WILSON’S DISEASE

(Hepatolenticular degeneration)

 

• Screening test: serum ceruloplasmin

• Confirmatory: urinary copper with penicillamine challenge test, liver biopsy

• Autosomal recessive disease
• Mutations on chromosome 13 (ATP7B gene)

 

 

Pathophysiology:

 

Absorption of copper from stomach and small intestine

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Enter into liver

↓

Incorporated into ceruloplasmin

↓

Excreted into bile

 

In Wilson’s disease there is failure of synthesis of ceruloplasmin and excretion into bile

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Deposition of copper into various organs mainly liver, basal ganglia, eye, kidney,  skeleton.

 

** Mutations in ATP7B in Wilson disease impair two aspects of copper metabolism: 

1. Reduced incorporation of copper into apoceruloplasmin and 
2. Decreased secretion of copper into the biliary system. 

 

The latter defect reduces the major pathway of copper elimination, while the former defect results in diminished formation and secretion of ceruloplasmin. 

 

Low serum concentrations of ceruloplasmin do not play a role in the clinical manifestations of Wilson disease

 

 

Clinical features:

Hepatic manifestations:

• Recurrent acute hepatitis of unknown cause especially when accompanied by haemolysis

Or

CLD of unknown cause under 40 years old suggest Wilson’s disease

• Episodes of acute hepatitis, sometimes recurrent can occur especially in children and may progress to acute fulminant hepatic failure (liberation of free copper into blood stream, causing massive haemolysis and renal tubulopathy)
• Chronic hepatitis can also develop insidiously and eventually present with established cirrhosis

 

Neuro-Psychiatric manifestations:

• Basal ganglia dysfunction (extrapyramidal features)
• Resting, postural or kinetic tremor  (Choreoathetosis)
• Dysarthria and Dysphagia (due to dystonia of bulbar musculature)
• Autonomic features:
  • Orthostatic hypotension
  • Sweating abnormalities
  • Bowel, bladder, and sexual dysfunction

 

• Others: Memory loss, migraine-type headaches, and seizures
• Psychiatric features:   
  • Behavioral and personality changes
  • Emotional lability
  • Dementia
  • Unusual clumsiness for the age may be an early symptom

       

Eye:

• Kayser-fleischer rings: (D/D: Arcus senilis, Gauchers disease)
  • Pathognomonic sign (seen in 60% of adult patients with Wilson’s disease)
  • Due to fine pigmented granular deposits in Descemet’s membrane in the cornea
  • Greenish-brown discoloration of  the corneal margin appearing first at the upper periphery
  • Sometimes seen with  naked eye  and is readily detected by slit-lamp examination
  • May be absent in children and with hepatic disease but almost always (>99 %) present in neurological disease
  • Disappear with treatment
  • Other causes of KF ring:
    • Long-standing obstructive liver disease e.g
      • PBC
      • Primary biliary atresia
      • Primary sclerosing cholangitis
      • Cryptogenic cirrhosis

• Sunflower cataracts

 

Muskuloskeletal

• Osteoporosis

 

Renal

• Nephrolithiasis 

• Microscopic hematuria is common,

• Increased urinary excretion of phosphates, amino acids, glucose, or urates may occur; however, a full-blown Fanconi syndrome is rare. 

• Proximal renal tubular acidosis  (Type 2)    

 

Cardiac:

• Electrocardiographic and other cardiac abnormalities have been reported but are not common.

 

 

Investigations:

• Serum ceruloplasmin levels: reduced
  • Ceruloplasmin also occurs in
    • Severe non-Wilson’s hepatic failure
    • Severe malnutrition
    • Protein-losing enteropathy
    • Nephrotic syndrome

• High free serum copper concentration ( Serum copper levels are usually lower than normal because of low blood ceruloplasmin, which normally binds >90% of serum copper)

• 24 hour urinary Cu: > 0.6 μmol / 24 hour                           

• Penicillamine challenge test: 24 hour urinary Cu while giving D-penicillamine (500 mg at 0 hr and 500 mg at 12 hours) is useful confirmatory test (> 25 μmol  /24 hrs is considered diagnostic of Wilson’s disease)

• Liver Biopsy: High hepatic copper content

 

 

Treatment:

• D-Penicillamine : (Cap Penamine / Penicillamin 250; 500 mg)

• • Reduce dose when patient is in remission and then continue for life even through pregnancy
  •  Abrupt discontinuation may cause acute liver failure
  • Pyridoxine (Tab Pyrovit 20 mg) should be given along with penicillamine
  • Side Effects: 
    • Rash, GIT upset, Fever,  Lupus like syndrome, 
    • Nephrotic syndrome, Bone marrow depression
  • Follow up: 
    • CBC, standard biochemical profiles,  urinalysis
    • 1 weekly for 1 month, 2 weekly for 2 months, 4 weekly 4 months, then 6 monthly.

 

• Zinc acetate 

• • If toxic effects of penicillamine is seen (rashes, protein losing enteropathy, lupus like syndrome, bone marrow depression)
  • Dose*:              
    • Adult: 50 mg 8 hourly   
    • Children:
      • 1-5 years: 25 mg BID
      • 6 – 16 yrs: 25 mg TID

*Each dose of Zinc separated from food and beverages other than water by at least 1 h, and separated from trientine or penicillamine doses by at least 1 h.

• Trientine dihydrochloride
• Tetrathiomolybdate 

 

Pregnant patients should be treated with zinc or trientine throughout pregnancy, but without tight copper control, because copper deficiency can be teratogenic.

Anticopper therapy must be lifelong. 

With treatment, liver function usually recovers after about a year, although residual liver damage is usually present. Neurologic and psychiatric symptoms usually improve between 6 and 24 months of treatment.

 

 

Prognosis:

1. The prognosis is excellent, provided treatment is started before there is irreversible damage. 
2. Siblings and children of patients with Wilson’s disease must be investigated and treatment should be given to all affected individuals, even if they are asymptomatic.

 

Other Inherited Liver Disease: Hemochromatosis

 

 

 

Self Assessment

Q. An 18-year-old boy with a previous history of recurrent jaundice was brought to you for melena. On examination, he had mild bilateral pedal edema and splenomegaly.

• Study the photograph of upper Gl endoscopy (esophageal varices) and give answers to the following questions:

 

Question 1. Give the clinical diagnosis to which the scenario fits best.

• Cirrhosis of liver / CLD (1) with portal hypertension (0.5) due to Wilson disease (0.5)

 

Question 2. Mention 4 (four) other important findings on physical examination that may help in reaching the diagnosis.

• Kayser-Fleischer ring / KF ring, Sunflower cataract, nystagmus, Movement disorders / dystonia
• Caput medusae / dilated vein, Ascites
• Testicular atrophy, Gynecomastia, Spider naevi, Leukonychia

 

Question 3. Mention 3 (three) blood tests to identify the underlying cause.

• Serum ceruloplasmin
• HBsAg/hepatitis B profile
• Alpha-1-antitrypsin level

 

Question 4. Mention 3 (three) initial measures for prevention of recurrence of bleeding in this patient.

• Esophageal band ligation / EBL
• Non-selective (0.25) beta blocker (0.25)/ propranolol / nadolol / carvedilol
• Proton pump inhibitor