WILSON DISEASEBY Dr. IRAPPA MADABHAVI

PATIENTS DETAILS 21 YR OLD MALE FROM SOLAN ADMITTED ON 5 / 7 /10 DISCHARGED ON 25 / 7 / 10

Weakness b/l lower limbs X 9 mon Weakness b/l upper limb X 4 mon Difficulty in speaking X 4 mon Drooling of saliva from mouth X 4 mon Flexion deformity of lt upper limb X 4 mon

Illness started 9 mon back when he started having weakness ( distal ) in the form of slipping of chappals.h/o swaying towards left side .no h/o dragging of legs. Pt can still walk.for last 4 mon he started having difficulty in holding things.and developed deformity in the form of flexion at elbow. Difficulty in speech last 4 mon.

NO HISTORY S/O SEIZURES LOSS OF CONSCIOUSNESS. FALL FEVER/ALTERED BEHAVIOR SENSORY INVOLVEMENT CRANIAL NERVE INVOLVEMENT S/O BLADDER OR BOWEL INVOLVEMENT NO HISTORY OF SIMILAR COMPLAINTS IN FAMILY

Family history 2 brothers and one sister . Other two had no such complaints. Parents are normal.

No pallor / icterus / cyanosis / clubbing / LAP/ pedal edema / JVP not raised Visible circumferential golden color ring present in b/l eyes continuous with limbus Resp / CVS normal Per abdomen spleen palpable 8 cm below costal margin , soft in consistency .

HMF - normal Speech dysarthria Cranial nerves normal Gait high stepping gait . Motor system attitude flexion at elbow , at wrist and extension and adduction of fingers Tone rigidity present b/l rt > lt Power 4/5 at all joints Deep tendon reflexes brisk Plantar - Flexor Sensory normal

EXTRAPYRAMIDAL INVOLVEMENT RIGIDITY DYSARTHRIA

SPLENOMEGALY (S/O PORTAL HTN) KF RING HEPATOLENTICULAR DEGENERATION

? WILSON S DISEASE

HBTLC

11.5 g%

6000 / CU MM

DLC

N60 L37 M2 E1

ESR

5 MM in 1ST HR

P/S

Mild anisocytosis with mild hypochromia

RBS

121 mg %

S . Urea / creatinine

32 / 0.7 mg%

Na / K / Cl

143 / 3.6 / 116

Serum protein total / albumin

6.8 / 3.4 gm%

Serum bilirubin total / conjugated

o.4 / nil

OT /PT / Alk phosphatase

44 / 36 / 228

PT / INR

17.7 / 13 sec 1.40

Urine alb , sug

nil

24 HOUR urinary volume 840 ml

24 HOUR urinary copper

142.4 ug / day ( 2 80 ug / day )

Serum ceruloplasmin

9.04 mg / dl ( 22 61 mg / dl)B /L KAYSER FLEISHER RINGS PRESENT

EYE

RADIOLOGICAL INVESTIGATIONS USG ABDOMEN LIVER multiple small hypoechoic nodules throughout the liver SPLEEN massively enlarged more than 20 cm Multiple collaterals at splenic hilum Clinical impression micronodular cirrhosis with massive splenomegaly with collaterals at porta and splenic hilum suggestive of portal hypertension

MRI BRAIN B/L SYMMETRICAL T2W hyperintensities in both putamen with diffuse cerebral and cerebellar atrophy and cerebellar atrophy

Findings favoured

WILSONS DISEASE

TREATMENT Advised not to use copper utensils for cooking Low copper diet Syrup Zn 20 12.5 ml bd Tab Cobadex CZS 1 bd. Advised serum ceruloplasmin levels and 24 hr urinary copper levels for siblings. KF RING negative in them.

WILSON,S disease named after Sammuel Kinnier Wilson. He published his experience of :Progressive lenticular degeneration : a a familial nervous disease associated with cirrhosis of the liver .in doctoral thesis. SAK Wilson Thesis, Univ. of Edinburgh, 1911

Synonyms of Wilson Disease Hepatolenticular Degeneration Progressive Lenticular Degeneration Kinnier Wilsons Diseases Westphal-Strumpell pseudosclerosis

History Kayser in 1902 and Fleischer in 1903 and 1912 described the rings of corneal pigmentation that are characteristic of Wilsons disease. Ceruloplasmin deficiency documented by Scheinberg and Gitlein. Impaired biliary excretion of copper by Frommer 1993 ATP7B was identified which is abnormal gene in Wilsons disease.

Wilson disease is an autosomal recessive inherited disorder of copper metabolism.prevalence

The genetic defect, localized to chromosome arm 13q, has been shown to affect the coppertransporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver

W

w

W

WW Ww

w

Ww ww

Daily requirement of copper is 1-2 mg Absorbed intestine Delievered to circulation ATP7A gene ATOX 1 chaperone protein directs copper. Metallothionein Apoceruloplasmin Biliary canaliculi

Pathology Earliest lesion is fatty infiltration within hepatocytes ,glycogen inclusions in nuclei and portal fibrosis As disease progresses it resembles chronic autoimmune hepatitis

Characterized by excessive deposition of copper in the liver, brain, and other tissues. Liver disease - first decade of life Neuropsychiatric illness - third decade What about INDIAN SUBCONTINENT ???

The patient presenting with liver disease, who is atleast 5 years old but under 40 years old decreased serum ceruloplasmin detectable Kayser-Fleischer rings, has been generally regarded as having classic WD.

Liver disease

Asymptomatic, with hepatic enlargement or abnormal serum aminotransferases found only incidentally. brief clinical illness resembling an acute viral hepatitis, and others may present with features indistinguishable from autoimmune hepatitis. only biochemical abnormalities or histologic findings of steatosis on liver biopsy.

Chronic liver disease and evidence of cirrhosis, either compensated or decompensated. Patients may present with isolated splenomegaly due to clinically inapparent cirrhosis with portal hypertension. acute liver failure with an associated Coombsnegative hemolytic anemia and acute renal failure.

NEUROLOGICAL MANIFESTATIONS

Neurological dysfunction- initial clinical manifestation in 4060% of individuals with Wilsons disease. The average age of symptom onset in persons who present with neurological dysfunction is 18.9 years, although neurological symptoms may appear as early as age 6 years.

Tremor = may be resting, postural, or kinetic,is the most frequent initial neurological feature of Wilsons disease. Proximal upper extremity tremor may take on a coarse, wing-beating appearance, but Wilsons disease tremor may also be distal and quite small in amplitude. Head titubation may also appear.

Dysarthria - either an extrapyramidal or a cerebellar character. Dystonia - tongue,face, and pharynx may produce dysarthria, drooling and an unusual perturbation of facial expression that results in a frozen grimace ( risus sardonicus ). Whispering dysphonia has been described in Wilsons disease, as has a laugh in which most of the sound is generated during inspiration.

Ophthalmic Involvement

Kayser-Fleischer ringsSunflower cataract

Abnormal ocular movements

Kayser-Fleischer rings are observed in up to 90% of individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations. Although Kayser-Fleischer rings are a useful diagnostic sign, they are no longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations.

Kayser-Fleischer rings are formed by the deposition of copper in the Descemet membrane in the limbus of the cornea. The color may range from greenish gold to brown

Sunflower cataract in wilsons disease

AASLD PRACTICE GUIDELINESApproach to diagnosis of Wilson ,s disease in a pt with unexplained liver disease

1. WD should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD 2. WD must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric manifestation . 3. In a patient in whom WD is suspected, KayserFleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of KayserFleischer rings does not exclude the diagnosis of WD, even in patients with predominantly neurological disease

Diagnosis Serum ceruloplasmin Basal 24 hour urinary copper Serum copper Imaging Liver biopsy

Serum ceruloplasmin Screening test. An extremely low serum ceruloplasmin level ( < 50 mg / L or < 5 mg/dL ) should be taken as strong evidence for the diagnosis of WD. Modestly subnormal levels suggest further evaluation is necessary . Serum ceruloplasmin within the normal range does not exclude the diagnosis . Abnormally low in menke,s disease , aceruloplasmimnemia , sprue , nephritic syndrome , protein losing enteropathy .

Serum copper Serum copper = bound copper + free copper Problem with serum copper Free copper = serum copper ceruloplasmin X 3 Normal range = 10 15 ug / dl.

Basal 24 hour urinary copper Basal 24-hour urinary excretion of copper should be obtained in all patients in whom the diagnosis of WD is being considered. The amount of copper excreted in the 24-hour period is typically >100 g (1.6 mol) in symptomatic patients, but finding > 40 g (>0.6 mol or >600 nmol) may indicate WD and requires further investigation (Class I, Level B). Normal values 20 50 ug/dl.

Diagnosis of WD in symptomatic children if basal urinary copper excretion is 1600g copper/24 hours (>25mol/24 hours) following the administration of 500 mg of D-penicillamine at the beginning and again 12 hours later during the 24hour urine collection are found in patients with Wilson disease. The predictive value of this test in adults is unknown (Class I, Level B).

Imaging Diagnosis Monitoring during therapy. MRI v/s CT. T1w images & T2w images Neuronal loss , gliosis ,degeneration ,vacuolization

Where diagnosis is not straightforwardHepatic parenchymal copper content > 250 ug/g dry weight provides critical diagnostic information In untreated patients, normal hepatic copper content (< 40-50 ug/g dry weight) almost always excludes a diagnosis of WD. Further diagnostic testing is indicated for patients with intermediate copper concentrations (70-250 g/g dry weight) especially if there is active liver disease or other symptoms of WD.

Treatment

4 Approaches Dietary therapy Reduce copper absorbtion by zinc tetrathiomolybdate Increase copper excretion by chelaters pencillamine trientine Liver transplantation

Zinc ( acetate , sulfate , gluconate ) maintenance therapy initial therapy in asymptomatic patients 24 hr urinary copper