Early Occurrence of Hypertransaminasemia in a 13-Month-Old Child With Wilson Disease

Wilson disease (WD) is an inherited autosomal recessive disorder of copper accumulation that is fatal unless detected and treated. Mutations of the gene responsible for WD (ATP7B) lead to failure of copper excretion in the bile. The genetic defect results in accumulation and toxicity of copper primarily in the liver and then in extrahepatic sites, such as the brain, eyes, kidneys, erythrocytes, and skeletal system (1). The age at onset and the manifestations of WD may vary markedly from one patient to another. A patient with WD may seek treatment for hepatic, neurologic, psychiatric, hematologic, renal, or skeletal symptoms; some patients are diagnosed presymptomatically by familial screening (2). Unexplained hypertransaminasemia not associated with clinical signs of liver disease is not usually reported among presentation modes of WD (1,2). It is of note that practically all patients with WD remain asymptomatic for their first 3 years of life (3) and that WD usually appears with evidence of liver damage during childhood, while symptoms related to neurologic or psychiatric disease tend to appear during adolescence or early adult life (S2). Early diagnosis is mandatory so that therapy can be started before hepatocellular damage is irreversible and to prevent brain damage. Although zinc is universally accepted as elective therapy for presymptomatic children, how early to start therapy is an open question. We report the case of a child with very early onset of WD, in whom hypertransaminasemia occurred at age 13 months and zinc therapy achieved a prompt normalization of liver enzymes. CASE REPORT The patient, a 13-month-old girl, whose 8-year-old brother was affected by WD, was referred to our observation to rule out WD. On physical examination, no abnormality was found. In particular, the patient did not show any sign of hepatic, neurologic, or hematologic disease. At first evaluation, laboratory investigations revealed aspartate transaminase, 168 IU/L (normal, <40 IU/L); alanine transaminase, 210 IU/L (normal, <40 IU/L); serum ceruloplasmin, 0.08 g/L (normal range, 0.2–0.6 g/L); serum copper levels <40 μg/dL; basal urinary copper excretion, 4 μg/24 h; and urinary copper levels after penicillamine challenge (at the standard dosage of 500 mg twice a day), 150 μg/24h. All principal causes of hypertransaminasemia (hepatitis A virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, toxoplasmosis, Brucella, autoimmune hepatitis, cystic fibrosis, biliary system diseases, drug-related toxicity, obesity, celiac disease, metabolic diseases other than WD, and extrahepatic causes of hypertransaminasemia such as myopathies) were ruled out. Because hypertransaminasemia persisted for the next 3 months, liver biopsy was performed. Liver histologic evaluation revealed rare focal inflammatory infiltrates with slight portal fibrosis. Quantitative determination of hepatic copper levels was found to be markedly elevated: 1,060 μg/g dry weight of liver tissue (diagnostic value >250 μg/g dry weight of liver tissue). Therefore, WD was diagnosed, and therapy with zinc sulfate, 200 mg daily in two divided doses, was started. Transaminase levels decreased to the normal range within 6 weeks and were maintained during the next 12-month follow-up period. The rapid normalization of transaminases with zinc therapy indirectly confirmed the relationship between WD and hypertransaminasemia. The molecular analysis did not reveal known mutations in either the patient or her brother. In the latter, WD was diagnosed based on hypoceruloplasminemia, increased levels of basal and post-penicillamine challenge cupriuria, and high hepatic copper concentration. DISCUSSION The described patient is an extreme example of an early presentation of WD. Although it is widely documented that children with WD do not have symptoms before aged 3 to 6 years (4–6), this case shows that hypertransaminasemia may occur earlier, before the onset of overt clinical signs typical of WD. This finding is particularly important in countries where evaluation of aminotransferase serum levels is included in routine evaluation (e.g., in candidates for surgical procedures, in patients hospitalized for diseases other than liver disease). So far, based on what has been reported in the literature for children with WD, this inborn error of metabolism has not been systematically researched in children aged less than 3 to 6 years with isolated hypertransaminasemia. In the present case, hypertransaminasemia was identified by chance in the context of a familial screening for WD for the presence of an affected sibling. In absence of the brother with WD, the identification of the cause of hypertransaminasemia would have been much more difficult. The causal relationship between WD and increased aminotransferase serum levels in our patient was based not only on the concomitance of the two conditions but also on the exclusion of the main causes of hypertransaminasemia and on the rapid normalization of transaminases soon after the start of zinc therapy. Although WD is an uncommon cause of liver disease in children and the real prevalence of young children with WD-related hypertransaminasemia is extremely low, it seems, however, reasonable to not overlook the possible causal role of WD in young children. This is extremely important because early diagnosis and early treatment of WD avoid the progression of disease. It is likely that liver damage may occur since the first months of life, as observed in our case in whom hypertransaminasemia (4.5 times the upper normal value) and histologic evidence of liver disease were already present at age 13 months. Furthermore, if we consider that children with acute liver failure have been observed at age 3 years (7), it seems reasonable to consider WD as possible cause of hypertransaminasemia in children aged less than 3 years. However, in the first years of life, diagnosis of WD, in particular in absence of other affected family members, is very challenging because 24-hour urinary copper excretion, basal and after penicillamine challenge, may be lower with regard to values considered diagnostic of WD (8). It has been suggested that the low levels of cupriuria are probably related to the absence of an advanced disease in children (8). In the described patient, cupriuria levels were low. Despite the low levels of cupriuria and the absence of known mutations on molecular analysis in the studied patient, diagnosis of WD was well documented by high levels of copper in liver in absence of cholestatic liver disease and was supported by hypoceruloplasminemia and presence of a sibling with proven WD. In the present case, concomitance of increased transaminase levels, unequivocally low ceruloplasmin, unremarkable urinary penicillamine test, and presence of a sibling with WD were clear indications for liver biopsy and quantitative hepatic copper determination. However, although it is imperative for all first-degree relatives of patients with WD to be screened for this genetic disorder, liver biopsy with hepatic copper determination must be reserved for diagnostic dilemmas (i.e., unremarkable urinary penicillamine test, equivocal ceruloplasmin, etc.) because in the majority of children, diagnosis of WD may be based on serum ceruloplasmin level, basal and post-penicillamine cupriuria, and molecular analysis. As for the impact of this case report on the approach to children aged less than 3 years with hypertransaminasemia in absence of family members with WD, the message of our case report is that even in children aged 1 year, increased transaminase levels should lead to exclusion of WD. Although efficacy of zinc therapy in presymptomatic patients with WD is well documented, the age at which presymptomatic patients with WD must be treated with zinc is still debated. Walshe (4) reported that “the best policy is to start treatment as soon as the diagnosis is made,” but in his study, no patient was aged less than 3 years. Also, Brewer (9) recommended an early treatment of presymptomatic patients, but in his study the patients' ages ranged from 2.3 to 17.6 years. Furthermore, in these two studies, the youngest patients did not show biochemical signs of liver disease (4,9). Therefore, the patient studied here represents the youngest subject with WD treated with zinc and in whom zinc therapy induced a rapid normalization of aminotransferase serum levels.