Diagnosis and Management of Wilson's Disease

Medici, Valentina; Trevisan, Carlo P.; D’Incà, R.; Barollo, Michela; Zancan, Lucia; Fagiuoli, Stefano; Martines, Diego; Irato, Paola; Sturniolo, Giacomo Carlo

doi:10.1097/01.mcg.0000225670.91722.59

Cited by 133 publications

(40 citation statements)

References 23 publications

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“…Only 2 patients deteriorated after 3 months of penicillamine therapy. Our results are somewhat similar to those of Brewer et al [3] and Medici et al [13] though the frequency of deterioration was lower than their studies. Our results are based on a large sample size, relatively homogenous sample (all neurological WD except 4) and we have used a quantitative neurological score (BFM) for defining worsening.…”

Section: Discussionsupporting

confidence: 77%

“…6 of these 13 patients who deteriorated never improved to baseline even after discontinuation of penicillamine [3]. In another study, initial neurological deterioration was observed in as high as 75% of patients following penicillamine whereas none deteriorated following zinc [13]. Many other studies, however, did not report deterioration following penicillamine [14,15,16,17,18,19].…”

Section: Discussionmentioning

confidence: 98%

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Worsening of Wilson Disease following Penicillamine Therapy

Kalita¹,

Kumar²,

Chandra³

et al. 2013

Eur Neurol

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Background: Penicillamine is a standard therapy for Wilson disease (WD) but some patients have paradoxical worsening. Predictors of such deterioration have not been evaluated. This study documents frequency and predictors of deterioration following treatment in WD. Methods: 59 consecutive patients with neurologic WD and 4 asymptomatic siblings were prospectively evaluated. Their clinical, laboratory, ultrasound abdomen and cranial MRI findings with and without worsening were compared. Patients were treated with oral penicillamine and/or zinc and followed up at 1, 3 and 6 months or earlier if needed. Deterioration was defined by >10% worsening in baseline Burke-Fahn-Marsden score or appearance of new neurological sign. Results: Patients' median age was 13 years and 13 were females. 19 patients (30.2%) worsened following treatment; 10 within 1 month, 7 in 1-3 months, and 2 after 3 months of treatment. Deterioration was associated with drooling, leukopenia, thrombocytopenia, splenomegaly and evidence of chronic liver disease. None of the asymptomatic patients following zinc therapy deteriorated. Conclusions: In the deteriorating group, withdrawal of penicillamine resulted in improvement/stabilization in 11 patients, 2 improved by trientine therapy and 4 continued to deteriorate till 3 months. 30.2% patients with WD deteriorated following penicillamine, especially those with chronic liver disease, leukopenia and thrombocytopenia.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 98%

Worsening of Wilson Disease following Penicillamine Therapy

Kalita¹,

Kumar²,

Chandra³

et al. 2013

Eur Neurol

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“…11,12 Although the course of the disease tends to be benign if it is diagnosed early, the response to copper chelation or zinc treatment varies and can be accompanied by many sideeffects. 13,14 …”

Section: Clinical Presentation and Treatment Of Wilson Diseasementioning

confidence: 99%

“…13 In a small study, zinc treatment improved the neurological symptoms in patients with WD. 14 A retrospective study that compared the effects of two copper chelation therapies in 405 patients with WD found more patients discontinued D-penicillamine compared with trientine due to adverse reactions. 16 Also, regardless of copper chelator, hepatic improvements were observed in more than 90% of patients, whereas 55% of patients experienced neurological improvements.…”

Section: Clinical Presentation and Treatment Of Wilson Diseasementioning

confidence: 99%

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

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Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.

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“…After initial treatment with D-penicillamine (23/35 patients) or zinc sulphate (12/35 patients), neurological symptoms worsened or remained stationary in 75% in patients treated with d-penicillamine, while 90% of patients treated with zinc showed improvement in neurological symptoms, while hepatic disease improved in both treatment groups. Four patients underwent liver transplantation, and while 3 patients survived a mean of 4.6 years, one patient, who previous to the transplant had severe neurological impairment, died shortly after transplantation due to central pontinemyelinolysis [141] . United by a possible founder effect that has been traced to Italian origins [16,17] , WD is very frequent in Costa Rica, favored by the high degree of consanguinity.…”

Section: Costa Ricamentioning

confidence: 99%

Wilson’s disease: A review of what we have learned

Rodríguez–Castro

Hevia‐Urrutia

Sturniolo

2015

WJH

134

123

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Wilson's disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.

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Diagnosis and Management of Wilson's Disease

Abstract: Penicillamine and zinc can effectively treat Wilson's disease, though the side effects of penicillamine may be severe enough to prompt its suspension. Liver transplantation remains the treatment of choice for end-stage liver disease.

Cited by 133 publications

References 23 publications

Worsening of Wilson Disease following Penicillamine Therapy

Worsening of Wilson Disease following Penicillamine Therapy

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Wilson’s disease: A review of what we have learned

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