Persistence of elevated aminotransferases in Wilson's disease despite adequate theraphy.
Authors: Raffaele Iorio, Mariangela D'Ambrosi, Matilde Marcellini, Christiana Barbera, Giuseppe Maggiore, Lucia Zancan, Raffaella Giacchino, Pietro Vajro, Maria Grazia Marazzi, Ruggiero Francavilla, Fabio Michielutti, Massimo Resti, Tullio Frediani, Maria Pastore, Angela Vegnente
Journal: Hepatology (2004)

Wilson's disease (WD) is characterized by a dramatic build-up of intracellular hepatic copper with subsequent hepatic and neurological abnormalities.1, 2 Prompt recognition of WD is crucial, because if not treated, the disease is fatal.2, 3 Most childhood cases of WD present with liver disease that mimics various liver disorders, while the typical neurological signs are usually absent. Hypertransaminasemia may be the only altered laboratory sign in early WD. Histological evidence of severe liver disease may occur in children with isolated hypertransaminasemia.4, 5 The response of serum transaminase levels to penicillamine and zinc treatment in WD is poorly understood, because the children with WD in earlier studies had a relatively advanced disease, and treatment efficacy was evaluated from parameters (i.e., jaundice, ascites, and neurological symptoms) other than serum transaminases.6-9 We retrospectively evaluated 107 consecutive children with WD (median age at diagnosis, 7.3 years; range, 1-18) treated for at least 12 months and observed in the last 20 years at 11 pediatric departments linked with the Italian Society of Pediatric Gastroenterology and Hepatology. Clinical, laboratory, and histological features at diagnosis and initial treatment were recorded. One hundred two patients had clinical and/or laboratory signs of liver disease (68 hepatomegaly and hypertransaminasemia; 25 isolated hypertransaminasemia; 5 liver failure; 4 neurological signs and hypertransaminasemia). At diagnosis, median alanine aminotransferase (ALT) value was 246 IU/L (range, 45-640 IU/L). Median hepatic copper concentration, evaluated in 95 patients, was 972 μg/g dry weight (range, 282-4067). No patient had haemolytic anaemia or abnormal renal laboratory function test results. Only one of the 5 patients with liver failure required liver transplantation. Eighty-six patients were first treated with penicillamine (median dosage, 20 mg/kg/day), and 21 with zinc sulphate (median dosage, 300 mg/day divided into 2-3 doses; range, 150-600 mg/day). Table 1 summarizes the main clinical and laboratory features of the two treatment groups. Fifty-six (65%) of 86 patients given penicillamine normalized serum ALT levels within a median of 17 months (range, 2-96 months). Of the 28 patients with persistent hyper-ALT, 17 (61%) switched to zinc; only 4 of these patients normalized ALT on zinc within a median period of 38 months (range, 7-48 months). Eleven (52%) of the 21 patients given zinc alone normalized ALT within a median period of 6 months (range, 1-36 months). Of the 10 patients with persistent hyper-ALT, 5 switched to penicillamine. Three of the latter normalized ALT within a median period of 6 months (range, 6-9 months). Overall, in penicillamine- and zinc-treated patients with persistent hypertransaminasemia, ALT decreased from a basal median of 224 IU/L (range, 54-640 IU/L) to a median of 75 (range, 46-960 IU/L) at the end of follow-up (P = .0245). An intriguing finding of this study is that 35% of children with WD-related liver disease had persistent hypertransaminasemia despite treatment with penicillamine or zinc. Evidence of poor compliance was detected in only 10% of these cases. Interestingly, despite longstanding hypertransaminasemia, no patient showed worsening of the liver disease or developed other WD-related symptoms. Although the pathogenetic mechanisms underlying the persistent abnormality of liver enzymes in patients with WD are unclear, physicians should be alert to this phenomenon to avoid expensive time-consuming diagnostic evaluations and ineffectual changes of therapy.