Wilson's Disease Flashcards
Wilson’ Disease
Wilson’s disease
Wilson’s disease is an autosomal recessive disorder characterised by excessive copper deposition in the tissues. Metabolic abnormalities include increased copper absorption from the small intestine and decreased hepatic copper excretion. Wilson’s disease is caused by a defect in the ATP7B gene located on chromosome 13.
The onset of symptoms is usually between 10 - 25 years. Children usually present with liver disease whereas the first sign of disease in young adults is often neurological disease
Features result from excessive copper deposition in the tissues, especially the brain, liver and cornea:
liver: hepatitis, cirrhosis
neurological: basal ganglia degeneration, speech and behavioural problems are often the first manifestations. Also: asterixis, chorea, dementia
Kayser-Fleischer rings
renal tubular acidosis (esp. Fanconi syndrome)
haemolysis
blue nails
Diagnosis
reduced serum caeruloplasmin
reduced serum copper (counter-intuitive, but 95% of plasma copper is carried by ceruloplasmin)
increased 24hr urinary copper excretion
Management
penicillamine (chelates copper) has been the traditional first-line treatment
trientine hydrochloride is an alternative chelating agent which may become first-line treatment in the future
tetrathiomolybdate is a newer agent that is currently under investigation
Wilson’s Disease - Diagnosis: Example Question
A 24 year old Greek man presented after his partner reported a personality change over the past three weeks. She reported that he had been very low in mood, and had been behaving strangely. He reported being a little fatigued over the past couple of weeks. Neurological examination was unremarkable other than a rest tremor in his right hand. There was evidence of scleral icterus, and the liver edge was just palpable below the costal margin.
Initial blood results are shown below:
Haemoglobin 98 g/L Platelets 156 x 10^9/l Mean corpuscular volume 89 fl White cell count 6.8 x 10^9/l Reticulocyte count 5% Alkaline phosphatase 142 U/L Bilirubin 55 mol/L Alanine transaminase 105 U/L Albumin 35 g/L
Which investigation is most likely to reveal the underlying cause of his anaemia?
Direct antiglobulin test > 24-hour urinary copper excretion Vitamin B12 level Iron profile Haemoglobin electrophoresis
The combination of neurological and hepatic disease in young adults raises suspicion of Wilson’s disease. Personality change and movement disorders (such as tremor) are common presenting features of Wilson’s disease.
Haemolytic anaemia occurs in 10 to 15% of patients with Wilson’s disease, and accounts for the anaemia in this case, as indicated by the normocytic anaemia with reticulocytosis. As such 24-hour urinary copper is the investigation most likely to reveal the underlying diagnosis in this case. The direct antiglobulin test (DAT) is positive in antibody-mediated haemolytic anaemia (such as warm and cold haemolytic anaemia, haemolytic disease of the new born, and haemolytic transfusion reactions). In Wilson’s disease haemolysis occurs due to excess copper rather than antibodies, so the DAT does not give a positive result.
Vitamin B12 and iron deficiency would not account for the combination of liver and neurological features seen in this case, and haemoglobin electrophoresis is used in the diagnosis of haemoglobinopathies, of which there is no evidence.
Wilson’s Disease Diagnosis
An 18-year-old male is brought into the Emergency Department by police with facial injuries following an altercation with a work colleague. They are accompanied by his tearful mother, who reports that her son has developed violent mood swings and become increasingly aggressive over the last 6 months. There is no relevant past medical history.
On examination, the patient is mildly dysarthric and tearful but denies drinking alcohol. His observations are normal and examination of the precordium is unremarkable. His abdomen is soft and non-tender. Peripheral neurological examination reveals the presence of mildly increased tone, although there is no weakness. A ‘wing-beating tremor’ is also observed.
Blood tests are as follows:
Hb 132 g/l Na+ 143 mmol/l Bilirubin 23 µmol/l Platelets 189* 109/l K+ 4.2 mmol/l ALP 189 u/l WBC 7.6* 109/l Urea 4.1 mmol/l ALT 342 u/l Neuts 5.3* 109/l Creatinine 76 µmol/l γGT 122 u/l Lymphs 2.1* 109/l Albumin 43 g/l Eosin 0.3* 109/l
Given the likely diagnosis, which of the following investigations should be performed next?
24-hour urinary copper > Serum caeruloplasmin Serum ferritin and transferrin saturations Anti-LKM antibody Viral hepatitis screen
The combination of neuropsychiatric features and deranged LFTs should alert you to a possible diagnosis of Wilson’s disease. Caeruloplasmin is the most appropriate investigation as extremely low levels provide strong evidence of Wilson’s disease and are considered diagnostic if associated with Keyser-Fleischer rings. 24-hour urinary copper is useful in confirming the diagnosis but is more difficult to perform and would not normally be requested first-line.
Serum ferritin and transferrin saturations are used to diagnose haemochromatosis, whilst anti-LKM antibodies are found in autoimmune hepatitis type 2. None of the final 3 options are likely to present in the manner described above.
Wilson’s - Mx: Example Question
A 19-year-old medical student presents to hepatology clinic with asymptomatic jaundice. She has noticed slow progression of her jaundice over the last three months. She has a past medical history of anxiety and asthma. Both are currently well controlled. She has a salbutamol inhaler which she has not used in over a year.
Blood tests also demonstrated transaminitis with elevated bilirubin. She undergoes a liver screen and is found to have elevated urinary copper and low serum copper, as well as low ceruloplasmin. Viral hepatitis tests show Hepatitis B immunity from vaccination. Clotting function, full blood count and renal function are all within normal range.
What is the most appropriate treatment at this point?
Trientine dihydrochloride Liver transplantation Low copper diet Pegylated interferon gamma > Penicillamine
The correct answer is penicillamine. This is a young patient with test results consistent with a diagnosis of Wilson’s disease. The first step in management is to remove accumulated copper. This is done by chelation and can be done with penicillamine or trientine (with other treatments being under investigation). Of these two, penicillamine is considered first line. Once the accumulated copper is removed, then a low copper diet is advised to help avoid copper re-accumulation. Liver transplantation is necessary for decompensated hepatic function refractory to treatment. Pegylated interferon gamma is treatment viral hepatitis.
Wilson’s Disease - Diagnosis: Example Question
A 22-year-old man with a tremor and worsening slowness. Lately, the patient has noticed that he is feeling more nauseated, has pain in is stomach and is indicating his right upper quadrant. His friends have commented that his eyes have changed colour and turning yellow.
Which investigation result is most supportive of a diagnosis of Wilson’s?
Elevated ceruloplasmin > Elevated 24-hour urinary copper excretion Elevated serum copper Elevated transaminases Elevated pro-thrombin time
The correct answer is elevated 24-hour urinary copper excretion. Whilst serum copper and serum ceruloplasmin levels are useful in the diagnosis of Wilson’s disease they are expected to be lowered rather than elevated. It would be very likely that the transaminases would be elevated in this patient as he has right upper quadrant pain and jaundice, but this is not specific for Wilson’s disease. It would be unlikely that hepatic function would be sufficiently impaired to affect pro-thrombin time for this patient, and even if this was the case it is not specific for Wilson’s disease.
Source:
Schilsky, Michael L. ‘Wilson Disease: Diagnostic Tests.’ UpToDate. N.p., 01 Dec. 2015.
Wilsons Disease - Example Question
An 18-year-old lady works as a nursery teaching assistant and has noticed her right arm always shakes as she stretches it out to write on the blackboard at school. She has also started dropping cups of tea because of shaking on picking them up. Her balance has become poor and she now falls over easily when playing hopscotch with the children. These problems have developed over 14 months slowly. Her neurological examination reveals a postural tremor of the upper limbs; right worse than left, as well as a broad-based ataxic gait. She has some co-existent rigidity of the right upper limb. Slit lamp examination reveals brown-green deposits in Descemet’s membrane of the cornea. The remainder of the clinical examination is unremarkable. What is the most appropriate treatment for the underlying condition?
Dimercaprol Levodopa Beta-interferon > D-penicillamine Calcium EDTA
The diagnosis is Wilson’s disease: an autosomal-recessive condition that produces neurological, psychiatric, and hepatic dysfunction. Presentation is usually in children and young adults in the form of a postural tremor that may look like essential tremor although may also be much larger in amplitude (wing-beating tremor). Some patients present with rigidity and bradykinesia or ataxia rather than tremor. Others present with an acute hepatitis. Clearly in a young adult multiple sclerosis (MS) is the other differential to exclude neurologically (MS plaques in the cerebellum are not uncommon), and the give-away here is the corneal findings described (they could give you a picture of them), which are typical of Wilson’s. The rigidity is also an extrapyramidal feature that might steer you away from multiple sclerosis (although of course, basal ganglia plaques would not be impossible).
The pathophysiology is that there is a failure of hepatic excretion of copper into bile, therefore copper accumulates in the liver and secondarily suppresses the synthesis of caeruloplasmin (a copper-carrying blood protein). Eventually, copper spills over into the circulation and deposits also in the:
basal ganglia - with neurological sequelae
kidneys - causing tubular degeneration and thus a Fanconi syndrome (aminoaciduria, glycosuria, phosphaturia,
renal tubular acidosis type 2 (proximal), rickets (children) or osteomalacia (adults))
cornea - with Kayser-Fleischer rings
bones and joints - erosions
parathyroid glands - altered calcium metabolism
Look out for any of these features in a stem.
The first test to pick in an exam stem if you suspect Wilson’s disease should be caeruloplasmin, which will be low (<20 mg/dl), and then an elevated urine 24-hour copper excretion (>40 micrograms/ml). If the diagnosis is still not certain, the liver biopsy can be useful: showing increased hepatic copper levels. However, in reality, these changes can be non-specific on their own therefore interpretation is made on their combination alongside the clinical features.
Treatment is with the copper-chelating trientine or penicillamine.
Wilson’s Disease - Example Question
A 23-year-old student presented with a tremor in his right arm. He had also noticed increasing difficulty with speech, clumsiness in both hands and unsteadiness walking. He reported being very stressed and anxious. His relationship with his long-term girlfriend had come to an end and his younger brother had recently been diagnosed with bipolar affective disorder.
This student had a past medical history of depression and was born prematurely at 29 weeks gestation requiring ventilatory support in the neonatal intensive care unit. He took no regular medications and denied recreational drug use. He was, however, a binge drinker, consuming at least 30 units of alcohol per week. He had a penicillin allergy.
On examination there was a bilateral resting tremor more marked in the right arm than the left. The tone of the right arm was slightly increased. The movements of his upper limbs and hands were slow with reduced dexterity although there was no weakness. Reflexes were present and symmetrical. There was no sensory disturbance. On walking this patient had a broad-based, slow, ataxic gait with small steps. Rombergs test was negative. Power, tone, reflexes and sensation in the lower limbs were normal.
Investigations:
Hb 11.0 g/dl
Platelets 110 * 109/l
WBC 10.5 * 109/l
International Normalised Ratio 1.3
Na+ 134 mmol/l
K+ 4.0 mmol/l
Urea 5.8 mmol/l
Creatinine 78 µmol/l
Bilirubin 80 µmol/l
ALP 211 u/l
ALT 94 u/l
Amylase 72 u/l
Given the most likely underlying diagnosis which of the following would be the most appropriate management plan?
Start penicillamine as an inpatient and prescribe an alcohol detoxification regimen Prescribe an alcohol detoxification regimen and refer to a geneticist Start pentoxifylline and prescribe an alcohol detoxification regimen > Start trientine as an inpatient and prescribe an alcohol detoxification regimen Refer to the psychiatric team
This presentation (ataxia, movement disorder, psychiatric disturbance and deranged liver function tests in a young patient) is highly suggestive of Wilsons disease. Wilsons disease is an autosomal recessive disorder of copper metabolism. Deposition of copper in the liver, brain and eyes results in hepatic, neurological, psychiatric and ophthalmological manifestations as outlined below:
Hepatic: acute hepatitis, steatosis, severe chronic liver disease, fulminant hepatic liver disease +/- haemolytic anaemia
Neurological: asymmetrical tremor (can be postural or resting), dysarthria, pseudobulbar palsy, ataxia and gait disturbances
Psychiatric: personality change, severe depression, neurotic behaviours
Ophthalmological: Kayser-Fleischer rings, sunflower cataracts, night blindness, optic neuritis
Renal: Fanconi syndrome, nephrocalcinosis
Cardiac: arrhythmias
A diagnosis of Wilsons disease is supported biochemically by a low serum caeruloplasmin, elevated 24 hour urinary copper excretion and increased hepatic parenchymal copper concentration on liver biopsy.
First line pharmacological treatment aims to prevent copper absorption by using chelating agents. Penicillamine is a potential first line treatment however, in this case, there is a high risk of a hypersensitivity reaction given this patients history of penicillin allergy.
Trientine is now a popular first line treatment of neurological and hepatic disease in Wilsons as it has a better side-effect profile than penicillamine. In this patient with a penicillin allergy it would certainly be the treatment of choice.
Zinc can be used for maintenance treatment following initial chelation therapy or during pregnancy.
This patient should be advised to eat a low copper diet and avoid alcohol as this worsens hepatotoxicity.
Referral to geneticist may be required later on but does not contribute to the acute management of this patient. There are several mutations that can cause Wilsons disease, all of which are of low prevalence, and therefore genetic testing is not routinely used in clinical practice.
Pentoxifylline is a treatment for alcoholic hepatitis not Wilsons disease.
Neuro + Liver disease in a young patient = Wilsons
The combination of neurological and hepatic disease in young adults raises suspicion of Wilson’s disease. Personality change and movement disorders (such as tremor) are common presenting features of Wilson’s disease.
Wilsons
The diagnosis is Wilson’s disease: an autosomal-recessive condition that produces neurological, psychiatric, and hepatic dysfunction.
Presentation is usually in children and young adults in the form of a postural tremor that may look like essential tremor although may also be much larger in amplitude (wing-beating tremor).
Some patients present with rigidity and bradykinesia or ataxia rather than tremor.
Others present with an acute hepatitis.
The pathophysiology is that there is a failure of hepatic excretion of copper into bile, therefore copper accumulates in the liver and secondarily suppresses the synthesis of caeruloplasmin (a copper-carrying blood protein).
Manifestations:
Liver: Acute hepatitis, steatosis, severe chronic liver disease, fulminant hepatic liver disease +/- haemolytic anaemia
Eventually, copper spills over into the circulation and deposits also in the:
Basal ganglia - with neurological sequelae - asymmetrical tremor (can be postural or resting), dysarthria, pseudobulbar palsy, ataxia and gait disturbances
Kidneys - causing tubular degeneration and thus a Fanconi syndrome (aminoaciduria, glycosuria, phosphaturia, nephrocalcinosis, renal tubular acidosis type 2 (proximal), rickets (children) or osteomalacia (adults)
Cornea - with Kayser-Fleischer rings, sunflower cataracts, night blindness, optic neuritis
Bones and joints - erosions
Parathyroid glands - altered calcium metabolism
Psychiatric: personality change, severe depression, neurotic behaviours
Cardiac: arrhythmias
Look out for any of these features in a stem.
Wilsons Ix
Ix:
LOW SERUM CAERULOPLASMIN
HIGH 24 HR URINARY COPPER
The first test to pick in an exam stem if you suspect Wilson’s disease should be caeruloplasmin, which will be low (<20 mg/dl), and then an elevated urine 24-hour copper excretion (>40 micrograms/ml).
If the diagnosis is still not certain, the liver biopsy can be useful: showing increased hepatic copper levels. However, in reality, these changes can be non-specific on their own therefore interpretation is made on their combination alongside the clinical features.
Mx:
First line pharmacological treatment aims to prevent copper absorption by using chelating agents.
Penicillamine is first line treatment.
If patient is pen allergic however, there is a high risk of a hypersensitivity reaction and Trientine is now a popular first line treatment of neurological and hepatic disease in Wilsons as it has a better side-effect profile than penicillamine. In a patient with a penicillin allergy it would certainly be the treatment of choice.
Zinc can be used for maintenance treatment following initial chelation therapy or during pregnancy.
This patient should be advised to eat a low copper diet and avoid alcohol as this worsens hepatotoxicity.
