Wilson Disease (hepatolenticular degeneration)
 - AR
 - The incidence is 1/500,000 to 1/100,000 births.

PATHOGENESIS

 - ...
CLINICAL MANIFESTATIONS.
presentations are variable, with a tendency to familial patterns. The
younger the patient, the mo...
o   Always present in patients CNS.

Psychiatric manifestations

  - Depression
  - Anxiety
  - Psychosis.

BLOOD

  - Coo...
- DD autoimmune hepatitis.
  - Fibrosis and cirrhosis
  - Ultrastructural changes
      o primarily the mitochondria
     ...
(usually <40 μg/day) is increased to >100 μg/day and
  often up to 1,000 μg or more per day.

  In equivocal cases, the re...
Genetic screening

 - linkage analysis
 -   Direct DNA mutation analysis is possible, especially if the
     mutation for ...
o   Toxic effects of penicillamine 10–20%
             Hypersensitivity reactions
             (Goodpasture syndrome, sy...
Zinc

  -    Used as adjuvant therapy
  -      Maintenance therapy, or primary therapy in
       presymptomatic patients
 ...
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Wilson disease

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Wilson disease

  1. 1. Wilson Disease (hepatolenticular degeneration) - AR - The incidence is 1/500,000 to 1/100,000 births. PATHOGENESIS - Abnormal gene 13q14.3). - This gene encodes a copper transporting P-type ATPase, - ATP7B. ATP7B is mainly but not exclusively expressed in hepatocytes and is thought to be critical for biliary copper excretion and for copper incorporation into ceruloplasmin. - Absence or malfunction of ATP7B results in decreased biliary copper excretion and diffuse accumulation of copper in the cytosol of hepatocytes. - When liver cells become overloaded, copper is redistributed to other tissues including the brain and kidneys, to which it is toxic, primarily as a potent inhibitor of enzymatic processes. - Ionic copper inhibits pyruvate oxidase in brain and ATPase in membranes, leading to decreased ATP- phosphocreatine and potassium content of tissue. - More than 250 mutations, making diagnosis by DNA mutational analysis a difficult task - Most patients are compound heterozygotes. raises
  2. 2. CLINICAL MANIFESTATIONS. presentations are variable, with a tendency to familial patterns. The younger the patient, the more likely hepatic involvement will be the predominant manifestation. Females are three times more likely than males to present with fulminant hepatic failure. After 20 yr of age, neurologic symptoms predominate. - hepatic disease o Asymptomatic hepatomegaly (with or without splenomegaly), o subacute or chronic hepatitis, and fulminant hepatic failure. o Cryptogenic cirrhosis, portal hypertension, o ascites, edema, variceal bleeding, o hepatic dysfunction o (Delayed puberty, amenorrhea, and coagulation defect) can be manifestations of Wilson disease. Neurologic disorders o insidiously or precipitously o Intention tremor o dysarthria, dystonia o lack of motor coordination o deterioration in school performance o behavioral changes. EYE - Kayser-Fleischer rings o May be absent in young patients with liver disease
  3. 3. o Always present in patients CNS. Psychiatric manifestations - Depression - Anxiety - Psychosis. BLOOD - Coombs-negative hemolytic anemia: may be an initial manifestation related to the release of large amounts of copper from damaged hepatocytes - Usually fatal without transplantation. - Urinary copper excretion and serum copper levels (non-ceruloplasmin-bound) are markedly elevated. KIDNEY - Fanconi syndrome OTHERS o Arthritis o cardiomyopathy, o Endocrinopathies (hypoparathyroidism). PATHOLOGY. All grades of hepatic injury - Steatosis - Heptocellular ballooning - Degeneration - Glycogen granules - Minimal inflammation, - Enlarged Kupffer cells.
  4. 4. - DD autoimmune hepatitis. - Fibrosis and cirrhosis - Ultrastructural changes o primarily the mitochondria o increased density of the matrix material, o inclusions of lipid and granular material, o increased intracristal space o Dilatation of the tips of the cristae. o Liver copper content is elevated. DIAGNOSIS. Wilson disease should be considered in children and teenagers with unexplained acute or chronic liver disease, neurologic symptoms of unknown cause, acute hemolysis, psychiatric illnesses, behavioral changes, Fanconi syndrome, or unexplained bone disease. The clinical suspicion is confirmed by study of indices of copper metabolism. CERULOPLASMIN LEVEL best screening test - Wilson disease have decreased ceruloplasmin levels. DUE TO failure of copper to be incorporated into ceruloplasmin leads to a plasma protein with a shorter half- - . FALSE NEGATIVE: elevated in acute inflammation and in states of elevated estrogen such as pregnancy, estrogen supplementation, or oral contraceptive use. Serum copper level may be elevated in early Wilson disease urinary copper excretion
  5. 5. (usually <40 μg/day) is increased to >100 μg/day and often up to 1,000 μg or more per day. In equivocal cases, the response of urinary copper output to chelation may be of diagnostic help. During the 24 hr urine collection patients are given two 500 mg oral doses of D-penicillamine 12 hr apart; affected patients excrete 1,200–2,000 μg/24 hr. Kayser-Fleischer rings which may not be present in younger children, requires a slit-lamp examination by an ophthalmologist. Liver biopsy - Determining the extent and Severity - Measurement of the hepatic copper content (normally <10 μg/g dry weight). In Wilson disease, hepatic copper content exceeds 250 μg/g dry weight. - In healthy heterozygotes, levels may be intermediate. Screening - Family members of patients with proven cases require screening for presymptomatic - Determination of the serum ceruloplasmin level - Urinary copper excretion. - If these results are abnormal or equivocal, liver biopsy should be carried out
  6. 6. Genetic screening - linkage analysis - Direct DNA mutation analysis is possible, especially if the mutation for the proband case is known or the patient is from an area where a specific mutation is known (in central and eastern Europe, the H1069Q mutation is present in 50–80% of patients). TREATMENT. DIET - Restrict copper intake to <1 mg/day. Foods such as liver, shellfish, nuts, and chocolate should be avoided. - If the copper content of the drinking water exceeds 0.1 mg/L, it may be necessary to demineralize. DRUGS - D-penicillamine (β,β-dimethylcysteine) o Dose: 1 g/day in two doses before meals for adults and 20 mg/kg/day for pediatric patients. o In response to penicillamine, urinary copper excretion markedly increases, and with continued administration, urinary copper levels may become normal, with marked improvement and the disappearance of Kayser-Fleischer rings. o 10–50% of patients initially treated with penicillamine for neurologic symptoms have a worsening of their condition.
  7. 7. o Toxic effects of penicillamine 10–20%  Hypersensitivity reactions  (Goodpasture syndrome, systemic lupus erythematosus, polymyositis),  Interaction with collagen and elastin, deficiency of other elements such as zinc, and aplastic anemia and nephrosis.  Antimetabolite of vitamin B6, additional amounts of this vitamin are necessary triethylene tetramine dihydrochloride (Trien, TETA, trientine) - For patients unable to tolerate penicillamine, - dose of 0.5–2.0 g/day for adults and 20 mg/kg/day for children. Ammonium tetrathiomolybdate - Alternate chelating agent under investigation for patients with neurologic disease - Dose: 120 mg/day (20 mg between meals tid and 20 mg with meals tid). - If a nighttime snack is eaten, another 20 mg is given with the snack. - Side effects o Anemia o Leukopenia o Thrombocytopenia o Mild elevations of transaminases.
  8. 8. Zinc - Used as adjuvant therapy - Maintenance therapy, or primary therapy in presymptomatic patients - Impair the gastrointestinal absorption of copper. - Zinc acetate dose ; adults at a dose of 25–50 mg of elemental zinc three times a day, and 25 mg three times a day in children >5 yr of age. PROGNOSIS. Untreated patients with Wilson disease die of the hepatic, neurologic, renal, or hematologic complications. The prognosis for patients receiving prompt ttt depends on the time of initiation of and the individual response to chelation. Liver transplantation should be considered for patients with fulminant liver disease, decompensated cirrhosis, or progressive neurologic disease; the latter indication remains controversial. Liver transplantation is curative with a survival rate of ≈85–90%. In asymptomatic siblings of affected patients, early institution of chelation therapy can prevent expression of the disease.

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