​ PATHOGENESIS CLINICAL PRESENTATION DIAGNOSTIC TEST TREATMENT PROGNOSIS MCQ’S

3. Introduction Rare AR inherited disorder of impaired copper excretion. Characterized by excessive deposition of copper in many tissues and organs, principally the liver, brain, and eye. Discovered by Samuel Alexander kinnier Wilson (1878-1937) 

4. Normal copper metabolism 1 2 3

5. Normal copper metabolism 4 5 6

6. What happens in wilson’s disease?

7. What happens in wilson’s disease?

8. Cont….What happens in wilson’s disease?

9. Cont….What happens in wilson’s disease?

10. Clinical presentation Vary widely, but key features of Wilson disease are Corneal Kayser - Fleischer rings Liver disease and cirrhosis Neuropsychiatric disturbances Acute episodes of hemolysis Most common presentations are with liver disease or neuro -psychiatric disturbances Symptoms usually arise between the ages of 5 and 45 years although it can present in adults in their fifties.

11. Kayser –Fleischer ring The clinical hallmark of WD. Caused by deposition of copper in Desçemet’s membrane of cornea Characterised by greenish-brown discoloration of the corneal margin appearing first at the upper periphery. Present in 95% of patients with neurologic symptoms and in >50% of those without neurologic symptoms Sometimes visible only by slit-lamp examination. They disappear with treatment Not entirely specific for WD (i.e. in chronic cholestatic diseases such as PBC or in children with neonatal cholestasis )

12. Liver disease The liver manifestations may be of almost any variety and severity. Presentation include Asymptomatic hepatomegaly Abnormal LFT even as early as the first year of life Fatty liver Acute hepatitis Resembling autoimmune hepatitis Cirrhosis: compensated or decompensated Acute liver failure The important practical message therefore is: suspect Wilson disease in any child with undiagnosed liver disease

13. Clinical presentation- Blood Coombs-negative haemolytic anemia May be the only initial symptom. Low-grade hemolysis may be associated with WD even when liver disease is not clinically evident. Marked hemolysis is commonly associated with severe liver disease. Decay of liver cells may result in the release of large amounts of stored copper, which further aggravates hemolysis .

14. Neurological disease Movement disorders (tremor, involuntary movements) Drooling, dysarthria Rigid dystonia Pseudobulbar palsy Dysautonomia Migraine headaches Insomnia Seizures

15. Cont…..Neurological disease May be first clinical manifestation, appearing simultaneously with hepatic signs, or years later. Can be extremely subtle , and inter- mingled for many years. May also develop very rapidly, leading within a few months to complete disability

16. Psychiatric disease Upto 30% of patients initially present with psychiatric abnormalities Presentation includes Depression Neurotic behaviours Personality changes Psychosis In children declining school performance, personality changes, impulsiveness, labile mood and inappropriate behavior are observed Are frequently misdiagnosed as behavioral problems associated with puberty.

17. Diagnostic test

18. Serum ceruloplasmin level Typically decreased in patients with neurologic Wilson disease May be in the low normal range in 50% of patients with active Wilson’s liver disease

19. 24-hour urinary copper More than 0.6 μmol /24 hrs (38 μg /24 hrs) Measuring 24-hour urinary copper excretion while giving D- penicillamine is a useful confirmatory test; more than 25 μmol /24 hrs is considered diagnostic of Wilson’s disease.

20. MRI of brain MRI is the most important diagnostic tool in patients with neurological presentation Almost all patients show an MRI abnormality: Non-specific changes in the brain such as diffuse brain atrophy and focal abnormalities.

21. Liver biopsy Method of choice for diagnosis of WD Hepatic copper content of >250ug/g (4umol/g) dry weight is confirmative of WD (sensi3vity 83.3%, specificity 98.6%)

22. Genetic testing Developments of new techniques in genetic and molecular biology have provided useful tools in the diagnosis in recent years. PCR is to detect mutations. H1069Q mutation is the most common mutation among the WD  

23. Treatment With proper therapy, disease progress can be halted and oftentimes symptoms can be improved. Treatment is aimed at Removing excess accumulated copper Best accomplished by copper chelation therapy using Penicillamine Trientine Ammonium tetrathiomolybdate Preventing its reaccumulation . Accomplished by zinc ingestion and by omitting copper-rich dietary components

24. Treatment Treatment for Wilson disease is a lifelong process. Treatment should be given to all affected individuals, even if they are asymptomatic.

25. Penicillamine Drug of choice. The dose given must be sufficient to produce cupriuresis and most patients require 1.5 μg /day (range 1–4 μg ). The dose can be reduced once the disease is in remission but treatment must continue for life, even through pregnancy. Care must be taken to ensure that re-accumulation of copper does not occur. Abrupt discontinuation of treatment must be avoided because this may precipitate acute liver failure

26. Zinc Acts by blocking the absorption of copper in the intestinal tract. This action both depletes accumulated copper and prevents its reaccumulation .

27. Liver transplantation May require in patients with severe hepatitis or liver failure. The value of liver transplantation in severe neurological Wilson’s disease is unclear.

28. Prognosis Excellent, provided treatment is started before there is irreversible damage

29. Take home message Wilson’s disease, the most common inherited disease of copper metabolism Clinical presentation of WD is vary variable. Most common presentations are with liver disease or neuro -psychiatric disturbances Characterized by low serum copper and ceruloplasmin concentrations coupled with the pathological accumulation of copper in tissue. WD can be treated successfully but treatment must be lifelong.

30. Mcq’s Kayser -Fleischer ring is seen in Wilson disease  Primary biliary cirrhosis  Primary sclerosing cholangitis All of the above

31. What is the inheritance pattern of Wilson's disease? AD AR  X-linked None

32. What is the primary abnormality in Wilson's disease  Reduced synthesis of ceruloplasmin   Increased intestinal absorption of copper  Reduced urinary excretion of copper.  Decreased excretion of copper in to bile

33. References Available at: http://www.eurowilson.org/en/professional/diagnosis/index.phtml. Accessed December 2, 2018. Available at: http://wilsonsdisease.ca/about-wilson-disease/treatments. Accessed December 5, 2018. De bie P, Muller P, Wijmenga C, Klomp LW. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet. 2007;44(11):673-88. Liu J, Luan J, Zhou X, Cui Y, Han J. Epidemiology, diagnosis, and treatment of Wilson's disease. Intractable Rare Dis Res. 2017;6(4):249-255.

34. THANK YOU

35. Poet- “eyes are the window to the soul” Doctor- “eyes are the window to the diagnosis of various diseases like wilson’s disease”