Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?

Abstract

Objectives: 

The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome.

Methods: 

We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg · kg⁻¹ · day⁻¹.

Results: 

Median follow-up was 60 (5–60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01–6.95) at baseline to 0.62 (0.01–4.57) μmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8–9.6) μmol/day approximating the therapeutic goal of 1.6 μmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).

Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg · kg⁻¹ · day⁻¹, median follow-up 60 [9–60] months), whereas in group 2 (>20 mg · kg⁻¹ · day⁻¹, median follow-up 60 [14–60] months), it was 63.6%.

Conclusions: 

TD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg · kg⁻¹ · day⁻¹ may increase the rate of adverse effects in pediatric patients.

What Is Known/What Is New

What Is Known

• Wilson disease is a rare autosomal-recessive disorder that impairs copper metabolism, and early therapy is necessary to prevent severe lifelong complications.
• Current guidelines recommend the use of D-penicillamine or trientine-dihydrochloride as first-line treatment of Wilson disease.
• Pediatric dosage recommendations for trientine-dihydrochloride to avoid side effects are vague in the current guidelines.

What is new?

• Trientine-dihydrochloride proves to be an efficacious and safe alternative chelating agent for children and adolescents with Wilson disease even for long-term treatment.
• Weight-based doses above the recommended 20 mg · kg⁻¹ · day⁻¹ do not achieve a better outcome but increase the rate of adverse effects in pediatric patients.

Wilson disease (WD) is a rare autosomal-recessive disorder that impairs copper metabolism. The disease is caused by various mutations in the adenosine triphosphatase (ATP) 7B gene that codes for a copper transporting ATPase. Dysfunction of the ATPase leads to decreased copper excretion via biliar system and defective incorporation of copper into ceruloplasmin ⁽¹⁾. Copper subsequently accumulates in the body, especially in liver and brain. In patients with WD, early lifelong therapy is necessary to maintain control of the clinical and biochemical status and to prevent severe lifelong complications.

Current guidelines recommend the use of chelating agents (D-penicillamine [DPA] or trientine-dihydrochloride [TD]) as first-line treatment of WD ⁽²⁾. Introduced in 1969, TD was approved as second-line treatment in patients intolerant to DPA ^(3,4). Several studies described similar efficacy of both chelating agents. Adverse effects were reported less frequently for TD therapy than under DPA-therapy ^(5–7). Dosage recommendations are vague in current guidelines and there are only a few publications on treatment strategies for pediatric patients ^(2,8,9). The issue of TD therapy in children has become very important as the usage of TD has risen among Western pediatric hepatologists ⁽¹⁰⁾. Still, studies on long-term data providing evidence for weight-based dosage strategies are not available but are needed to prevent therapy failure or overdosage in children ⁽¹¹⁾.

Therefore, in this study, we have focused on TD therapy in pediatric patients. The aim was to investigate the efficacy of TD, whether different weight-related dosage patterns influence the clinical and biochemical outcome as well as side effects, and thus to find an approach for an optimal dosage.

METHODS

Out of 85 pediatric patients with WD, we were able to include 31 (36.5%) in the present study. These patients met the inclusion criteria with confirmed diagnosis of WD, age <18 years and TD as first- or second-line therapy. Apart from 2 patients who were cared for in Vienna, all others are cared for in Heidelberg. The diagnosis of WD was reviewed using the Leipzig score according to the guidelines of the European and American Association for the Study of the Liver (EASL/AASLD) ^(2,12,13). Diagnosis was confirmed with a Leipzig score of >3.

All data were collected retrospectively from the original medical records of our centers. Baseline data were collected at the beginning of primary therapy and included sex, age at diagnosis, manifestation of first symptoms and initiation of treatment as well as the presence of hepatic or neurologic symptoms, presence of Kayser-Fleischer rings, liver fibrosis or cirrhosis, liver copper content, and ATP7B mutational analysis.

Follow-up examinations were performed 1, 3, 6, and every 12 months after the initiation of TD therapy over a period of 60 months. At each point weight, laboratory results, drug dosage and adverse effects were recorded. In order to examine the efficacy of treatment various laboratory parameters indicating therapy success or failure were assessed. Among these, we examined parameters of copper metabolism, such as 24-h-urinary copper excretion, photometric measured serum ceruloplasmin levels, serum copper concentration, and nonceruloplasmin-bound copper (NCC; “free-copper”). Moreover, liver function parameters (alanine-aminotransferase [ALT], aspartat-aminotransferase [AST], gamma-glutamyl- transferase [GGT], albumin, international ratio [INR], total bilirubin, and platelets), white blood cells [WBC], hemoglobin [Hb], and creatinine were assessed to monitor outcome and safety of therapy ^(14,15).

The mean weight-based dose applied per day was recorded during the whole observation period. When calculating the mean weight-based dose per day the latest recorded dose and measure of body weight were used, respectively. With this information, we were then able to divide the study population into 2 groups for further investigations. As a cut-off, 20 mg · kg⁻¹ · day⁻¹ TD was taken, which corresponded to the current Clinical Practice Guideline ⁽²⁾ dosage recommendation of TD.

Graphs were created using Excel 2016 for Windows software version 16. Statistical analyses were performed with SPSS Statistics for Windows software version 24.0 (IBM, Chicago, IL). P-value was calculated using Student's t, Mann-Whitney U, Wilcoxon signed-rank and chi-squared test whenever appropriate and was considered significant when under 0.05. Results were pooled for statistical analysis when data were not available for single parameters at certain follow-up points. Results are expressed as median and range.

The study was performed in accordance with the principles of the Declaration of Helsinki and protocol was approved by the ethical review committee of the medical faculty of Heidelberg University (Nummer S-319/2010).

RESULTS

The study population consisted of 31 pediatric patients who received TD as first- or second-line therapy under the age of 18 years. Characteristics of study population, diagnosis, and treatment course is shown in Table 1. Once diagnosis was confirmed, chelation treatment was started. Twenty-five had slightly elevated transaminases as the only symptom at the initiation of treatment. One presented purely neurological symptoms with dysarthria and tremor. Neurological symptoms improved over time. The remaining 5 patients had both neurological and hepatic symptoms. Two of them suffered from hepatic failure (New Wilson Index =9). Both recovered under TD therapy.

TABLE 1 - Characteristics of total study population, group 1 (<20 mg/kg trientine-dihydrochloride) and group 2 (>20 mg/kg trientine-dihydrochloride)

	Study population		Group 1 (< 20 mg/kg TD)		Group 2 (> 20 mg/kg TD)		Group 1+2
Characteristics	Total n	n (%) | median (range)	Total n	n (%) | median (range)	Total n	n (%) | median (range)	P value
Sex	n = 31		n = 15		n = 11		0.614
Male		11 (35.5%)		4 (26.7%)		4 (36.4%)
Female		20 (64.5%)		11 (73.3%)		7 (63.6%)
Age at diagnosis, years	n = 31	11.07 (3.45–17.82)	n = 15	13.59 (3.45–17.82)	n = 11	7.96 (3.53–14.8)	0.051
Time from initial symptoms to diagnosis, years	n = 28	0.46 (0.0–9.95)	n = 13	0.26 (0.0–9.95)	n = 11	0.49 (0.0–1.0)	0.126
Initial presentation	n = 31		n = 15		n = 11		0.747
Hepatic		25 (80.6%)		13 (86.7%)		9 (81.8%)
Neurologic		1 (3.2%)		0 (0%)		0 (0%)
Mixed		5 (16.1%)		2 (13.3%)		2 (18.2%)
Kayser-Fleischer ring	n = 31	6 (19.4%)	n = 15	2 (14.3%)	n = 11	1 (9.1%)	0.706
Liver copper, μg/g	n = 18	1052 (215–1556)	n = 9	684 (215–1280)	n = 7	1333 (570–1556)	0.047
Cirrhosis	n = 31	6 (19.4%)	n = 15	4 (33.3%)	n = 11	1 (12.5%)	0.317
ATP7B genotype	n = 29		n = 14		n = 11		0.800
Homozygous		5 (17%)		3 (21%)		2 (18%)
Comp. – hetero.		16 (55%)		8 (58%)		4 (36%)
Heterozygous		8 (28%)		3 (21%)		5 (46%)
First-line therapy	n = 31		n = 15		n = 11		0.393
DPA		26 (83.9%)		13 (86.7%)		8 (72.7%)
TD		5 (16.1%)		2 (13.3%)		3 (27.3%)
Duration of DPA therapy, years	n = 26	1.88 (0.05–12.61)	n = 13	1.97 (0.05–6.79)	n = 8	1.9 (0.44–12.61)	0.438
Adverse effects because of DPA	n = 26	24 (92.3%)	n = 13	12 (92.3%)	n = 8	8 (100%)	0.447
Reason for discontinuation of DPA	n = 26		n = 13		n = 8		0.447
Adverse effects		24 (92.3%)		12 (92.3%)		8 (100%)
Therapy failure		1 (3.8%)		0 (0%)		0 (0%)
Reason unknown		1 (3.8%)		1 (7.7%)		0 (0%)
Discontinuation of TD	n = 31	7 (22.6%)	n = 15	3 (20%)	n = 11	2 (18.2%)	0.912
Adverse effects because of TD	n = 31	10 (32.3%)	n = 15	1 (6.7%)	n = 11	7 (63.6%)	0.001
Reason for discontinuation of TD	n = 7		n = 3		n = 2		0.219
Adverse effects		4 (57.1%)		1 (33.3%)		2 (100%)
On demand		3 (42.9%)		2 (66.7%)		0 (0%)
Concomitant zinc therapy	n = 31	7 (22.6%)	n = 15	3 (20%)	n = 11	2 (18.2%)	0.912
Median TD dosage T0–60, mg · kg−1 · day−1	n = 26	18.91 (8.82–35.64)	n = 15	16.93 (8.82–19.66)	n = 11	24.46 (21.2–35.64)	<0.001

% = percent; comp.-hetero. = compound-heterozygous; DPA = D-penicillamine; n = number; TD = trientine-dihydrochloride.

D-penicillamine Treatment

Of the 31 children included, 26 (83.9%) children received DPA as first-line treatment. The change to TD occurred after a median time of 1.88 (0.05--12.61) years. In our cohort, the main reason for discontinuation of DPA was severe adverse events in 24 (92.3%) patients (Table, Supplemental Digital Content, https://links.lww.com/MPG/B922). In all of them, before the change of therapy, an initial attempt was made to reduce the DPA dose and thereby reduce the adverse events. In the remaining 2 patients, the therapy was changed in 1 case because of a lack of therapy response and in the other, the reason for the change was not clearly documented. In 21 patients (80.8%) the side effects disappeared after switching to TD. Three of them, however, continued to suffer from the same side effects (ulcerative colitis; gingival and breast hypertrophy; elevation of transaminases) as under DPA therapy, albeit less intense.

Trientine-dihydrochloride Treatment

In this study population, TD was mainly used as second-line drug following DPA therapy, as previously recommended in the EASL guideline. In 5 patients (16.1%), TD was used as first-line therapy. In 3 of them, it was the clear wish of the parents. Another patient already had a limited synthesis capacity and high bilirubin at the time of diagnosis, so that the treated physicians decided to use TD together with his parents. In the case of the last one, it was a joint decision after detailed discussion of the advantages and disadvantages. These patients presented with higher levels of transaminases and NCC at the beginning of TD therapy in comparison with those receiving TD as second-line treatment. The pre-treatment with DPA had already resulted in a decrease in transaminases. Laboratory parameters did not differ between the groups over the course of treatment.

Concomitant Zinc Therapy

Seven children (22.6%) received zinc medication in addition to their treatment with TD. In 2 patients, it was the wish of the parents. In 3 patients, the additional zinc therapy was carried out in the context of an intermittent increase in transaminases and was left in therapy after normalization. For 2 patients, we are unfortunately unable to name the reason as the reason was not clearly documented. Clinical outcome and laboratory results showed no remarkable differences compared with TD monotherapy during the whole observation period.

Liver Function Tests

No significant difference in the overall group was measured for the laboratory parameters either, with clear improvement in the pathological values in individual patients. Only albumin showed a significant increase for the median of the whole group (P = 0.028) (Table 2).

TABLE 2 - Biochemical parameters and copper metabolic parameters at initiation, after 24 and 60 months of trientine therapy of study population

Parameter	No∗	Baseline median (range)	24 months median (range)	60 months median (range)	P value† baseline 60 months
AST, U/L	24	28 (8–168)	29 (17–68)	31 (16–69)	0.131
ALT, U/L	24	31 (8–371)	37 (10–151)	42 (18–203)	0.516
GGT, U/L	24	30 (6–122)	22 (8–59)	26 (11–87)	0.299
Bilirubin, U/L	22	0.40 (0.13–10.6)	0.48 (0.20–1.00)	0.43 (0.2–1.3)	0.344
Creatinine, mg/dL	22	0.60 (0.33–1)	0.63 (0.13–1.03)	0.63 (0.35–1.04)	0.566
Albumin, g/L	22	43.1 (27–49)	45 (35–51.9)	46.2 (41–52.9)	0.028
INR	20	1.01 (0.9–2)	1.03 (0.95–1.50)	1.04 (0.95–1.11)	0.248
WBC, 109/L/nL	23	6.01 (3.25–16.4)	5.86 (3.92–10.90)	6.23 (4–10.4)	0.497
Hb, g/dL	23	13.1 (6.2–15.6)	12.9 (11.4–15.7)	12.9 (11.4–15.4)	0.267
Platelets, 109/L/nL	23	258 (104–514)	253 (108–385)	253 (163–425)	0.809
Ceruloplasmin, g/L	19	0.09 (0.01–0.2)	0.10 (0.02–0.23)	0.08 (0.02–0.17)	0.196
Serum copper, μmol/L	18	6.97 (1.9–10)	5.0 (0.8–11.9)	4 (1.5–9.8)	0.017
NCC, μmol/L	18	1.53 (0.01–6.95)	0.89 (0.01–3.084)	0.62 (0.01–4.57)	0.289
Urinary copper excretion, μmol/day	22	2.97 (0.36–187.2)	1.94 (0.86–6.03)	1.85 (0.8–9.6)	0.322

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transferase; Hb = hemoglobin; INR = international normalized ratio; n = number; NCC = nonceruloplasmin-bound copper; WBC = white blood cells.

^∗Data was not available for all patients at all times.

^†P-value was obtained using paired sample t-test, only paired values were included in the statistical calculation.

Copper Metabolic Parameters

The probably most important parameter for monitoring chelation therapy is the 24-h-urinary copper excretion ^(16,17). The median copper excretion could be reduced from an initial 2.97 (0.36–187.2) μmol/day to a median of 1.85 (0.8–9.6) μmol/day after 60 months. Thus, the therapeutic goal of <1.6 μmol/day ⁽²⁾ could be almost reached. The decrease goes along with a simultaneous reduction of the body's copper load. NCC decreased by around 60%, indicating the efficacy of TD therapy (Table 2).

Trientine-dihydrochloride Safety

Median follow-up in the overall cohort was 60 (5–60) months. Under therapy with TD only, 10 patients (32.3%) reported adverse effects (Table 3). Among these, the most frequent was an elevation of transaminases (n = 3/10), which remained clinically silent with a common terminology criteria for adverse events (CTCAE) grade 1. Neurologic deterioration was found in 2 patients after the starting of TD. In patient #21, neurologic symptoms (dysarthria, ataxia) initially worsened. Patient #26 developed neurologic symptoms (cognitive impairment) de novo. Both patients, however, improved over time, and treatment with TD could be continued. Therapy with TD was discontinued in 7 (22.6%) patients. In 4 cases, therapy was terminated because of adverse effects (#12; #16; #23; #31) and therapy was continued with zinc, which was possible because of normal liver enzymes and good 24-h-urinary copper excretion. In 3 cases, TD was terminated at the request of the patients. Two of them were further treated with zinc and 1 again with DPA.

TABLE 3 - Adverse effects during trientine therapy

Patient	Adverse effects	CTCAE grade	Discontinuation because of AE	Group
No. 12	Ulcerative colitis	2	Y	1
No. 16	Gingival hypertrophy, breast hypertrophy	2	Y	2
No. 18	Arthralgia, elevation of ANA-titer	1	N	2
No. 19	Elevation of transaminases	1	N	2
No. 21	Dysarthria, ataxia†	2	N	2
No. 23	Elevation of transaminases	1	Y	2
No. 25	Elevation of transaminases	1	N	2
No. 26	Initial cognitive impairment†	1	N	2
No. 28	Thrombocytopenia	1	N	–∗
No. 31	Hirsutism	2	Y	–∗

AE = adverse event; ANA = antinuclear antibody; CTCAE = common terminology criteria for adverse events.

^∗Not included in the subgroup analysis.

^†Initial deterioration, then significant improvement.

Correlation Between Weight-based Dosage and Outcome Measures

In 26 of our patients, body weight and dosage regimen were recorded at several follow-up appointments. This enabled us to perform a retrospective cohort study about the effect of weight-based dosage adjustment on the efficacy and safety of TD therapy in children with WD. Group 1 (n = 15) received less than 20 mg · kg⁻¹ · day⁻¹ at an average, group 2 (n = 11) was administered more than 20 mg · kg⁻¹ · day⁻¹ at an average. All patients fulfilled this criterion for the whole period of record; though, 1 patient in group 2 fell below the cut-off level during the whole first year of observation. With an abrupt increase of TD dose to approximately 28 mg · kg⁻¹ · day⁻¹ after 1 year, this patient reached an average weight-based dose of 23.95 g · kg⁻¹ · day⁻¹ over 60 months. As outcome measures were mainly regarded at the end of observation period, the patient was finally assigned to group 2. Median follow-up was 60 (9–60) months in group 1 (< 20 mg/kg TD) and 60 (14–60) months in group 2 (> 20 mg/kg TD).

Baseline Data of Groups 1 and 2

Groups did not differ statistically in terms of sex, median age, initial presentation form, presence of Kayser-Fleischer ring, liver cirrhosis or ATP7B genotype. Neither did they differ in the use of TD as first- or second-line treatment (Table 1). In group 1, 13 out of 15 (86.7%) patients were first medicated with DPA, and all of them were then converted to TD after a median of 1.97 (0.05–6.79) years. In group 2, 8 of 11 (72.7%) patients received DPA as primary treatment with a median time to conversion of 1.9 (0.44–12.61) years.

Liver Tests in Groups 1 and 2

None of the biochemical parameters used for examination of the course of liver function tests differed statistically between the groups before and after 60 months of treatment with TD (Fig. 1A--C). Group 2 presented with slightly higher levels of transaminases during the whole period of records. In 3 patients (27%) of group 2, elevated transaminases were described as immediate adverse reaction to the application of TD.

FIGURE 1: Median of (A) AST, (B) ALT, (C) albumin, (D) serum copper, (E) nonceruloplasmin-bound copper, (F) urinary copper excretion in group 1 (< 20 mg/kg TD) and group 2 (>20 mg/kg TD) during trientine therapy. ALT = alanine aminotransferase; AST = aspartate aminotransferase; TD = trientine-dihydrochloride.

Copper Metabolic Parameters in Groups 1 and 2

Serum copper could seemingly be reduced more effectively in group 2 with higher dosage regimen. This might have been caused by the fact that serum copper concentration was lower in group 1 compared with group 2 at the initiation of observation. The course of NCC appeared to be similar (Fig. 1D and E). A drastical decline of NCC concentration of more than 80% could be observed in group 2. Group 1 on the contrary presented with a strong initial reduction followed by a steady reincrease to 1.21 (0.01–4.57) μmol/l. 24-h-urinary copper excretions showed a similar developing in both groups (Fig. 1F).

With regard to these results, we could not prove any major advantage of different weight-based dosages for the enhancement of biochemical outcome in pediatric patients with WD (Table, SDC 2, https://links.lww.com/MPG/B923).

Weight-based Dosages and Adverse Effects

Under the aspect of weight-based dosage, a notable difference (P = 0.002) between group 1 (<20 mg/kg TD) and group 2 (>20 mg/kg TD) was observed with regard to the number of adverse effects. In group 1, only 1 of 15 (6.7%) presented serious adverse effects. In contrast, adverse effects were recorded in 7 of 11 (63.6%) children receiving more than 20 mg/kg per day. So, it could be assumed that group 2 might have been overdosed in terms of clinical safety. These patients rather tended to suffer from adverse effects than patients receiving a lower dose of TD (Table 3).

DISCUSSION

In our cohort of children with WD, TD treatment results in efficacious copper control and consequently to disease with normalized hepatic outcome measures. Recognizing the lack of controlled clinical data, the WD treatment recommendations published by the ESPGHAN-Hepatology Committee ⁽⁹⁾ on chelation therapy favor neither of the 2 chelating agents. This is because of the fact that neither chelator agent outperforms the other with a clearly better clinical outcome. There may be fewer side effects with TD. Here, we present results of a weight-based TD dosage regimen in pediatric WD patients.

In terms of genetics, compound-heterozygous or homozygous pathogenic variant could be found in 21 (72%) patients. Most often a compound-heterozygous status can be detected. In the meantime more than 800 mutations are known. In the literature, no mutation is found in up to approximately 17% of clear cut WD patients ⁽¹⁸⁾. There is unfortunately not a single test that is specific per se. In order to diagnose WD, various findings must be made and the diagnosis must be made after an algorythm (e.g. Leipzig score). It is important, however, to note that other diseases may show a similar picture. There are reports in the literature about patients with multidrug-resistant 3-Protein (MDR3) deficiency, which were initially treated like WD ^(19–22). The reported cases also had an increased 24-h-urinary copper excretion and an increased copper content in the liver biopsy. The ceroluplasmin was normal in all of them. Five percentage of WD patients also have ceruloplasmin within the normal range. Therefore, it is important to reconsider diagnosis of WD in case of missing ATP7B mutations, lack of response to therapy or progress of liver fibrosis under therapy. In our study, all patients undergoing therapy with a chelating agent showed lab value improvement and no patient showed progression of fibrosis/cirrhosis. Despite limitations, this makes the presence of an MDR3 defect unlikely.

Treatment Efficacy

In contrast to several reports in adults ^(4,5,7,23), only few retrospective studies ^(15,24) have been performed previously to examine efficacy of TD therapy in pediatric cohorts: Arnon et al ⁽¹⁵⁾ reported 10 children with elevated transaminases at the beginning of therapy with TD as first-line therapy and with a follow-up between 12 and 18 months. All patients showed a decrease in liver enzyme levels (AST/ALT) over time. In 70%, however, the transaminase levels were not normalized at the last follow-up. Taylor reported of 16 children under TD therapy, of whom only 3 receiving TD as first-line therapy. Median follow-up was 6.43 years. Again, transaminase levels decreased but did not completely normalize in all patients. In this respect, the authors discussed whether this is to be considered as mild hepatotoxicity of TD therapy. Similarly, under therapy with DPA, 33% of patients failed to normalize liver values ⁽²⁵⁾. It should be mentioned, however, that in our study, most patients had already been pretreated with DPA and this had already resulted in a decrease in transaminases. Therefore, no significant decrease could be observed during the course of therapy with TD. Also in our cohort, a normalization of transaminases could not be demonstrated in all patients. Slightly elevated values of ALT were still seen in 66.7% of cases after 60 months with TD therapy. One reason for a lack of normalization of transaminases could be low liver copper content. An association between low copper content and moderate/severe steatosis in patients with nonalcoholic fatty liver disease without metabolic syndrome was described ^(26,27). In addition Aigner et al ⁽²⁷⁾ reported that a restriction in dietary copper in rats also leads to hepatic steatosis. Thus, functional copper deficiency can cause an increase in transaminases but is then accompanied by a decrease in NCC. In our study, there was no significant difference in NCC over time. Another reason could be nonadherence, which is hard to prove.

In both reported TD studies in children ^(15,24), success of treatment was documented by normalization of transaminases and urinary copper excretion. Neither of the 2 studies included a broader selection of laboratory measures. In our study, in addition to transaminases, the courses of GGT, bilirubin, WBC, Hb, creatinine, albumin, INR, and platelets were also evaluated and reported. Concerning the stable course or even improvement of liver function tests and liver scores over the whole period, we can confirm the safe usage of TD in pediatric patients. Additionally, the results of copper metabolic parameters are providing evidence for the efficient use of TD as an alternative chelating agent.

Adverse Events

TD was once introduced as an alternative chelating agent in order to prevent an adverse clinical course and reduce severe adverse effects caused by DPA therapy ^(3,4). To date, there is no study that directly compares DPA and TD. A high number of patients with DPA develop side effects. Merle et al ⁽⁶⁾ reported in their study, side effects in 70.3% of patients. In contrast, TD is reported to have fewer side effects than DPA therapy. Nevertheless, TD could be accounted for a number of side effects in adults ^(6,28–30). In our pediatric population, similar results were reported. Ten of 31 patients (32.3%) suffered from adverse effects caused by TD. In contrast, the pediatric cohort of Arnon et al ⁽¹⁵⁾ showed no side effects. This is, however, certainly because of the small group size and short follow-up time. In our study, the TD therapy was discontinued in only 4 cases (12.9%) because of severe side effects. The rate of discontinuation previously reported in our adult cohort ⁽⁷⁾ was 7.1%. In comparison, the rate of therapy discontinuation was 4 times higher in DPA treatment. Therefore, TD was apparently better tolerated than DPA ^(3,7). It should be, however, noted that we only had a small number of patients who received TD as first-line therapy. In Germany, normally DPA is started as first-line therapy because of history, the guidelines and as TD was not automatically covered by the health insurance companies in terms of cost. This also explains why we have such a high number of patients here who primarily had DPA and then switched to TD. For further studies, it would be nice to include more patients who receive TD as first-line therapy. This might allow a direct comparison between DPA and TD.

A very important side effect of TD is iron-deficiency anemia. In our study, there was no significant difference between Hb at T0 and T60. In particular, the 3 patients with slightly lowered Hb were in the group with dose <20 mg/kg. Unfortunately, our study is a retrospective study and we cannot make a statement about iron, ferritin, or transferrin saturation. This should be considered in future research.

In view of the lower incidence of adverse effects and a lower treatment discontinuation rate, TD even appears to be the preferred alternative to DPA in the first-line treatment of children. The above-mentioned limitations of our paediatric population must be, however, taken into account.

Impact of Trientine-dihydrochloride Dosage

There is still no long-term data available that provides sufficient evidence for individualized dosage strategies to prevent either overdosage or therapy failure ^(11,31). As a consequence, recommendations about TD dosage strategies are lacking and weight-based dosage regimen is still not established ⁽¹²⁾. This has led to a significant variation in the approach to the treatment of children with WD among pediatric hepatologists. Subsequently remarkable differences in their clinical outcome were reported, too ⁽¹⁰⁾. With the objective of making an approach towards optimal TD dosage concepts in children, we calculated the weight-based dosage in our patients. In the group with the higher TD dosage, transaminases were shown to be higher during the course. But there was no difference in the normalization of transaminases with respect to the TD dose. Hepatotoxicity of TD has not been well investigated so far but it is assumed that deleterious effects are caused by inhibition of a certain copper-zinc-superoxide dismutase ⁽³²⁾. Hence, a correlation between liver affection and weight-based dosage can be presumed. The higher the administered dose, the more liver-affecting side effects could be expected.

With regards to adverse effects, our studies showed that patients receiving a dose below 20 mg · kg⁻¹ · day⁻¹ had only 6.7% adverse effects as compared with the group receiving more than 20 mg · kg⁻¹ · day⁻¹ with 63% adverse effects. The rate of adverse effects differed significantly between the 2 groups. This fact made us hypothesize that pediatric patients with higher TD dosage regimen were more likely to suffer from adverse effects than those with lower dosages. In terms of clinical safety, the use of doses below 20 mg · kg⁻¹ · day⁻¹ showed slight advantage compared with a higher dosage regimen. In addition, the compliance rate has been increased by reducing side effects ⁽³³⁾. Also, a lower dose of TD implies the possibility of administering single daily doses to children. Single daily dose was proved to be almost as efficacious as split dose in adult patients ⁽³⁴⁾.

CONCLUSIONS

This study demonstrates that TD is an efficacious alternative to DPA in the treatment of pediatric WD patients. Different weight-based dosages did not show any major impact on the biochemical outcome. The application of doses below the recommended 20 mg · kg⁻¹ · day⁻¹ likely diminishes the rate of adverse effects in children. Still, these results are to be confirmed in prospective clinical trials with lager sample sizes.