Wilson's Disease¶

VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Draft - Pending Review

DIAGNOSIS: Wilson's Disease (Hepatolenticular Degeneration)

ICD-10: E83.01 (Wilson's disease), E83.09 (Other disorders of copper metabolism), G25.5 (Other chorea — for movement disorder presentation), G25.2 (Other specified forms of tremor — for tremor-predominant presentation), F06.8 (Other specified mental disorders due to known physiological condition — psychiatric presentation)

SYNONYMS: Wilson disease, WD, hepatolenticular degeneration, progressive lenticular degeneration, Westphal-Strümpell pseudosclerosis, copper storage disease, ATP7B deficiency, hepatocerebral degeneration, Wilson's, copper overload disease, hepatolenticular syndrome, Kinnier Wilson disease

SCOPE: Diagnosis and management of Wilson's disease in adolescents and adults presenting with neurologic, hepatic, or psychiatric manifestations. Covers diagnostic workup (ceruloplasmin, 24-hour urine copper, slit-lamp exam, hepatic copper, genetic testing), chelation therapy (D-penicillamine, trientine), zinc maintenance therapy, liver transplant evaluation, symptomatic management of neurological symptoms (dystonia, tremor, parkinsonism, psychiatric), and family screening. Excludes other copper metabolism disorders (Menkes disease), isolated non-Wilson hepatic cirrhosis, and drug-induced movement disorders.

DEFINITIONS: - Wilson's Disease (WD): Autosomal recessive disorder caused by mutations in the ATP7B gene (chromosome 13q14.3), resulting in defective copper excretion into bile and incorporation into ceruloplasmin, leading to toxic copper accumulation in liver, brain, cornea, kidneys, and other organs - Kayser-Fleischer (KF) Rings: Golden-brown deposits of copper in the Descemet membrane of the cornea; detected by slit-lamp exam; present in >95% of neurologic WD and ~50% of hepatic-only WD - Wing-Beating Tremor: Coarse, irregular, proximal tremor elicited with arms outstretched and elbows flexed; characteristic (though not pathognomonic) of WD - Ceruloplasmin: Copper-carrying glycoprotein synthesized in the liver; typically low (<20 mg/dL) in WD but can be normal in 5-15% of neurologic WD - Free (Non-ceruloplasmin-bound) Copper: Calculated as total serum copper minus ceruloplasmin-bound copper; elevated in WD (>25 mcg/dL) - Leipzig Score: Diagnostic scoring system for WD incorporating KF rings, neurologic symptoms, ceruloplasmin, Coombs-negative hemolytic anemia, hepatic copper, urinary copper, and mutation analysis (score ≥4 = established diagnosis)

KEY CLINICAL FEATURES:

Neurologic Manifestations (40-50% of presentations): - Movement disorders: Dystonia (most common neurologic feature), tremor (resting, postural, wing-beating), parkinsonism, choreoathetosis, athetosis - Bulbar symptoms: Dysarthria (most common initial neurologic symptom), dysphagia, drooling, dysphonia - Gait disturbance: Ataxia, postural instability - Other: Seizures (rare, 6%), risus sardonicus (fixed grin from facial dystonia)

Hepatic Manifestations (40-50% of presentations): - Asymptomatic transaminase elevation - Chronic hepatitis - Cirrhosis (compensated or decompensated) - Fulminant hepatic failure (with Coombs-negative hemolytic anemia)

Psychiatric Manifestations (30-40%, often earliest): - Depression, anxiety - Personality change, irritability - Psychosis (rare) - Cognitive decline, declining school/work performance - Behavioral disinhibition

Other Manifestations: - Ophthalmologic: KF rings, sunflower cataracts - Hematologic: Coombs-negative hemolytic anemia - Renal: Fanconi syndrome, renal tubular acidosis, nephrolithiasis - Musculoskeletal: Osteoporosis, arthropathy - Cardiac: Cardiomyopathy (rare)

PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════

1. LABORATORY WORKUP¶

1A. Essential/Core Labs¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Serum ceruloplasmin (CPT 82390)	URGENT	STAT	ROUTINE	STAT	Low in 85-95% of WD; screening test; may be normal in acute liver failure or inflammation	<20 mg/dL (often <10 mg/dL in WD); normal does NOT exclude WD
Serum copper (total) (CPT 82525)	URGENT	STAT	ROUTINE	STAT	Low-normal total copper (paradoxically) but elevated free copper in WD	Total copper low-normal (40-80 mcg/dL); calculate free copper
24-hour urine copper (CPT 82525)	-	STAT	ROUTINE	STAT	Gold standard screening; elevated in WD; >100 mcg/24h suggestive; >40 mcg/24h in children	>100 mcg/24h (often >200 in symptomatic WD); normal <40 mcg/24h
CBC with differential (CPT 85025)	STAT	STAT	ROUTINE	STAT	Coombs-negative hemolytic anemia; baseline; thrombocytopenia (hypersplenism)	Hemolytic anemia, thrombocytopenia suggest WD
CMP (BMP + LFTs) (CPT 80053)	STAT	STAT	ROUTINE	STAT	AST/ALT elevation; synthetic function (albumin, bilirubin); renal function	Elevated AST/ALT (often AST > ALT); low albumin; elevated bilirubin in advanced disease
Direct and indirect bilirubin (CPT 82248)	STAT	STAT	ROUTINE	STAT	Elevated indirect bilirubin in hemolysis; elevated direct in hepatic disease	Elevated (especially indirect if hemolysis)
PT/INR (CPT 85610)	STAT	STAT	ROUTINE	STAT	Hepatic synthetic function; coagulopathy in liver failure	Elevated INR in advanced disease; INR >1.5 suggests significant hepatic dysfunction
Reticulocyte count (CPT 85045)	URGENT	STAT	ROUTINE	STAT	Elevated in hemolytic anemia	Elevated (>2%) suggests active hemolysis
Direct Coombs test (DAT) (CPT 86880)	URGENT	STAT	ROUTINE	STAT	NEGATIVE in WD hemolysis (Coombs-negative hemolytic anemia is classic)	Negative (positive Coombs suggests other etiology)
Haptoglobin (CPT 83010)	URGENT	STAT	ROUTINE	STAT	Low/undetectable in hemolysis	Low or undetectable in active hemolysis
LDH (CPT 83615)	URGENT	STAT	ROUTINE	STAT	Elevated in hemolysis	Elevated in hemolysis
Urinalysis (CPT 81003)	STAT	STAT	ROUTINE	STAT	Renal tubular dysfunction (glycosuria, proteinuria, aminoaciduria — Fanconi syndrome)	Glycosuria with normal serum glucose; proteinuria
Phosphorus (CPT 84100)	STAT	STAT	ROUTINE	STAT	Hypophosphatemia from renal tubular loss	Low (Fanconi syndrome)
Uric acid (CPT 84550)	-	ROUTINE	ROUTINE	ROUTINE	Low uric acid suggests renal tubular dysfunction	Low (<2 mg/dL suggests renal copper toxicity)
Blood glucose (CPT 82947)	STAT	STAT	ROUTINE	STAT	Baseline; glycosuria with normal glucose suggests Fanconi	Normal (but glycosuria present = renal tubular)

1B. Extended Workup (Second-line)¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Free (non-ceruloplasmin-bound) copper (calculated)	-	STAT	ROUTINE	STAT	Calculated: total serum copper (mcg/dL) minus (3 x ceruloplasmin [mg/dL]); elevated in WD	>25 mcg/dL (often >50 in symptomatic WD); most specific biochemical marker
Penicillamine challenge test (24-hour urine copper after 500 mg penicillamine x 2 doses)	-	ROUTINE	ROUTINE	-	Used in equivocal cases, especially pediatric; less validated in adults	>1600 mcg/24h highly suggestive of WD (>25 mcmol/24h)
ATP7B gene sequencing (CPT 81406)	-	ROUTINE	ROUTINE	-	Definitive diagnosis; identifies pathogenic variants; essential for family screening	Two pathogenic variants = confirmed WD; one variant + clinical findings = probable WD
Peripheral blood smear (CPT 85060)	URGENT	STAT	ROUTINE	STAT	Schistocytes, spherocytes in hemolytic anemia	Fragmented RBCs, polychromasia
Ammonia level (CPT 82140)	STAT	STAT	-	STAT	Hepatic encephalopathy assessment in liver failure	Normal <35 mcmol/L; elevated in hepatic failure
Lactate (CPT 83605)	STAT	STAT	-	STAT	Tissue hypoperfusion in fulminant hepatic failure	Elevated in liver failure
Alpha-fetoprotein (AFP) (CPT 82105)	-	ROUTINE	ROUTINE	-	HCC screening in cirrhotic patients	Normal; elevated suggests HCC
Hepatitis panel (HAV, HBV, HCV) (CPT 80074)	-	ROUTINE	ROUTINE	-	Exclude concurrent viral hepatitis	Negative
ANA, anti-smooth muscle antibody (CPT 86235)	-	ROUTINE	ROUTINE	-	Exclude autoimmune hepatitis (may coexist or mimic)	Negative or low titer
Iron studies (CPT 83540)	-	ROUTINE	ROUTINE	-	Exclude hemochromatosis in hepatic presentation	Normal ferritin and transferrin saturation
TSH (CPT 84443)	-	ROUTINE	ROUTINE	-	Thyroid dysfunction can present with tremor/psychiatric symptoms	Normal
Vitamin B12 (CPT 82607)	-	ROUTINE	ROUTINE	-	B12 deficiency can cause neuropsychiatric symptoms	Normal

1C. Rare/Specialized (Refractory or Atypical)¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Hepatic copper concentration (liver biopsy) (CPT 82525)	-	ROUTINE	ROUTINE	-	Gold standard for diagnosis; required when non-invasive testing equivocal; >250 mcg/g dry weight diagnostic	>250 mcg/g dry weight (normal <50 mcg/g); values 50-250 can be seen in heterozygotes or cholestatic disease
Radioactive copper incorporation study (⁶⁴Cu or ⁶⁷Cu)	-	EXT	EXT	-	Measures copper incorporation into ceruloplasmin over 48h; absent second peak in WD; rarely available	Absent secondary rise at 48h (failure of copper incorporation into ceruloplasmin)
Relative exchangeable copper (REC) ratio	-	EXT	EXT	-	Emerging biomarker; ratio of exchangeable copper to total copper; highly sensitive/specific	>18.5% diagnostic of WD
Paraneoplastic antibody panel (CPT 86255)	-	EXT	EXT	-	If atypical neurologic features not explained by WD alone	Negative
Heavy metal screen (lead, mercury, arsenic)	-	EXT	EXT	-	Toxic metal exposure can cause neuropsychiatric symptoms	Normal
Urine amino acids	-	EXT	EXT	-	Fanconi syndrome confirmation (generalized aminoaciduria)	Elevated (generalized aminoaciduria in Fanconi)
Bone densitometry (DEXA) (CPT 77080)	-	-	ROUTINE	-	Osteoporosis screening; copper toxicity causes bone loss	T-score > -2.5

2. DIAGNOSTIC IMAGING & STUDIES¶

2A. Essential/First-line¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
Slit-lamp examination (ophthalmology)	URGENT	STAT	ROUTINE	STAT	At initial evaluation; do NOT rely on naked-eye exam	Kayser-Fleischer rings (present in >95% neurologic WD, ~50% hepatic-only); sunflower cataracts	None
MRI brain without contrast (CPT 70551)	URGENT	URGENT	ROUTINE	URGENT	Within 24-48h if neurologic symptoms	T2/FLAIR hyperintensity in basal ganglia (putamen — "face of the giant panda" sign on midbrain), thalamus, caudate, brainstem, cerebellum, white matter; T1 hyperintensity (copper/manganese deposition); cerebral atrophy	Pacemaker, metallic implants
MRI brain with contrast (CPT 70553)	-	ROUTINE	ROUTINE	-	If additional characterization needed	Rarely enhances; helps exclude other pathology	Contrast allergy, GFR <30
Abdominal ultrasound with Doppler (CPT 76700)	URGENT	STAT	ROUTINE	STAT	At diagnosis	Hepatomegaly, splenomegaly, cirrhotic changes, portal hypertension, ascites	None significant
Chest X-ray (CPT 71046)	URGENT	ROUTINE	-	STAT	On admission for fulminant hepatic failure; baseline for ICU	Aspiration, atelectasis, pleural effusion, pulmonary edema	None significant

2B. Extended¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
CT abdomen with contrast (CPT 74178)	-	ROUTINE	ROUTINE	-	If ultrasound equivocal; HCC screening	Cirrhosis, portal hypertension, hepatic lesions	Contrast allergy, renal impairment
MRI abdomen (liver) (CPT 74183)	-	ROUTINE	ROUTINE	-	Liver characterization; iron vs copper deposition	Hepatic signal abnormalities; excludes HCC	Per MRI
FibroScan (transient elastography) (CPT 91200)	-	-	ROUTINE	-	Non-invasive fibrosis assessment	Liver stiffness <7.1 kPa = minimal fibrosis; >12.5 kPa = cirrhosis	Ascites, obesity (limited), pacemaker
Upper endoscopy (EGD) (CPT 43239)	-	ROUTINE	ROUTINE	-	Variceal screening in cirrhotic patients	No varices; if present, grade and treat	Active GI perforation
ECG (12-lead) (CPT 93000)	URGENT	ROUTINE	ROUTINE	URGENT	Baseline; cardiac involvement	Arrhythmias, conduction abnormalities	None
Echocardiogram (CPT 93306)	-	ROUTINE	ROUTINE	-	If cardiac symptoms or cardiomyopathy suspected	Normal function; WD cardiomyopathy rare	None significant
NCS/EMG (CPT 95907-95913 / 95886)	-	-	ROUTINE	-	If peripheral neuropathy suspected	Rule out concurrent neuropathy	None significant
EEG (CPT 95816)	URGENT	ROUTINE	-	URGENT	If seizures suspected or encephalopathy	Generalized slowing in encephalopathy; epileptiform discharges	None

2C. Rare/Specialized¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
PET brain (FDG) (CPT 78608)	-	-	EXT	-	If atypical features or diagnostic uncertainty	Hypometabolism in basal ganglia, cerebellum	Per PET
MR spectroscopy (brain) (CPT 76390)	-	EXT	EXT	-	Research; metabolic characterization	Reduced NAA (neuronal loss) in basal ganglia	Per MRI
DaTscan (CPT 78830)	-	-	EXT	-	Differentiate WD parkinsonism from idiopathic PD if uncertain	May show reduced uptake (presynaptic dopaminergic loss); less specific in WD	Pregnancy, iodine allergy
Liver biopsy (CPT 47000)	-	ROUTINE	ROUTINE	-	When non-invasive testing equivocal; hepatic copper quantification	Copper >250 mcg/g dry weight = diagnostic; histology shows steatosis, hepatitis, cirrhosis	Coagulopathy (INR >1.5), ascites (use transjugular), thrombocytopenia

3. TREATMENT¶

3A. Acute/Emergent¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
N-acetylcysteine (NAC)	IV	Fulminant hepatic failure; hepatoprotection	150 mg/kg :: IV :: loading :: 150 mg/kg IV over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h (standard NAC protocol for liver failure)	None absolute	Anaphylactoid reaction, bronchospasm; monitor LFTs, INR	STAT	STAT	-	STAT
Fresh frozen plasma (FFP)	IV	Coagulopathy in fulminant hepatic failure	10-15 mL/kg :: IV :: PRN :: 10-15 mL/kg IV; target INR <1.5 for procedures; use as bridge to transplant	Volume overload; IgA deficiency	INR, fibrinogen, volume status	STAT	STAT	-	STAT
Vitamin K (phytonadione)	IV	Coagulopathy; hepatic synthetic failure	10 mg :: IV :: daily :: 10 mg IV daily x 3 days; limited efficacy in WD fulminant failure (hepatocyte loss)	Allergy	INR response	STAT	STAT	-	STAT
Lactulose	PO	Hepatic encephalopathy	30 mL :: PO :: TID :: 30 mL PO TID; titrate to 3-4 bowel movements/day	Bowel obstruction	Mental status, ammonia, stool output	STAT	STAT	-	STAT
Rifaximin	PO	Hepatic encephalopathy (adjunct to lactulose)	550 mg :: PO :: BID :: 550 mg PO BID; add if lactulose alone insufficient	C. difficile (relative)	Mental status, hepatic function	-	ROUTINE	-	ROUTINE
Albumin (25%)	IV	Ascites management; hepatorenal syndrome	1 g/kg :: IV :: daily :: 1 g/kg/day (max 100 g); for large-volume paracentesis or hepatorenal syndrome	Heart failure	Volume status, serum albumin	-	STAT	-	STAT
Platelet transfusion	IV	Thrombocytopenia with active bleeding or pre-procedure	Dose per protocol :: IV :: PRN :: 1 unit apheresis platelets; target >50K for procedures, >10K if no bleeding	ITP, TTP (relative)	Platelet count post-transfusion	STAT	STAT	-	STAT
Plasmapheresis/Plasma exchange	Extracorporeal	Fulminant WD with severe hemolysis; removes free copper	1-1.5 plasma volumes :: Extracorporeal :: daily :: Daily exchange x 3-5 days; rapidly reduces free copper	Hemodynamic instability, severe sepsis	Copper levels, hemolysis markers, coagulation	-	STAT	-	STAT
DVT prophylaxis: Enoxaparin	SC	Immobilized hospitalized patients	40 mg :: SC :: daily :: 40 mg SC daily; hold if INR >1.5 or platelets <50K or active bleeding	Active bleeding, severe coagulopathy, CrCl <30 (use UFH)	Platelets, signs of bleeding	-	ROUTINE	-	ROUTINE

3B. Symptomatic Treatments¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Baclofen	PO	Dystonia, spasticity	5 mg :: PO :: TID :: Start 5 mg TID; titrate by 5 mg/dose every 3 days; target 30-80 mg/day divided TID; max 80 mg/day	Severe renal impairment; abrupt withdrawal risk	Sedation, weakness; do NOT stop abruptly (withdrawal seizures)	-	ROUTINE	ROUTINE	ROUTINE
Trihexyphenidyl	PO	Dystonia (focal or generalized)	1 mg :: PO :: daily :: Start 1 mg daily; increase by 1 mg every 3-5 days; target 6-15 mg/day divided TID; max 15 mg/day	Glaucoma, urinary retention, dementia, age >65	Confusion, dry mouth, urinary retention, cognitive impairment	-	ROUTINE	ROUTINE	-
Levodopa/Carbidopa	PO	Parkinsonism (rigidity, bradykinesia)	100 mg :: PO :: TID :: Start 25/100 mg TID; titrate by 25/100 mg q1-2 weeks; limited efficacy in WD parkinsonism (response variable)	Narrow-angle glaucoma	Dyskinesia, nausea, orthostatic hypotension; often poor response in WD	-	ROUTINE	ROUTINE	-
Clonazepam	PO	Tremor, dystonia, chorea, sleep disturbance	0.5 mg :: PO :: BID :: Start 0.5 mg BID; titrate by 0.5 mg q3-5 days; max 4 mg/day	Respiratory depression, severe hepatic disease, addiction risk	Sedation, respiratory depression, dependence; adjust dose in hepatic impairment	-	ROUTINE	ROUTINE	ROUTINE
Botulinum toxin (OnabotulinumtoxinA)	IM	Focal dystonia (cervical, oromandibular, limb)	Dose per target :: IM :: q3 months :: Site-specific dosing: cervical dystonia 100-300 units; limb dystonia 50-200 units per muscle; q12 weeks	Infection at injection site, myasthenia gravis	Weakness at injection site, dysphagia (cervical injections)	-	-	ROUTINE	-
Propranolol	PO	Tremor (postural/action component)	20 mg :: PO :: BID :: Start 20 mg BID; titrate to 120-240 mg/day; limited efficacy for wing-beating tremor	Asthma, COPD, bradycardia, decompensated heart failure	HR, BP	-	ROUTINE	ROUTINE	-
Sertraline	PO	Depression, anxiety (common in WD)	25 mg :: PO :: daily :: Start 25 mg daily; titrate to 100-200 mg/day	MAOI use; caution with hepatic impairment (reduce dose)	Hepatic function (use lower doses in liver disease); suicidality in young adults	-	ROUTINE	ROUTINE	-
Quetiapine	PO	Psychosis, agitation, behavioral disturbance	12.5 mg :: PO :: QHS :: Start 12.5 mg QHS; titrate cautiously to 50-200 mg/day; avoid typical antipsychotics (worsen movement disorder)	QTc prolongation; avoid typical antipsychotics (D2 blockade worsens dystonia/parkinsonism)	QTc, metabolic panel, sedation; use ONLY atypical antipsychotics	-	ROUTINE	ROUTINE	ROUTINE
Gabapentin	PO	Neuropathic pain, tremor (adjunctive)	300 mg :: PO :: TID :: Start 300 mg QHS; increase by 300 mg/day every 3 days; target 900-1800 mg/day TID	Severe renal impairment (dose adjust)	Sedation, dizziness	-	ROUTINE	ROUTINE	-
Omeprazole	PO	GI protection during chelation therapy	20 mg :: PO :: daily :: 20 mg PO daily; take 30 min before chelator	None absolute	Long-term: B12, Mg levels	-	ROUTINE	ROUTINE	-

3C. Second-line/Refractory¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Liver transplantation evaluation	Referral	Fulminant hepatic failure; decompensated cirrhosis unresponsive to chelation; severe neurologic WD refractory to 6+ months chelation (controversial)	Refer to transplant center :: - :: - :: Urgent evaluation in fulminant WD (New Wilson Index ≥11 = transplant); King's Wilson criteria; MELD score >15 or acute liver failure	Absolute contraindications per transplant center protocol	Pre-transplant workup; transplant corrects metabolic defect (no lifelong chelation needed post-transplant)	-	URGENT	ROUTINE	STAT
Continuous venovenous hemofiltration (CVVH)	Extracorporeal	Fulminant WD with renal failure or massive hemolysis; bridge to transplant	Per ICU protocol :: Extracorporeal :: continuous :: Continuous copper removal; bridge therapy to transplant	N/A (life-saving in ICU)	Copper levels, hemodynamics, electrolytes	-	-	-	STAT
Molecular adsorbent recirculating system (MARS)	Extracorporeal	Fulminant WD; albumin dialysis removes copper	Per protocol :: Extracorporeal :: per session :: Albumin dialysis; available at specialized centers; bridge to transplant	Hemodynamic instability	Copper levels, bilirubin, coagulation, hemodynamics	-	EXT	-	EXT
Tetrathiomolybdate (ammonium or bis-choline)	PO	Investigational chelator; neurologic WD (may have less neurologic worsening than penicillamine)	20 mg :: PO :: TID :: 20 mg TID with meals + 20 mg TID between meals (total 120 mg/day); investigational — available through clinical trials or compassionate use	Severe hepatic failure; not yet widely approved	CBC (bone marrow suppression), LFTs, copper levels, iron studies (iron deficiency from over-decoppering)	-	EXT	EXT	-

3D. Disease-Modifying Therapies (Chelation & Zinc)¶

Treatment	Route	Indication	Dosing	Pre-Treatment Requirements	Contraindications	Monitoring	ED	HOSP	OPD	ICU
D-Penicillamine (Cuprimine)	PO	First-line chelation (symptomatic WD — hepatic or neurologic); removes copper via renal excretion	250 mg :: PO :: daily :: Start 250-500 mg/day; increase by 250 mg every 4-7 days; target 1000-1500 mg/day divided BID-QID; take on empty stomach (1h before or 2h after meals); SLOW titration reduces neurologic worsening risk	Baseline: CBC, UA, CMP, 24h urine copper; pyridoxine 25 mg/day (penicillamine depletes B6); pregnancy test in women of childbearing age	Penicillin allergy (may cross-react); pregnancy (teratogenic — switch to zinc); lupus-like syndrome; prior severe adverse reaction	CBC weekly x1 month then monthly x6 months then q3 months; UA for proteinuria every 2 weeks x3 months then monthly; LFTs monthly; 24h urine copper q3-6 months (target 200-500 mcg/24h on treatment); watch for neurologic WORSENING in first 6-8 weeks (occurs in 10-50%)	-	STAT	ROUTINE	STAT
Trientine (Syprine, TETA)	PO	Alternative first-line chelator; preferred if penicillamine intolerant or neurologic presentation (lower risk of neurologic worsening); removes copper via renal excretion	250 mg :: PO :: BID :: Start 500-750 mg/day divided BID-TID; target 750-1500 mg/day; take on empty stomach (1h before or 2h after meals); available as trientine dihydrochloride or trientine tetrahydrochloride (Cuvrior — different dosing)	Baseline: CBC, CMP, 24h urine copper; iron studies (trientine chelates iron); pregnancy test	Pregnancy (teratogenic — switch to zinc); iron deficiency anemia (monitor closely)	CBC monthly x6 months then q3 months; LFTs monthly x6 months then q3 months; 24h urine copper q3-6 months (target 200-500 mcg/24h); iron studies q6 months (sideropenia risk); watch for neurologic worsening (less common than penicillamine, ~10-15%)	-	STAT	ROUTINE	STAT
Zinc acetate (Galzin)	PO	Maintenance therapy (after initial decoppering with chelator); mild/presymptomatic WD; pregnancy (safest option); family members with pre-clinical WD	50 mg :: PO :: TID :: 50 mg elemental zinc TID (taken as zinc acetate 150 mg TID); take on empty stomach separated from meals by ≥1 hour; separate from chelator by ≥2 hours if used concurrently	Baseline: CBC, CMP, 24h urine copper, serum zinc level	None absolute; GI intolerance common (nausea); do NOT use as sole therapy in symptomatic/severe WD (too slow onset)	24h urine copper q3-6 months (target <75 mcg/24h on zinc monotherapy); serum zinc level q3-6 months (target 125-150 mcg/dL); 24h urine zinc (confirms compliance: >2 mg/24h); LFTs q3-6 months; CBC q6 months (zinc-induced copper deficiency can cause neutropenia)	-	ROUTINE	ROUTINE	-
Zinc sulfate (alternative zinc formulation)	PO	Alternative to zinc acetate for maintenance therapy; more GI side effects but less expensive	220 mg :: PO :: TID :: 220 mg zinc sulfate TID (contains ~50 mg elemental zinc per 220 mg); take on empty stomach separated from meals by ≥1 hour; separate from chelator by ≥2 hours if used concurrently	Baseline: CBC, CMP, 24h urine copper, serum zinc level	GI intolerance common (nausea, gastric irritation); do NOT use as sole therapy in symptomatic/severe WD (too slow onset)	24h urine copper q3-6 months (target <75 mcg/24h on zinc monotherapy); serum zinc level q3-6 months (target 125-150 mcg/dL); 24h urine zinc (confirms compliance: >2 mg/24h); LFTs q3-6 months; CBC q6 months (zinc-induced copper deficiency can cause neutropenia)	-	ROUTINE	ROUTINE	-
Pyridoxine (Vitamin B6)	PO	Required supplement with D-penicillamine therapy (penicillamine depletes B6)	25 mg :: PO :: daily :: 25 mg PO daily; co-administer with penicillamine	None	None	Clinical assessment; peripheral neuropathy symptoms	-	ROUTINE	ROUTINE	-

4. OTHER RECOMMENDATIONS¶

4A. Referrals & Consults¶

Recommendation	ED	HOSP	OPD	ICU	Indication
Hepatology consultation	STAT	STAT	ROUTINE	STAT	All WD patients; liver disease staging, transplant evaluation, chelation management
Neurology consultation	URGENT	STAT	ROUTINE	STAT	All neurologic WD; movement disorder management, monitoring for chelation-related worsening
Movement disorder specialist	-	ROUTINE	ROUTINE	-	Dystonia, tremor, parkinsonism management; botulinum toxin injections
Ophthalmology (slit-lamp exam)	URGENT	STAT	ROUTINE	-	ALL suspected WD — Kayser-Fleischer ring assessment; sunflower cataract screening
Genetics / Genetic counselor	-	ROUTINE	ROUTINE	-	ATP7B testing confirmation, family screening, reproductive counseling
Transplant hepatology/surgery	-	STAT	ROUTINE	STAT	Fulminant hepatic failure, decompensated cirrhosis, New Wilson Index ≥11
Psychiatry	-	ROUTINE	ROUTINE	-	Depression, psychosis, personality change, behavioral disturbance (common in WD)
Neuropsychology	-	-	ROUTINE	-	Baseline cognitive assessment; monitor for cognitive decline
Speech-language pathology (SLP)	-	ROUTINE	ROUTINE	-	Dysarthria, dysphagia evaluation and management
Physical therapy (PT)	-	ROUTINE	ROUTINE	-	Dystonia management, gait training, falls prevention
Occupational therapy (OT)	-	ROUTINE	ROUTINE	-	ADL assistance, handwriting aids, adaptive equipment
Nutrition / Dietitian	-	ROUTINE	ROUTINE	-	Low-copper diet counseling; hepatic diet if cirrhotic
Social work	-	ROUTINE	ROUTINE	-	Chronic disease support, medication access (chelators are expensive), disability resources

4B. Patient/Family Instructions¶

Recommendation	ED	HOSP	OPD	ICU
Wilson's disease is a lifelong condition requiring CONTINUOUS treatment — never stop chelation or zinc without physician guidance	-	STAT	ROUTINE	-
Take chelation medication (penicillamine or trientine) on an EMPTY STOMACH — 1 hour before or 2 hours after meals	-	ROUTINE	ROUTINE	-
If taking zinc, separate from chelator by at least 2 hours; take zinc between meals	-	ROUTINE	ROUTINE	-
Return to ED if: worsening jaundice, confusion, vomiting blood, black stools, new neurologic symptoms, worsening speech or swallowing, severe abdominal pain	STAT	ROUTINE	ROUTINE	-
Report ANY new neurologic symptoms during the first 2-3 months of chelation (worsening is possible and requires dose adjustment)	-	STAT	ROUTINE	-
Avoid HIGH-COPPER FOODS during initial treatment: liver/organ meats, shellfish (especially lobster, oysters), chocolate, mushrooms, nuts, dried fruits, soy products	-	ROUTINE	ROUTINE	-
Avoid drinking water through copper pipes (consider water testing; use filter or bottled water if copper pipes present)	-	ROUTINE	ROUTINE	-
Alcohol is STRICTLY prohibited — causes additional liver damage	-	ROUTINE	ROUTINE	-
Women of childbearing age: pregnancy requires switching from chelator to zinc (chelators are teratogenic); discuss family planning with physician BEFORE conception	-	ROUTINE	ROUTINE	-
ALL first-degree relatives (siblings, children, parents) MUST be screened for Wilson's disease — siblings have 25% risk	-	ROUTINE	ROUTINE	-
Carry a medical alert card/bracelet indicating Wilson's disease and current medications	-	ROUTINE	ROUTINE	-
Regular follow-up is ESSENTIAL — blood and urine tests needed every 3-6 months lifelong	-	ROUTINE	ROUTINE	-

4C. Lifestyle & Prevention¶

Recommendation	ED	HOSP	OPD	ICU
Low-copper diet during initial decoppering phase (avoid >1 mg copper/day); can liberalize slightly once stable on treatment	-	ROUTINE	ROUTINE	-
Regular exercise as tolerated; may improve dystonia and mood	-	ROUTINE	ROUTINE	-
Strict alcohol avoidance (lifelong — hepatotoxic)	-	ROUTINE	ROUTINE	-
Smoking cessation (impairs liver function and overall health)	-	ROUTINE	ROUTINE	-
Hepatitis A and B vaccination if not immune (protect remaining liver function)	-	ROUTINE	ROUTINE	-
Avoid hepatotoxic medications (acetaminophen limit <2 g/day; avoid NSAIDs if cirrhotic; avoid statins if decompensated)	-	ROUTINE	ROUTINE	-
Genetic counseling for reproductive planning; autosomal recessive — both parents are carriers; 25% risk for each sibling	-	-	ROUTINE	-
Mental health support; depression and anxiety are common and treatable components of WD	-	ROUTINE	ROUTINE	-
Screen all first-degree relatives: ceruloplasmin, 24h urine copper, LFTs, slit-lamp exam, ATP7B genetic testing	-	-	ROUTINE	-

═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════

5. DIFFERENTIAL DIAGNOSIS¶

Alternative Diagnosis	Key Distinguishing Features	Tests to Differentiate
Autoimmune hepatitis	Young women, positive ANA/SMA/anti-LKM, elevated IgG, no KF rings, no neurologic features; can coexist with WD	ANA, SMA, IgG level, liver biopsy; ceruloplasmin, copper studies
Drug-induced parkinsonism	Temporal relationship to dopamine-blocking medication, symmetric, resolves with drug withdrawal	Medication review; ceruloplasmin normal; no KF rings
Idiopathic Parkinson's disease	Asymmetric onset, rest tremor (pill-rolling), levodopa-responsive, age >50 typically, no hepatic involvement	DaTscan; ceruloplasmin, 24h urine copper; slit-lamp (no KF rings)
Juvenile Huntington's disease	Family history (AD), progressive chorea, behavioral changes, caudate atrophy on MRI	Genetic testing (HTT CAG repeat); ceruloplasmin normal
Dystonia (primary/DYT)	Isolated dystonia without hepatic features, family history, onset typically in limb, no KF rings	Genetic testing (DYT1, etc.); ceruloplasmin normal; no hepatic involvement
Hemochromatosis	Iron overload, skin bronzing, diabetes, arthropathy, hepatic disease, no neurologic copper features	Iron studies (elevated ferritin, transferrin saturation); HFE gene; ceruloplasmin normal
Non-alcoholic fatty liver disease (NAFLD)	Metabolic syndrome, obesity, insulin resistance, no neurologic features, no KF rings	Metabolic workup; ceruloplasmin normal; liver biopsy (steatosis without copper)
Viral hepatitis (B, C)	Exposure risk factors, positive viral serologies, no KF rings or neurologic features	Hepatitis panel; ceruloplasmin normal
Alcoholic liver disease	Alcohol use history, AST:ALT ratio >2, no KF rings, no neurologic copper features	History; ceruloplasmin normal; liver biopsy
Neuroacanthocytosis	Orofacial dyskinesia, chorea, self-mutilation, acanthocytes on blood smear	Peripheral smear (acanthocytes); CK (elevated); ceruloplasmin normal
Menkes disease	X-linked; presents in infancy (not adolescent/adult); kinky hair, seizures, failure to thrive	Age of onset; genetic testing (ATP7A); ceruloplasmin very low but different gene
Pantothenate kinase-associated neurodegeneration (PKAN)	"Eye of the tiger" sign on MRI (globus pallidus), dystonia, retinopathy	MRI (iron deposition pattern differs from WD); PANK2 gene
Acquired hepatocerebral degeneration	Chronic liver disease from ANY cause; parkinsonism, ataxia; MRI shows T1 basal ganglia signal (manganese)	Underlying liver disease diagnosis; ceruloplasmin may be low from liver failure but 24h urine copper not markedly elevated; no ATP7B mutations
Multiple sclerosis	Relapsing white matter disease, optic neuritis, spinal cord lesions; no hepatic involvement	MRI brain/spine (demyelination); LP (oligoclonal bands); ceruloplasmin normal

6. MONITORING PARAMETERS¶

Parameter	ED	HOSP	OPD	ICU	Frequency	Target/Threshold	Action if Abnormal
24-hour urine copper	-	STAT	ROUTINE	STAT	q3-6 months on chelation; q6-12 months on zinc maintenance	Chelation target: 200-500 mcg/24h; Zinc target: <75 mcg/24h	Adjust chelator dose if outside range; <200 suggests over-chelation or non-compliance
Serum free (non-ceruloplasmin-bound) copper	-	STAT	ROUTINE	STAT	q3-6 months	<15 mcg/dL on treatment; negative values suggest over-treatment	Reduce chelator if over-treated; increase if still elevated
LFTs (AST, ALT, bilirubin, albumin)	STAT	STAT	ROUTINE	STAT	Monthly x6 months, then q3-6 months	Normalizing or stable	If worsening on treatment: assess compliance, consider dose adjustment, transplant evaluation
CBC with differential	STAT	STAT	ROUTINE	STAT	Weekly x1 month (penicillamine), then monthly x6 months, then q3 months	WBC >3000, platelets >100K, Hgb stable	Penicillamine: hold if WBC <3000 or platelets <100K (bone marrow suppression); neutropenia on zinc (copper deficiency)
INR/PT	STAT	STAT	ROUTINE	STAT	Monthly x6 months, then q3-6 months	Normalizing (<1.3)	Worsening INR suggests progressive liver disease; transplant evaluation if persistent
Urinalysis (for proteinuria)	-	ROUTINE	ROUTINE	-	Every 2 weeks x3 months on penicillamine, then monthly	No proteinuria (>1+ protein warrants investigation)	Penicillamine nephrotoxicity: hold if >1 g/24h proteinuria; may require switch to trientine
Serum zinc level	-	ROUTINE	ROUTINE	-	q3-6 months on zinc therapy	125-150 mcg/dL (therapeutic range)	Low: assess compliance; High: reduce dose
24-hour urine zinc	-	-	ROUTINE	-	q6-12 months	>2 mg/24h confirms compliance	Low suggests non-compliance
Neurologic exam (dystonia, tremor, speech, gait)	URGENT	STAT	ROUTINE	STAT	Each visit; monthly during initial chelation	Stable or improving; no new deficits	If WORSENING in first 2-3 months: reduce chelator dose, consider switch to trientine or add zinc; persistent worsening → transplant evaluation
Slit-lamp exam (KF rings)	-	STAT	ROUTINE	-	Annually on treatment	Gradual fading of KF rings (may take 3-5 years)	Persistence or reappearance suggests inadequate treatment or non-compliance
MRI brain	-	ROUTINE	ROUTINE	-	Baseline; repeat at 6-12 months; then annually x3 years if neurologic	Improving or stable signal abnormalities; resolving edema	Worsening lesions suggest inadequate treatment or chelation-induced worsening
Hepatic fibrosis assessment (FibroScan or biomarkers)	-	-	ROUTINE	-	Annually if cirrhotic	Stable or improving stiffness	Worsening fibrosis despite treatment: re-evaluate; transplant referral
Iron studies	-	ROUTINE	ROUTINE	-	q6 months on trientine	Normal ferritin and iron	Trientine chelates iron → sideropenia; supplement iron if deficient (separate from trientine by 2h)
Bone density (DEXA)	-	-	ROUTINE	-	Baseline; repeat q2 years	T-score > -2.5	Treat osteoporosis; calcium/vitamin D supplementation
Depression/psychiatric screening	-	ROUTINE	ROUTINE	-	Each visit	Stable mood, no psychosis	Psychiatric referral; adjust medications

7. DISPOSITION CRITERIA¶

Disposition	Criteria
Discharge home	Diagnosis established; chelation/zinc initiated and tolerated; stable neurologic exam; no hepatic decompensation; able to take oral medications; understands dietary restrictions and medication timing; follow-up arranged within 1-2 weeks
Admit to floor	New diagnosis requiring inpatient workup; initiation of chelation therapy with monitoring; hepatic decompensation (ascites, jaundice, coagulopathy); moderate neurologic symptoms requiring inpatient management; inability to take oral medications
Admit to ICU	Fulminant hepatic failure (encephalopathy, coagulopathy, renal failure); severe hemolytic crisis; status epilepticus; severe dystonic crisis with airway compromise; pending liver transplant evaluation
Transfer to liver transplant center	Fulminant Wilson's disease (New Wilson Index ≥11); decompensated cirrhosis unresponsive to chelation; King's criteria met; MELD score >15 with progressive decline
Outpatient management	Stable on chelation or zinc maintenance; routine monitoring labs; presymptomatic WD diagnosed through family screening; mild hepatic or neurologic disease responding to treatment
Inpatient rehabilitation	Severe dystonia or parkinsonism affecting function; dysphagia requiring supervised feeding; gait instability requiring intensive PT

8. EVIDENCE & REFERENCES¶

Recommendation	Evidence Level	Source
Ceruloplasmin <20 mg/dL as screening test for WD	Class II, Level B	Ferenci et al., Liver Int 2003 PubMed: 14506258
24-hour urine copper >100 mcg as diagnostic criterion	Class II, Level B	Roberts & Schilsky, Hepatology 2008 (AASLD Practice Guidelines) PubMed: 18506894
D-Penicillamine as first-line chelation therapy	Class II, Level B	Walshe, Lancet 1956; Roberts & Schilsky, Hepatology 2008 PubMed: 18506894
Trientine as alternative first-line chelator with lower neurologic worsening risk	Class II, Level B	Walshe, Lancet 1982; Weiss et al., J Hepatol 2013 PubMed: 23485523
Zinc acetate for maintenance therapy	Class II, Level B	Brewer et al., Arch Neurol 1987; Czlonkowska et al., Ann Neurol 1996 PubMed: 8967753
Neurologic worsening occurs in 10-50% of patients starting D-penicillamine	Class II, Level B	Brewer et al., Arch Neurol 1994 PubMed: 7944997; Walshe & Yealland, J Neurol Neurosurg Psychiatry 1993 PubMed: 8505642
Liver transplantation for fulminant WD and decompensated cirrhosis	Class I, Level B	Arnon et al., Hepatology 2011 PubMed: 21254169; Dhawan et al., Gut 2005 PubMed: 15753547
New Wilson Index ≥11 predicts need for transplantation in pediatric fulminant WD	Class II, Level B	Dhawan et al., Gut 2005 PubMed: 15753547
Kayser-Fleischer rings present in >95% of neurologic WD	Class II, Level B	Walshe, Brain 1976; Ala et al., Lancet 2007 PubMed: 17276780
Leipzig Scoring System for WD diagnosis (score ≥4 = established)	Class IIa, Level C	Ferenci et al., Liver Int 2003 (8th International Meeting on Wilson Disease) PubMed: 14506258
ATP7B gene testing for definitive diagnosis and family screening	Class I, Level B	Loudianos & Gitlin, Semin Liver Dis 2000 PubMed: 11200483; EASL Clinical Practice Guidelines 2012 PubMed: 22276820
MRI brain findings: T2 hyperintensity in putamen ("face of giant panda" sign)	Class II, Level C	King et al., Mov Disord 1996 PubMed: 8866494; Sinha et al., AJNR 2006 PubMed: 16551993
Low-copper diet during initial decoppering phase	Class III, Level C	Expert consensus; EASL Clinical Practice Guidelines 2012 PubMed: 22276820
Plasmapheresis for acute hemolytic crisis in fulminant WD	Class IIb, Level C	Jhang et al., J Clin Apher 2007 PubMed: 17722038; Akyildiz et al., Ther Apher Dial 2004 PubMed: 15255163
Free (non-ceruloplasmin-bound) copper as monitoring parameter	Class II, Level B	Walshe, Ann Clin Biochem 2003 PubMed: 12880538; EASL Clinical Practice Guidelines 2012 PubMed: 22276820
Pregnancy management: switch to zinc; chelators are teratogenic	Class II, Level C	Brewer et al., J Lab Clin Med 2000 PubMed: 10638697; Tarnacka et al., Fertil Steril 2000 PubMed: 10685533
Family screening with ceruloplasmin, 24h urine copper, and ATP7B genotyping	Class I, Level B	EASL Clinical Practice Guidelines 2012 PubMed: 22276820; Roberts & Schilsky, Hepatology 2008 PubMed: 18506894
AASLD Practice Guidelines for Wilson Disease	Class I (Guidelines)	Roberts & Schilsky, Hepatology 2008 PubMed: 18506894; Schilsky, Clin Liver Dis 2017 PubMed: 28364808
EASL Clinical Practice Guidelines on Wilson's Disease	Class I (Guidelines)	European Association for the Study of the Liver, J Hepatol 2012 PubMed: 22276820
Trientine tetrahydrochloride (Cuvrior) as improved formulation	Class II, Level B	Weiss et al., Lancet Gastroenterol Hepatol 2022 PubMed: 35276119
Bis-choline tetrathiomolybdate for neurologic WD (phase 3 data)	Class II, Level B	Weiss et al., Lancet Gastroenterol Hepatol 2022 (WTX101-301 trial) PubMed: 35276119

NOTES¶

Wilson's disease is a TREATABLE cause of liver failure and neurologic decline — early diagnosis is critical
Consider WD in ANY patient <50 years with unexplained liver disease, movement disorder, or psychiatric illness
Ceruloplasmin alone misses 5-15% of cases; always obtain 24-hour urine copper and slit-lamp exam
The Leipzig Score integrates multiple tests for diagnostic certainty (score ≥4 = WD established)
D-penicillamine is effective but causes neurologic WORSENING in 10-50% of patients during initial weeks; many experts now prefer trientine as first-line for neurologic WD
Zinc monotherapy is too slow for symptomatic disease but is ideal for maintenance and presymptomatic patients
NEVER stop chelation/zinc abruptly — can precipitate fulminant hepatic failure or neurologic crisis
Avoid typical antipsychotics (haloperidol, etc.) — D2 blockade worsens dystonia and parkinsonism; use quetiapine or clozapine if antipsychotic needed
Fulminant Wilson's disease: Coombs-negative hemolytic anemia + acute liver failure + low ALP + low ALP-to-bilirubin ratio is classic triad; requires urgent transplant evaluation
All first-degree relatives MUST be screened; siblings have 25% risk of being affected
Liver transplantation CURES the metabolic defect — post-transplant patients do not need chelation
MRI brain may lag behind clinical improvement by months; initial worsening of MRI does not necessarily indicate treatment failure
When using combined chelation + zinc therapy, separate zinc from chelator by ≥2 hours (zinc blocks chelator absorption if given together); some experts use chelator + zinc simultaneously for initial treatment of symptomatic WD

CHANGE LOG¶

v1.1 (January 30, 2026) - Fixed ICD-10 codes: removed K74.3 (primary biliary cirrhosis — not a WD code) and G25.0 (essential tremor — not appropriate for WD tremor); added G25.2 (other specified forms of tremor) per C3, C4 - Removed "Combined chelation + zinc" row from Section 3D (used cross-references "Per individual agents"); moved combination note to NOTES section per C1, R1 - Made Zinc sulfate row fully self-contained: expanded Pre-Treatment, Contraindications, and Monitoring fields (previously "Same as zinc acetate") per C2, R2 - Updated Pyridoxine Monitoring from "None specific" to "Clinical assessment; peripheral neuropathy symptoms" and Contraindications from "None specific" to "None" per M5 - Standardized starting doses: Propranolol (20 mg), Sertraline (25 mg), Quetiapine (12.5 mg) — changed from ranges per R5, M2-M4 - Updated Plasmapheresis Route to "Extracorporeal" (was "-") per S1, R9 - Updated CVVH Route to "Extracorporeal" (was "IV") and MARS Route to "Extracorporeal" (was "-") per S2 - Updated Liver transplantation evaluation Route to "Referral" (was "-") per S2 - Added ICU column to Section 4B (Patient/Family Instructions) and Section 4C (Lifestyle & Prevention) tables per S3, S4 - Added Chest X-ray to Section 2A (Essential imaging) for ICU/fulminant hepatic failure patients per R6 - Added PubMed citation links to all 22 references in Section 8 per R7 - Added REVISED date to header metadata - Version bump from 1.0 to 1.1

v1.0 (January 30, 2026) - Initial template creation - Comprehensive diagnostic workup including Leipzig Score components - Chelation therapy with structured dosing (D-penicillamine, trientine, zinc) - Symptomatic management for dystonia, tremor, parkinsonism, psychiatric symptoms - Fulminant hepatic failure acute management - Liver transplant evaluation criteria - Family screening recommendations - 22 evidence-based references with author, journal, and year