Wilson Disease Treatment
Failures?
Fred Askari MD, PhD
Director, Wilson Disease Program
Associate Professor, University of Michigan
Medical Center
Ann Arbor, Michigan
Wilson Disease
• Familial Copper Toxicity
• Variable Time Course
• Pleiotropic Effects
– Psychiatric
– Neurologic
– Hepatic
– Vascular, Cardiac, Renal
– Treatment toxicity
COPPER BACKGROUND – WILSON’S
DISEASE
Copper Accumulates and Causes Brain and Liver Toxicity
• Due to a Failure of Biliary Excretion
• Fatal if Untreated
• Earlier Anticopper Drug Penicillamine is Quite Toxic,
Trientine Moderately Toxic
• Occurs 1 in 40,000 in Most Populations’
• Gene Codes for a Copper Binding ATPase
Mayo Clinic Treatment Study Showed 30% Mortatlity
over 10 years
Presentation / Recognition a Problem
Types of Presentations
•Neurological
•Psychiatric
•Hepatic
•“Presymptomatic”
•Other
Treatments
•
•
•
•
•
•
BAL--no longer used
Chelation: Penacillamine, Trientine
Zinc
TM—not approved
Plasmapheresis
Liver Transplant
Definition of Success?
Definition of Failure?
•
•
•
•
•
•
Death—Natural History of Life and Disease
Symptom Progression
Symptom Persistence
Symptom Resolution
Toxicity
Time Course—Early Failure, Late Failure,
Treatment Not Fast Enough, Success not Long
Enough
Physician’s Definitions and Patient’s
Definitions
•
•
•
•
•
•
My child did not get into Harvard
Bad Marriage
Bad Job
Fractured Personal Relationships
Cannot Sleep
People Keep Wanting to Put Me in Assisted
Living
• I don’t like taking medicines
Response to Therapy
•
•
•
•
Not the same for everyone
Variable Ability to Compensate
Variable Treatment Adherence
Variable Disease Manifestations and Time of
Progression
• Variable Enzironment
Treatment Failures—>Chelation
Toxicity
Drug
Problems
Penicillamine
Makes 50% of New Neurologic Patients Worse and 25%
Permanently Worse.
Acute Hypersensitivity Syndrome in 25% of Patients.
Early Side Effects of Bone Marrow Depression And
Proteinuria.
Late Side Effects of Autoimmunity, Connective Tissue
Problems, and Immune Suppression.
Trientine
Early and Late Side Effects of Type Seen with
Penicillamine Occur, But Less Frequently.
Effects on New Neurologic Patients Can Accelerate
Worsening.
Neurolgoic Worsening on Therapy
• In people with Neurologic Symptoms,
Penicillamine and trientine both cause a high
incidence (25-50%) of neurologic worsening,
• Mechanism probably by mobilizing copper
stores and further elevating brain copper.
• Patients who experience neurological
worsening very often never recover fully
Neurologic Worsening
• TM Open Label Study: 2 of 55 patients in
showed Neurologic Worsening (3.6%)
• TM vs. Trientine Study: 1 of 25 (4%)people
treated with TM showed Neurologic
Worsening, While 6 of 23 (26%) people
treated with Trientine showed Neurologic
Worsening
TM THERAPY REDUCTION OF FREE
COPPER
6
Figure 1.
Free Copper
(
mM)
5
4
*
**
**
**
**
4
5
6
7
8
3
2
1
0
0
1
2
3
Weeks of TM Therapy
TM vs. Trientine
7
6
p = 0.04
Figure 2.
Free Copper
(
mM)
5
p = 0.01
4
Trientine
3
TM
2
1
**
***
*
**
0
0
1
2
3
4
5
6
Weeks of TM or Trientine Treatm ent
7
8
Trientine Free Copper and Neurologic
Deterioration
Patient # 76
30
30
20
*
10
10
0
0
-10
0
10
20
30
40
50
60
Study Day
30
Patient # 233
30
= Neurological
20
20
*
10
10
0
0
-10
0
10
20
Study Day
30
40
Free Copper
(
mM)
30
< Free Copper
Neurological Score
Patient # 238
30
20
= Neurological
*
20
10
10
0
0
-10
0
10
20
30
Study Day
40
50
60
Neurological Score
< Free Copper
Free Copper
(
mM)
Free Copper
(
mM)
= Neurological
20
Neurological Score
< Free Copper
Weeks on TM Two Dosing Arm
Comparison
6
Figure 4.
Free Copper (mM)
5
4
Arm 2
3
2
**
1
Arm 1
*
0
0
1
2
3
4
5
Weeks on TM Therapy
6
7
16
8
Zinc Therapy
•
•
•
•
•
Least Toxic
Main Concern is GI upset
Over Treatment, Under Treatment
Urine Testing
Monitor Levels
Treatment Failures
• Transplant
– 20% Renal Failure Long Term Toxicity from
Immunosuppresants
– 10 year Mortality 46%--all causes
– Increased Incidence of Cardiac Disease, Cancer,
Infections
– 1/3 of late deaths due to graft failure, remainder
split between cardiovascular deaths, malignancies
and infections
Treatment Failures—Fortunately the
Minority of Cases
• 20% Incidence of Significant Non-adherence
• Disease Universally Fatal if Left Untreated
• Take your copper reduction therapy and do
follow up testing
• The vast majority of treated patients do
exceptionally well
• Chronic Disease which can be managed