Wilson Disease - Our Experience

Transcription

1 Wilson Disease Our Experience Hussein Shamaly M.D.. Pediatric Gastroenterology Unit Pediatric Department Clalit Health Services French Hospital, Nazareth

2 Key Concepts Wilson disease is more often considered than found, but if not considered will not be found. Prevalence 1: Rarely before 34 y old. Usually appears IIed IVth decade WD should be considered in the D.D. of any unexplained liver disease, especially in these with liver disease & neurological or psychiatric symptoms.

3 Autosomal recessive gene localized to chromosome 13q14.3q21.1. Gene encodes a ptype ATPase ATP7B. It is responsible for copper excretion in bile and copper incorporation in ceruloplasmin Key Concepts biliary copper excretion Hepatic copper accumulation Copper deposition in extra hepatic sites Pathophysiology related to copper over load

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5 Ceruloplasmin 132 kd protein, synthesized in liver. Acute phase reactant, copper carrying protein. Increased Decreased Inflammation Neonatal period Heperestrogenemia Pregnancy Oral contraceptive Aceruloplasminemia Renal disease Enteric loss End stage liver disease Copper deficiency Early infancy

6 Indications for Testing Unexplained abnormal liver enzymes Unexplained hemolysis Neurological disturbances Fanconi s syndrome Hypouricemia Keiser Fleisher ring Siblings of affected patients

7 Clinical Features Hepatic (50%) Neurologic ( 4050%) Psychiatric (1025%) Hemolytic anemia (15%) Renal Fanconi s syndrome (rare)

8 Hepatic Manifestations Hepatomegaly Elevated liver enzymes Recurrent hepatitis Chronic Active hepatitis Cirrhosis portal hypertension Acute liver failure, fulminant hepatitis

9 Neurologic Manifestations Movement disorders: tremor & chorea Dystonia Pseudobulbar palsy Seizures Hypokinesis Drooling Dysarthria

10 Psychiatric Manifestations Personality disturbances Depression Neurosis Psychosis

11 Other Systems Blood hemolytic anemia Renal aminoaciduria, nephrolithiasis Skeletal osteoporosis, arthritis Cardiac cardiomyopathy, dysrhytmias GYN infertility, amenorrhea, repeated miscarriages Pancreatitis Hypoparathyroidism

12 Wilson Disease Diagnosis

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14 Mean Hepatic Cu ( mcg/gr dry weight) Disease Wilson s Disease Primary Biliary Cirrhosis Primary Sclerosing Cholangitis Extra hepatic Biliary Obstruction Indian Childhood Cirrhosis Alcoholic /Cryptogenic Cirrhosis Normal

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16 KayserFleischer Ring

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20 MRI Deposition of Copper in the Basal Ganglia Wilson Normal A. D. Patel and M. Bozdech Arch Ophthalmol. 2001;119:

21 Genetic Test Large gene & protein >200 mutation Compound heterozygote Homozygote

22 Treatment Lifelong treatment Asymptomatic & active disease Diet DPenicillamine Trientine Zinc Ammonium tetrathiomolybdate Liver Transplantation

23 Diet: Eliminate Copper Rich Diet Organ meats Shellfish Nuts Chocolate Mushrooms Dried fruits or beans Water supply

24 DPenicillamine General chelator Induce cupriuria Induce metallothionein Well absorbed, meal decrease absorption Monitoring: urinary copper ug Normalization of nonceruloplasmincopper

25 DPenicillamine Side Effects Neurologic deterioration at initial treatment common Hypersensitivity reaction: fever, rash, lupus like Bone marrow suppresion: aplastic anemia, leukopenia, thrombocytopenia Renal: Nephritis, nephrosis Dermatologic: interferes with collagen synthesis Degenerative changes, wound healing Hepatotoxicity

26 Trientine General chelator; induces cupriuria Better safety profile than penicillamine Ideal drug to Pt with penicillamine intolerance Poorly absorbed

27 Trientine Side effects: Neurologic deterioration at initial treatment rare Gastritis Rare side effects Aplastic anemia Sideroblastic anemia

28 Zinc Mode of action: Mettallothionenin inducers Blocks intestinal absorption of copper Usage: For asymptomatic, maintenance pregnancy and in combination therapy

29 Zinc No neurologic deterioration Poorly absorbed with food Side effects: Gastric irritation, Gastritis Pancreatitis biochemical Zinc accumulation Possible change in immunologic function Monitoring: urinary copper < 75ug, normalization of nonceruloplasmin copper

30 Tetrathiomolybdat e Mode of action: General chelator Blocks intestinal absorption of copper Induces intestinal and urinary copper loss Side effects: Anemia Neutropenia

31 Fulminant Hepatic Failure May cause fatigue,hepatic insufficiency, extreme jaunduce ( because of accompanying hemolysis),severe coagulopathy,ascites,hepatic coma,renal failure and death if liver transplantation is not performed Interventions to reduce secondary organ injury while awaiting a suitable donor organ: albumin dialysis, plasmapheresis, exchange transfusion Liver transplant remains the treatment of choice for fulminant

32 Our Patients 7 children with elevated liver enzymes which were found in routine blood testing 3 of them were diagnosed as WD No patient was found with hepatic, neurological, psychiatric or hemolytic manifestations Clinical examination normal

33 Laboratory Viral: HBsAg HCV Ab HAV Ab EBV IgM CMV IgM Tests Immunologic: Immunoglobulins Antiparietal cell Ab Anti mithochondril Ab Anti smooth muscle Ab ANA LKM Anti endomesial Ab

34 Abed 5 M Fatty liver Age (years) Gender Relatives with Wilson AST (u/l) ALT (u/l) US Ceruloplasmin(mg/dl) Cu in serum (mcg/l) Cu in urine (24h) ( mcg/l) Moad 10 M N Nur 6 F Fatty liver Cu after penicillamin (mcg/l) KeiserFleisher ring Liver histology: Steatosis Orcein Rhodenin Cirrhosis Cu in liver( mcg/gr dry weight)) _ Homoz

35 Adham Age (years) Hadil 9.5 Loay 13 Ali 8 M Fatty liver Gender Relatives with Wilson AST(u/l) ALT(u/l) US Ceruloplasmin(mg/dl) Cu in serum( mcg/dl) Cu in urine (24h) (mcg/dl) Cu after penicillamin(mcg/dl) KeiserFleisher ring Liver histology: Steatosis Orcein Rhodenin F N _ 37 M Fatty liver M Fatty liver _ 16 Cirrhosis 48 Cu in liver (mcg/gr dry weight)

36 oay Hadil Adham Ali Nur Moad Abed Age(year) M F M M F M M Gender + + Relatives with Wilso AST(u/l) ALT(u/l) atty iver N Fatty liver Fatty liver Fatty liver N Fatty liver US Ceruloplasmin(mg/dl Cu in serum(mcg/dl) Cu in urine (24h)(mcg dl) Cu after penicilineam (mcg/dl) _ KeiserFleisher ring Liver histology: Steatosis + Orcein Rhodenin + Cirrhosis

37 Conclusions All were asymotomatics All were found within normal examination All without Keiser Fleischer ring US of Abdomen was not informative, liver mostly fatty AST not always > ALT

38 Conclusions Cont. Ceruloplasmin was low in 2 patients Ceruloplasmin >20mg% in 1 patients Cu in serum low in 1 patient. Normal in others Cu in urine in 24 hours collections is indicative Cu in urine after penicillamine is indicative

39 Conclusions Cont Liver Histology: Most with steatosis Orcein stain Positive in 1 patient Rhodanin stain Negative Cirrhosis in 1 patient (6 years old) Cu level in hepatic tissue is diagnostic

40 Take Home Message Consider WD Do large evaluation Send to specialist Early diagnosis & TRT may prevent complications and save lives

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