Introduction

Wilson’s disease (WD), also known as hepatolenticular degeneration, is familial disease of copper overload characterized by neurological and hepatic complications.

An autosomal recessive inheritance of a mutation in the gene called ATP7B is the underly pathology (see “Copper metabolism and pathophysiology” below).

Incidence = 1/30,000.

Prevalence = 3/100,000.

 

Copper metabolism and pathophysiology

Hepatocyte copper handling

Copper is required as a co-factor in metabolic reactions. Most people ingest 1-2mg copper/day. It is absorbed by enterocytes in the stomachduodenum and jejunum then transported to the liver bound to albumin.

Copper is processed by the liver in two ways (illustrated on the diagram opposite):

  • Used to synthesize the cooper-containing protein caeruloplasmin, which is secreted into plasma. Or,
  • Binds to the ATPase WDP (Wilson’s disease protein) and excreted into the bile.

ATP7B (found on chromosome 13) is the gene for WDP, which is required for transmembrane movement of copper. The mutation present in WD reduces the excretion of copper and the incorporation of copper into caeruloplasmin. The accumulation of copper inside hepatocytes results in toxic damage to hepatocytes, leading to chronic hepatitis and ultimately cirrhosis.

Copper is also released into the blood where is it deposited in other organs, primarily:

  • Brain (especially in the basal ganglia).
  • Corneas.
  • Kidneys.

Copper is also toxic to red blood cell membranes, resulting in haemolysis.

 

Presentation

Most present at 3-40 years.

Childhood presentation is usually as a consequence of liver disease:

  • Chronic hepatitis or cirrhosis.
  • Complications of cirrhosis (or portal hypertension).
  • Acute liver failure, associated with acute kidney injury and Coomb’s negative haemolysis.
  • An important differential diagnosis in children is autoimmune hepatitis. There may be similar clinical and biochemical findings.

Adolescents and young adults tend to present with neurological or psychiatric features:

  • Movement disorders, including tremor, involuntary movements and Parkinsonism.
  • Speech and swallowing impairment from dysarthria, dystonia or psuedobulbar palsy.
  • Depression.
  • Neurotic behaviors or personality change.

Kayser-Fleischer (K-F) rings are green-brown coloured areas around the edge of the corneas, resulting from copper deposition in Decement’s membrane.

  • K-F rings can only be accurately examined using a slit-lamp.
  • If neurological signs are present then K-F rings are usually also found.
  • Not specific to WD, also seen in conditions with chronic cholestasis (e.g. primary biliary cirrhosis, primary sclerosis cholangitis).

    See below for a full list of the features of WD.

     

    Kayser-Fleischer rings. Fred H, van Dijk H. Images of Memorable Cases: Case 9 [Connexions Web site].

    Other features of WD

    Hepatobiliary

    Asymptomatic hepatomegaly or splenomegaly

    Transient jaundice (as a result of haemolysis)

    Acute hepatitis / liver failure

    Compensated or decompensated cirrhosis

     

    Psychiatric

    Depression

    Psychosis

    Delusions

     

    Renal

    Nephrolithiasis

    Aminoaciduria (due to a form of renal tubular acidosis)

     

    Endocrine

    Hypoparathyroidism

    Mentrual irregularity, miscarriage and infertility

     

    Cutaneous

    Lunulae ceruleae (blue colour found at the base of the fingernails due to copper accumulation)

    Neurological

    Micrographia

    Drooling

    Dystonia

    Pseudobulbar palsy (causing dysphagia and therefore at risk from aspiration)

    Autonomic dysfunction

    Migraines

    Insomnia

    Seizures (rarely)

     

    Cognitive

    Reduced intelligence

    Impaired memory

    Mutism

     

    Skeletal

    Premature osteoporosis

    Osteoarthritis

     

    Cardiovascular

    Cardiomyopathy

    Arrhythmias

     

    Gastrointestinal

    Pancreatitis

     

    OSCE long-case of WD

    History

    A childhood presentation will give history of acute liver failure with rapid onset jaundice, nausea and vomiting, bleeding, confusion (from hepatic encephalopathy) and upper right quadrant pain (due to liver capsule stretch). They will have been very unwell.

    An adolescent presenting with WD can give almost any variety of neuropsychiatric symptoms, with or without a tremor. They may describe difficulty in formulating words (dysarthria) or swallowing (dysphagia) however it would be rare to have limb weakness (which would point towards a diagnosis of motor neurone disease). A further history may be one of a personality change or psychosis that is unresponsive to conventional medication.

     

    Examination

    • On general inspection, comment on the age of the patient and gender (because acute failure is twice as common in women). Also look for a tremor and notice dysarthria when the patient speaks.
    • Hands: lunulae ceruleae, clubbing, palmar erythema, Dupytren's contracture (rare in children).
    • Face: icteric sclerae, brown discolouration of the cornea (a slit-lamp is required to formally state that they are K-F rings).
    • Abdomen: hepato-/spleno-megaly.

    Investigations and diagnosis

    In practice diagnosis is difficult because biochemical results may be inconsistent.

    Slit-lamp examination should be performed to examine for K-F rings.

    24-hour urine collection for copper.

    • >3mmol is found in 65% of patients with WD.
    • If given penicillamine, then 95% of patients will excrete >25mmol in 24 hours, which is diagnostic.

    Serum caeruloplasmin is <200mg/L in 85% of patients.

    • However it is also an acute phase protein, so any concurrent inflammatory process will also increase caeruloplasmin.
    • Other causes of low caeruloplasmin: chronic liver disease (of other causes), end-stage renal disease and protein-losing enteropathy.

    Liver function tests:

    • Changes are often non-specific.
    • Raised ALT but usually <200U/L, even during acute liver failure.
    • Transaminases may be persistently raised.

    Serum copper is usually low (<11mmol/L) however can be high from hepatocyte necrosis during acute hepatitis.

    Liver biopsy gives histology and allows assessment of copper content.

    • Histology can vary depending on the stage of disease, including non-specific features such as chronic hepatitis, necrosis or cirrhosis (with irregular nodules).
    • There may be fatty change and positive staining for copper.
    • Hepatic copper content is the gold standard test, with >250micrograms/g dry weight being diagnostic.

    Genetic analysis of ATP7B is difficult due to multiple potential mutations. The most common mutation is His1069Gly, which accounts for 50% of patients in Europe and the USA.

    A CT or MRI scan of the head may show structural abnormalities of the basal ganglia.

    Management

    Acute liver failure

    More common in children and twice as frequent in women. Occurs when there is massive hepatocyte necrosis and causes release to large quantities of copper into the circulation. This results in intravascular haemolysis and acute kidney injury. Present with a coagulopathy unresponsive to intravenous vitamin K therapy. Management is the same as for acute failure of any cause however transplant is usually required to survive.

     

    Chronic liver disease (in the absence of acute decompensation). Advise a low-copper diet, by avoidance of chocolate and shellfish.

    D-penicillamine is chelator that promotes urinary excretion of copper.

    • It should be prescribed with pyridoxine to prevent vitamin B6 deficiency.
    • Side effects: rash, fever, proteinuria, blood disorders (any cytopenia).
    • 24 hour urinary copper is used for monitoring; if the patient is compliant then their excretion should be very high.

    Trientine is an alternative chelator that promotes urinary excretion. Its side effects are rash, gastritis and sideroblastic anaemia.

    Zinc salts can be given to reduce gastrointestinal absorption of copper

    • More commonly used for maintenance.
    • Gastritis is their main side-effect.
    • 24 hour urinary copper is again used for monitoring however these patients should have very low excretion.

     

    Further management

    First-degree relatives of those affected should be screened. When the patient has decompensated cirrhosis or early hepatocellular carcinoma, liver transplant is the treatment of choice. As the genetic abnormality is localised to the liver, transplant is curative because the ability to excrete copper is restored.

     

    Prognosis

    Early intervention helps to delay liver damage however transplant is usually ultimately required. Neurological degeneration is permanent and liver transplantation will not reverse the damage.

    Most common causes of death are: infection, variceal bleeding or liver failure.

    References

    Image "Kayser-Fleischer rings" from: Fred H, van Dijk H. Images of Memorable Cases: Case 9 [Connexions Web site]. December 8, 2008. Available at: http://cnx.org/content/m15007/1.3/

    Image "Hepatocyte copper handling: from: User:Jfdwolff. Copper Metabolism. 2008. English Wikipedia. Available at: http://en.wikipedia.org/wiki/File:Copper_metabolism.png

    Roberts E., Schilsky M. Diagnosis and treatment of Wilson disease: An update. Hepatology (2008) 47;6:2089-2111

    Kumar P., Clark M. Clinical Medicine 7th Edition (2009). Elsevier Saunders

    Longmore M., Wilkinson I., et al. Oxford handbook of clinical medicine 8th Edition (2010). Oxford University Press

    Bloom S., Webster G. Oxford handbook of gastroenterology and hepatology (2006). Oxford University Press

     

    Advertisement

    Fastbleep © 2019.