Sánchez-Albisua, Icíar; Garde, Teresa; Hierro, Loreto; Camarena, Carmen; Frauca, Esteban; de la Vega, Angela; Díaz, María Carmen; Larrauri, Javier; Jara, Paloma
Wilson's disease (WD) is a genetic disorder transmitted through a recessive gene located on chromosome 13. The basic defect remains unknown, but it is clear that the progressive accumulation of copper in the liver and other organs causes the clinicopathologic features of WD. In initial stages it can have no or nonspecific symptoms, but early diagnosis and treatment are important in avoiding severe complications (1).
Wilson's disease appears to be rare in liver diseases of childhood, but the availability of an efficient treatment makes its identification crucial. Reports usually include mostly adults (2-4), with more advanced disease, which could have implications in clinical description and usefulness of diagnostic methods, i.e., Kayser-Fleischer ring and liver copper stains.
To emphasize the special features of WD in its initial stages, we conducted a retrospective review of clinical and laboratory data of 26 affected children.
PATIENTS AND METHODS
Clinical and laboratory data of 26 children with diagnosed WD from 1982 to 1996 were reviewed. Twenty-four had been referred to the Children's Hepatology Unit from the reference area or from other hospitals. The remaining 2 children were studied because of positive family history of WD. Eleven of them (42%) were girls and 15 (58%) were boys. Mean age at first medical visit was 9.8 ± 3.4 years (range, 4-16 years).
Hepatic dysfunction led to performance of laboratory tests to exclude WD as a routine procedure, once autoimmune and viral hepatitis had been ruled out. Chronic cholestatic childhood diseases and α1-antitrypsin deficiency were also excluded. To evaluate copper metabolism, serum concentrations of ceruloplasmin (normal range, 20-40 mg/dl; level in WD, <15 mg/dl) and copper (normal level, >90 µg/dl; level in WD, <90 µg/dl) were measured, and 24-hour urinary copper excretion (normal level, <40 µg per day; level in WD, >100 µg per day) was determined. Serum and urinary copper concentrations were measured by atomic absorbance spectroscopy and ceruloplasmin by nephelometry. The presence of Kayser-Fleischer ring was investigated in 17 patients by slit lamp.
Transaminases, bilirubin, and cholinesterase were measured in all children by a standard test (Hitachi, Tokyo Japan). Laboratory data of hepatic failure was defined as prothrombin activity below 50%. Histologic study was performed in all but two patients, who had severe clotting abnormalities and insufficient sample.
Patients were considered to have WD if the following criteria were met: the alteration of two or more copper metabolism test results; or the alteration of one copper metabolism test result combined with any of the following: positive rubeanic acid or orcein stain or hepatic copper concentration of more than 200 µg/g dry weight, excluding other causes that can justify an increased liver copper content.
All patients but one were treated with oral penicillamine at a dose of 20 mg/kg per day in four daily doses (maximum daily dose 1 g). Penicillamine caused severe toxicity in one patient and was replaced by trientine. Four children required liver transplants because of hepatic failure. Three of them had received penicillamine for 12, 45, and 70 days.
None of the 26 patients was lost to follow-up, with a mean follow-up of 4.5 ± 3.3 years (range, 1 month-14 years). The comparison of baseline values was performed using the Mann-Whitney test.
The most common reason to consult our department were abnormalities in results of liver blood tests, which were performed because of nonspecific symptoms in 11 patients (42%), or as a routine procedure in 5 patients (19%). This was followed in frequency by: symptoms of hepatic disease in 7 children (27%) and neurologic symptoms in 1 (4%). The 2 remaining children (8%) were siblings of patients with diagnosed disease and were studied in a family screening; 1 of them was asymptomatic and the other had nonspecific symptoms. Asthenia, anorexia, arthralgia, headache, abdominal pain, nausea, vomiting, low-grade fever, polydipsia, and polaquiuria were considered to be nonspecific symptoms. Hepatopathy manifested as epistaxis, jaundice, hepatosplenomegaly, and ascites. Only one patient had initial neuropsychiatric symptoms at the age of 13 (tremor, rigidity, ataxic gait, antisocial behavior).
Hepatomegaly was found in 13 patients (50%); in 6 (33%) of 18 patients with no or nonspecific symptoms (less than 2.5 cm in all of them), in 6 (85%) of 7 children with symptoms of hepatopathy, and in the patient with neurologic symptoms.
The presence of Kayser-Fleischer ring was investigated in 17 patients and was found in only 3 (19%), ages 7, 12, and 15. None had neuropsychiatric symptoms, but all had severe liver disease: Two had chronic, active hepatitis and the third cirrhosis with subacute hepatic failure.
Two children, ages 9 and 11, had slight, compensated hemolysis at the time of diagnosis. Three patients had renal tubular dysfunction: Two had only hypophosphoremia and hypouricemia, and the third had Fanconi syndrome. All had laboratory data indicative of hepatic failure.
Serum α1-antitrypsin levels were normal in all patients. Antibodies related to autoimmune hepatitis and serologic testing of hepatitis B and C were negative in all subjects.
Results of liver function tests are shown in Table 1. As shown, laboratory and histologic involvement and liver copper concentrations were higher in the group of patients with symptoms of liver disease. There were data indicating hepatic failure (clotting abnormalities) in 7 patients (27%), increased transaminases in 18 (69%), and increased bilirubin with a normal alanine aminotransferase level in one patient (4%).
Total serum copper was low in 21 children (81%), urinary copper excretion was high in 21 (81%), and ceruloplasmin concentration was less than 15 mg/dl in 23 (88%). All copper metabolism test results showed impairment in 62% of patients, two in 27%, and one in 11%. This last group consisted of 3 patients, all of whom had increased 24-hour copper excretion and cirrhosis; liver copper had increased in 2 patients (1445 and 6313 µg/g) and orcein and rubeanic stains were positive in the remaining one.
All copper metabolism test results showed impairment in 13 (72%) of 18 children with no or nonspecific symptoms. Two test findings were abnormal in the other 5 patients (28%), with all of them showing compatible histologic findings; liver copper content was additionally measured and had increased in 1 patient.
Histologic findings were portal fibrosis with steatosis in 7 children (29%), cirrhosis in 5 (21%), portal fibrosis in 5 (21%), lesions compatible with chronic active hepatitis in 3 (12%), and minimal lesions or normal histologic results in 4 (17%). Rubeanic acid stain was positive in 3 (20%) of 15 patients, and orcein stain in 2 (11%) out 19. Copper concentration in the liver was measured in 8 patients and showed a median value of 750 µg/g dry weight (range, 256-6313 µg/g dry weight). Rubeanic acid stain was negative in 7 of the 8 patients in whom liver copper content was quantified.
Effect of Treatment
All but one patient, who required an emergency liver transplant, received treatment with penicillamine at a dose of 20 mg/kg per day. Tolerance was generally good. Slight adverse effects occurred in three patients: thrombocytopenia, which resolved with oral prednisone in one, and dermopathy in two. Penicillamine was replaced by trientine in one patient, in whom severe toxicity developed (a lupuslike syndrome).
The mean time after beginning therapy until the normalization of hepatic function was 12 ± 6 months (range, 6 months-1.8 years). Five patients had liver dysfunction with alanine aminotransferase values more than 100 U/L, which may have been because of the short duration of therapy (less than 1 year) in four of them. Liver function tests at the end of follow-up are detailed in Table 2.
Three patients with liver failure had recovered after 1 year of treatment. Four children required liver transplantation. In two of them the indication was massive gastrointestinal bleeding: one of these two had been treated for 12 days with penicillamine; disease was diagnosed in the other after transplantation, by means of quantification of liver copper content in the removed liver. The two remaining children underwent transplantation because of the persistence of liver failure after 45 and 70 days of treatment. The condition of the liver grafts is good in all of them.
In our pediatric series, we found two special features, in contrast to other series that include adults: First, most children had no or nonspecific symptoms at the moment of diagnosis; second, hepatic forms were largely overrepresented. Therefore, if a chronic liver enzyme impairment was found, the possibility of WD had to be taken into account, even if the child was doing well clinically.
Thus, the most common form in children was hepatic (96% in our series). In one patient (4%) the initial clinical manifestation was neuropsychiatric. A total of 11.5% had renal tubulopathy and 8% hemolysis in addition to severe hepatic disease. The hepatic manifestation in our series was even higher than that reported by other investigators: 83% in patients younger than 10 years and 52% in patients aged between 10 and 18 years, according to the combined data of Walshe and Scheinberg summarized by Sokol (1). Moreover, it is much higher than in the series that included adults (29-67%) (1). The absolute predominance of hepatic involvement was not caused by the possible bias of our department's being a hepatology unit, because there are no other cases of WD in the neurology unit in Children's Hospital.
Most children had no (23%) or nonspecific (46%) symptoms at the time of diagnosis. In series published in the past few years (2-7), 18% of patients (41 of 230) were asymptomatic and disease was diagnosed in 34% of them during family screening of a patient. Therefore, a high index of suspicion is required. It is important to investigate, among others, copper metabolism if a chronic transaminase elevation is found.
No copper biochemical marker is 100% sensitive or specific, and both serum ceruloplasmin and 24-hour urine excretion should be used as a screening procedure. Ceruloplasmin levels in three patients of our series with cirrhosis and jaundice were normal, probably because it is an acute-phase reactant (8). Low ceruloplasmin concentrations may be found in patients with protein deficiency of any cause (9-11), in normal neonates (12), in patients with hypoceruloplasminemia (13), and in 10% to 20% of people heterozygous for WD (14). False-positive and false-negative results of 24-hour urine copper excretion have also been reported (11,15); specificity can be improved when excretion is measured after a penicillamine challenge (16,17). As shown in Table 1, total serum copper level showed no advantage as a screening tool over the determination of serum ceruloplasmin in our series, and probably only reflects that the ceruloplasmin fraction was decreased. Total serum copper represents the copper contained in ceruloplasmin and the nonceruloplasmin (free) fraction (18).
Serum free-copper concentration has also been proposed as a diagnostic tool (8), as has the rate of incorporation of radiolabeled copper into ceruloplasmin, which is particularly useful in patients with normal serum ceruloplasmin levels (18-20). Genetic diagnosis will probably become more important; the gene has already been isolated and characterized (21-24).
The usefulness of Kayser-Fleischer rings in childhood is limited. They were present in only three of our patients, all of whom had severe liver disease. Kayser-Fleischer rings are invariably seen in patients with neurologic manifestations of WD, but they may be absent in patients with less extrahepatic involvement (1,25).
Liver biopsy is mandatory in childhood to elucidate the nature and severity of the disease. Orcein and rubeanic acid stains are less sensitive in childhood. Hepatic copper quantification is considered the gold standard, and other diseases with copper overload (i.e., longstanding cholestasis and Indian childhood cirrhosis) can be easily excluded on clinical grounds (25). In people homozygous for WD, the hepatic copper concentration is in excess of 250 µg/g dry tissue, whereas this value is not exceeded in heterozygotes (26). Even though the copper is not uniformly distributed in the liver (27), the range of hepatic copper concentrations encountered in asymptomatic homozygotes is far above the upper limit of that of heterozygous carriers (26).
The natural evolution of the disease without treatment is always fatal (1,28,29). The efficacy of penicillamine is well established. Its mode of effect is both detoxifying and decoppering (30-35). Repair of hepatic function took the same time as that reported by other researchers (36). Recovery is also good in patients with uncomplicated liver failure, in accordance with results in most series, even if cirrhosis persists (28,36). Nazer et al. (37) proposed a prognostic index based on abnormality of serum aspartate aminotransferase, bilirubin, and prothrombin time on admission, which enabled complete separation of fatal and nonfatal cases. One of our patients, who recovered with medical treatment, had a score within the fatal range (jaundice with serum bilurubin of 6.5 mg/dl, serum aspartate transferase more than 300 U/L, and severe clotting abnormalities with prothrombin activity of 29%). Thus, it is possible to avoid a premature liver transplantation in patients who show good compliance, even if clotting abnormalities persist during the first year of therapy. Liver transplantation, which normalizes copper metabolism (38), would remain as a possibility for intolerable complications during the time the liver takes to recover its function.
Adverse effects of penicillamine include: worsening of neurologic symptoms in patients who initially manifest neurologic disease; initial hypersensitivity that can result in fever, rash and adenopathy; bone marrow depression; proteinuria; abnormal scar formation; and autoimmune disorders (30,36). Tolerance of penicillamine in our series was good. We observed a smaller percentage of patients with adverse effects (11.5%) than did other investigators (25-32%) (7,8), which is perhaps because of gradual introduction and slow increase of the dose or because of better tolerance in childhood. The slight adverse effects observed disappeared after temporary therapy with prednisone. Severe side effects occurred in one patient. The condition of the patient who had initial neurologic symptoms did not worsen and subsequent progress was satisfactory. Monitoring of renal status and blood cell count every three months is advisable (5).
In conclusion, with a high index of suspicion of liver disease, WD was detected in our series of children who had no or nonspecific symptoms. Drug therapy was effective-even in some cases of hepatic insufficiency-and was well tolerated.
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