Introduction 1,2
Wilson’s disease is a rare genetic disorder caused by mutations in the ATP7B gene, leading to dangerous amounts of copper accumulation in our vital organs like the liver, brain, and cornea. If left untreated, patients face liver failure, neurological degeneration, and psychiatric crises.
Wilson’s Disease: Pathogenesis and Clinical Manifestations 1,2
Wilson’s disease arises from mutations in the ATP7B gene, which encodes a copper-transporting ATPase enzyme essential for biliary copper excretion. Over 800 mutations have been identified, with H1069Q common in European populations and R778L prevalent in Asia.
These mutations disrupt copper transport, causing systemic accumulation at rates exceeding 5 mg/day-far above the 1–2 mg/day excreted by healthy individuals.
What Happens in Wilson’s? 2
The disease manifests in varying ways depending on the organs affected.
- Eye issues: Greenish-brown deposits of copper may be seen in eye examinations; these are referred to as “Kayser-Fleischer rings.”
- Liver issues: Liver issues are common in pediatric patients with Wilson’s disease. Liver issues can range from acute jaundice to cirrhosis to even liver failure, which happens because of hemolysis caused by copper release.
- Neurological issues: Common in young adults. Neurological issues include movement problems, speech problems as well as anxiety and psychosis. Tremors, rigidity, slurred speech etc, are common neurological symptoms seen in Wilson’s disease
How does Copper Accumulation cause Organ Dysfunction? 2, 3
Excess copper generates oxidative stress through Fenton reactions, where copper ions react with hydrogen peroxide to produce hydroxyl radicals.
These radicals deplete glutathione reserves, damage mitochondrial membranes, and trigger hepatocyte apoptosis. Over time, this leads to liver fibrosis and liver cirrhosis.
Copper accumulation also damages the kidneys and hematuria (blood in urine) is one of the first incidental findings in upto 10% of patients. 2
In the brain, copper disrupts dopamine metabolism by inhibiting dopamine β-hydroxylase, reducing norepinephrine synthesis in the locus coeruleus. MRI scans often reveal hyperintensities in the putamen and thalamus, correlating with motor deficits. Without intervention, copper overload causes irreversible organ damage, underscoring the need for early chelation therapy.
The solution? 4
Wilson’s disease requires lifelong treatment to remove excess copper and prevent re-accumulation. The main approaches include chelation therapy, zinc salts, and in severe cases, liver transplantation.
Traditional Management Approaches:
A. Chelation Therapy :
Penicillamine has been the First-line chelator for decades. ItBinds to copper and promotes its urinary excretion, but it comes with its side effects:
- Early hypersensitivity (fever, rash, lymphadenopathy)
- Long-term toxicity (bone marrow suppression, proteinuria, lupus-like syndrome)
- Neurological worsening in ~10-50% of patients (due to rapid copper mobilization)
B. Zinc Salts (Zinc Acetate, Zinc Gluconate) :
These salts block intestinal copper absorption by inducing metallothionein. While these have fewer side effects than Penicillamime, they are slow-acting and not suitable for acute episodes.
These are mainly used for:
- Maintenance therapy (after initial chelation)
- Asymptomatic or presymptomatic patients
C. Liver Transplantation:
May be needed in Acute liver failure which is unresponsive to therapy. Liver transplantation is also indicated in Advanced cirrhosis with decompensation
- A Liver Transplant may also have curative effects in Wilson’s disease (replaces the defective ATP7B gene function).
Introducing Syprine (Trientine Dihydrochloride) 5
Syprine is an alternative chelator to penicillamine. It also binds to copper and promotes its urinary excretion (similar to penicillamine but is far less toxic with fewer side effects).
Syprine is Preferred in:
- Penicillamine-intolerant patients
- Neurological Wilson’s disease (lower risk of worsening symptoms)
How Syprine works: 6
Syprine works by binding free copper ions in the bloodstream, forming stable complexes which get excreted through urine. Unlike penicillamine, Syprine lacks sulfhydryl groups, this is crucial in its ability to minimize the autoimmune side effects eg. lupus-like syndrome.
Its selectivity for toxic copper spares other essential metals like zinc, reducing the risk of deficiencies. Pharmacokinetically, Syprine has an 8–12% oral bioavailability. It undergoes minimal hepatic metabolism, with 70% excreted unchanged in urine.
Comparative Efficacy of Syprine vs. Other Chelating Agents 5,7
Syprine offers a safer alternative to penicillamine, which, despite higher cupriuretic effects (320 mcg/6hr vs. Syprine’s234 mcg/6hr), frequently causes severe adverse reactions like proteinuria and cytopenias. Zinc, another option, blocks intestinal copper absorption but acts too slowly, especially for acute cases.
The 2021 DECISION trial demonstrated Syprine’s non-inferiority to penicillamine in achieving hepatic remission, with 50% fewer side effects. For penicillamine-intolerant patients, Syprine provides comparable efficacy with improved tolerability, making it a cornerstone of long-term management.
Syprine serves as a critical therapy for those unable to tolerate first-line treatments like penicillamine8. In India, where Syprine remains unapproved, patients rely on Rx4U’s Named Patient Purchase (NPP) program, which imports the drug through compliant global supply chains under CDSCO’s regulatory exemptions. This article explores Syprine’s role, efficacy, and how Indian patients can safely access this life-saving therapy.
Monitoring Parameters and Biomarkers for Treatment Response 9
Regular monitoring ensures therapeutic efficacy and safety. The gold standard is 24-hour urinary copper excretion, targeting 200–500 mcg/day. Various scoring systems are in use to evaluate the severity of Wilson’s disease and predict the prognosis of a patient, past a certain score, patient may have to opt for a liver transplant. It is essential to report any side-effect or symptoms to the health-care provider so that treatment response can be correctly monitored and Wilson’s disease can be managed minimally as well as effectively.
Adverse Effects and Risk Mitigation Strategies 10
Syprine’s most common side effect is iron deficiency anemia due to non-selective chelation of dietary iron. Patients are advised to take iron supplements two hours post-dose. Gastrointestinal discomfort, reported in 20–30% of users, can be mitigated by splitting doses or taking the drug with bland foods. Rare complications include hypersensitivity reactions (e.g., rash, eosinophilia) and proteinuria, requiring immediate discontinuation and corticosteroid therapy. Routine blood tests-CBC, renal function, and urinalysis-are recommended every three months.
Dietary and Lifestyle Considerations for Wilson’s Disease Management 2, 4, 10
A copper-restricted diet (
Alcohol is strictly prohibited to reduce hepatic stress. Exercise regimens should focus on low-impact activities like swimming or yoga, which improve motor coordination without excessive fatigue.
Patient Access in India: Rx4U’s Named Patient Purchase Program
Rx4U’s NPP program simplifies access to Syprine, which is unapproved in India. Rx4u is a platform dedicated to bringing life-saving medications from across the world to your doorstep. Rx4u’s global supply network ensures the timely delivery of authentic medications. Syprine offers life-saving copper chelation with fewer immunological risks than penicillamine & Indian patients can now access Syprine through Rx4u.
Visit https://rx4u.in/ for more information.
Conclusion
Syprine remains indispensable for Wilson’s disease, balancing efficacy with tolerability. For Indian patients, Rx4U’s NPP program ensures reliable access to this unapproved therapy through compliant global supply chains. Emerging treatments like gene editing promise transformative outcomes, emphasizing the need for continued innovation in rare disease care.
Disclaimer: Syprine is an unapproved drug in India and must be procured under medical supervision via Named Patient Purchase programs.
Note:
The information provided is for educational purposes only and is subject to prescribing information of the drug and the guidance of your treating physician. Always consult your healthcare provider before making any medical decision for starting your treatment.
References
1. Wilson Disease Association. Treatment Guidelines.https://wilsondisease.org
3. NIH. Neurological Manifestations of Wilson’s Disease.https://www.ninds.nih.gov
5. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/19194-S005_Syprine.pdf
5. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/19194-S005_Syprine.pdf
6. https://go.drugbank.com/drugs/DB06824
7. PubMed. Penicillamine vs. Trientine.https://pubmed.ncbi.nlm.nih.gov/6121964/
8. https://www.ncbi.nlm.nih.gov/books/NBK595409/
9. https://www.ncbi.nlm.nih.gov/books/NBK441990/
10. https://www.drugs.com/mtm/syprine.html
