Abstract
Background
Wilson’s disease (WD) is an autosomal recessive disorder in which copper (Cu) accumulates in organs, particularly in the liver and central nervous system. This study aimed to investigate the prevalence, incidence, and treatment patterns of WD patients in Korea.
Methods
National Health Insurance System (NHIS) claims data from 2010 to 2020 were analyzed. patients with WD as a primary or additional diagnosis at least once were identified using the International Classification of Diseases (ICD)-10 disease code E83.0 and a record for a registration program for rare intractable diseases in Korea.
Results
The average age- and sex-adjusted prevalence and incidence of WD between 2010 and 2020 were 3.06/100,000 and 0.11/100,000, respectively. The mean age of the patients with newly diagnosed WD was 21.0 ± 15.9 years. Among the 622 WD incident cases during the study period, 19.3% of the patients had liver cirrhosis and 9.2% had received liver transplantation. Psychological and neurological diseases were present in 40.7% and 48.1% of the patients, respectively. Regarding the diagnosis of WD, liver biopsy was performed in only 51.6% of new cases. D-penicillamine, trientine, or zinc were prescribed in 81.5% of the incident cases, and the treatment uptake rates decreased with increasing age.
Conclusion
The prevalence of WD in Korea is 3.06/100,000 and approximately 1,800 patients use medical services annually. A significant proportion of patients are diagnosed at the cirrhotic stage and not treated with Cu-chelating therapeutics, suggesting the need for early diagnosis and adequate treatment to improve prognosis.
Keywords: Wilson’s Disease, Epidemiology, Penicillamine, Trientine, Zinc
Graphical Abstract
INTRODUCTION
Wilson’s disease (WD) is an inherited autosomal recessive disorder of copper (Cu) metabolism. Mutations of the intracellular copper transporter ATP7B gene on chromosome 13 leads to Cu excretion failure1 and excessive Cu accumulation in organs, particularly in the liver and central nervous system.2,3,4 The worldwide prevalence of WD has been reported to be 1:30,000–1:50,000.5
Typically, serum ceruloplasmin levels decrease and the 24-hour urinary Cu excretion increases in patients with WD. A Kayser-Fleischer (KF) ring detected by the slit-lamp test is one of the specific findings for diagnosing WD. When the KF ring is absent, additional confirmatory tests, such as liver Cu quantification or genetic testing, can be helpful. However, no single diagnostic test is confirmatory for WD; therefore, most WD diagnoses rely on the clinician’s interpretation based on a scoring system.2,3,6 Medical treatment patterns for WD can vary according to the physician’s decision. In addition to dietary restrictions for Cu, oral chelating agents such as d-penicillamine and trientine, are widely used.7,8 Zinc can be used to reduce the intestinal absorption of Cu.9 Besides medical therapy, liver transplantation is necessary to treat patients with acute liver failure and end-stage liver disease; however, advanced neuropsychiatric WD without marked liver disease is a controversial indication for liver transplantation.
To date, only one epidemiological study on WD has been conducted in South Korea. This study used the National Health Insurance claims data for the period 2010–2016 and showed that the prevalence and incidence of the WD were 38.7/1,000,000 and 3.8/1,000,000, respectively.10 The results were highly likely to have been overestimated because the authors did not exclude WD cases diagnosed more than a year before the first diagnosis date during the study period. Moreover, a detailed pattern of medical therapies that reflects real-world practice was not described in the study. Therefore, in this study, we aimed to clarify the prevalence and incidence of WD and document the diagnostic test utilization and treatment profiles from 2010 to 2020 in South Korea by using nationwide data.
METHODS
Data source and case definition
The National Health Insurance System (NHIS) claims data from January 2002 to December 2020 were used in the present study to accurately calculate the incidence with a maximal wash-out period before WD diagnosis. Because enrollment in the NHIS is mandatory for all residents, it is the most representative national data source for medical service usage in South Korea. The NHIS claims data contain detailed information on diagnosis, length of stay, treatment costs, services received, prescription history (drug code, days prescribed, and daily dosage), income, demographics, and death data.11
A WD case was defined as a person 1) with WD as the primary or additional (from 1st to 4th) diagnosis according to the International Classification of Disease, 10th Revision (ICD-10) disease code E83.0 and 2) who was registered in a program for rare intractable diseases (RIDs, V119) during the study period of 2010 to 2020, which had started in 2009. Because a physician must submit objective evidence to the RID registry, the registration record is mostly accurate in affirming the diagnosis.
Comorbid diseases
Because WD involves multiple organs, various clinical manifestations can be misdiagnosed as other diseases before the final WD diagnosis. To determine the frequencies of diseases suggesting multi-organ involvement in patients with WD, possible related diseases were identified using the ICD-10 codes as the primary or additional (from 1st to 4th) diagnoses and on the basis of whether there was at least one instances of hospitalization or more than two outpatient visits between 2002 and 2020. The diseases identified were as follows: 1) liver cirrhosis (K74.6); 2) hepatocellular carcinoma (C22 and V119); 3) biliary diseases including choledocho/cholelithiasis (K80), cholecystitis (K83), and cholangitis (K81); 4) anemia (D50-59); 5) psychiatric diseases (F00-F99), in particular schizophrenia or similar diseases (F20, F21, F25), bipolar disorder (F31), and depressive disorders (F32, F33); and 6) neurologic diseases (G00-G99), especially Parkinson’s disease/movement disorder (G20-26), epilepsy or seizures (G40-47), nerve disorders (G50-65), and cerebral palsy or other paralytic syndromes (G80-83).
Diagnostic tests
The diagnostic tests considered were as follows: 1) serum ceruloplasmin (claim code C2350 and D4700), 2) quantitative serum or 24-hour urinary Cu (C4503, C4504, C4522, C4523, D5323, D5333, D5335, D5503, and D5511), 3) solid-organ tissue Cu quantification (C4507, C4508, C4526, C4527, D5512, D5504, D5336, D5334, and D5324), 4) slit-lamp test (E6810), 5) ATP7B genotyping (C5809, C5802, CY629, and CZ612), 6) liver biopsy (C5911 and C8513), 7) abdominal ultrasonography (EB441, EB442, and E9441), and 8) brain/hippocampus magnetic resonance imaging (MRI; HJ101, HJ201, HJ401, HJ501, HJ601, HJ635, HJ701, HJ735, HE101, HE135, HI101, HI201, HI401, HI501, HI135, HI235, HI535, HJ235, and HJ535). In claims data, the serum and 24-hour collected urine Cu quantification tests were not distinguishable with diagnostic test codes.
Treatment
Liver transplantation was defined as at least one claim with an ICD-10 code Z94.4 or T86.4 between 2002 and 2020 in patients with WD who met the case definition criterion. Medical therapy with d-penicillamine, zinc, or trientine was classified using prescription records from 180 days before the first WD diagnosis to the end of the observation period. Cases with a short treatment period (less than 15 days) were categorized as “unspecified” because medical therapy for a short duration would not be effective or representative enough.
Outcomes
Mortality was defined using NHIS data and linked to the Cause of Death Statistics provided by Statistics Korea.
Statistical analyses
For the prevalence analyses, data from 2010 to 2020 were used, which were collected 1 year after the RID registration program had started. Age- and sex-adjusted prevalence rates were calculated as the number of WD cases in each age or sex group divided by the age- or sex-specific standard population. The population at the end of 2015, as recorded by the Ministry of Government Administration and Home Affairs of the Republic of Korea, was considered the standard population.12
Individuals who were diagnosed with WD (E83.0) as the primary or additional (1st > 4th) diagnoses between 2002 and 2009 were excluded from the incidence analyses. The incident date was determined as the first date of WD diagnosis during the study period (2010 to 2020). Age- and sex-adjusted incidence rates were calculated as the number of newly detected WD cases divided by the age- or sex-specific standard population.
The fatality rate was calculated as the number of mortalities divided by the number of prevalent WD cases in the same year. To compare the frequencies of comorbid disease or drug prescription, the χ2 test was used. All statistical analyses were performed using the SAS enterprise guide 7.1 (SAS Institute, Cary, NC, USA). Statistical significance was set at P < 0.05.
Ethics statement
The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Bundang Hospital (X-2202-736-904). The requirement of written informed consent was waived because all data were anonymized.
RESULTS
Prevalence, incidence, and case-fatality rates of WD in South Korea
As shown in Table 1, the average WD prevalence rate was 3.06 per 100,000. A total of 17,262 cumulative cases were documented in this study period, and the average annual number of WD prevalent cases was 1,569 ± 14. The prevalence in men (3.51 per 100,000) was higher than that in women (2.61 per 100,000). Most (77.5%) of the patients were younger than 40 years of age; 2% were older than 60 years.
Table 1. Prevalence, incidence, and annual case-fatality rates of Wilson’s disease in South Korea.
| Variables | No. of Wilson’s disease (by year) | Average (average annual adjusted rate) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2010 | 2011 | 2012 | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 | 2020 | ||||
| Prevalence | ||||||||||||||
| Totala | 1,182 (2.15) | 1,294 (2.39) | 1,390 (2.61) | 1,474 (2.80) | 1,542 (2.96) | 1,600 (3.11) | 1,659 (3.25) | 1,714 (3.40) | 1,761 (3.54) | 1,806 (3.68) | 1,840 (3.80) | 1,569 (3.06) | ||
| Sex | Age adjusted prevalence rates (/100,000) | |||||||||||||
| Men | 689 (2.49) | 746 (2.75) | 800 (2.99) | 851 (3.23) | 884 (3.39) | 921 (3.58) | 945 (3.71) | 977 (3.88) | 1,002 (4.04) | 1,028 (4.21) | 1,045 (4.34) | 899 (3.51) | ||
| Women | 493 (1.82) | 548 (2.04) | 590 (2.22) | 623 (2.37) | 658 (2.53) | 679 (2.63) | 714 (2.80) | 737 (2.92) | 759 (3.03) | 778 (3.15) | 795 (3.26) | 670 (2.61) | ||
| Age | Sex adjusted prevalence rates (/100,000) | |||||||||||||
| 0–9 | 96 (2.01) | 91 (1.94) | 101 (2.16) | 114 (2.46) | 106 (2.31) | 107 (2.33) | 110 (2.41) | 94 (2.12) | 88 (2.05) | 77 (1.85) | 68 (1.71) | 96 (2.12) | ||
| 10–19 | 293 (4.28) | 313 (4.68) | 324 (5.02) | 328 (5.26) | 330 (5.51) | 337 (5.89) | 337 (6.15) | 335 (6.32) | 327 (6.38) | 323 (6.52) | 313 (6.53) | 324 (5.69) | ||
| 20–29 | 365 (5.33) | 382 (5.69) | 390 (5.89) | 401 (6.09) | 423 (6.37) | 426 (6.36) | 438 (6.48) | 455 (6.68) | 451 (6.61) | 448 (6.58) | 446 (6.56) | 420 (6.24) | ||
| 30–39 | 275 (3.29) | 305 (3.07) | 330 (4.04) | 358 (4.47) | 372 (4.76) | 394 (5.14) | 389 (5.16) | 396 (5.37) | 424 (5.83) | 435 (6.15) | 457 (6.64) | 376 (4.96) | ||
| 40–49 | 99 (1.12) | 137 (1.55) | 166 (1.88) | 179 (2.01) | 204 (2.28) | 215 (2.43) | 250 (2.84) | 278 (3.20) | 297 (3.50) | 328 (3.91) | 331 (3.99) | 226 (2.61) | ||
| 50–59 | 44 (0.62) | 54 (0.72) | 66 (0.85) | 78 (0.97) | 89 (1.08) | 98 (1.18) | 108 (1.28) | 118 (1.39) | 127 (1.47) | 131 (1.51) | 142 (1.64) | 96 (1.16) | ||
| 60+ | 10 (0.13) | 12 (0.15) | 13 (0.15) | 16 (0.18) | 18 (0.20) | 23 (0.24) | 27 (0.27) | 38 (0.36) | 47 (0.42) | 64 (0.55) | 83 (0.67) | 32 (0.30) | ||
| Incidence | Total (average annual adjusted rate) | |||||||||||||
| Totala | 79 (0.14) | 66 (0.12) | 78 (0.15) | 72 (0.14) | 53 (0.10) | 51 (0.01) | 54 (0.11) | 54 (0.11) | 45 (0.09) | 39 (0.08) | 31 (0.07) | 622 (0.11) | ||
| Sex | Age adjusted incidence rates (/100,000) | |||||||||||||
| Men | 44 (0.16) | 31 (0.11) | 46 (0.17) | 41 (0.15) | 25 (0.10) | 32 (0.12) | 28 (0.11) | 30 (0.12) | 24 (0.10) | 22 (0.09) | 17 (0.07) | 340 (0.12) | ||
| Women | 35 (0.13) | 35 (0.13) | 32 (0.12) | 31 (0.12) | 28 (0.11) | 19 (0.07) | 26 (0.10) | 24 (0.10) | 21 (0.08) | 17 (0.07) | 14 (0.06) | 282 (0.10) | ||
| Age | Sex adjusted incidence rates (/100,000) | |||||||||||||
| 0–9 | 23 (0.48) | 15 (0.32) | 21 (0.45) | 25 (0.54) | 16 (0.35) | 16 (0.35) | 15 (0.33) | 17 (0.38) | 16 (0.37) | 9 (0.22) | 9 (0.23) | 182 (0.37) | ||
| 10–19 | 22 (0.32) | 20 (0.30) | 24 (0.37) | 23 (0.37) | 11 (0.18) | 12 (0.21) | 19 (0.35) | 7 (0.13) | 8 (0.16) | 12 (0.24) | 8 (0.17) | 166 (0.25) | ||
| 20–29 | 11 (0.16) | 11 (0.16) | 12 (0.18) | 10 (0.15) | 13 (0.02) | 11 (0.16) | 5 (0.07) | 11 (0.16) | 5 (0.07) | 4 (0.06) | 5 (0.07) | 98 (0.13) | ||
| 30–39 | 13 (0.16) | 7 (0.08) | 8 (0.01) | 5 (0.06) | 4 (0.05) | 7 (0.09) | 4 (0.05) | 4 (0.05) | 3 (0.04) | 4 (0.06) | 4 (0.06) | 63 (0.07) | ||
| 40–49 | 7 (0.08) | 7 (0.08) | 7 (0.08) | 5 (0.06) | 4 (0.04) | 1 (0.01) | 5 (0.06) | 9 (0.1) | 5 (0.06) | 1 (0.01) | 1 (0.01) | 52 (0.05) | ||
| 50–59 | 2 (0.03) | 3 (0.04) | 5 (0.06) | 3 (0.04) | 3 (0.04) | 1 (0.01) | 4 (0.05) | 3 (0.04) | 4 (0.05) | 2 (0.02) | 2 (0.02) | 32 (0.04) | ||
| 60+ | 1 (0.01) | 3 (0.04) | 1 (0.01) | 1 (0.01) | 2 (0.02) | 3 (0.03) | 2 (0.02) | 3 (0.03) | 4 (0.04) | 7 (0.06) | 2 (0.02) | 29 (0.03) | ||
| Annual case-fatality | ||||||||||||||
| Total | 9 (0.76) | 10 (0.77) | 11 (0.79) | 11 (0.75) | 15 (0.97) | 18 (1.13) | 13 (0.78) | 15 (0.88) | 16 (0.91) | 12 (0.66) | 8 (0.43) | 138 (0.80) | ||
Values are presented as number (%).
aAge and sex-adjusted rates.
During the study period, 622 patients were newly diagnosed with WD. The incidence of WD in South Korea was 0.11 per 100,000. The incidence rates in men and women were similar (0.12 and 0.10 per 100,000, respectively). Most of the new diagnoses were in patients younger than 30 years of age; therefore, the incidence rates decreased to less than 0.1/100,000 after that age (Table 1).
Although the number of incident cases decreased over time, the incidence and prevalence of WD increased gradually from 2010 to 2020 (Fig. 1). A total of 138 deaths were recorded during the study period. The average annual case-fatality rate was 0.8% (0.84% in men and 0.75% in women) (Table 1). The detailed causes of death are described in Supplementary Table 1.
Fig. 1. Prevalence (A) and incidence (B) of Wilson’s disease in South Korea during 2010–2020.
The bars indicate the number of patients with Wilson’s disease, and the line indicates the age- and sex-adjusted rates per 100,000 each year.
Comorbid diseases with WD
Of the 622 patients newly diagnosed with WD, 19.3% had liver cirrhosis and 1.6% had hepatocellular carcinoma (Table 2). A total of 57 (9.2%) underwent liver transplantation. The proportions of cases of liver transplantation were 3.8% (7/182), 16.9% (28/166), 4.1% (4/98), 9.5% (6/63), 15.4% (8/52), 12.5% (4/32), and 0% (0/29) in groups aged 0–9, 10–19, 20–29, 30–39, 40–49, 50–50, and ≥ 60 years, respectively (data not shown). Biliary stones and possibly related diseases were observed in 104 patients (16.7%). Anemia was observed in 374 patients (60.1%). Of the 253 (40.7%) patients diagnosed with a psychiatric disease, only 46 (7.4%) had known physiological conditions or factors (F01-09 and F50-59) indicative of WD. Of the 253 patients diagnosed with a psychiatric disease, 171 (67.3%) were diagnosed with various psychiatric diseases before the first diagnosis of WD (data not shown). Neurological diseases were noted in 299 (48.1%) patients with WD (Table 2), and in 197 patients (65.9%), these diagnoses (50%) were made prior to the WD diagnosis (data not shown). Movement disorders, including Parkinson’s disease and similar disorders, were the most prevalent (n = 188, 30.2%; Table 2). The mean age at diagnosis among the patients with movement disorders was 33.8 ± 12.4 years, and 61.2% of these patients were men. In addition, epilepsy/seizure-like disorders were found in 25.6% of incident cases (n = 159; Table 2). Most of them (n = 117, 73.6%, data not shown) were diagnosed before WD was diagnosed in the affected patients, and the mean age of these patients at the first neurologic disease diagnosis was 29.6 ± 17.2 years (data not shown).
Table 2. Comorbidities of Wilson’s disease patients in South Korea.
| Comorbid diseases | Total incident cases (N = 622) | Men (n = 340) | Women (n = 282) | |
|---|---|---|---|---|
| Advanced liver diseases | 187 (30.1) | 91 (26.8) | 96 (34.0) | |
| Liver cirrhosis (K746) | 120 (19.3) | 66 (19.4) | 54 (19.1) | |
| Hepatocellular carcinoma (C220, C24)a | 10 (1.6) | 6 (1.8) | 4 (1.4) | |
| Liver transplantation (Z944, T864) | 57 (9.2) | 19 (5.6) | 38 (13.5) | |
| Biliary diseases | 104 (16.7) | 46 (13.5) | 58 (20.6) | |
| Choledocho/cholelithiasis (K80) | 81 (13.0) | 35 (10.3) | 46 (16.3) | |
| Cholangitis (K81) | 14 (2.2) | 7 (2.1) | 7 (2.5) | |
| Cholecystitis (K83) | 9 (1.4) | 4 (1.2) | 5 (1.8) | |
| Anemia (D50–64) | 374 (60.1) | 177 (52.1) | 197 (69.9) | |
| Iron deficiency (D50) | 209 (33.6) | 100 (29.4) | 109 (38.7) | |
| Vitamin B12/folate deficiency anemia (D51–53) | 5 (0.8) | 3 (0.9) | 2 (0.7) | |
| Hemolytic anemia (D55–D59) | 16 (2.6) | 6 (1.8) | 10 (3.5) | |
| Psychiatric diseases (F00–F99) | 253 (40.7) | 135 (39.7) | 118 (41.8) | |
| Related with known physiological factors (F01–09, F50–59) | 46 (7.4) | 23 (6.8) | 23 (8.2) | |
| Anxiety, dissociative, or somatoform disorder (F40-48) | 173 (27.8) | 87 (25.6) | 86 (30.5) | |
| Schizophrenia/Schizotypal/Schizoaffective disorders (F20, 21, 25) | 11 (1.8) | 6 (1.8) | 5 (1.8) | |
| Bipolar disorder (F31) | 39 (6.3) | 21 (6.2) | 18 (6.4) | |
| Depressive disorder (F32, F33) | 49 (7.9) | 20 (5.9) | 29 (10.3) | |
| Neurologic diseases (G00–G99) | 299 (48.1) | 161 (47.4) | 138 (48.9) | |
| Parkinson's disease/movement disorder (G20–26) | 188 (30.2) | 115 (33.8) | 73 (25.9) | |
| Epilepsy/seizures/other paroxysmal disorder (G40–47) | 159 (25.6) | 78 (22.9) | 81 (28.7) | |
| Nerve disorders (G50–65) | 26 (4.2) | 13 (3.8) | 13 (4.6) | |
| Cerebral palsy/other paralytic syndromes (G80–83) | 50 (8.0) | 29 (8.5) | 21 (7.4) | |
Values are presented as number (%).
aConfirmed by a registration program for rare intractable diseases (V193) in National Health Insurance Service.
Diagnostic tests to detect WD in South Korea
Table 3 shows the frequency of diagnostic tests in the 622 patients with newly diagnosed WD before or after the first diagnosis. Most patients underwent serum ceruloplasmin testing (n = 615, 98.9%) and ophthalmic examinations using a slit lamp (n = 588, 94.5%). Although serum or 24-hour collected urinary Cu was measured in 607 (97.6%) patients, hepatic tissue Cu was quantified in only 87 (14.0%). Liver biopsies were performed in 321 patients (51.6%). ATP7B genotyping was performed in 162 patients (26.0%). Abdominal ultrasonography was not performed in 167 (26.8%) patients.
Table 3. Diagnostic tests used to detect Wilson’s disease patients in South Korea.
| Diagnostic tests | Total incident cases during the study period (N = 622) | Men (n = 340) | Women (n = 282) | Age at the first diagnostic test (years old) | |
|---|---|---|---|---|---|
| Serum ceruloplasmin | 615 (98.9) | 336 (98.8) | 279 (98.9) | 22.0 ± 17.7 | |
| Copper quantification | |||||
| Serum or 24 hr-urinary excretion | 607 (97.6) | 333 (97.9) | 274 (97.2) | 21.7 ± 17.4 | |
| Tissue | 87 (14.0) | 55 (16.2) | 32 (11.3) | 22.8 ± 16.5 | |
| Slit lamp test | 588 (94.5) | 318 (93.5) | 270 (95.7) | 17.0 ± 16.8 | |
| ATP7B genotyping | 162 (26.0) | 92 (27.1) | 70 (24.8) | 22.0 ± 17.9 | |
| Biopsy | 321 (51.6) | 175 (51.5) | 146 (51.8) | 26.8 ± 18.2 | |
| Brain/hippocampus MRI | 181 (29.1) | 101 (29.7) | 80 (28.4) | 29.7 ± 18.6 | |
| Abdominal ultrasonography | 455 (73.2) | 243 (71.5) | 212 (75.2) | 23.3 ± 17.0 | |
Values are presented as number (%) or mean ± standard deviation.
MRI = magnetic resonance imaging.
Medical treatment for WD in South Korea
Among the patients with newly diagnosed WD, 57 (9.2%) received liver transplantation (Table 2). An oral chelating agent (d-penicillamine or trientine) or zinc had been prescribed in 507 (81.5%) of the incident cases. As shown in Fig. 2A, many patients were treated with more than two drugs. The detailed prescription patterns are shown in Table 4. Single oral chelating agent therapy with d-penicillamine or trientine was the most commonly used regimen (n = 254, 40.8%). Of these, 61 (24.0%) patients changed the drug sequentially or alternatively, indicating possible adverse drug events13 or a lack of efficacy. Thirty-six patients were maintained on zinc monotherapy during the study period. Other patients were prescribed a combination of oral chelating agents and zinc therapy. The treatment pattern (P = 0.246) and uptake rates (P = 0.903) were not significantly different between men and women (Table 4) but were significantly different for each age group (P < 0.001). For children and adolescents (younger than 19 years), triple therapy was preferred, and zinc was combined in 224 patients (64.4%). In adults, a single oral chelating agent accounted for approximately half of all treatments. The treatment uptake rates decreased with age, especially among patients in their 30s, 40s, and 60s (Fig. 2B).
Fig. 2. Medical treatments for Wilson’s disease in South Korea during 2010–2020. (A) Drugs prescribed to patients with newly diagnosed Wilson’s disease in South Korea during 2010–2020. Numbers of patients treated with the drug (percentage of total incident cases). (B) Medical treatment uptake rates of patients with newly diagnosed Wilson’s disease according to the age group.
Table 4. Medical treatments for Wilson’s disease patients in South Korea.
| Drugs | Total incident cases (N = 622) | Sex | Age at the first diagnosis | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Men (n = 340) | Women (n = 282) | P value | 0–9 (n = 182) | 10–19 (n = 166) | 20–29 (n = 98) | 30–39 (n = 63) | 40–49 (n = 52) | 50–59 (n = 32) | 60+ (n = 29) | P value | |||||
| Single oral chelating agent | 254 (40.8) | 139 (40.9) | 115 (40.8) | 0.246 | 50 (27.5) | 75 (45.2) | 40 (40.8) | 34 (54.0) | 26 (50.0) | 19 (59.4) | 10 (34.5) | < 0.001 | |||
| D-penicillamine | 119 (19.1) | 66 (19.4) | 53 (18.8) | 24 (13.2) | 30 (18.1) | 19 (19.4) | 16 (25.4) | 13 (25.0) | 11 (34.4) | 6 (20.7) | |||||
| Unspecifieda | 11 (1.8) | 4 (1.2) | 7 (2.5) | 1 (0.5) | 5 (3.0) | 0 (0.0) | 2 (3.2) | 1 (1.9) | 1 (3.1) | 1 (3.4) | |||||
| Trientine | 74 (11.9) | 39 (11.5) | 35 (12.4) | 17 (9.3) | 21 (12.7) | 10 (10.2) | 10 (15.9) | 8 (15.4) | 5 (15.6) | 3 (10.3) | |||||
| Unspecifieda | 2 (0.3) | 1 (0.3) | 1 (0.4) | 1 (0.5) | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| D-penicillamine or Trientine | 61 (9.8) | 34 (10.0) | 27 (9.6) | 9 (4.9) | 24 (14.5) | 11 (11.2) | 8 (12.7) | 5 (9.6) | 3 (9.4) | 1 (3.4) | |||||
| Sequential | 35 (5.6) | 21 (6.2) | 14 (5.0) | 7 (3.8) | 13 (7.8) | 8 (8.2) | 4 (6.3) | 2 (3.8) | 0 (0.0) | 1 (3.4) | |||||
| Penicillamine - Trientine | 20 (3.2) | 11 (3.2) | 9 (3.2) | 3 (1.6) | 7 (4.2) | 6 (6.1) | 4 (6.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| Trientine - Penicillamine | 15 (2.4) | 10 (2.9) | 5 (1.8) | 4 (2.2) | 6 (3.6) | 2 (2.0) | 0 (0.0) | 2 (3.8) | 0 (0.0) | 1 (3.4) | |||||
| Alternative | 24 (3.9) | 13 (3.8) | 11 (3.9) | 2 (1.1) | 10 (6) | 3 (3.1) | 4 (6.3) | 3 (5.8) | 2 (6.3) | 0 (0.0) | |||||
| Unspecifieda | 2 (0.3) | 0 (0.0) | 2 (0.7) | 0 (0.0) | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (3.1) | 0 (0.0) | |||||
| Zinc | 36 (5.8) | 14 (4.1) | 22 (7.8) | 18 (9.9) | 9 (5.4) | 2 (2.0) | 2 (3.2) | 3 (5.8) | 2 (6.3) | 0 (0.0) | |||||
| Unspecifieda | 1 (0.2) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| D-penicillamine + Zinc | 38 (6.1) | 16 (4.7) | 22 (7.8) | 12 (6.6) | 9 (5.4) | 7 (7.1) | 5 (7.9) | 5 (9.6) | 0 (0.0) | 0 (0.0) | |||||
| Sequential | 21 (3.4) | 7 (2.1) | 14 (5.0) | 9 (4.9) | 5 (3.0) | 1 (1.0) | 4 (6.3) | 2 (3.8) | 0 (0.0) | 0 (0.0) | |||||
| Penicillamine - Zinc | 19 (3.1) | 6 (1.8) | 13 (4.6) | 9 (4.9) | 5 (3.0) | 0 (0.0) | 3 (4.8) | 2 (3.8) | 0 (0.0) | 0 (0.0) | |||||
| Zinc - Penicillamine | 2 (0.3) | 1 (0.3) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 1 (1.0) | 1 (1.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| Simultaneous | 9 (1.4) | 5 (1.5) | 4 (1.4) | 2 (1.1) | 1 (0.6) | 4 (4.1) | 0 (0.0) | 2 (3.8) | 0 (0.0) | 0 (0.0) | |||||
| Alternative | 4 (0.6) | 0 (0.0) | 4 (1.4) | 1 (0.5) | 1 (0.6) | 1 (1.0) | 1 (1.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| Unspecifieda | 4 (0.6) | 4 (1.2) | 0 (0.0) | 0 (0.0) | 2 (1.2) | 1 (1.0) | 0 (0.0) | 1 (1.9) | 0 (0.0) | 0 (0.0) | |||||
| Zinc + Trientine | 77 (12.4) | 46 (13.5) | 31 (11.0) | 20 (11) | 29 (17.5) | 16 (16.3) | 5 (7.9) | 3 (5.8) | 2 (6.3) | 2 (6.9) | |||||
| Sequential | 13 (2.1) | 7 (2.1) | 6 (2.1) | 1 (0.5) | 4 (2.4) | 3 (3.1) | 1 (1.6) | 3 (5.8) | 1 (3.1) | 0 (0.0) | |||||
| Zinc - Trientine | 6 (1.0) | 2 (0.6) | 4 (1.4) | 1 (0.5) | 2 (1.2) | 3 (3.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| Trientine - Zinc | 7 (1.1) | 5 (1.5) | 2 (0.7) | 0 (0) | 2 (1.2) | 0 (0.0) | 1 (1.6) | 3 (5.8) | 1 (3.1) | 0 (0.0) | |||||
| Simultaneous | 43 (6.9) | 25 (7.4) | 18 (6.4) | 12 (6.6) | 17 (10.2) | 10 (10.2) | 1 (1.6) | 0 (0.0) | 1 (3.1) | 2 (6.9) | |||||
| Alternative | 17 (2.7) | 12 (3.5) | 5 (1.8) | 6 (3.3) | 6 (3.6) | 3 (3.1) | 2 (3.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| Unspecifieda | 4 (0.6) | 2 (0.6) | 2 (0.7) | 1 (0.5) | 2 (1.2) | 0 (0.0) | 1 (1.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| D-penicillamine + Zinc + Trientine | 102 (16.4) | 63 (18.5) | 39 (13.8) | 50 (27.5) | 27 (16.3) | 16 (16.3) | 3 (4.8) | 3 (5.8) | 3 (9.4) | 0 (0.0) | |||||
| Simultaneous | 100 (16.1) | 61 (17.9) | 39 (13.8) | 50 (27.5) | 25 (15.1) | 16 (16.3) | 3 (4.8) | 3 (5.8) | 3 (9.4) | 0 (0.0) | |||||
| Unspecifieda | 2 (0.3) | 2 (0.6) | 0 (0.0) | 0 (0.0) | 2 (1.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||||
| Total | 507 (81.5) | 276 (81.2) | 230 (81.6) | 0.903 | 150 (82.5) | 149 (89.7) | 81 (82.6) | 49 (77.8) | 40 (76.9) | 26 (81.2) | 12 (41.4) | < 0.001 | |||
Values are presented as number (% of incident cases).
aUnspecified: total treatment duration less than 15 days.
DISCUSSION
In this study, we estimated the prevalence and incidence of WD in South Korea by using nationwide data. The average WD prevalence was 3.06 per 100,000 (1:32,680), and the annual incidence rate was 0.11 per 100,000 from 2010 to 2020. Liver cirrhosis was present in 19.3% of the patients with newly diagnosed WD, and 9.2% required liver transplantation. Neuropsychiatric diseases, which can be another clinical manifestation of WD, were comorbid in approximately half of the incident cases. Of the 81.5% of patients who received medical therapy, 40.8% used a single oral chelating agent, and 34.9% used a combination of zinc and oral chelators. The treatment rate was the highest in patients younger than 20 years of age and the lowest among those aged 30–49 years.
According to our data, WD prevalence in South Korea is similar to the worldwide average (1:30,000–50,000).5,14,15,16,17 A previous study conducted in South Korea and comparable to ours reported a high WD prevalence of 1:25,839.10 However, the authors of the previous study did not use the RID registration code to define WD cases. Because the primary diagnostic code can be input for possible diagnoses in the NHIS system, cases without RID registration may not be identified as WD. Based on ATP7B genetic studies, the estimated allele carrier frequencies in South Koreans varied from 1:44 to 1:88.18,19,20,21 However, all the studies included patients who agreed to pay for the genetic study, and not a random general population. Hence, the results may be overestimated. A French report showed that the carrier frequency was 1:31 at a clinical prevalence of 1.5/100,00015 which was approximately half of that in South Korea, indicating that the real clinical prevalence in South Korea would be even lower than our findings. Our data revealed a gradual rise in the detection of WD in South Korea as of late. This trend could potentially be attributed to increasing awareness rather than alterations in the allele frequency, considering the concurrent decrease in the number of incidents and the birth rate. The proportion of individuals diagnosed with WD before the age of 10 remained consistent between 2010 (n = 23, 29.1% of 79 incident WD cases in 2010) and 2020 (n = 9, 29% of 31 incident WD cases in 2020); however, there was a discernible increase in the proportion of diagnoses occurring during the patients’ 20s, ascending from 13.9% in 2010 to 16.1% in 2020.
Although there is a suggested diagnostic algorithm for WD,22 definitive WD diagnosis remains challenging, and the pattern is diverse. As our data show (Table 3), most clinicians used serum ceruloplasmin (98.9%) to diagnose WD; however, a low serum ceruloplasmin level (< 20 mg/dL) had a low positive predictive value (5.9%)23 as a single test because of low specificity (84.5%; 95% confidence interval, 72.6–95%),24 although it is very sensitive to screen WD. However, even the slit-lamp test, which is the most used test for confirming the clinical manifestation of a KF ring, was not performed in 5.3% of the incident cases. In the present study, the frequency of urinary Cu excretion could not be determined because the electronic data interchange codes for serum and urinary Cu quantification were the same. Nonetheless, the sum of serum and urine Cu test rates was 97.6%, which meant that not all incident cases were diagnosed based on the 24-hour urinary Cu excretion level. Although liver Cu level is one of the gold standard diagnostic tests for WD, the tissue Cu quantification was performed in only a limited number of patients (n = 87, 14.0%; Table 3). The relatively infrequent utilization of tissue copper quantification in real-world practice could be attributed to the inherent challenges of obtaining sufficient fresh non-formalin-fixed tissue, separately from the standard biopsy samples, posing practical difficulties. On the other hand, a considerable number of patients could be diagnosed with WD prior to undergoing a liver biopsy, relying on non-invasive markers such as low ceruloplasmin and increased urinary copper excretion. Genetic testing is the most reliable tool for establishing a diagnosis of WD; however, it is rarely performed in adults, and 60% of ATP7B tests are performed in patients younger than 20 years of age. Although Cu quantification in the liver tissue is one of the gold-standard diagnostic tests, it was only performed in 14% of patients.
The most alarming finding of our study was that abdominal ultrasound was performed in only approximately three-quarters of the WD cases (73.2%). Because Cu accumulates in the liver of patients with WD, it can cause chronic liver disease, including cirrhosis, which is a major indication for liver cancer screening with ultrasound. In our study, 15.4% of the incident population in their 40s and 12.5% in their 50s were diagnosed with late-stage liver disease requiring liver transplantation (data not shown). Our data suggest that physicians need to be well aware of updated practice guidelines about the importance of sufficient diagnostic and follow-up methods for WD, because early diagnosis results in a longer life expectancy for patients.
After a prompt diagnosis, lifelong treatment to reduce excess Cu levels in the body is crucial for patients with WD.2,6 As shown in Table 4, approximately 20% of patients with WD in South Korea did not receive pharmacotherapy. The proportion of patients without therapeutic drug prescriptions increased with age. Although some misdiagnoses were possible in patients newly diagnosed in their 60s who showed the lowest treatment uptake rate (41.4%), the low treatment rates among patients in their 30s (77.8%) and 40s (76.9%) were remarkable. Because these patients are in an economically active age, they may have less access to medical services. Therefore, attending physicians should provide sufficient information about how patients’ survival depends on compliance with medical treatment.
This study has several limitations. First, the diagnosis of WD was based on the claims code, which was not confirmed by a detailed review of the clinical records. Nonetheless, the South Korean NHIS had a special registration system for RIDs, including WD, and it requires a physician’s official note with at least two diagnostic results of proof. Thus, we believe that the likelihood of incorrect registration using this system was as low as possible. Second, the frequency of comorbidities could have been overestimated because the ICD-10 codes for the diseases were not specified in detail. Some of the comorbidities may not be related to WD per se even though we collected data only from cases that had the WD diagnostic code. To minimize the possibility of non-specific combined disease diagnoses, the start of comorbidity data acquisition was limited to 180 days prior to the first WD diagnosis. Third, medical treatment uptake rates in the real world might be lower than our findings suggest. As shown in Table 4, some pharmacotherapies were discontinued within 15 days (accounting for 5.1% of the treated cohort). The most prescribed drug in the short term was d-penicillamine, which may be a diagnostic challenge. Furthermore, our analysis did not differentiate medical therapy patterns based on liver disease severity. Advanced liver disease in our dataset was solely identified using ICD-10 codes, including liver cirrhosis and hepatocellular carcinoma. Thus, the subclassification of the severity of liver disease was not available. Nevertheless, our data revealed that combination therapy was not directly correlated with the presence of liver cirrhosis but was predominantly observed in pediatric patients. Among the 102 patients undergoing triple therapy (D-penicillamine, zinc, and trientine), nearly half (49%) of them were under the age of 20. Lastly, the specific causes of death remained indeterminate in 44.9% of mortality cases (Supplementary Table 1). This limitation arises from the data from the Statistics Korea, which only provides the primary cause of death via disease codes and does not encompass secondary or subsequent causes.
In conclusion, the prevalence of WD in South Korea during the study period was 3.06/100,000 and approximately 1,800 patients used medical services annually during this period. Furthermore, the incidence of WD was 0.11/100,000, which was less than the global average. A significant proportion of patients with WD also have neuropsychiatric diseases. However, the importance of adequate diagnostic methods and lifelong medical treatment for WD still needs to be emphasized to improve life expectancy.
Footnotes
Funding: This study was supported by the Gyeonggi-Inchoen Area Research Fund (2019) of the Korean Association for the Study of the Liver.
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Jang ES, Choi HY, Ki M, Kim BH, Kim KA, Jeong SH.
- Data curation: Choi HY, Jeong SH.
- Formal analysis: Jang ES, Choi HY.
- Methodology: Choi HY, Ki M, Jeong SH.
- Project administration: Jeong SH.
- Writing - original draft: Jang ES.
- Writing - review & editing: Choi HY, Ki M, Kim BH, Kim KA, Jeong SH.
SUPPLEMENTARY MATERIAL
Causes of death among patients with Wilson’s disease in South Korea (2010–2020)
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Associated Data
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Supplementary Materials
Causes of death among patients with Wilson’s disease in South Korea (2010–2020)