Introduction

 Wilson disease (W. D.) is a progressive hepatolenticular disease , and actually it  is a genetic condition in which copper is  accumulated in some tissues(1).This   disease  may  be presented  as fulminant hepatic failure (coagulopathy, coombs negative  haemolitic  anemia and encephalo -pathy) in about 5% of cases.

The symptoms of chronic liver disease may be in the form of Spider angioma ,  portal hypertention, ascites and splenomegaly(2).

Young patients with unexplained chronic liver disease, with or without cirrhosis, should be screened for W.D(1).

 Chronic active hepatitis may cause liver cirrhosis, but unlike the other causes in which cirrhosis increases the risk of hepatocellular carcinoma ,this risk  is very low about the WD(3). 50 % of patients have psychological and neurologic symptoms of WD(4).

Ophthalmic findings include Kaiser-flesher (KF) ring and cataract which both are curable after pharmaceutical treatments and liver transplantation (5).

Hypoparathyroidism , tubular acidosis, cardiomyopathy, infertility and abortion are rare symptoms of WD(6). WD may be detected based on the occurrence of any of the foregoing symptoms or when close relatives are involved. In General, there is no a specific test for WD.

Most of the times, a slight increase in the level of the liver enzyme, and bilirubin is seen. If the damage of hepatic cells be severe, low level of albumin and long PT would be present.

 Serum ceruloplasmin  concentrations of less than 200 mg/L are considered roughly equivalent with WD and its association  with KF ring confirms diagnosis(1).

 The 24-hour Urinary secretion of copper more than 100 µg is suggestive for WD (7).Because interpretation of 24-hour urine copper secretion test is difficult and the results obtained from a variety of liver diseases are overlapped, a D-penicillamine challenge test is used in children. Urinary copper secretion more than 1,600 µg /24-hour is considered as a diagnostic test in the WD in children (7(.

 The gold standard diagnostic test for WD is liver biopsy, in which the amount of copper is over 250µg/g dried liver tissue (7).

The drugs used in the treatment of Wilson disease include copper-binding agents, drugs enhancing the urinary excretion of copper and zinc salts.

Patients and Methods:

This study was a case series study, Inwhich all patients with Wilson disease who admitted during the years 2003-2012 in the children's Medical Center were included. The Census sampling was performed ,so it was not necessary  to determine the sample size. Given that the information was extracted from the patients ' records and the name and other information would remain confidential, informed consent of the parents was not necessary. Statistical analysis of the data was performed using SPSS 16 software.

Results:

In this study 62 child who admitted during the years 2012- 2003 in children's Medical Center with the Wilson disease diagnosis were included. 35 cases (56.5%) Patients were male and 27 patients (43.5%) were female. The average age of the patients  at the time of diagnosis was 9.73±2.35 years(5-17 years).This average in patients with hepatic and neurologic involvement was 9.30±2.58 and 11.14±1.34 years respectively, that no significant differences was observed. (p=0.085)

The main manifestation of the disease at the time of diagnosis

At the time of diagnosis, 36 patients (58%) had only hepatic involvement and 7 patients (11.3%) had only neurologic symptoms. 8 patients (12.9%) were presented with combined neurologic and hepatic symptoms:4 patients presented with neurologic symptoms first, and then  the hepatic symptoms occurred, in 3 patients hepatic involvement was occurred before neurologic symptoms, and one patient had simultaneous hepatic- neurologic involvement.

Wilson's disease were diagnosed in a patient following an accidental detection of abnormalities in the patient's liver enzymes and in 5 patients (8%) by screening  because of positive family history of disease in one of the siblings. Five patients (8%) also at the time of Wilson's disease diagnosis had other symptoms.

 KF ring were seen during ophthalmologic examination of 46 patients (74.2%).The frequency of the occurrence of this sign in patients with primary hepatic and neurologic involvement was 76.9% &81.8% ,respectively.

17 patients (27.4%) had a positive family history for Wilson's disease.

The frequency of various clinical patterns of hepatic involvement in 40 patients with primary hepatic involvement was as follows:

      -hepatic cirrhosis: 22 patients (35.48%)

      -fulminant   hepatic failure:8 patients (12.9%)

       -acute hepatitis: 6 patients (9.67%)

       -chronic liver disease: 3 patients (4.83%)

        -isolated abnormal liver tests: 1 patient(1.61%)

The frequency of a variety of neurological symptoms and signs in 11 patients with primary neurologic involvement: was as follows:

-disartria and movement disorders: 4 patients (6.45%)

- isolated movement disorders:2 patients (3.2%)

- Seizures: 2 patients (3.2%)

-movement disorders& migraine headaches& disartria:1 patient (1.6%)

-seizure and migraine headaches: 1 patient (1.6%)

-pseudobulbar paralysis: 1 patient (1.6%)

Totally, the most common symptoms in this group of patients was movement disorders (11.49%).

Finally, in one patient simultaneous primary neurologic and hepatic involvement was seen in which clinical pattern involved fulminant hepatitis, pseudobulbar paralysis and tremor.

In 4 patients (6.5%), liver transplantation was performed that 2 patients died after liver transplant. During the study, 14 patients died of disease:  11 patients belonged to the ((primary hepatic involvement)) group, 1 patient to ((primary neurologic involvement)) group, and the last two  patients had combined primary hepatic & neurologic involvement. The cause of death was hepatic encephalopathy in 57% of patients.

Type of drugs used to treat the patients and treatment side effects:

52 patients (83.9%) Treated with D-Penicillamine ,4 patients (6.5%) initially treated with D-Penicillamine  that because of the lack of recovery later changed them to Trientine. In one patient, treatment with Trientine began, a patient undergone liver transplantation as first treatment and for one patient treatment included ursodeoxycholic acid & zinc salts. Data about how to treat 3 patients (4.8%) was not available.

In 36 cases (73.1%) treated with D-penicillamine , no complication occurred, in  6 patients (11.5%)  haematuria  was seen,7 patients (13.4%) experienced bone marrow suppression and one patients(1.9%) presented with nephrotic syndrome as treatment complication. Two patients (3.8%) had skin lesions like pemphigoid.

Discussion:

 Wilson disease (W. D.) is a progressive hepatolenticular disease , and actually it  is a genetic condition in which copper is  accumulated in some tissues(1).

In our study, 40 patients (64.51%) had primary hepatic involvement at the time of diagnosis ,but  in three of them, neurologic symptoms also presented later. The most common form of hepatic involvement was cirrhosis (36%) And  fulminant hepatitis (12.9%) respectively.

 In 40 years follow-upping of 36 patients with Wilson disease in Brazil, the frequency of the primary organ involvement was as follows: hepatic (38.9%), neurologic (25%) and combined hepatic-neurologic(30.6%) (12).

In a study  by Tatsumity and colleagues in 2007 on 30 Japanese patient with Wilson disease, the first manifestation of the disease was hepatic (61%) and neurologic(13%),respectively(13).In another study by Asadi et al in 2005 on 111 Iranian patients,the initial manifestation of the disease was  hepatic in 83.8%  and neurologic in 24.3% of patients (14).In a study  by  Walter Oder on 45 patients with Wilson disease  in 2005, the primary involved organs were liver( 60% ) and nervous system(26%) ,respectively(15).

 Generally, the most common primary symptoms/signs in children with Wilson disease is hepatic, our study also confirms this.

In our study, the average age of the patients at the time of diagnosis was 9.3 & 11.9 years in (primary hepatic involvement group) and (primary neurologic involvement group), respectively, in which this difference was not significant (p=0.85).  

In one study by Merteu et al in 2007, the average age of the patients at the time of diagnosis was 15.7 years in cases with primary hepatic presentations and 20.2 years in patients with primary neurologic manifestations, but there was no significant difference between two groups (16).

74.2 percent of our patients at the time of diagnosis were KF positive. This frequency was higher in patients with primary neurologic presentation (81%) than those with primary hepatic involvement (77%).

In a study conducted in Brazil on 36 patients, 55 percent of patients were KF positive that this frequency was higher in patients who have neurological involvement (77.8%)(12).

In another study in 2007 on 163 German patients ,KF ring was observed in 66% of them(16).Totally, our study and other similar studies suggest that  more than half of the patients were KF positive at the time of  diagnosis and this sign is more common in patients with neurological involvement.

A positive family history of Wilson disease was reported in 27% of our patients. In a similar study by Asadi and his colleagues on the 111 Iranian patients, 36% of patients have a family history of the disease, which is partially similar to our patients group (14).

In our study, 83.8% of patients were treated with D-Penicillamine , but adverse drug reactions were seen in  30% of cases.

In a study conducted in Brazil in , 94% of patients were treated with D-Penicillamine  and in  78% of the cases, primary clinical response to therapy were seen, so this results had not significant difference when compared with our study. In a study conducted by Merteu and his colleagues, the adverse drug reactions were seen in 74% of patients treated with D-Penicillamine, which was higher than our study (16).

 This difference may be due to the difference in genetic aspects, in population size, or the quality of the drugs.

Conclusion

 Considering that the most common initial manifestation of the Wilson disease was hepatic in our study and the majority of other studies, this condition should be excluded in each patient with unexplained hepatic symptoms. Family members of patients with Wilson disease should be screened for this disease. Also, in patients with unexplained Neurologic symptoms, particularly movement disorders, Wilson disease should not be neglected.

Although the side effects of D-Penicillamine  is  more than Trientine, but also with respect to the low cost and availability of  the former drug, D-Penicillamine is a good choice for the treatment of Wilson's disease.

Of course, regular CBC and U/A tests may be helpful in early detection of serious side effects of this drug.

Ethical considerations and limitations

This study was approved by the Ethics Committee of Tehran University of Medical Sciences. In our non-interventional study, the principle of confidentiality was considered.

 Some of the records in the patients files were incomplete and we had no access to some patients, but these had no significant effect on study results.

Acknowledgements

The authors would like to thank all medical staff of pediatric gastroenterology ward and employees of the ward of medical records   of Children’s Medical Center and W.D patients and their families because of their cooperation to do this study.