In the name of God

Wilson diseasePresented by A.H. Hosseini MD

COPPER METABOLISM

• Recommended – 0.9 mg/d

• Absorbed from duodenum & prox.SI

• Transported in portal circulation bound protein

to liver

• Liver synthesize Cu bound ceruloplasmin &

excrete copper into bile

• Stored in liver bound with metallathionein

HISTORY

• 1912- by Samuel alexander Kinnear Wilson : “progressive lenticular degeneration”

• In 1921, Hall further characterized hepatic involvement and introduced the term hepatolenticular degeneration.

• Using positional cloning techniques in 1993, three groups independently reported the identification of the gene responsible for Wilson’s disease, designated ATP7B

EPIDEMIOLOGY

• autosomal recessive inheritance, thus consanguinity is relatively common in affected families

• a worldwide prevalence of approximately 1 in 30,000 and the heterozygote carrier state in approximately 1 in 90 persons

• marked differences in organ system involvement and biochemical findings, suggesting that polygenic or environmental factors may play a role in expression of the disease

• Forty to 60% of patients: hepatic presentation in the second decade of life

• The remainder of patients come to clinical attention during the third and fourth decades with a primarily neurologic (34%) or psychiatric (10%) presentation

• All patients have liver involvement, although it may be asymptomatic and well compensated

GENETICS

• Wilson’s disease gene is on the long arm of chromosome 13

• over 250 distinct mutations identified from patients with Wilson’s disease

• Most of these are small deletions or missense mutations,

• Missense mutations are associated with a predominance of neurologic symptoms and a later clinical presentation.

• Deletions and other mutations causing premature stop codons are associated with an earlier clinical presentation predominated by symptoms of liver disease

• Haplotype analysis (microsatellite markers) may be particularly helpful in evaluating relatives of a known case

PATHOGENESIS

• Mutations in ATP7B• impaired biliary copper excretion ,

• progressive accumulation of copper in the liver followed by subsequent deposition in other organs.

• defective hepatocyte incorporation of copper into ceruloplasmin

• failure to clear the high hepatic copper burden

• intestinal absorption of copper was not increased

• Serum ceruloplasmin levels are low in Wilson’s disease because of decreased synthesis of holoceruloplasmin and rapid clearance of apoceruloplasmin

• Heterozygotes for Wilson’s disease may have low ceruloplasmin levels yet no pathologic accumulation of copper in tissues

• The normal ceruloplasmin level results from ceruloplasmin being an acute phase reactant. In addition, circulating apoceruloplasmin may be detected by newer immunologic assays for ceruloplasmin

CLINICAL FEATURES OF WILSON’S DISEASE

• clinical manifestations of Wilson’s disease are rarely apparent before age 5 years

• before age 10 years: 83% of patients presented with hepatic symptoms and 17% with neuropsychiatric manifestations;

• between 10 and 18 years: 52% presented with hepatic and 48% with neuropsychiatric symptoms;

• after age 18 years: 24% presented with hepatic and 74% with neuropsychiatric symptoms

• all ages: approximately 49% of patients present with hepatic and 46% with neuropsychiatric symptoms

AS A RULE…

A combination of liver dysfunction and other organ system involvement, at any age, should suggest Wilson’s disease.

KAYSER–FLEISCHERRING RINGS

• After hepatic saturation, copper accumulating in the ocular cornea

• a greenish brown ring at the periphery of the cornea on its posterior surface in Descemet’s membrane

• Slit lamp examination

• Treatment with copper chelators results in gradual resolution of the rings over 3–5 years

• The K-F ring does not interfere with visual function

• The K-F ring is virtually always present at the time when neurologic or psychiatric symptoms develop, although there are rare exceptions (5% of patients with neurologic symptoms)

• The K-F ring is not pathognomonic for Wilson’s disease ; prolonged cholestatic, liver disease, such as chronic hepatitis, chronic intrahepatic and neonatal cholestasis, cryptogenic cirrhosis, and primary biliary cirrhosis

• Absence of KF rings doesn’t exclude diagnosis even in neurological disease

• grayish brown “sunflower cataract” ; deposits of copper in the anterior and posterior lens capsule

• they rarely interfere with vision and resolve with therapy

The other circumstance in which these cataracts may develop is from a copper-containing foreign body lodged intraocularly (chalcosis)

spectrum of disease

HEPATIC PRESENTATION

• Clinical symptoms of liver disease virtually never occur before age 3–5 years

• asymptomatic mild elevation of serum amino transferase levels

All children and adults who have unexplained chronically elevated serum aminotransferase levels require a serum ceruloplasmin, slit-lamp examination, 24-hour urine copper excretion, and most likely, a liver biopsy to establish the underlying diagnosis

• acute hepatitis(Clinical signs of jaundice, anorexia, nausea, malaise, pale stools, and dark urine mimic infectious hepatitis

• fulminant hepatic failure (Symptoms progress to fatigue, hepatic insufficiency, extreme jaundice (because of the accompanying hemolysis), severe coagulopathy, ascites, hepatic coma, renal failure, and death if liver transplantation is not performed )

• In one study of patients in this clinical setting, a ratio of

ALP (IU/L) /Total Bili(mg/dL) less than 2 AST/ALT ratio greater than 4 o appeared to be diagnostic of Wilson’s disease

POINT!!!

• A similar, and unfortunate, fulminant presentation has been described in patients who had been successfully treated for up to 20 years with copper chelators but who discontinued therapy or became noncompliant for as little as 8 months’ time

• Similar presentations have occurred after the discontinuation of zinc therapy

• Chronic hepatitis (during adolescence or young adulthood, Malaise, anorexia, fatigue, abdominal pain, and nausea may precede the onset of jaundice and hepatic dysfunction )

polyarthralgias, edema, gynecomastia, ascites, clubbing, or spider angiomata, when present, indicate the chronic nature and likelihood of hepatic fibrosis or cirrhosis

• cirrhosis (Although cirrhosis and its complications are relatively common presenting features of Wilson’s disease in childhood, the disease may remain silent and asymptomatic well into adulthood, when patients present with neurologic, psychiatric, endocrine, or other symptoms.

AS A RULE…..

• all children age 3–4 years or older with cirrhosis should undergo evaluation for Wilson’s disease

• Cholelithiasis: common in adolescents with Wilson’s disease and results from ongoing hemolysis in the presence of cirrhosis

• Abdominal pain in a patient with Wilson’s disease should prompt ultrasonographic evaluation for gallstones.

• Interestingly, the copper content of gallstones removed from Wilson’s disease patients was significantly lower than that in pigment stones.

• intra-abdominal malignancies (primarily hepatomas, cholangiocarcinomas, and poorly differentiated adenocarcinomas)

• No case of hepatocellular carcinoma has been reported in an affected child or adolescent.

NEUROLOGICAL

• - Neurologic symptomatology is generally limited to motor manifestations of extrapyramidal or cerebellar dysfunction

• often second-third decade

• Tremor (resting, intention)

• Drooling, hypersalivation

• Dysarthria

• Coordination defects, clumsiness DystoniaWriting difficulties Choreiform movements

• Ataxic gaitHeadacheSeizures

BRAIN MRI CORRELATION OF NEUROLOGIC FINDINGS

• pseudoparkinsonian

• pseudosclerosis

• dyskinesia

PSYCHIATRIC

• Organic dementia

• Neuroses, Anxiety,

• depression,

• Obsessive/ compulsive disorder

• Schizophrenia

• Bipolar disorder

• Antisocial behavior

• Alcoholism

RENAL

• Nephrolithiasis

• Proximal renal tubular dysfunction.

• Distal renal tubular acidosis is reflected by the inability to acidify urine to a pH of less than 5.2 in response to an ammonium chloride load

• increased tendency for formation of renal stones

• end-stage liver disease may develop severe renal insufficiency requiring temporary dialysis.

• Isosthenuria

• severe proteinuria and the nephrotic syndrome or a Goodpasture- like syndrome are more likely to occur as a consequence of penicillamine administration rather than of copper toxicity

HEMATOLOGICAL

• - Coombs neg. hemolytic anemia

- transient jaundice

- acute intra vascular hemolysis

• When associated with the acute fulminant hepatic presentation, hemolysis is a poor prognostic factor, contributing to renal failure by excess hemoglobinuria

• circulating hepatic-derived coagulation factor levels may be low, platelets may have impaired function, and portal hypertension may cause splenomegaly and resultant thrombocytopenia and leukopenia

CARDIAC INVOLVEMENT

• Electrocardiographic, including left ventricular hypertrophy, ST wave depression, and T wave inversion.

• Arrhythmias

• orthostatic hypotension (although asymptomatic), indicating autonomic dysfunction.

SKELETAL MANIFESTATIONS

• may even be the first clinical symptoms of the disease

• Bone demineralization is the most common feature possibly caused by the hypercalciuria and hyperphosphaturia resulting from renal tubular dysfunction

• Other radiologic changes include rickets and osteomalacia, osteoporosis, spontaneous fractures, bone fragmentation near joints

• Stiffness of larger joints is a complaint of many patients

SKIN MANIFESTATIONS

• Skin pigmentation on the anterior aspect of the lower legs, because of deposition of melanin

• acanthosis nigricans

• Blue lunulae of the fingernails

ENDOCRINE ABNORMALITIES

• Hormonal imbalance secondary to chronic liver disease has been thought to lead to amenorrhea in women and gynecomastia in boys

• increased androgen levels and abnormalities in the hypothalamic–pituitary–testicular axis in males

• Additional infrequent associations with Wilson’s disease include diabetes mellitus exocrine pancreatic insufficiency & hypoparathyroidism

Laboratory Findings

• Patients with Wilson’s disease may present with almost any combination of abnormalities in liver blood tests, or even no abnormality at all

• Serum aminotransferase levels are characteristically only mildly to moderately elevated, with AST > ALT

• Serum alkaline phosphatase is usually in the low range

• Serum phosphate and uric acid may be low because of renal tubular losses

• Changes on radiologic evaluation of the skeleton may include osteoporosis, rickets, osteomalacia, localized demineralization, osteoarthritis, and other lesions

DIAGNOSIS

• No single laboratory test result can establish this diagnosis without confirmatory clinical and laboratory data, with the possible exception of genetic testing under certain circumstances

• Liver function tests

• Serum ceruloplasmin

• Urinary copper excretion

• Hepatic parenchymal copper concentration

• Liver biopsy

• Neuro radiological imaging

• Genetic studies

SERUM OR PLASMA CERULOPLASMIN• Synthesized in liver-acute phase reactant

• level less than 20 mg/dL suggests the diagnosis of Wilson’s disease

• LOW levels seen in patients with massive protein loss, kwashiorkor, severe copper deficiency, severe hepatic insufficiency, hereditary hypoceruloplasminemia, or aceruloplasminemia, or fulminant hepatitis; in the normal neonate; in those with Menkes’ syndrome; and in 10% of heterozygotes for Wilson’s disease

• Level < 5 mg/dl: strong evidence of WD

• If the serum ceruloplasmin concentration is greater than 20 but less than 35 mg/dL, the diagnosis of Wilson’s disease is not excluded

• If ceruloplasmin is normal but there is a high index of suspicion, then

① a 24-hour urine copper excretion (best after penicillamine challenge),

② slit-lamp examination, and

③ liver biopsy

should be performed to confirm or exclude the diagnosis.

• If a sibling has Wilson’s disease, then haplotype analysis can potentially be performed.

the diagnosis of Wilson’s disease must be confirmed by

• an elevated urine 24-hour copper excretion above 100 μg/24 hr (normal, <40 μg/ 24 hr),

• an elevated urine copper during a penicillamine challenge

• the presence of a K-F ring (and the absence of other cholestatic liver disorders),

• elevated hepatic copper content (>250 μg/g dry weight) with consistent liver histology

URINARY COPPER• 24 hr urinary Cu excretion

• Dx & monitoring

• Basal 24 hr urine Cu > 100 µg in symptomatic WD

• But > 40 µg may indicate WD , req. further test

• Pencillamine challenge test 500 mg D-pencillamine orally at beginning and

repeat after 12 hr during 24hr urine collection

> 1600 µg Cu/24 hr urine - positive

24 HOUR URINE

• Urine must be collected in copper-free containers to avoid contamination

• Additionally, determining if the collection was a full 24-hour collection should be confirmed by measuring total urinary creatinine excretion (normal, 10–20 mg/kg/ 24 hr).

• False-positive results of a 24-hour urine copper excretion (i.e., >100 μg/24 hr) may be seen if the patient is receiving any type of copper chelation therapy, if the collection is contaminated by exogenous copper, or if the patient has chronic active hepatitis, cholestatic cirrhosis, or nephrotic syndrome

SERUM FREE COPPER

• Increased level of serum “free” copper

• Serum free Cu is non-ceruloplasmin bound Cu

• Total S.Cu (mcg/dl)- 3x serum ceruloplasmin Cu (µg/dl)

• Normal level<15 mcg/dl

• > 25 mcg/dl in untreated WD

• < 5mcg/dl indicates over-treated

HEPATIC PARENCHYMAL COPPER CONCENTRATION

• Normal - <40-50µg/g dry wt. liver

• Critical value- > 250 µg/g dry wt.

• Further evaluation needed if 70- 250µg/g ,if

active liver d/s or symptoms of WD

LIVER BIOPSY

• Mild steatosis- earliest

• Auto immune hepatitis histologic findings

• Cirrhotic changes-macronodular

• marked hepatocellular degeneration & parenchymal collapse

• Cu staining is variable- poor predictive value

NEURO-IMAGING Brain CT abnormalities:

• 73% with ventricular dilation, 63% cortical atrophy, 55% brainstem atrophy, 45% hypodense areas in basal ganglia, and 10% posterior fossa atrophy.

• MR imaging- evaluate neurologic WD & prior to

treatment

• MRI- T2 hyperintensity in basal ganglia,thalami

GENETIC STUDIES• Molecular genetic testing has been available in recent years and is most helpful if the

diagnosis remains in doubt

• DNA mutation analysis can be performed for a defined ATP7B mutation,

• common mutations in the appropriate ethnic population

• haplotype (microsatellite) marker analysis if a first-degree relative has Wilson’s disease.

• Prenatal diagnosis ???

Tests that appear to be of no value in establishing the diagnosis of Wilson’s disease

• computed tomography (CT) scanning &

• MRI of the liver,

because liver copper content cannot currently be detected or quantitated by these modalities

AN ASYMPTOMATIC PATIENT IN WHOM A K-F RING IS FOUND ON ROUTINE OPHTHALMOLOGIC EXAMINATION

① a serum ceruloplasmin level should be performed.

② If it is low or there is high suspicion and it is normal,

③ a 24-hour urine copper excretion should be performed and consideration given to a liver biopsy.

④ Elevated urine copper excretion, a low ceruloplasmin, and a K-F ring establish the diagnosis.

⑤ However, if the liver or spleen is enlarged or liver blood tests are abnormal, a liver biopsy should be performed.

ASYMPTOMATIC SIBLINGS OF WILSON’S DISEASE PATIENTS

① screened for the disease after age 3 or 4 years unless hepatomegaly or abnormal aminotransferase levels are found earlier.

② A thorough history and physical examination, slit-lamp examination, and laboratory analysis should be performed

③ If all tests are normal, it is very unlikely that the relative has Wilson’s disease

④ However, if any of those tests are abnormal, a liver biopsy should be performed for histology, electron microscopy, and quantitative copper analysis.

⑤ An alternative, less invasive approach is to evaluate the known patient, the sibling, and the parents for DNA haplotype (microsatellite markers) to determine if the sibling in question has inherited the Wilson’s disease gene.

⑥ Haplotype analysis is informative in over 90–95% of cases

⑦ Another approach is to genotype the affected relative and if ATP7B mutations are identified, to test the sibling in question for these mutations.

⑧ Finding two mutations or informative microsatellite markers will establish the diagnosis of Wilson’s disease and preclude the need for liver biopsy unless there are signs or symp- toms of chronic liver disease

treatment

• Anti –copper drugs-

-D-Pencillamine

- Zinc

- Trientene

- Tetrathiomolybdate(TM)

• Diet

• Drinking water

• Concomitant hepatic,neurological management

• Liver transplantation

D-PENICILLAMINE

• a sulfhydryl- containing metabolite of penicillin

• The actual mechanism on how this drug works is not known

• “decoppering effect,”

• “detoxification effect”

• It is recommended to begin the penicillamine therapy with one fourth to half of the desired dose and increase the dose slowly over 1–2 weeks.

• The dosage for older children and adults is 1 g of penicillamine orally per day in four divided doses given ideally at least 30 minutes before or 2 or more hours after meals.

• If an overtly ill patient fails to show clinical improvement, the dosage can be increased to 1.5–2.0 g/d.

• In young children, a dosage of 20 mg/kg/d rounded to the nearest multiple of 250 mg is given ideally in three divided doses

• After stabilization, the dose may be divided into two or three daily doses not to be given with meals

• D-penicillamine may have an antipyridoxine effect, thus all treated patients should also receive 25–50 mg of pyridoxine daily

• During the first month of penicillamine therapy, the patient should be monitored weekly for fever or rash.

• A complete blood count and platelet count, urinalysis, and renal and liver blood tests should be obtained every 1–2 weeks

• If the patient responds appropriately with resolution of symptoms and normalization of liver blood tests, monitoring is performed every 1–3 months for the first year and every 6–12 months thereafter.

• An annual 24-hour urinary copper excretion is helpful in mon- itoring chronic penicillamine therapy

• In 10–50% of patients, neurologic symptoms worsened shortly after penicillamine therapy was started

• Continued or altered penicillamine therapy generally resulted in reversal of this worsening although irreversible neurologic abnormalities have been reported

• Thus, it is recommended that the penicillamine dosage be reduced to 250 mg/d if neurologic symptoms worsen and gradually increased every 4–7 days by 250 mg/d until urinary copper excretion exceeds 2000 μg/d

TRIETHYLENE TETRAMINE DIHYDROCHLORIDE (TRIENTINE)

• It does not contain sulfhydryl groups; rather it chelates copper by forming a stable complex with copper through its four nitrogen atoms in a planar ring.

• better safety profile.

• The initial dosage for adolescents and adults is 750–1500 mg daily in two to three divided doses before meals.

• Maintenance therapy is typically 750 or 1000 mg/d.

• In children, the dose generally used is 20 mg/kg/d rounded off to the nearest 250 mg.

• The toxicity includes bone marrow suppression (a sideroblastic anemia), nephrotoxicity, and skin and mucosal lesions .

• Female patients may become iron deficient and require iron supplementation

AMMONIUM TETRATHIOMOLYBDATE

• an alternative approach to the treatment of Wilson’s disease is based on whether the patient presents with neurologic or hepatic symptoms

• Because up to 50% of patients in an earlier series who had neurologic disease showed worsening of their symptoms with penicillamine therapy, ammonium tetrathiomolybdate, for initial therapy in neurologically affected patients

• it is absorbed and complexes with copper and albumin in blood, preventing cellular uptake and resulting in decreased intracellular copper stores

• After 8 weeks, the drug was stopped and patients were maintained on oral zinc acetate, 50 mg three times a day

- inhibit CU absorption

- bind with copper (chelator)

- used in neurological WD

- S/E- anemia,neutropenia,

hepatotoxicity

- 120 mg/d ie. 20mg x 3 with meal

60mg bed time

- 8 weeks therapy

- weekly neurological examination

ZINC THERAPY

• Zinc has been proposed as maintenance or adjunctive therapy for Wilson’s disease.

• Zinc inhibits intestinal absorption of copper

• The dosage of zinc acetate, given between meals, that currently is advocated is 50 mg of elemental zinc three times daily or zinc sulfate, 150– 220 mg three times daily

• Common side effects include headache and gastrointestinal upset, which are perhaps less common with zinc acetate.

• Because of its slower onset of action, zinc therapy is generally not used as initial therapy for symptomatic patients.

• Zinc therapy may play a role in presymptomatic patients or siblings

• It should also be stressed that patients have deteriorated and developed fulmi- nant liver failure after the discontinuation of zinc therapy.

ANTIOXIDANT THERAPY

• Vitamin E, 400–1200 IU/d, may be given orally in divided doses with meals safely.

• Because high-dose vitamin E may interfere with vitamin K–dependent clotting factor synthesis, the prothrombin time should be monitored and vitamin K supplementation used if necessary.

LIVER TRANSPLANTATION

• acute fulminant hepatic failure,

• those with fulminant hepatic failure after inadvisably discontinuing copper chelation therapy

• decompensated cirrhosis unresponsive to medical therapy

• To better determine the criteria for referral for liver transplantation , Nazer et al. developed a prognostic index based on grading from 1–4 points the serum bilirubin concentration, serum AST, and prolongation of prothrombin time

NAZER PROGNOSTIC INDEXLab measurement

normalvalue

Score 0

Score 1

Score 2

Score 3

Score 4

Serumbilirubin

0.2-1.2 <5.8 5.8-8.8 8.9-11.7 11.8-17.5 >17.5

SGOT 10-35 <100 100-150 151-200 201-300 >300

PT prolongation diff.

12-14s <4s 4-8s 9-12 13-20 >20

NAZER INDEX

• Mild hepatic failure- score <6 survived with medical therapy

• Moderate hepatic failure- 7-9

• Severe hepatic Failure - >9 fatal courses or required transplantation

• The authors developed a new index based on serum bilirubin, INR, AST, albumin, and WBC at presentation.

• A score greater than 11 of a possible 20 was predictive for death, with a 93% sensitivity, 98% specificity, and 88% positive predictive value

SPECIAL CIRCUMSTANCES

PREGNANCY

• During pregnancy, it is advisable to continue penicillamine therapy at a dosage of 750–1000 mg/d

• Several patients who have discontinued therapy for longer periods during pregnancy have had episodes of acute hemolysis or worsening of liver disease including fulminant hepatic failure.

• All children fathered by patients with Wilson’s disease have been normal

• Although infants may be at a small risk for a connective tissue or skin abnormality during penicillamine therapy, the risk to mother and infant of discontinuing copper chelation therapy appears to be greater.

• If cesarean section is anticipated, some authorities recommend reducing the dose of penicillamine to 250 mg/d 6 weeks before delivery to reduce the risk for impaired wound healing

SURGERY

• Penicillamine has inhibitory effects on collagen cross- linking

• Therefore, to prevent interference with wound healing, it is recommended that when patients with Wilson’s disease undergo surgery, the dose of penicillamine be reduced, but not stopped, for 10–14 days postoperatively

DIET

• Avoid liver ,shell fishes,nuts,chocolate,mushroom

• After 6-12 months Rx, one meal + shell fish/ wk

• If enteral feeding,Cu <1.5 mg/d

• Drinking water - < 0.1 ppm Cu

ANTI COPPPER DRUGSDrugs Mode of action Neurological

deteriorationS/E Dosage monitoring

D-pencillamine Chelator inducescupuria

1

20-40 % in initial phase

BM suppression,nephrotic syndrome,Hepatotoxicity,fever,

250-500mg/d,incremental 250mg4-7dMax.1-1.5g/d ( 2-4 doses)Maint-750mg-1gPyridoxine-25mg/d

24hr.U Cu-200-500µgFree Cu- 10-15µg/dl

1,3,6,12,18,24 monthsThenannually

DRUGS MODE OF ACTION SIDE EFEECTS DOSAGE MONITOR

Trientine Chelator induces cupuria

Gastritis,aplastic anemia rare,Sideroblastic anemia

750-1500mg/d(2-3 doses)20mg/kg/d(childMaint-750-1000mg

24hr U.Cu &Non-ceruloplasBound copper1,3,6,12,18,24 months-annually

Zinc

Metallothione inducer,Inhibits Cuabsoption

Gastritis,pancreatitis,Zn accumulation

150mg/d in 3 divided doses75mg/d (child, <50 kg)

24hr .U.Cu-50-125µg/d &24h.U.Zn > 2mg/d3,6 months,6 month 2yr,then yearly

SUMMARY• WD- is an medical enigma with wide spectrum

• Proper clinical examinations

• Integrated diagnostic approach

• Treatment for various clinical profiles

• Zinc as a new paradigm shift in Rx

• Hepatic transplantation

• Monitoring., and prognosis

• Lifelong Rx and normal expectancy

• Fatal if not treated.