WILSON DISEASE

BY 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

HB
TLC

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

WW Ww

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 rings
Sunflower 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 GUIDELINES

Approach 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 <100 g/24 hours (1.6 mol/24 hours).
Values for the penicillamine challenge test of >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 straightforward

Hepatic 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 <75 ug /day D pencillamine baseline copper metabolic parameters , CBC , Platelet count , urine analysis and 24 hr urinary protein. Liver transplantation decompensated liver disease unresponsive to medical therapy.

Penicillamine

Hepatic disease

Trientine

Hepatic disease (or first choice?) Neurological disease Penicillamine side effects Neurological disease Maintenance treatment Pregnancy Neurological patients?

Zinc

Tetrathiomolybdate?

Monitoring drug treatment in wilson,s disease

Family Screening

Avoid Copper Rich Foods Patients will also need to take vitamin B6 and follow a low-copper diet , which means avoiding mushrooms, chocolate, nuts dried fruit , liver. no eating and cooking in copper utensils and shellfish

Future therapy
Gene therapy Lentiviral gene transfer (ATP7B)
Increased levels of ceruloplasmin Reduced hepatic copper Improved hepatic fibrosis Hepatocytes transplantation 6 months after transplant: liver was extensively repopulated with hepatocytes ATP7B expression, increased Cp, reduced hepatic Cu Improved liver histology

thanks

 WD is a very peculiar medical situation,

genetic but treatable disorder, almost complete resolution of symptoms with appropriate and timely therapy
Early diagnosis and early therapy are

mandatory
Compliance to medical treatment is crucial

thanks

 Progressive lenticular degeneration a familial nervous disase associated with cirrhosis of the liver SAK Wilson Thesis, Univ. of Edinburgh, 1911

Laboratory Studies: - Serum ceruloplasmin: Approximately 90% of all patients with Wilson disease have ceruloplasmin levels of less than 20 mg/dL (reference range, 20-40 mg/dL). Ceruloplasmin is an acute phase reactant and may be increased in response to hepatic inflammation, pregnancy, estrogen use, or infection. Falsely low ceruloplasmin levels may be observed in any protein deficiency state, including nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition. - Urinary copper excretion: The urinary copper excretion rate is greater than 100 mg/d (reference range, <40 mg/d) in most patients with symptomatic Wilson disease. The rate may also be elevated in other cholestatic liver diseases. Both the sensitivity and the specificity of this test are suboptimal for use as a screening test; however, it may be useful to confirm the diagnosis and to evaluate the response to chelation therapy. - Hepatic copper concentration: This test is regarded as the gold standard for diagnosis of Wilson disease. A liver biopsy with sufficient tissue reveals levels of more than 250 mcg/g of dry weight even in asymptomatic patients.

 A. Kinnier Wilson masterfully provided the first detailed, coherent description of both the clinical and pathological details of the entity that now bears his name. . Ceruloplasmin deficiency in Wilsons disease was documented independently by Scheinberg and Gitlin9 and by Bearn and Kunkel in1952, and the presence of impaired biliary excretion ofcopper by Frommer in 1974.

GENETICS
A mutation in the ATP7B gene, located on chromosome 13, is responsible for Wilsons disease. The number of specific mutations that have been identified is now approaching 300. Although missense mutations are most frequent, deletions, insertions, nonsense, and splice site mutations all occur. nonsense and frameshift mutations may correlate with earlier onset of symptoms and more severe disturbance of copper metabolism.

 Copper is an essential element for cellular function, yet free copper is extremely toxic and can produce irreversible cellular damage. To cope with this, elegant systems have evolved that bind the copper molecule to ensure safe transport of necessary copper to intended sites and safe elimination of excess copper through the biliary system.

 ATP7B protein normally resides in the trans-Golgi network in hepatocytes, where it mediates the incorporation of six copper molecules into apoceruloplasmin,forming ceruloplasmin. Under high copper conditions, however, ATP7B is also redistributed to cytoplasmic vesicles where it transports excess copper across the hepatocyte apical membrane into the bile canaliculus for subsequent biliary excretion. In individuals with Wilsons disease, mutation in the ATP7B gene results in defective ATP7B protein that cannot perform these functions

 ATP7B protein normally resides in the trans-Golgi network in hepatocytes, where it mediates the incorporation of six copper molecules into apoceruloplasmin,forming ceruloplasmin. Under high copper conditions, however, ATP7B is also redistributed to cytoplasmic vesicles where it transports excess copper across the hepatocyte apical membrane into the bile canaliculus for subsequent biliary excretion. In individuals with Wilsons disease, mutation in the ATP7B gene results in defective ATP7B protein that cannot perform these functions

 Chelating agents (Penicillamine, Trientine) Zinc Tetrathiomolybdate (?) Diet Liver Transplantation

 ATP7B encodes a metal transporting P- type ATP ase which is expressed mainly in hepatocytes and functions in transmembrane transport of copper within hepatocytes. Absent or reduced function of ATP7B protein leads to decreased hepatocellular excretion of copper into bile. Failure to incorporate copper into ceruloplasmin is an additional consequence of loss of functional ATB7B gene

 They may also be observed in patients with carotenemia arcus senilis, chronic active hepatitis, chronic cholestasis, chronic jaundice, cryptogenic cirrhosis, intraocular foreign body with <85% copper, multiple myeloma, primary biliary cirrhosis,topical copper solution treatment of the eye, and trypanosomiasis. The finding of a Kayser-Fleischer ring is a useful indicator of severe copper overload. If the ring is not detected by clinical inspection, the cornea should be examined under a slit lamp by an experienced ophthalmologist. Kayser-Fleischer rings are present in 95% of patients with neurological symptoms, in 50-60% of patients without neurological symptoms and in only 10% of asymptomatic siblings.

 As the doctor says of a wasting disease, to start with it is easy to cure but difficult to diagnose; after a time, unless it has been diagnosed and treated at the outset, it becomes easy to diagnose but difficult to cure .

Niccolo Machiavelli, The Prince, 1514 (transl. George Bull