Wilson's disease

Question 1

Summarise Wilson’s disease

Answer 1

Wilson’s disease is an autosomal-recessive disease of copper accumulation and toxicity caused by a defect in an enzyme involved in the biliary excretion of excess copper.

Affects up to 1 in 40,000 people.

Diagnosis often missed; should be considered in patients aged 10 to 40 years with hepatitis, cirrhosis, hepatic decompensation, and symptoms suggestive of movement or psychiatric disorders.

Screening and diagnostic tests: 24-hour urine copper measurement, ophthalmological slit-lamp examination for Kayser-Fleischer (KF) rings, blood ceruloplasmin levels, and liver biopsy with measurement of quantitative copper.

Unlike many genetic disorders, it is treatable. Hepatic presentations are treated with a combination of trientine and zinc (liver transplantation if liver failure severe). Neurological presentations are treated with zinc.

Maintenance and pre-symptomatic therapy: zinc. If zinc-intolerant, trientine next best choice for maintenance.

Question 2

Define Wilson’s disease

Answer 2

Wilson’s disease is an autosomal-recessive disease of copper accumulation and copper toxicity caused by mutations in the ATP7B gene, which is part of the biliary excretion of copper pathway.[1][2][3] Patients are usually aged 10 to 40 years and present with either hepatic disease or a movement disorder neurological disease. Siblings of a patient have a 25% chance of being affected, and family work-up allows the diagnosis to be made in those who do not yet have symptoms.

Question 3

Describe the epidemiology of Wilson’s disease

Answer 3

The worldwide incidence of Wilson’s disease is in the order of 30 cases per million.[8] Wilson’s disease affects around 1 in 30,000 to 1 in 40,000 births.[9][10][11] This gives a theoretical caseload of about 7500 to 10,000 patients in the US if all patients were diagnosed and lived a normal life span. The disease does not favour a particular sex and all ethnic groups are affected equally. Clinical disease usually appears from about the age of 10 to 40 years

Question 4

Describe the aetiology of Wilson’s disease

Answer 4

Wilson’s disease is an autosomal-recessive disease caused by mutations in the ATP7B gene. Over 250 causative mutations have been discovered, such that in most countries, most patients are compound heterozygotes.[1][2][3][12][13] The gene product of ATP7B is involved in excretion of excess copper in the bile and subsequent elimination in the stool. A normal diet contains about 1.0 mg/day of copper, and about 0.25 mg of this is excess.

Question 5

Describe copper accumulation in the pathophysiology of Wilson’s

Answer 5

Copper accumulation leads to higher than normal levels of free copper (i.e., copper not bound covalently to proteins). High levels of free copper probably cause toxicity by oxidant damage.[14] Copper damage to biological systems is widespread, including the mitochondria, peroxisomes, microtubules, DNA, and plasma membranes. The result is cell injury, inflammation, and cell death. Ceruloplasmin, synthesised in the liver, is the major copper-carrying protein in the blood.

Question 6

Which two organs are particularly susceptible to copper toxicity

Answer 6

In Wilson’s disease, excess copper is initially stored in the liver, where inflammation and cell injury results in hepatitis. With continued exposure to high levels of copper, fibrosis (cirrhosis) occurs. Clinically this progresses to end-stage liver disease and hepatic failure.

The basal ganglia and areas of the brain that coordinate movement are most sensitive to copper accumulation. Occasionally white matter is also affected. Copper toxicity results in inflammation, neuronal injury, and neuronal death. Inflammatory areas are seen as an increased signal on MRI brain. Later, MRI may show volume loss.

Question 7

Describe hepatic involvement in the classification of Wilson’s disease

Answer 7

Hepatic involvement
Patients with hepatic involvement usually present between the age of 10 and 30 years with a hepatitis picture, which may be recurring, or with chronic cirrhosis or hepatic failure. Hepatic failure may be classified as mild, moderate, or severe using the Nazer score

Question 8

Describe neurological/psychiatric involvement in the classification of Wilson’s disease

Answer 8

Patients presenting with neurological and psychiatric involvement are usually between the ages of 10 and 40 years. They present with one or more symptoms of a movement disorder, which may include dysarthria, tremor, incoordination, dysphagia, drooling, dystonia, dysdiadochokinesia, rigidity, postural abnormality, or gait abnormality.[6] These symptoms may be accompanied or preceded by behavioural abnormalities including depression, inability to focus on tasks, poor memory, insomnia, delusions, emotional lability, impulsiveness, disinhibition, and other bizarre behaviours

Question 9

Describe mixed neurological and hepatic involvement in the classification of Wilson’s

Answer 9

Occasionally, patients present with both hepatic and neurological/psychiatric involvement.

Question 10

Describe pre-symptomatic classification of Wilson’s

Answer 10

These patients are usually diagnosed as a result of family work-up, although they may occasionally be diagnosed by chance observations of Kayser-Fleischer (KF) rings or elevated aminotransferase enzymes.

Question 11

Describe one case history for Wilson’s

Answer 11

A 20-year-old previously healthy man has an episode of jaundice associated with tiredness. He is found to have elevated serum aminotransferase enzymes (AST 150 units/L, ALT 175 units/L) and elevated serum bilirubin 77.0 micromols/L (4.5 mg/dL). Ophthalmological examination for Kayser-Fleischer rings is negative.

Question 12

Describe a second case history for Wilson’s

Answer 12

An 18-year-old woman presents with bilateral tremor of the hands. She is a senior in high school and during the year her grades have plummeted to the point that she is failing. She says her memory is now poor, and she has trouble focusing on tasks. Her behaviour has changed in the past 6 months in that she has frequent episodes of depression, separated by episodes of bizarre behaviour, including shoplifting and excessive drinking. Her parents and other authorities have begun to suspect her of using street drugs, which she denies. Her handwriting has become very sloppy. Her parents have noted slight slurring of her speech. Physical examination reveals upper extremity tremor, mild dystonia of the upper extremities and mild incoordination involving her hands. Slit-lamp examination reveals Kayser-Fleischer rings.

Question 13

Describe some other presentations of Wilson’s

Answer 13

Liver disease may present as acute hepatitis, which will relapse if the disease remains undiagnosed. However, the liver involvement may remain subclinical with no jaundice, and patients can present with cirrhosis or complications of cirrhosis, such as variceal bleeding. Occasionally patients present with acute, severe, liver failure as their first manifestation of the disease. If haemolysis is also present, the diagnosis is almost certain to be Wilson’s disease.

Neurological presentation may be dominated by a single symptom, such as tremor, that has been present for years. Alternatively the patient may exhibit a range of movement disorder symptoms as an acute presentation. About half of the patients who present neurologically have had significant behavioural symptoms for some time (2-3 years). Wilson’s disease may be clinically mistaken for Parkinson’s disease if there is facial rigidity and difficulty initiating movement, such as walking.

Question 14

Outline a basic approach to the diagnosis of Wilson’s

Answer 14

Wilson’s disease is uncommon and the diagnosis is often missed. It can manifest itself as liver disease (with tiredness, jaundice, and possibly ascites and oedema) or as a neurological movement disorder (with tremor, dystonia, and rigidity), or it can be diagnosed at the pre-symptomatic stage.[16][9][17][14][10][11][6][18]

Early diagnosis is important because therapy is effective, and the less the damage caused by copper toxicity, the greater the likelihood of recovery. A family history of Wilson’s disease and ATP7B gene mutation may be present and family members of the diagnosed patient should be screened

Question 15

Describe an approach to the hepatic presentation of Wilson’s

Answer 15

A patient presenting with liver disease secondary to Wilson’s disease may have a history of unexplained hepatitis or aminotransferase elevations noted in a routine screening, low platelet counts or white cell counts, or gastrointestinal bleeding because of portal hypertension.

Patients are often mistaken as having alcoholic cirrhosis or viral hepatitis. Both are more common than Wilson’s disease.

On physical examination of the patient presenting with hepatitis there may be jaundice, and occasionally liver tenderness is present.

If the patient presents with cirrhosis, there may be spider angiomata, gynaecomastia, ascites, peripheral oedema, easy bruising, hepatojugular reflux, or encephalopathy.

Question 16

Describe an approach to the neurological presentation of Wilson’s disease

Answer 16

A patient with neurological disease may have a history of symptoms of a movement disorder, including tremor, incoordination, sloppy handwriting, dysarthria, muscle stiffness, rigidity, postural abnormality, gait abnormality, or drooling.

Patients often have bizarre behaviour, emotional lability, and occasionally delusions.[7] Other forms of behavioural abnormalities that may be present are temper tantrums, depression, loss of memory, inability to focus on tasks, impulsiveness, and sexual disinhibition.

Patients can be mistaken for having Parkinson’s disease or multiple sclerosis (although there is no sensory deficit).

Question 17

Describe an approach to the physical exam in patients with Wilson’s disease

Answer 17

On physical examination of the patient presenting with neurological disease, the following may be noted.

Tremor (of any type).
Dystonia and rigidity of any part of the body but most often the hands. This can cause postural and gait abnormalities.
Dysdiadochokinesis and evidence of clumsiness or lack of coordination.
Handwriting is often sloppy, but may be small (micrographia).
Speech may be abnormal, but the abnormalities are not specific for Wilson’s disease. Words may be slurred and they may be of low volume (hypophonia). It may be almost stuttering in type (echolalia).
Dysphagia may cause the patient to drool and have difficulty with muscles of the lips and face.
Extraocular movements are occasionally abnormal.
Kayser-Fleischer (KF) rings may be apparent
Sensation is normal, as are muscular strength and reflexes.

Question 18

Summarise LFTs, including prothrombin times in patients with Wilson’s

Answer 18

Liver function tests (LFTs) are always abnormal in patients with hepatic presentation. In jaundice, there may be raised aminotransferases and raised bilirubin. In liver failure, albumin may have lowered.

In patients with neurological presentation, results of LFTs may also be abnormal, particularly aspartate aminotransferase and alanine aminotransferase levels, because patients usually have some liver involvement.

Question 19

Summarise 24-hour urinary copper measurement in patients with Wilson’s

Answer 19

The sample should be collected in a container free of trace elements. Twenty-four-hour urinary copper >100 micrograms indicates Wilson’s disease.

Question 20

Summarise the slit-lamp experiment for Kayser-Fleischer rings

Answer 20

KF rings are gold-brown pigment representing copper deposition in the membrane of Descemet of the cornea.

Hepatic presentation:

Often not present in hepatic (only 50% to 62%) and pre-symptomatic patients
Rarely found in patients with cholestatic liver diseases such as primary biliary cirrhosis.
Neurological/psychiatric presentation:

Almost always (>99%) present in neurologically symptomatic Wilson's disease
KF rings plus 24-hour urine copper >100 micrograms are adequate for diagnosis in patients with neurological symptoms.

Question 21

Summarise blood Ceruloplasmin and free copper

Answer 21

Ceruloplasmin, synthesised in the liver, is the major copper-carrying protein in the blood. A low ceruloplasmin provides some evidence for Wilson’s disease. Normal level is 200 to 350 mg/L (20-35 mg/dL). Blood ceruloplasmin is not always diagnostic because 10% to 25% of patients have results within normal range. Because of heterozygous carriers, around 1% of the population has intermediately low ceruloplasmin level. Assay by the enzymatic method seems most accurate.[19]

About 90% of patients with a neurological presentation, 75% of patients with an hepatic presentation, and 90% of pre-symptomatic patients have a low or intermediately low ceruloplasmin level.

Direct assay of free copper has been suggested to help in diagnosis.

Question 22

When is follow-up with liver biopsy and imaging not needed

Answer 22

A patient with neurological or psychiatric symptoms typical of Wilson’s disease and who is positive for KF rings does not need further work-up. A patient with hepatitis and a raised urine copper of >100 micrograms/24 hours likewise has Wilson’s disease.

Question 23

Describe when follow up with liver biopsy and imaging are needed

Answer 23

If the diagnosis is uncertain the definitive diagnostic test is a liver biopsy with quantitative assay of copper (normal is 20 to 50 micrograms/g dry weight of tissue: in Wilson’s disease the level is >200 micrograms/g). Absence of copper stain on the liver tissue does not rule out Wilson’s disease.

Hepatic presentation: in the absence of chronic obstructive liver disease, histological stain for copper is inadequate and quantitative liver copper assay is the definitive test. Liver biopsy and assay of copper >250 micrograms/g dry weight indicates liver disease. Histological analysis of liver damage should also be done. In chronic obstructive liver disease, liver and urine copper can be elevated into the Wilson’s disease range. Sometimes such cases require a therapeutic trial. A liver copper level of <150 micrograms/g dry weight rules out Wilson’s disease.
Neurological/psychiatric presentation: a value >200 micrograms/g dry weight indicates Wilson’s disease in a patient with neurological symptoms. It is not necessary to biopsy most patients with neurological Wilson’s disease because the diagnosis can be established through urine copper and KF rings.

Question 24

Summarise the use of MRI in Wilson’s

Answer 24

MRI of the brain is useful in neurological presentation. The most common findings are:

Increased density in the basal ganglia
The ‘face of the giant panda’ sign is seen in T2-weighted images of the midbrain.
These findings are sensitive for Wilson’s disease in cases of neurological presentation only. They are not specific for Wilson’s disease. MRI findings can be similar in other neurological disorders.

Question 25

Summarise DNA testing for mutations in the ATP7B gene

Answer 25

The problem with this approach in the past has been that in many populations, there are several hundred mutations that cause Wilson’s disease, making it difficult to identify specific mutations in a patient. However, this field has matured such that currently a good DNA lab, depending on the population, can make the diagnosis of Wilson’s disease in 50% to 75% of patients. It is necessary that a Wilson’s disease mutation be shown for both copies of the ATP7B gene to make the diagnosis by DNA test.

DNA analysis can also be used very effectively to genotype siblings of a diagnosed Wilson’s disease patient. It is not necessary to know the specific ATP7B mutation or mutations in the patient. DNA markers on both sides of both copies of the ATP7B gene in the patient are characterised. If a sibling matches both sets of markers they are affected, if they match one set they are a carrier, and if they match neither they are clear

Question 26

Describe the key common diagnostic factors of Wilson’s disease

Answer 26

tremor
May be of any type: fine, intentional, or wing-beating.

dysarthria
Speech may be slurred or hypokinetic, and may exhibit echolalia but not of a specific character.

dystonia
Most common in upper extremities.

incoordination
Interferes with such things as handwriting, buttoning, and eating.

sloppy or small handwriting
Due to incoordination, handwriting is often sloppy and may be small (micrographia).

history of hepatitis
Previous episode of hepatitis common with hepatic presentation.

history of behavioural abnormalities
Can vary from loss of control of emotions to depression, delusions, loss of memory, inability to focus on tasks, impulsiveness, sexual disinhibition, and other bizarre behaviours.

Question 27

Describe some other diagnostic factors of Wilson’s disease

Answer 27

dysdiadochokinesis
Slowness in alternating hands from prone to supine position.

abnormal extraocular movements
Esotropia (in-turning of the eyes), abnormal ocular pursuit, abnormal saccadic (rapid, intermittent) eye movements, diplopia (double vision) and distractibility of gaze and fixation.

normal sensation, muscular strength, and reflexes
These are all normal on examination in Wilson’s disease.

Question 28

Describe some uncommon diagnostic features of Wilson’s

Answer 28

peripheral oedema
May be seen with cirrhosis.

bruising
May be seen with cirrhosis.

hepatojugular reflux
May be seen with cirrhosis.

encephalopathy
Mental fuzziness; difficulty performing simple mental tasks. May be seen with cirrhosis.

dysphagia
May be seen with neurological/psychiatric presentation.

jaundice
May be seen with hepatitis.

liver tenderness
May be seen with hepatitis.

spider angiomata
May be seen with cirrhosis.

gynaecomastia
May be seen with cirrhosis.

ascites
May be seen with cirrhosis.

history of gastrointestinal bleeding
Due to portal hypertension and subsequent oesophageal varices.

Question 29

Describe as strong risk factor for Wilson’s disease

Answer 29

ATP7B gene mutation

Determined by genetic testing, with patients possessing 2 mutated copies of the ATP7B gene. Penetrance is almost 100%.

Question 30

Describe a weak risk factor for Wilson’s

Answer 30

non-vegetarian diet
Diet, particularly vegetarianism, may play a protective role.[15] Copper is much less bioavailable from vegetables than from meat.

Question 31

Describe LFTs as the first line investigation in Wilson’s

Answer 31

Liver function tests (LFTs) are always abnormal in hepatic presentation. May have raised aminotransferases and raised bilirubin if the patient has jaundice. May have lowered albumin if in liver failure.

In patients with neurological presentation, results of LFTs may also be abnormal, particularly aspartate aminotransferase and alanine aminotransferase levels, because patients usually have some liver involvement.

Result:
Abnormal

Question 32

Describe 24-hour urinary copper as an investigation to consider

Answer 32

Sample collected in trace element-free containers. Level >100 micrograms indicates disease.

Result:
>100 micrograms

Question 33

Describe the FBC in Wilson’s

Answer 33

Caused by portal hypertension and splenic sequestration.

low platetelet count and low WBC count

Question 34

Describe the slit-lamp examination as an investigation to consider in Wilson’s

Answer 34

Almost always (>99%) present in neurologically symptomatic Wilson’s disease.

Often not present in hepatic (only 50% to 62%) and pre-symptomatic patients.

Result:
Kayser-Fleishcer rings

Question 35

Describe blood Ceruloplasmin as an investigation to consider in Wilson’s

Answer 35

A normal ceruloplasmin 200 to 350 mg/L (20-35 mg/dL) is not helpful, as 10% to 15% of affected patients have a normal ceruloplasmin level.

Level <180 mg/L (18 mg/dL) is positive for Wilson’s disease.

Result:
<180 mg/L (18 mg/dL)

Question 36

Describe a liver biopsy for the hepatic presentation as an investigation to consider for Wilson’s

Answer 36

Liver biopsy and assay of copper >250 micrograms/g dry weight indicates liver disease.

A liver copper level of <150 micrograms/g dry weight rules out Wilson’s disease.

Result:
liver copper >250 micrograms/g

Question 37

Describe liver biopsy for the neurological presentation as an investigation to consider

Answer 37

Liver biopsy and assay of copper >200 micrograms/g dry weight indicates Wilson’s disease.

Result:
liver copper >200 micrograms/g

Question 38

Describe an MRI of the brain as an investigation to consider

Answer 38

Only useful in neurological presentation cases with a high index of suspicion of Wilson’s disease.

Not specific for Wilson’s disease. MRI findings can be similar in other neurological disorders.

Result:
involvement of basal ganglia - most commonly, increased density in the basal ganglia; ‘face of the giant panda sign’ seen in T2-weighted images of the midbrain

Question 39

Describe blood free copper as an investigation. to consider

Answer 39

Copper levels have been found to be elevated at least 6-fold in Wilson’s disease

Result:
Elevated

Question 40

Describe DNA testing for ATP7B mutation as an investigation to consider

Answer 40

Depending on the laboratory and population, well over 50% of Wilson’s disease patients may be diagnosed using this procedure.

Result:
Causative mutations found on both copies of the gene definitively diagnose Wilson’s disease. A causative mutation found on one gene indicates a heterozygous carrier.

Question 41

Describe DNA haplotype testing (sibling of affected patient) as an investigation to consider

Answer 41

It is not necessary to know about the causative mutation in the affected sibling to apply this test.

Result:
Two haplotype matches indicate affected. One match indicates carrier. Zero matches indicates clear.

Question 42

Describe viral hepatitis B as a differential

Answer 42

Patients with viral hepatitis may have a history of a febrile illness or blood transfusion, but otherwise the symptoms and signs may be identical.

Investigations:
Hepatitis B antigen positive.

Question 43

Describe Viral hepatitis C as a differential

Answer 43

Patients with viral hepatitis may have a history of a febrile illness or blood transfusion, but otherwise the symptoms and signs may be identical.

Investigations:
Hepatitis C antigen positive

Question 44

Describe haemochromotosis as a differential

Answer 44

Patients with haemochromatosis may present with other features such as diabetes, skin pigmentation, arthritis, impotence in males, and cardiac enlargement with or without symptoms and signs of heart failure.

Investigation:
Iron parameters and liver biopsy are diagnostic.

Question 45

Describe alpha-1-anti-trypsin deficiency as a differential

Answer 45

Patients with alpha-1 antitrypsin deficiency may have chronic lung disease such as emphysema occurring earlier than expected (in the 40- to 50-year-old age group) as well as liver disease.

Investigations:
Tests will show enzyme to be deficient

Question 46

Describe auto-immune hepatitis as a differential

Answer 46

Patients may have other associated auto-immune conditions and will respond to steroid therapy. However, Wilson’s disease should be excluded before this diagnosis is assumed.

Investigations:
Patients may have a positive auto-antibody screen including ANA, primarily in a homogeneous pattern, anti-smooth muscle antibody, anti-liver-kidney microsomal antibody, and others.

Question 47

Describe steatohepatitis as a differential

Answer 47

Patients with steatohepatitis tend to be obese with clinical features of hepatitis. Wilson’s disease should be excluded before this diagnosis is assumed.

Investigations;
Fatty liver and inflammation on biopsy.

Question 48

Describe alcoholic hepatitis as a differential

Answer 48

Patients may have a history and signs of alcohol excess. Wilson’s disease should be excluded before this diagnosis is assumed, even if the patient drinks.

No investigations

Question 49

Describe haemolytic anaemia as a differential

Answer 49

If hepatic bouts are severe in Wilson’s disease then haemolysis may occur. Haemolysis in the presence of liver disease in a person aged <40 years should prompt testing for Wilson’s disease.

Investigations:
Tests for alternative causes of haemolytic anaemia, including Coombs antibody, haemoglobin electrophoresis for HbS, and auto-antibody screening for auto-immune diseases, are used to determine the diagnosis.

Question 50

Describe essential tremor as a differential

Answer 50

Tremor with no other neurological symptoms of a movement disorder. May have positive family history.

Wilson’s disease should be excluded before you make this diagnosis especially in all patients aged under 40 years and in many aged under 50 years.

No investigations

Question 51

Describe Parkinson’s as a differential

Answer 51

Parkinson’s disease usually occurs in older people (>50 years), but the movement disorders are often identical. The diagnosis of Parkinson’s disease is made on history and neurological examination.

No investigations

Question 52

Describe psychiatric disease as a differential

Answer 52

Psychiatric disease unrelated to Wilson’s disease will not be accompanied by features of Wilson’s disease. Wilson’s disease patients with primary psychiatric disease are more likely to have early childhood problems, and these patients almost always have Kayser-Fleischer rings.

No investigations

Question 53

Summarise screening for Wilson’s

Answer 53

Currently research is ongoing and general population screening is not available.

Screening first-degree relatives of a diagnosed patient:

In about one third of cases for Kayser-Fleischer (KF) rings are present
An elevated urine copper (>100 micrograms) and KF rings are sufficient to make the diagnosis
If diagnosis is uncertain, a liver biopsy is required. A value >200 micrograms/g dry weight is diagnostic of Wilson’s disease in such patients. In gene carriers it will be ≤125 micrograms.