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�Wilson’s Disease

Hope Askew, Pharm.D.

PGY1 Pharmacy Resident

Parkland Health and Hospital System

September 23^rd, 2021

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Objectives

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Describe the pathophysiology of Wilson’s Disease

Understand and interpret lab values and imaging associated with Wilson’s Disease

Identify common clinical presentations and symptoms associated with Wilson’s Disease

Compare the pharmacologic treatment options for Wilson’s Disease

Design a treatment plan for a patient with Wilson’s Disease

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Our Patient

KL, a 39-year-old Asian female who presented to Parkland’s ED on 8/31/20 secondary to multiple falls with altered mental status…

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Patient: KL

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Presented with generalized fatigue, weakness, and multiple falls that started x 1 day
Postural instability/ gait ataxia x 5 months
Tremors of upper extremities and dysarthria x 8 months
Slowed speech x 9 months
Worsening depressed mood, irritability, and personality changes x 9 months
Denies ETOH, tobacco, illicit drug use

HPI per patient, husband, and brother:

Intracranial Hemorrhage (2014)
Liver Cirrhosis – unknown etiology; told it was “genetic” from an outside hepatologist (2014)

PMH:

Biological mother died of liver disease (unknown etiology in her 30’s)
Dad: liver cirrhosis, alive, unknown age of Dx
2 sisters: liver cirrhosis, unknown age of Dx

Family History:

No family hx of EtOH abuse

Per our patient's husband and brother:

She presented to parkland with generalized weakness and multiples falls that started about a day prior to admission
They also reported gait abnormalities that started ~5 months ago
Tremors of her upper extremities that started ~ 8 months ago
And an overall change in her mood that occurred ~ 9 months ago. It was reported that she has become more depressed and irritable
The patient as well as her family denied any ETOH, tobacco, or illicit drug use

PMH is significant for intercranial hemorrhage which occurred in 2014 where she went to the hospital ~7 years ago for a headache and was told that she had bleeding in her brain

-has had intermittent headaches since then and take 2 tabs of APAP a day for pain

-diagnosed with cirrhosis of unknown etiology during the same visit and is being followed by a GI doctor every 3-6 months for blood test

And significant family history shows a commonality of liver disease within her close family members

-all of which had no hx of EtOH abuse

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Review of System and Physical Exam (9/1/20)

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General	She is oriented to person, place, time Well-developed, well-nourished, and in no distress Positive for malaise/fatigue Negative for chills and fever
HEENT	Normocephalic and atraumatic Positive Headache Negative for congestion, ear pain and sore throat Negative for pain, discharge and redness of eyes. Visible Kayser-Fleischer rings on exam Normal range of motion. No JVD present
Respiratory	Negative for cough, hemoptysis, sputum production and shortness of breath
Cardiac	Normal rate, regular rhythm, normal heart sounds and intact distal pulses Negative leg edema

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Review of System and Physical Exam (9/1/20)

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Skin	Negative jaundice, palmar erythema, spider angiomata, caput medua
Abdominal	Soft, non-tender, non-distended Negative ascites Mild hepatomegaly
Musculoskeletal	Positive for falls Negative for joint pain, myalgias and neck pain Normal range of motion No tenderness, deformity or edema
Neurological	Positive for tremors, abnormal speech, and general weakness Negative for sensory change, focal weakness and seizures
Psychiatric/ Behavioral	Positive for depression + irritability

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Medication List at Admission

TYLENOL 650 MG 2 TABLETS DAILY FOR HEADACHE

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No known drug allergies

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Objective (8/31/20)

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Vitals
Height	60 in
Weight	56.7 kg
BMI	24.5 kg/m
Heart Rate	59 bpm
Blood Pressure	108/67
Temperature	98.1 degrees F
SpO2	100%

HAV: immune (prior infection) HBV: immune HCV: no infection CrCl: 80 mL/min

24-Hr Urinary Copper Level: 196 mcg/hr (>2x ULN)

Ceruloplasmin: 10.5 mg/dL

Ammonia: 12 umol/L

Lipase: 89 u/L

INR: 1.2

AST/ALT: 46/38 u/L

Vitals and Chemistry were pretty unremarkable

We see she is well norished, BP is within normal range, no fever, and her oxygen saturation is good
Her CBC and BMP were all within normal range with a CrCl of 80 mL/min

Differential = chronic viral Hepatitis B (given country of origan = Vietnam) 🡪 ruled out!

However, her AST/ALT are elevated (normal <35), ammonia is low, lipase is elevated, and normal INR

-But looking more specifically at copper related labs we see her 24-hr urinary copper level is significantly elevated at > 2x ULN and her ceruloplasmin is 10.5 🡪 if you are unfamiliar with these last to labs, I will go more into detail later

Differential = chronic viral Hepatitis B (given country of origan = Vietnam) 🡪 ruled out!

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-Hepatitis A does not lead to long-term complications, such as cirrhosis, because the infection only lasts a short time.

-Hep B immune (HBs AB = reactive, HBs Ag = non-reactive, and HBc Total Ab = non-reactive= immune to HBV infection – never had the infection but was vaccinated)

-Hep C AB = non-reactive = non-immune

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Imaging

Liver Biopsy (completed in 2014)

Showed cirrhosis with severe steatosis with steatohepatitis – completed at outside facility so unable to obtain copper staining

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Chest X-Ray (8/31/20)

No acute cardiopulmonary process identified

Liver Ultrasound (9/1/20)

Cirrhotic appearing liver with hyperechoic lesions concerning for hepatocellular carcinoma

MRI Brain (9/1/20)

No evidence of acute infract, intracranial mass (no active bleeding) – hx of hemorrhage
Increased T2/FLAIR signal within the thalami, midbrain and pons 🡪 Panda Sign

Slit Lamp Examination (9/1/20)

Positive for Kayser-Fleischer rings

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Wilson’s Disease

Pathophysiology and Epidemiology

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https://www.wdrxaccess.com/what-is-wilsons

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What is Wilson’s Disease?

Wilson’s Disease (also called hepatolenticular degeneration) is caused by mutations in the ATP7B gene 🡪 decreased transport of copper from the liver into bile, leading to copper excess in the liver

Excess hepatic copper leads to hepatocyte injury
Increased hepatic copper combined with hepatocyte damage results in the release of copper into the blood

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Mutations can occur anywhere (there have been over 500 mutations described)

Wilson’s Disease

Normal

Neurol Res 2014; 36:157.

Best Pract Res Clin Gastroenterol. 2010;24(5):531-539

Wilson’s Disease and Iron Overload: Pathophysiology and Therapeutic Implications. Clinical Liver Disease, 17: 61-66

So what exactly is Wilson’s disease

**suggest discussing the role of ceruloplasmin in Wilson's disease and how it relates to helping diagnosing Wilson's disease.***

Lin LJ, Wang DX, Ding NN, et al. Comprehensive analysis on clinical features of Wilson's

disease: an experience over 28 years with 133 cases. Neurol Res 2014; 36:157.

Huster D. Wilson disease. Best Pract Res Clin Gastroenterol. 2010;24(5):531-539. doi:10.1016/j.bpg.2010.07.014

Pak, K., Ordway, S., Sadowski, B., Canevari, M. and Torres, D. (2021), Wilson’s Disease and Iron Overload: Pathophysiology and Therapeutic Implications. Clinical Liver Disease, 17: 61-66. https://doi.org/10.1002/cld.986 🡪 figures

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The transport of copper within hepatocytes are regulated by ATP7B (the copper transporting intracellular protein affected in Wilsons disease

-In Wilson disease, there is decreased incorporation of copper into apoceruloplasmin and decreased transport of copper from the liver into bile, leading to copper excess in tissue despite low circulating levels of ceruloplasmin (the major form of circulating copper)

Hepatocyte injury is due to enhanced free radical production and oxidative injury to cellular organelles
The increase in “free” serum copper (not bound by ceruloplasmin) presumably is the proximate cause of extrahepatic copper deposition and subsequent toxicity in the brain and other tissues
So even though ceruloplasmin is low, blood levels of Copper is high 🡪 ATP7B is mutated so not packing Cu in apo-ceruloplasmin so it cant become ceruloplasmin so blood level labs will show its low but there are a ton of Cu in the blood via the 24 hr urine lab b/c it is just spilling out of the hepatocytes

Ceruloplasmin is a protein made in your liver. It stores and carries the mineral copper around your body. Ceruloplasmin carries 65% to 90% of the copper found in blood. Copper is vital to many processes in your body. These include building strong bones and making melanin. But having too much copper in your body can be toxic.

-Your liver normally takes copper from your bloodstream and puts it into ceruloplasmin proteins. The ceruloplasmin is then released into blood plasma. Ceruloplasmin carries copper around your body to the tissues that need it

-In Wilson disease, copper is not put in ceruloplasmin. The disease also keeps your liver from sending extra copper to be eliminated in your bowel movements. Instead, copper builds up in your liver until it overflows into the bloodstream. From there, copper builds up in your brain, corneas, kidneys, liver, bones, and small glands near the thyroid. If not treated, the liver and brain damage due to copper poisoning from Wilson disease is fata

ATP7B can be affected by mutations at many different sites. Over 500 different mutations in the ATP7B gene have been identified in patients with Wilson disease

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Wilson’s Disease is caused by a genetic mutation…

Rare autosomal recessive disorder
Must have mutation in BOTH copies of gene but it does not have to be the same mutation
Prevalence: 1 in 30,000

1 in 90 are carriers of the mutation

Symptoms are not exclusive for Wilson’s. Patients present with:

Psychiatric: 10-100%
Hepatic Damage: 18-84%
Neurologic: 18-73%

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Age of onset: 5-35 years (mean age of 13)

https://www.aboutkidshealth.ca/Article?contentid=881&language=English

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Wilson’s Disease

Clinical Presentation and Diagnosis

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https://www.wdrxaccess.com/what-is-wilsons

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Clinical Presentation…

Psychiatric

May precede hepatic or neurologic signs in 1/3 patients

Decreased academic performance
Personality changes (impulsive, labile, irritable)
Paranoia (may be mistaken for schizophrenia)
Depression

Hepatic

Varies from asymptomatic elevations of liver enzymes to fulminant liver failure (rare)
Maybe indistinguishable from:

acute viral hepatitis with elevated AST/ALT levels
Jaundice
Abdominal pain

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Neurologic

98% of patients with Wilson disease with neurologic manifestations have Kayser-Fleischer rings.
In patients with known cirrhosis, neurologic manifestations may be mistaken for hepatic encephalopathy
Most common neurologic manifestation:

Dysarthria
Gait abnormalities
Tremor - “Wing Beating”
Urinary Incontinence

Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci 2010; 1184:173.

Wilson’s Disease patients will typically present with either:

Psychiatric signs

Which may occur prior to any hepatic or neurological signs
These may present as personality changes like irritability or even schizophrenia. But most often it presents as depression

Hepatic signs

Can vary from asymptomatic elevation of liver enzymes to very rarely fulminant liver failure

Neurologic

And a vast majority of WD patients who present with neurologic manifestation will also show signs with KF rings
Most common neurologic signs will present with gait abnormalities, and a unique tremor called wing beating *show video*

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https://www.youtube.com/watch?v=2cF4Z28O91U

Psychiatric:

Happens b/c of copper deposition in the brain
Occurs in ~2/3 of all pts
In about 1/3 of these pts they had symptoms of Wilson’s at the beginning
Not uncommon for a ppt to be miss diagnosed with depression (depression is most common symptom)

Since Wilson’s first happens during mid to late teens: an example where a pt goes away to college get “depressed” “anxious” and its thought to just be due to major life changes 🡪 they get put on an antidepressant 🡪 maybe it gets better, but then they develop a little tremor 🡪 oh well that can happen with antidepressants 🡪 can you can see how this can be missed if providers are not on the look out for it (especially b/c depression and anxiety is very common in this age group so its almost impossible to look for it in everyone)
Its really not until there are more severe liver problems or neurologic problems that they are diagnosed with Wilson’s Disease

Hepatic:

The degree of aminotransferase elevation in patients with Wilson disease is usually less compared with patients with acute viral hepatitis or ischemic hepatitis
In some patients, the symptoms will resolve spontaneously (though Wilson disease is still present and requires treatment), whereas others may rapidly deteriorate and develop acute liver failure

Neurologic

-wing beating tremor -> could not find in the patients chart where the noted her tremor being “wing beating” but in WD tremor’s are typically wing beating

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Both Equally

Males

Females

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Brain Imaging

Brain MRIs are typically abnormal. Especially when patients present with neurological symptoms:

Increased T2/FLAIR signal within the thalami, midbrain and pons demonstrating the “Panda” sign
May improve with treatment

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Dina A. Jacobs, Clyde E. Markowitz, David S. Liebeskind, Steven L. Galetta

Neurology Oct 2003, 61 (7) 969; DOI: 10.1212/01.WNL.0000085871.98174.4E

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Clinical Diagnosis

Routine Blood Tests

CBC

Anemia and low platelets

Liver Function Tests

Elevated AST and ALT
Elevated INR (increased bleeding)
Elevated bilirubin (causes jaundice)

Organs Involved

Liver (abdominal pain, bleeding, jaundice)
Brain (depression, behavior changes, dystonia, dysarthria)
Blood (hemolysis, thrombocytopenia)
Cornea (Kayser-Fleisher Rings)

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European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease.

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Specific Tests

Serum Ceruloplasmin

95% of Wilson patients will have a low serum ceruloplasmin (<20 mg/dL)

If <5 mg/dL strongly suggests Wilson’s Disease

Low Ceruloplasmin + KF Rings = Diagnostic

Kayser-Fleischer (KF) Rings

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Difficult to diagnosis even with proper equipment
“Sunflower cataracts” due to copper deposits within the lens
Present in 95% of patients with Neurologic/ Psychiatric involvement & 50% with Hepatic involvement

European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease.

Stremmel W, Meyerrose KW, Niederau C, et al. Wilson disease: clinical presentation, treatment, and survival

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Specific Tests

24- Hour Urinary Copper Excretion

Diagnosis: >100 mcg (1.6 micromol)
Also used to monitor treatment efficacy (level depends on chosen therapy)
Indicates increased plasma non-ceruloplasmin bound copper
If not properly collected in container 🡪 May result falsely low

Genetic Testing (exon sequencing of ATP7B gene)

Used if diagnosis is not clear from other tests
Not 100% reliable but very close
Can be useful for screening siblings if patient is positive

Liver Biopsy

Traditionally considered “Gold Standard”
Not necessary if diagnosis is clear (not everyone has to have it 🡪 genetic testing become more popular)

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Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111

Arora K. Wilson disease. PathologyOutlines.com website

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AASLD

American Association for the Study of Liver Diseases
Published 2008

EASL

European Association for the Study of Liver
Published 2012

ESPGHAN

European Society of Paediatric Gastroenterology, Hepatology and Nutrition
Published 2018

Guidelines

in Wilson’s Disease

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Differences of Diagnostic Criteria

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Diagnostic Criteria	AASLD	EASL	ESPGHAN
Clinical and biochemical parameters	Primary		Primary
Leipzig score		Primary	Used in a step wise approach
ATP7B Mutation via Genetic Testing			Secondary

Clinical and Biochemical Parameters = slit lamp exam for Kayser-Fleischer (KF) rings, serum ceruloplasmin, 24-hour urine copper, Liver biopsy for histology and copper quantification
Leipzig score

Variation on the interpreted score depending on which guidelines is used

Genetic Testing per ESPGHAN Guidelines

> 1 mutation plus “definite” signs and symptoms = diagnostic
2 mutations in asymptomatic children = diagnostic

1 American Association for Study of Liver Diseases (AASLD) 2 European Association for Study of Liver (EASL) 3 Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. (ESPGHAN)

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Diagnostic Tool: Leipzig Score

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Our Patient Presented with:

Positive for Kayser-Fleischer

Not directly noted in the chart if severe or mild neurologic symptoms (Panda Sign shown on Brain MRI)

Ceruloplasmin = 0.105 g/L (L)

Liver biopsy previously completed, no record of copper staining

24- Hour Urinary Copper = >2x ULN

Genetic Testing was not completed due to high suspension of Wilson’s due to low ceruloplasmin and elevated urinary copper as well as ams presentation

https://digestivedashboard.nl/2020/11/12/leipzig-score-for-wilsons-disease/

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Approach to diagnosis of Wilson disease (WD) in a patient with unexplained liver disease

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Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111

Our patient presented with a

Ceruloplasmin = 10.5 mg/dL

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Wilson’s Disease

Treatment Options

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https://www.wdrxaccess.com/what-is-wilsons

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Clinical Guideline Recommendations for Wilson’s Disease

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	Initial Therapy – Symptomatic	Zinc Adjunct Therapy	Initial Therapy – Asymptomatic	Maintenance Therapy	Transplant	Treatment Monitoring
AASLD	Chelating Agent (penicillamine or trientene)	Yes – decompensated cirrhosis	Chelator or Zinc	maintenance-dose chelator or zinc	Liver transplant in Acute Liver Failure and decompensated cirrhosis unresponsive to medical treatment	24- hour urinary copper excretion: -maintenance chelator therapy: 200–500 μg (3–8 μmol) per day -Zinc: 75-100 μg per day
EASL		Yes – if neurological symptoms	Chelator or Zinc	maintenance-dose chelator or zinc
ESPGHAN		Yes – decompensated cirrhosis	Favors Zinc monotherapy	Favors Zinc monotherapy

1 Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD) 2 European Association for Study of Liver (EASL) 3 Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. (ESPGHAN)

AASD = American Association for the Study of Liver Diseases

EASL = European Association for the Study of Liver

ESPGHAN = European Society of Paediatric Gastroenterology, Hepatology and Nutrition

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Medication Options: Chelating Agents

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Drug	MOA	Initial Dose	Maintenance Dose	Dose Reductions	Adverse Effects	Warnings	Potency	Parkland Price
D-penicillamine *adjunct therapy: Pyridoxine (Vitamin B6) 25mg daily – penicillamine inactivates pyridoxine	Chelates copper and promotes urinary excretion	250-500 mg/day Titrate in 250mg increments every 4-7 days	1g/day, divided in 2 doses (max: 1.5g/day) Taken 1 hr before or 2 hrs after meals (effects absorption) Take 1 hr apart from other drugs, milk, antacids, zinc products	Pregnancy: -decrease to minimum effective dose to limit fetal exposure during 1^st trimester (~25-50% reduction) Surgery: -dose reduction to 250 mg/day prior to procedures	Worsening neurologic symptoms, diarrhea, rash, proteinuria, thrombocytopenia, leukopenia, anemia, lupus-like reaction May switch to alternative therapy if worsening Neurological Symptoms occur	Avoid use in CrCl <50 mL/min Caution in patients with PCN allergy Toxicity: fever, sore throat, chills, bruising, or bleeding	Very effective – more copper binds compared to trientine (~5-10mg/day)	$0.01 per 250mg capsule (Brand)
Trientine *less studied; recommended in patients who are unable to tolerate d-penicillamine, renal insufficiencies, and thrombocytopenia	Chelates copper and promotes urinary excretion (absorbed less compared to penicillamine)	50 to 1,250 mg/day; divided in 2-4 doses (increase dose if concentration of serum copper is >20 mcg/dL)	Titrate up to 1.25g/day, divided in 2-4 doses Taken 1 hr before or 2 hrs after meals	Pregnancy: ~25-50% reduction	iron deficiency, gastritis, muscle spasms, systemic lupus, anemia	Anemia	Less effective in obtaining a negative copper balance (~2-3mg/day)	$0.01 per 250 mg capsule

Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111

long-term maintenance dosage should be determined at 6- to 12-month intervals

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Medication Options: Other Agents

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Drug	MOA	Dose	Side Effects	Warnings	Potency	Price
Zinc Acetate *use in asymptomatic patients or in patients who experienced worsening neurologic symptoms with chelating agents	Induces metallothionein in the GI epithelium 🡪 endogenous chelator that inhibits copper absorption	Initial: 25 mg 3 times daily Maintenance: 50 mg 3 times daily	GI upset	Not recommended for initial treatment of Wilson disease in symptomatic patients - use as maintenance therapy after patient is stabilized on initial chelation therapy	Weakest (<1mg/day) less effective at preventing hepatic deterioration compared to chelating agents	$6 per 100 tablets
ALXN 1840 pipeline – phase 3 trial first drug to be studied for Wilsons in >30 years	Targeted demoblization-coppering therapy that selectively and tightly binds to and removes copper from tissue and blood	Once daily dosing	n/a	n/a	n/a	n/a

Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111

Compliance is an issue with ALL current medication options due to having to be taken multiple times a day on an empty stomach

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Future of Wilson’s Disease Medication Therapy -ALXN1840 (AztraZeneca)

FoCus Trail is a Phase 3, Randomized, Rater-Blinded, Multi-Centered Study
Designed to evaluate efficacy and safety of ALXN1840 vs. Standard of Care in patients with Wilson’s Disease greater than 12 years old
Total Participants: 215

Inclusion Criteria = established diagnosis of Wilson’s Disease with a Leipzig Score > 4
Exclusion Criteria = decompensated hepatic cirrhosis, AST >2 ULN, ALT >5 ULN, Hgb < 9g/dL, hx of seizures, pregnant/breast feeding, active infection with HBV or seropositive for HCV, CKD-Stage 5 or CrCl <30 mL/min

2 Arm’s (randomized 2:1)

Experimental = ALXN1840 given orally daily x 48 weeks (starting dose 15 mg QOD and titrated to 60 mg daily)
Standard of Care = dependent on site/region; received trientine, penicillamine, zinc, or combo administered according to standard of care

Primary Outcome

ALXN1840 demonstrated 3x more copper mobilization from tissues when compared to standard of care treatment

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Treatment Overview

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May treat with zinc monotherapy

Asymptomatic:

Chelating agent (d-penicillamine or trientine)
Maintenance therapy = zinc monotherapy

Symptomatic:

Clinical Improvement can be seen within ~1-3 months into therapy
Lab Goals: consistent results of 24-hour urinary copper < 500 mcg/day on tx; expected within 6-12 months

Goal: Establish a negative copper balance & reduce dietary copper intake to < 1.0 mg/day of copper

Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111

Essentially the goal is to get ride of more copper than is being taken in

-reduce the amount consumed & increase the amount that is excreted out of the body

Asymptomatic (if found had the mutation b/c routine test was slightly abnormal or sibling had it) -> tx w/ zinc alone to prevent disease symptoms or progression

Symptomatic we chelate to bind the copper -> pull it out of the liver and get it out of the body faster (zinc just blocks how much is absorbed)

Adequate studies regarding the timing of this change-over in treatment of adult patients with hepatic WD are not available, and only limited data are available for children

No matter how well a patient appears, treatment should never be terminated indefinitely. Patients who discontinue treatment altogether risk development of intractable hepatic decompensation

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Treatment Overview

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Liver transplantation immediately

Acute Liver Failure due to Wilson's Disease:

Liver transplantation consult and evaluation

Decompensated Cirrhosis unresponsive to chelating treatment:

Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111

Essentially the goal is to get ride of more copper than is being taken in

-reduce the amount consumed & increase the amount that is excreted out of the body

Asymptomatic (if found had the mutation b/c routine test was slightly abnormal or sibling had it) -> tx w/ zinc alone to prevent disease symptoms or progression

Symptomatic we chelate to bind the copper -> pull it out of the liver and get it out of the body faster (zinc just blocks how much is absorbed)

Adequate studies regarding the timing of this change-over in treatment of adult patients with hepatic WD are not available, and only limited data are available for children

No matter how well a patient appears, treatment should never be terminated indefinitely. Patients who discontinue treatment altogether risk development of intractable hepatic decompensation -> unless liver transplant is done

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Dietary Restrictions: Low Copper

White meat
Fish
Bread, pasta, rice
Dairy & eggs
Vegetables
Fruits

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Liver and other organs
Nuts
Beans
Mushrooms
Bitter-sweet chocolate

Diagnosis and treatment of Wilson disease: An update.

Hepatology, 47: 2089-2111

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Our Patient

KL, a 39-year-old Asian female newly diagnosed with Wilson’s disease…

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Assessment and Plan – Wilson’s Disease:

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Primary Team

Initiated on:

Penicillamine 250mg daily
Zinc Acetate 50mg TID
Pyridoxine 25mg daily

My Recommendations

I agree with initiating penicillamine vs. trientine due to its effectiveness as a copper chelator and adjuncting with zinc and pyridoxine
Monitoring Plan:

CBC, BMP, 24H Urine Copper at follow-up appointment

Continue maintenance therapy for 1-3 months and follow-up with outpatient neurology post discharge

Titrated to goal of:

Penicillamine 1.5g daily
Zinc Acetate 50mg TID
Pyridoxine 25mg daily

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Patient Update

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Current medications as of September 2021:

Penicillamine 500mg TID
Zinc 50mg TID
Pyridoxine 25 mg daily

Recent follow-up visits:

Neurology clinic 6-8-2021; mentioned improvement in ataxia, tremor, dysarthria
GI and liver clinic 9-9-2021; mentioned improvement in neurological symptoms – lab results:

Serum copper: 34 ug/dL

Previously 61 ug/dL on 9-1-20 (admission)

Per recent notes, there has been a medication adherence problem

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Questions?

Hope Askew, Pharm.D.

PGY1 Pharmacy Resident

Email: Hope.Askew@phhs.org

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References

WDRxAccess – Official Website. 2021. What is Wilson's Disease?. [online] Available at: <https://www.wdrxaccess.com/what-is-wilsons> [Accessed 1 September 2021].
Aboutkidshealth.ca. 2013. AboutKidsHealth. [online] Available at: <https://www.aboutkidshealth.ca/Article?contentid=881&language=English> [Accessed 1 September 2021].
Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci 2010; 1184:173.
Lin LJ, Wang DX, Ding NN, et al. Comprehensive analysis on clinical features of Wilson’s disease: an experience over 28 years with 133 cases. Neurol Res 2014; 36:157.
Huster D. Wilson disease. Best Pract Res Clin Gastroenterol. 2010;24(5):531-539. doi:10.1016/j.bpg.2010.07.014
Pak, K., Ordway, S., Sadowski, B., Canevari, M. and Torres, D. (2021), Wilson’s Disease and Iron Overload: Pathophysiology and Therapeutic Implications. Clinical Liver Disease, 17: 61-66. https://doi.org/10.1002/cld.986
Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089-111
European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012;56:671-85.
Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:334-44.4. Ferenci P, Caca K,
Arora K. Wilson disease. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverwilsonsdisease.html. Accessed September 6th, 2021
Dina A. Jacobs, Clyde E. Markowitz, David S. Liebeskind, Steven L. Galetta. Neurology Oct 2003, 61 (7) 969; DOI: 10.1212/01.WNL.0000085871.98174.4E
ALXN1840 focus phase III trial in Wilson Disease met primary endpoint demonstrating improvement in copper mobilisation from tissues. AstraZeneca. https://www.astrazeneca.com/media-centre/press-releases/2021/alxn1840-wilson-phase-iii-met-primary-endpoint.html. Published August 26, 2021.
Efficacy and safety of ALXN1840 (formerly named WTX101) administered for 48 weeks versus standard of care in participants with Wilson disease with an extension period of up to 60 months - Full Text view. Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT03403205.
Wilson's disease with wing beating Tremor Tremors Spring Video Atlas. YouTube. https://www.youtube.com/watch?v=2cF4Z28O91U. Published June 13, 2018. Accessed September 20, 2021.

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