Wilson Disease: an Update / 대한간학회지

Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin (100 microgram), high hepatic copper content (>250 microgram/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.

Analysis of time-dependent recovery from beryllium toxicity following chelation therapy and antioxidant supplementation.

Efforts have been made to minimize the toxic effect caused by beryllium. Adult cyclic rats of Sprague Dawley strain were administered a bolus dose of 50mg/kg beryllium nitrate intramuscularly. The chelation therapy with glutathione (GSH), dimercapto propane sulfonic acid (DMPS)+ selenium (Se) and D-Penicillamine (DPA) + Se was given for 3 days followed by a rest of 1,3 and 7 days respectively. The results revealed a significant fall in the blood sugar level, serum alkaline phosphatase activity, serum proteins. A significant rise in the transaminases i.e. aspartate aminotranferase and alanine aminotranferase pattern is indicative of leakage of enzymes from liver resulting in alterations in the cell permeability. A rise in the hepatic lipid peroxidation activity is a direct indication of oxidative damage resulting in free radical generation. Results of the distribution studies by atomic absorption spectrophotometry reveal an increased concentration of beryllium in liver and kidney followed by lung and uterus. The relative ability of 3 chelating agents to act as antagonists for acute beryllium poisoning have been examined in liver, kidney, lungs and uterus. The appreciable change in the beryllium concentration in various organs is duration-dependent during the entire period being highly significant after 7 days rest. From the biochemical assays, and distribution studies it can be assumed that DPA+Se was the most effective therapeutic agent followed by DMPS+Se and GSH. Thus it can be concluded that DPA+Se is a better therapeutic agent as compared to DMPS+Se and GSH.

Wilson's disease.

Wilson's disease (WD), an inborn error of copper (Cu) metabolism, is now one of the leading liver diseases in children in India. The clinical presentation can be extremely varied viz.,--all forms of acute and chronic liver disease, minimal to severe neurological disease, psychiatric problems, bony deformities, hemolytic anemia and endocrine manifestations. A high index of suspicion is necessary along with a judicious battery of investigations for diagnosis. Hepatic copper estimation is the most reliable test but is not easily available in India. Liver biopsy may not be possible because of bleeding problems and histological features are often not diagnostic of WD. In the absence of hepatic Cu, a low ceruloplasmin, high 24 hour urinary copper and presence of KF rings aid in making the diagnosis. The mainstay of initial therapy is Cu-chelators like D-Penicillamine, and Trientine for reduction in body copper to sub-toxic levels. Subsequent maintenance therapy is necessarily lifelong with D-Penicillamine, Trientine or Zinc. Children on therapy must be monitored regularly for response, side-effects, compliance and rehabilitation. Response to therapy may be unpredictable, but acute and early presentations like fulminant hepatic failures have a poor outcome. All siblings must be screened for WD as early diagnosis and treatment result in a good outcome. The identification of the WD gene on chromosome 13 has led to the possible use of molecular genetics (haplotype and mutational analyses) in the diagnosis of WD. Parent groups/associations must take active part in holistic management of WD.

Mercury inhalation poisoning and acute lung injury

Acute mercury inhalation poisoning is a rare cause of acute lung injury. It is usually fatal because of progressive pulmonary failure. We experienced a patient with acute respiratory distress syndrome (ARDS) after illicit use of mercury vapor for hemorrhoid treatment; he developed acute chemical pneumonitis following exposure to mercury vapor. Prompt treatment with corticosteroids and penicillamine for acute chemical pneumonitis was instituted; radiologic pulmonary infiltrates disappeared within a week, but late phase neurologic sequelae and pulmonary interstitial fibrosis progressed.

Enfermedad de Wilson: una revisión a propósito de experiencia clínica en 16 pacientes / Wilson's disease: a review apropos of clinical experience in 16 patients

Wilson's disease is an inherited disorder of copper metabolism. We report 16 patients (6 males) with the disease; 6 had hepatic involvement and 3 were asymptomatic. The age onset was 9 years for hepatic and 17 years for neurologic involvement. The mean delay in diagnosis was 14 months. Chronic hepatitis, cirrhosis and fulminant hepatic failure were the clinical forms of liver disease. Patients with neurologic disorders had behavioral disturbances and extrapyramidal manifestations such as dystonia and parkinsonism. Patients had a good response to penicillamine, except 3 that died of liver complications, in whom the treatment was delayed or discontinued. We conclude that this metabolic disease must be suspected in pubertal children and in adults of less than 30 years old with liver disease of unknown origin or behavioral alterations associated to an extrapyramidal syndrome

Estudio comparativo con prednisona y prednisona/D-penicilamina en el tratamiento de la fibrosis pulmonar difusa idiopática / Comparative study with prednisone and prednisone/D-penicillamine in the treatment of diffuse idiopathic pulmonary fibrosis

La fibrosis pulmonar idiopática(FPI), es una entidad cuya patogenia no ha sido establecida; hasta donde se sabe actualmente, la colágena pulmonar y la inflamación alveolar, juegan un papel importante en su génesis. Su tratamiento, se ha basado principalmente en la utilización de esteroides solos o combinados con otros fármacos como los inmunosupresores, sin que se haya obtenido hasta el momento actual, mejoría en el pronóstico. En este trabajo, mostramos los resultados obtenidos con el manejo de 2 grupos de 20 pacientes cada uno, con FPI ya diagnosticada. El grupo A recibió tratamiento con prednisona y el B prednisona/D-penicilamina. Fueron evaluados mediante espirometría y gasometría al inicio, a los 6 y a los 12 meses del tratamiento. Observamos que la capacidad vital se incrementó en el grupo A, 6.59 por ciento y en el B, 9.82 por ciento; la PaO2 mejoró 5 por ciento en 4 de los casos del grupo A y en 13 del B. El incremento porcentual total de mejoría en el grupo A fue 0.84 y de 5.49 en el B. Se concluye que la combinación prednisona/D penicilamina debe considerarse como arma terapéutica en el tratamiento de FPI, sin embargo, se requiere de observaciones a más largo plazo, para establecer con precisión, la influencia que sobre el pronóstico pueda ejercer la combinación ensayada

Consideraçöes a respeito do tratamento da degeneraçäo hepatolenticular / The management of hepatolenticular degeneration

Säo revistos aspectos referentes ao tratamento da degeneraçäo hepatolenticular. Inicialmente é abordada a evoluçäo dos conhecimentos a respeito da terapêutica dessa moléstia. Analisa-se posteriormente dados relativos ao modo de emprego da D-Penicilamina e seus efeitos colaterais, assim como os resultados obtidos com o uso dessa droga. Finalmente, säo avaliados os meios auxiliares e alternativos de tratamento, particularmente os sais de zinco

Intoxicación por talio. Experiencia con 50 pacientes / Thallium intoxication. Experience with 50 patients

Durante los últimos nueve años estudiamos cincuenta casos de intoxicación por talio. Veintiocho casos fueron mujeres y vientidos fueron hombres. Uno de los casos fue un recién nacido, cuya madre sufrió este tipo de intoxicación durante el tercer trimestre de su embarazo. Las edades variaron de un día hasta 84 años de edad y en todos los casos la fuente de talio fue una solución raticida administrada oralmente, excepto en el recién nacido en quien la vía de acceso fue a través de la placenta y en una paciente en que fue transdérmica. En veintitrés casos la intoxicación fue accidental, con fines suicidas en veintiuno y con fines homicidas en cinco. En un caso la fuente de intoxicación fue desconocida. En todos los casos los niveles de talio se midieron en la orina, en algunos en la sangre y en el líquido cefalorraquídeo. Las principales manifestaciones clínicas fueron las de una neuropatía periférica severa de tipo mixto, con dolor abdominal, náusea, vómito y alopecia y en algunos casos manifestaciones psiquíatricas. En varios casos se practicaron estudios electrofisológicos, biopsia de nervio con examen de microscopía electrónica en tres pacientes, resonancia nuclear magnética y tomografía axial computarizada de abdomen y de cráneo en dos pacientes. Sólo uno de los pacientes murió y el resto se recuperó prácticamente en forma completa. Se revisan la patofisiología y las bases farmacológicas del manejo de este tipo de neurointoxicación

Síndrome nefrótico en artritis reumatoidea tratada con penicilamina / Penicillamine- induced nephrotic syndrome

Presentamos un caso de Artritis Reumatoídea seronegativa, tratada con Penicilamina durante 11 meses desarrollando un Síndrome Nefrótico a lesiones mínimas, que remite espontáneamente a los dos meses de suspendida la droga

Degeneracion hepatolenticular (Enfermedad de Wilson) / Hepatolenticular degeneration (Wilson's Disease)

Se presenta el caso de una nina de 13 anos con Enfermedad de Wilson y se hace un resumen de los aspectos mas importantes de la enfermedad hepatolenticular una de las afecciones "degenerativas", cuyo trastorno del metabolismo del cobre se origina en defectos enzimaticos de la ceruloplasmina. Un hallazgo importante en este caso fueron los depositos de cobre en las encias. La escanografia mostro atrofia cerebral y cavitaciones paraventriculares.

Chronic industrial exposure to lead in 63 subjects. II. Evaluation of chelation therapy.

Efficacy of chelation therapy with intravenous calcium disodium edetate, oral Ca EDTA, and oral penicillamine was tested in 63 subjects with chronic minimal industrial exposure to lead. All three agents increased the urinary lead excretion. The effect was greatest with intravenous Ca EDTA, next with oral penicillamine and least with oral Ca EDTA. Symptoms, particularly colicky abdominal pain, improved during the period of chelation therapy. Anaemic subjects showed improvements in haematological parameters. It is recommended that subjects with chronic minimal industrial exposure to lead receive chelation therapy. The relative merits of the three agents are discussed.