Significant heterogeneity in the diagnosis and long-term management of Wilson disease: Results from a large multicenter Spanish study / Elevada heterogeneidad en el diagnóstico y tratamiento a largo plazo en la enfermedad de Wilson: resultados de un estudio multicéntrico español

There is uncertainty regarding Wilson's disease (WD) management. Objectives: To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers. Methods: Data on WD patients followed at 32 Spanish hospitals were collected. Results: 153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response. Conclusions: Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored. (AU)

Existe incertidumbre con respecto al manejo de la enfermedad de Wilson (EW). Objetivos: Evaluar, en un estudio de cohorte retrospectivo español multicéntrico, si el abordaje de la EW es homogéneo entre los centros. Métodos: Se recogieron datos sobre pacientes con EW seguidos en 32 hospitales españoles. Resultados: Un total de 153 casos, 58% hombres, 20,6 años al diagnóstico, 69,1% presentación hepática, fueron seguidos durante 15,5 años. Se objetivaron resultados discordantes en parámetros de laboratorio no invasivos en el 39,8%. La concentración intrahepática de cobre fue patológica en el 82,4%. Las pruebas genéticas solo se realizaron en el 56,6% con resultados positivos en el 83,9%. Un diagnóstico definitivo de EW (puntuación de Leipzig ≥4) se confirmó retrospectivamente en el 92,5% de los casos. Los agentes quelantes fueron la terapia inicial estándar (75,2%) con modificaciones frecuentes (57%), particularmente hacia zinc de mantenimiento. La normalización enzimática no se logró en un tercio, más comúnmente en el contexto de un cumplimiento deficiente, ausencia de mutaciones genéticas y/o presencia de factores de riesgo cardiometabólicos. Aunque sin alcanzar significación estadística, observamos diferencias entre hombres y mujeres en el número de casos, edad en el momento del diagnóstico y la respuesta bioquímica. Conclusiones: De este estudio multicéntrico que incluye centros de referencia pequeños y grandes se desprende una heterogeneidad significativa en el diagnóstico y manejo de los pacientes con EW. La incorporación de pruebas genéticas ha mejorado el diagnóstico. Las diferencias de sexo deben explorarse más a fondo en estudios futuros. (AU)

Significant heterogeneity in the diagnosis and long-term management of Wilson disease: Results from a large multicenter Spanish study.

There is uncertainty regarding Wilson's disease (WD) management. OBJECTIVES: To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers. METHODS: Data on WD patients followed at 32 Spanish hospitals were collected. RESULTS: 153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response. CONCLUSIONS: Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored.

Enfermedad de Wilson rápidamente evolutiva y con presentación inusual / Wilson’s disease with unusual presentation and rapid evolution

Presentamos el caso de un paciente con enfermedad de Wilson que tuvo un comportamiento poco habitual. Previoa la aparición de las manifestaciones neurológicas, tuvo tos como único síntoma, sospechándose una discinesiarespiratoria como forma de presentación. La forma clínica de su enfermedad fue de tipo neurológico puro y sin evidencias de compromiso hepático. No hubo una respuesta satisfactoria al tratamiento instituido y la evolución fue rápida y fatal en poco tiempo.

We present a case of Wilson’s disease with an unusual course. Before the onset of neurological manifestations, cough was the only symptom, suggesting a respiratory dyskinesia as the form of presentation. The disease took a purely neurological type, without signs of hepatic compromise. There was no response to medical treatment, and the evolution was rapid and fatal.

Enfermedad de Wilson rápidamente evolutiva y con presentación inusual / WilsonÆs disease with unusual presentation and rapid evolution

Presentamos el caso de un paciente con enfermedad de Wilson que tuvo un comportamiento poco habitual. Previoa la aparición de las manifestaciones neurológicas, tuvo tos como único síntoma, sospechándose una discinesiarespiratoria como forma de presentación. La forma clínica de su enfermedad fue de tipo neurológico puro y sin evidencias de compromiso hepático. No hubo una respuesta satisfactoria al tratamiento instituido y la evolución fue rápida y fatal en poco tiempo.(AU)

We present a case of WilsonÆs disease with an unusual course. Before the onset of neurological manifestations, cough was the only symptom, suggesting a respiratory dyskinesia as the form of presentation. The disease took a purely neurological type, without signs of hepatic compromise. There was no response to medical treatment, and the evolution was rapid and fatal.(AU)

Avaliação do metabolismo oxidativo de ovinos intoxicados por cobre e tratados com tetratiomolibdato associado ou não a vitaminas antioxidantes / Oxidative metabolism in copper poisoning sheep treated with tetrathiomolybdate and/or antioxidative vitamins

Para avaliar o efeito da utilização parenteral das vitaminas C e/ou E associadas ao quelante de cobre, tetratiomolibdato de amônio (TTM), no tratamento de ovinos com intoxicação cumulativa por cobre (ICC), foram analisados o metabolismo oxidativo, através das concentrações sanguíneas de glutationa reduzida (GSH), séricas de malondialdeído (MDA) e ácido úrico, e a habilidade de redução férrica plasmática (HRFP) desses animais. Foram utilizados 24 ovinos machos, da raça Santa Inês, com peso médio de 25 kg e distribuídos em quatro tratamentos: TTM, TTM e vitamina C (TTM+VC), TTM e vitamina E (TTM+VE) e TTM e vitaminas C e E (TTM+VCE). O quadro de intoxicação cúprica provocou intensa formação de radicais livres, com redução da concentração de GSH e aumento do MDA, apesar do aumento na capacidade antioxidante plasmática, decorrente do aumento da concentração de ácido úrico e da HRFP. Não foi observado benefício algum da utilização das vitaminas antioxidantes, isoladamente ou associadas, com o tratamento clássico baseado na administração de TTM, na redução do estresse oxidativo.

The effects of vitamins C and/or E associated to amonium tetrathiomolybdate (TTM) in the treatment of cumulative copper intoxication (ICC) in sheep were analyzed throughout oxidative metabolism. Reduced glutathione (GSH), malondialdehyde (MDA), uric acid and the ferric reducing ability of plasma (FRAP) concentrations were evaluated. Twenty four male sheep, Santa Ines breed, with 25 kg BW was distributed in four treatments: TTM, TTM and vitamin C (TTM+VC), TTM with vitamin E (TTM+VE) and TTM with vitamins C and E (TTM+VCE). The intoxication status caused an intensive formation of free radicals with reduction of the GSH concentration and increase of MDA. Despite the increase in the capacity of plasmatic antioxidant observed with the increase of uric acid and FRAP concentrations, it was not observed any benefit with treatments using oxidant vitamins, isolatedly or together with classic treatment only with TTM.