WILSONTherapy

Treatment strategy with a pharmacologic agent or liver transplantation depends on the phenotypic
expression of the disease in a given individual. Medications effective for the treatment of WD include D-
penicillamine, trientine, zinc salts, tetrathiomolybdate, and dimercaprol. Therapy can be divided into initial
treatment or maintenance therapy and follows the algorithm illustrated in Fig. 4.

(Enlarge Image)
Figure 4.
Treatment algorithm. Patients with a confirmed diagnosis of Wilson disease are
divided into three distinct categories, which have different approaches to
treatmentboth pharmacological and surgical.
The first agents such as BAL, were developed over 60 years ago and were based on copper chelation.
Other agents since then have been introduced and have been the mainstay of treatment. These include
penicillamine, trientine, zinc, tetrathiomolybdate, and dimercaprol. Although all patients require lifelong
treatment, patients can generally be divided in independent phases: those patients with asymptomatic
liver disease and those treated to steady state who continue on with maintenance therapy; those with
symptomatic liver disease only; and those with a combination of symptomatic liver, neurologic, or
psychiatric disease.
Symptomatic Disease
The goal of treatment is to attain a negative copper balance and remove copper from toxic sites within the
liver and the central nervous system. Accordingly, patients should be started on chelation therapy from
the outset with first-line agents such as penicillamine (with pyridoxine supplementation) or trientine.
Dosages are ramped up slowly and are generally ~30 to 50% higher than maintenance therapy. Some
have advocated the use of combined therapy with zinc to block copper absorption along with chelation,
but this does require temporal spacing of medications from food and each other.
[71]
A summary of the
current pharmacologic regimens are summarized in Table 2. Clinical signs of symptomatic liver disease
such as portal hypertension; ascites, encephalopathy should be closely followed along with biochemical
monitoring of liver function tests such as bilirubin, serum albumin, and prothrombin time/INR. These
values should be checked initially and at periodic intervals dependent on the disease severity. For those
with severe and advanced liver disease, transplant evaluations may need to be considered.
Patients with active neurologic or psychiatric symptoms are considered symptomatic and should be
treated similar to those with symptomatic liver disease with attention to their neurologic and psychiatric
condition along with their liver disease. Again, frequent monitoring is needed early on, and combined
treatments may be considered as well.
Successful treatment will result in improvement in liver tests and clinical signs and symptoms, though
there may be a lag time of 3 to 12 months before biochemical studies show a return toward normal. In
some patients with advanced liver disease and portal hypertension, persistent abnormalities in INR and
evidence of thrombocytopenia may persist. Once the patient has shown stabilization at 6 to 12 months,
then they should transition to maintenance therapy.
Asymptomatic Liver Disease and Maintenance Therapy
This group of patients usually benefit from monotherapy with a chelating agent or with a zinc salt. Options
to begin either agent depend on physician or patient preference. Recent data from Austrian and German
cohorts
[72]
suggest less-frequent late decompensation in patients with initial hepatic presentations on
chelation therapy, but successful therapy is achievable for both treatment categories. Treatment goals for
these individuals is to prevent any disease progression, and although monitoring may be less frequent it
should include both urine copper excretion on therapy as well as liver tests and blood counts. Repeat liver
biopsy should be reserved for those with possible treatment failure and is not needed for most patients.
Acute Liver Failure
Wilson disease accounts for ~5% of all cases of ALF. The signs and symptoms of ALF are virtually
indistinguishable across many etiologies. There are some distinct findings that may heighten suspicion
and aid in the diagnosis of ALF due to WD such as Coombs-negative hemolytic anemia, elevated serum,
and 24-hour urine copper and K-F rings. In this setting, serum ceruloplasmin is unreliable as it may be
falsely elevated as an acute-phase reactant in inflammatory conditions. However, the results of 24-hour
urine studies will not be immediately available and ~50% of patients with ALF due to WD will not have K-F
rings. Therefore, it is useful to be able to look at parameters that can be easily obtained in a timely
fashion. Uniquely, the alkaline phosphatase is inappropriately depressed for the level of cholestasis. In
addition, the ratio of alkaline phosphatase to total bilirubin ratio of <4 and AST:ALT> 2.2 are excellent
diagnostic clues.
[64]

Patients with ALF due to WD should be evaluated for emergent liver transplant as the mortality rate in this
subgroup approaches 100%. In this setting, there is typically massive hemolysis and marked elevation of
circulating copper in addition to other features of WD. Treatment of the patient to reduce the high level of
copper in the circulation may help achieve better outcomes. Renal insufficiency is often present in these
patients, and the molecular adsorbents recirculating system (MARS) has shown superiority over
continuous veno-venous hemodialysis (CVVHD) for clearing excess copper from the circulation, but
albumin dialysis, exchange transfusion, and plasmapheresis have all been utilized with success with
endpoints being reducing hemolysis, and slowing both hepatic and renal injury.
[73]
Very rare patients have
survived ALF due to WD with intensive medical therapy; however, there are no clear identifiers to predict
survival in the face of data that would indicate liver failure.
[7477]

Pregnancy
Therapy for WD should be continued during pregnancy with some modifications.
[78,79]
Concerns regarding
the chelating agents' effect on teratogenicity and postpartum wound healing have been raised. Hence,
dose reduction using these medications has been advised. Recent treatment guidelines recommend that
patients reduce the dose to below maintenance dosing (~10 mg/kg/d) before or early on during their first
trimester because this is the highest period of risk for teratogenicity. Patients on zinc monotherapy
therapy do not need to change the dose. Alternatively, one can consider switching to a zinc salt at the
onset of pregnancy, if tolerated.
Asymptomatic Children
Zinc therapy is the preferred agent to treat WD in this population because it has an excellent side-effect
profile. Asymptomatic children, particularly those who are prepubertal must have adequate copper for
proper bone, connective tissue, and mental development balanced with anticopper therapy to prevent
copper toxicity. Close monitoring should include 24-hour urine copper levels maintained in the high-
normal range (4050 g/24 h) and complete blood cell count, observing for early signs of overtreatment
and copper deficiency such as hypochromic microcytic anemia and leukopenia.
[80]

Liver Transplantation
Indications for liver transplantation include end-stage liver disease-related hepatic insufficiency,
decompensated cirrhosis that fails to respond to medical therapy, and acute liver failure. Liver transplant
for neurologic WD have given mixed results. Although a German group
[81]
reported favorable results,
others from an Italian group
[82]
suggest poorer outcomes. In the era of organ shortage, in general, it is
controversial to transplant patients based solely on the presence of neurologic WD because these
patients may respond to medical therapy alone.
Neurologic Disease
Liver transplantation may improve survival and quality of life in patients with neurologic disease.
[83]
Some
argue, liver transplantation is indicated in patients with severe motor abnormalities even in those with
normal liver function, however this is not recommended
[58]
without concurrent liver failure. The neurologic
manifestations most commonly identified include tremor, dysarthria, dystonia, sialorrhea, ataxia,
increased muscle tonus, myoclonus, aphasia, and bradykinesia. In one study, all patients with neurologic
symptoms prior to liver transplant showed marked neurologic improvement, albeit with minor residual
symptoms in 5.2 years mean follow-up.
[81]

Treatment
The initial therapy is with a chelator, either penicillamine or trientine with or without zinc salts. After the
initial treatment, monitor for clinical and biochemical improvement, specifically, regression of K-F rings,
hepatosplenomegaly, dysarthria, tremor, hemolysis, and normalization of hepatic function tests.
[42]
Serum
copper may be used as an indicator of degree of chelation (free copper <10 g/dL). As 24-hour urine
copper levels approach normal levels on chelating medications (200500 g/d), symptomatic therapy
may be switched to maintenance therapy as once daily dosing.
Adjunct Therapy With Antioxidants
Vitamin E has been proposed as a potential agent for WD based on decreased circulating serum vitamin
E levels and plasma vitamin E/lipid ratios measured in patients with WD when compared with healthy
adult controls.
[84,85]
Experimentally, incubation of copper-overloaded rat hepatocytes with -tocopheryl
succinate improved both cell viability and completely reduced oxidant injury to that of control
hepatocytes.
[86]
In addition, curcumin treatment of a transiently transfected cell line with comparable
expression and function to WD partially restored protein expression of the ATP7B mutants.
[87]

Future Treatments
Proof of principle has demonstrated the feasibility of hepatocyte transplant and gene therapy in
successfully treating rodent models of WD.
[88]
In these animals, both therapies have been shown to
increase biliary copper excretion, and cell transplant therapy has been shown to ameliorate and prevent
disease progression.
[89]
Likely there are too many independent gene mutations leading to WD for gene
therapy to be effective for the population at large. However, in select populations where there is a
dominant mutation, this may hold some future promise. Other variations of current treatment involve
combination therapies of a chelation agent plus zinc in a simplified maintenance therapy of once daily
chelating dosing.
[90

Terapia
La estrategia de tratamiento con un agente farmacolgico o trasplante de hgado depende de la
expresin fenotpica de la enfermedad en un individuo dado. Medicamentos eficaces para el
tratamiento de WD incluyen D-penicilamina, trientina, sales de zinc, tetratiomolibdato, y dimercaprol. La
terapia puede ser dividido en el tratamiento inicial o el tratamiento de mantenimiento y sigue el
algoritmo ilustrado en la figura. 4.
Algoritmo de tratamiento. Los pacientes con un diagnstico confirmado de enfermedad de Wilson se
dividen en tres categoras distintas, que tienen diferentes enfoques para el tratamiento farmacolgico y
quirrgico.
Los primeros agentes tales como BAL, se desarrollaron ms de 60 aos y se basa en la quelacin de
cobre. Otros agentes, desde entonces, se han introducido y han sido el pilar del tratamiento. Estos
incluyen la penicilamina, trientina, zinc, tetratiomolibdato y dimercaprol. Aunque todos los pacientes
requieren tratamiento de por vida, los pacientes generalmente se pueden dividir en fases
independientes: los pacientes con enfermedad heptica asintomticos y aquellos tratados hasta el
estado estacionario que continuar con la terapia de mantenimiento, los que tienen enfermedad
heptica sintomtica solamente, y aquellos con una combinacin de heptica sintomtica , neurolgico
o enfermedad psiquitrica.
Enfermedad sintomtica
El objetivo del tratamiento es lograr un equilibrio negativo de cobre y eliminar el cobre de sitios txicos
en el hgado y el sistema nervioso central. En consecuencia, los pacientes deben comenzar con la terapia
de quelacin desde el principio con frmacos de primera lnea, tales como penicilamina (con
suplementos de piridoxina) o trientina. Las dosis son en rampa lentamente y son generalmente ~ 30 a
50% ms alta que la terapia de mantenimiento. Algunos han abogado por el uso de la terapia combinada
con zinc para bloquear la absorcin de cobre junto con la quelacin, pero esto requiere espacio
temporal de los medicamentos de los alimentos y de los dems. [71] Un resumen de los actuales
regmenes farmacolgicos se resumen en la Tabla 2. Los signos clnicos de la enfermedad heptica
sintomtica como la hipertensin portal, ascitis, encefalopata debe ser seguido de cerca junto con el
control bioqumico de las pruebas hepticas como la bilirrubina, la albmina srica y tiempo de
protrombina / INR. Estos valores deben ser revisadas inicialmente y a intervalos peridicos que
dependen de la gravedad de la enfermedad. Para aquellos con enfermedad heptica grave y avanzado,
las evaluaciones de trasplante puede necesitar ser considerado.

Los pacientes con sntomas neurolgicos activos o psiquitricos se consideran los sntomas y deben ser
tratadas de forma similar a los pacientes con enfermedad heptica sintomtica con atencin a su
condicin neurolgica y psiquitrica a lo largo de su enfermedad heptica. Una vez ms, la
monitorizacin frecuente es necesaria desde el principio, y tratamientos combinados pueden ser
considerados as.
El xito del tratamiento se traducir en una mejora de las pruebas hepticas y signos y sntomas clnicos,
aunque puede haber un retraso de tiempo de 3 a 12 meses antes de los estudios bioqumicos muestran
un retorno a la normalidad. En algunos pacientes con enfermedad heptica avanzada e hipertensin
portal, alteraciones persistentes en el INR y la evidencia de trombocitopenia puede persistir. Una vez
que el paciente ha mostrado una estabilizacin a 6 a 12 meses, entonces deberan transicin a terapia
de mantenimiento.
Enfermedades del Hgado asintomtica y terapia de mantenimiento
Este grupo de pacientes generalmente se benefician de la monoterapia con un agente quelante o con
una sal de zinc. Opciones de comenzar cualquiera de los agentes depender de las preferencias del
mdico o del paciente. Los datos recientes de cohortes de Austria y Alemania [72] sugieren menos
frecuente la descompensacin tarda en pacientes con presentaciones hepticas iniciales sobre la
terapia de quelacin, pero la terapia exitosa es factible para ambas categoras de tratamiento. Los
objetivos del tratamiento para estas personas es evitar que cualquier progresin de la enfermedad, y
aunque la vigilancia puede ser menos frecuente que debera incluir tanto la excrecin de cobre en orina
terapia, as como pruebas de funcin heptica y recuentos sanguneos. Repetir la biopsia heptica se
debe reservar para los pacientes con insuficiencia tratamiento posible y no es necesario para la mayora
de los pacientes.
Insuficiencia heptica aguda
Wilson enfermedad es responsable de cerca del 5% de todos los casos de ALF. Los signos y sntomas de
la ALF son prcticamente indistinguibles a travs de mltiples etiologas. Hay algunas conclusiones
distintas que pueden aumentar la sospecha y la ayuda en el diagnstico de ALF debido a WD como
Coombs negativa anemia hemoltica srica elevada, y 24 horas de cobre en orina y los anillos de KF. En
este contexto, la ceruloplasmina srica no es fiable, ya que puede estar falsamente elevada como un
reactante de fase aguda en las enfermedades inflamatorias. Sin embargo, los resultados de estudios de
orina 24-horas no estar disponible inmediatamente y ~ 50% de los pacientes con ALF debido a WD no
tendr anillos KF. Por lo tanto, es til ser capaz de ver los parmetros que pueden ser fcilmente
obtenidos en el momento oportuno. nicamente, la fosfatasa alcalina est deprimido inapropiada para
el nivel de colestasis. Adems, la relacin de la fosfatasa alcalina al total de bilirrubina proporcin de <4
y AST: ALT>. 2,2 son excelentes pistas de diagnstico [64]
Los pacientes con WD debido a ALF deben ser evaluados para trasplante de hgado emergente como la
tasa de mortalidad en este subgrupo se acerca al 100%. En esta configuracin, hay tpicamente
hemlisis masiva y marcada elevacin de la circulacin de cobre, adems de otras caractersticas de WD.
El tratamiento del paciente para reducir el alto nivel de cobre en la circulacin puede ayudar a lograr
mejores resultados. La insuficiencia renal es a menudo presente en estos pacientes, y los adsorbentes
moleculares (MARS sistema de recirculacin) ha demostrado superioridad sobre veno-venosa continua
hemodilisis (CVVHD) para limpiar el exceso de cobre de la circulacin, pero dilisis con albmina, la
exanguinotransfusin y la plasmafresis han sido todos utilizado con xito con los puntos finales son la
reduccin de la hemlisis, y la desaceleracin tanto heptica y lesin renal [73] Los pacientes muy raras
han sobrevivido ALF debido a WD con terapia mdica intensiva;. Sin embargo, no existen identificadores
claros para predecir la supervivencia en la cara de datos que indicara una insuficiencia heptica. [74-77]
Embarazo
Terapia para WD debe continuarse durante el embarazo con algunas modificaciones. [78,79] Las
preocupaciones sobre los agentes quelantes efecto sobre la teratogenicidad y la cicatrizacin de heridas
post-parto se han planteado. Por lo tanto, la reduccin de dosis de uso de estos medicamentos ha sido
advertido. Las pautas actuales recomiendan que los pacientes a reducir la dosis a la dosis de
mantenimiento a continuacin (~ 10 mg / kg / d) antes o temprano durante el primer trimestre porque
este es el periodo ms alto de riesgo de teratogenicidad. Los pacientes en tratamiento con monoterapia
de zinc no es necesario cambiar la dosis. Alternativamente, se puede considerar el cambio a una sal de
cinc en el inicio del embarazo, si se tolera.
Los nios asintomticos
Terapia de zinc es el agente preferido para el tratamiento de WD en esta poblacin, ya que tiene un
excelente perfil de efectos secundarios. Nios asintomticos, especialmente aquellos que son
prepberes debe tener suficiente cobre para el hueso adecuado, el tejido conectivo y el desarrollo
mental equilibrado con terapia anticopper para prevenir la toxicidad de cobre. Estrecha supervisin
debe incluir 24 horas los niveles de cobre en orina se mantienen en el rango alto de la normalidad (40-
50 g/24 h) y el recuento completo de clulas sanguneas, la observacin de los signos tempranos de
sobretratamiento y la deficiencia de cobre, tales como anemia hipocrmica microctica y leucopenia. [
80]
Trasplante de Hgado
Las indicaciones para el trasplante de hgado incluyen en fase terminal de la enfermedad heptica
relacionada con la insuficiencia heptica, cirrosis descompensada que no responde al tratamiento
mdico, y la insuficiencia heptica aguda. Trasplante de hgado para neurolgico WD han dado
resultados mixtos. Aunque un grupo alemn [81] reportaron resultados favorables, otros de un grupo
italiano [82] sugieren peores resultados. En la era de la escasez de rganos, en general, es controvertido
a pacientes de trasplantes basado nicamente en la presencia de WD neurolgico debido a que estos
pacientes pueden responder a la terapia mdica sola.
Enfermedades Neurolgicas
El trasplante de hgado puede mejorar la supervivencia y la calidad de vida en pacientes con enfermedad
neurolgica. [83] Algunos argumentan, el trasplante heptico est indicado en pacientes con
alteraciones motoras severas, incluso en aquellos con funcin heptica normal, sin embargo esto no se
recomienda [58], sin heptica concurrente fracaso. Las manifestaciones neurolgicas ms comunes
identificadas incluyen temblor, disartria, distona, sialorrea, ataxia, aumento del tono muscular,
mioclonas, afasia y la bradicinesia. En un estudio, todos los pacientes con sntomas neurolgicos previos
a un trasplante de hgado mostr una marcada mejora neurolgica, aunque con leves sntomas
residuales en 5,2 aos promedio de seguimiento. [81]
Tratamiento
El tratamiento inicial es con un quelante, ya sea penicilamina o trientina con o sin sales de zinc. Despus
del tratamiento inicial monitor, para la mejora clnica y bioqumica, especficamente, la regresin de los
anillos de KF, hepatoesplenomegalia, disartria, temblor, hemlisis, y la normalizacin de las pruebas de
funcin heptica. [42] de cobre en suero se puede usar como un indicador del grado de quelacin (
cobre libre de <10 mg / dL). Como 24 horas los niveles de cobre en orina de aproximarse a los niveles
normales en medicamentos quelante (200-500 mg / d), la terapia sintomtica puede ser conmutado a la
terapia de mantenimiento como la dosificacin una vez al da.
Tratamiento adjunto con antioxidantes
La vitamina E se ha propuesto como un agente potencial para WD basado en disminucin de los niveles
sricos circulantes de vitamina E y vitamina E en plasma / lpido coeficientes medidos en pacientes con
WD en comparacin con controles sanos adultos. [84,85] Experimentalmente, la incubacin de cobre-
sobrecargado hepatocitos de rata con -tocoferil succinato mejor tanto la viabilidad de las clulas y
completamente reducido dao oxidante a la de los hepatocitos de control. [86] Adems, la curcumina
tratamiento de una lnea de clulas transfectadas transitoriamente con la expresin y la funcin
comparable a la expresin WD protena parcialmente restaurada de la ATP7B mutantes. [87]
Tratamientos futuros
Prueba de principio ha demostrado la viabilidad del trasplante de hepatocitos y la terapia gnica en el
tratamiento exitoso de modelos de roedores de WD. [88] En estos animales, ambas terapias han
demostrado aumentar la excrecin biliar de cobre, y la terapia de trasplante de clulas se ha
demostrado para mejorar y prevenir progresin de la enfermedad. [89] Probablemente hay mutaciones
independientes demasiados genes que conducen a WD para la terapia gnica para ser eficaz para la
poblacin en general. Sin embargo, en poblaciones seleccionadas donde hay una mutacin dominante,
esto puede tener alguna promesa futuro. Otras variaciones de tratamiento actuales incluyen terapias de
combinacin de un agente de quelacin con cinc en una terapia de mantenimiento simplificado de
dosificacin una vez al da quelante. [90
http://www.medscape.com/viewarticle/756588_8

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230
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Medication Summary
The mainstay of therapy for Wilson disease is the use of chelating agents and medications that block
copper absorption from the gastrointestinal (GI) tract.
Zinc and penicillamine are lifelong medications for patients with Wilson disease. Dosages vary with the
severity of the disorder. Patients who do not respond to zinc therapy and who have increased activities of
liver enzymes should be identified so that chelating agents may be added to the therapeutic regimen.
[14, 15]

Other medications used to treat Wilson disease include anticholinergics, baclofen, gamma-aminobutyric
acid (GABA) antagonists, and levodopa, to treat parkinsonism and dystonia symptoms; antiepileptics to
treat seizures; and neuroleptics to treat psychiatric symptoms. In addition, protein restriction, lactulose, or
both are used to treat hepatic encephalopathy.
medicacin Resumen
El pilar de la terapia para la enfermedad de Wilson es el uso de agentes quelantes y medicamentos que bloquean
la absorcin de cobre desde el tracto gastrointestinal (GI).

El zinc y la penicilamina son medicamentos de por vida para los pacientes con enfermedad de Wilson. Las dosis
varan con la gravedad del trastorno. Los pacientes que no responden a la terapia de zinc y que han aumentado las
actividades de las enzimas del hgado debe ser identificado de manera que los agentes quelantes se pueden aadir
al rgimen teraputico. [14, 15]

Otros medicamentos utilizados para tratar la enfermedad de Wilson incluyen anticolinrgicos, baclofeno, gamma-
aminobutrico (GABA antagonistas del cido) y levodopa, para tratar los sntomas de parkinsonismo y distona;
antiepilpticos para el tratamiento de convulsiones, y neurolpticos para tratar los sntomas psiquitricos.
Adems, la restriccin de protenas, lactulosa, o ambas se usan para el tratamiento de la encefalopata heptica.