Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2025 Jul 1.
Published in final edited form as: Eur J Gastroenterol Hepatol. 2024 Apr 23;36(7):929–940. doi: 10.1097/MEG.0000000000002777

The cost implications of Wilson Disease among hospitalized patients: analysis of US hospitals

David Uihwan Lee 1, Ashton Harmacinski 1, Aneesh Bahadur 2, Ki Jung Lee 2, Hannah Chou 2, Mohammed Rifat Shaik 1, Harrison Chou 2, Gregory Hongyuan Fan 2, Jean Kwon 2, Reid Ponder 2, Kevin Chang 2, KeeSeok Lee 2, Zurabi Lominadze 1
PMCID: PMC11147697  NIHMSID: NIHMS1982994  PMID: 38652529

Abstract

Background & Aim:

Wilson Disease (WD) is copper overload and deposition in the liver damage and ultimate liver failure. In this study, we used a national database to investigate the admissions, mortality rates and costs over the captured period to assess specific subpopulations at higher burden.

Method:

Patients with WD were selected using the National Inpatient Sample (NIS) database from 2016–2019. Weighted charge data was determined using inflation-adjusted charge-to-cost ratios to calculate the admission costs. The weighted estimates and patient data were stratified into cohorts of patient demographics and medical characteristics. Polynomial regression curves were graphed and assessed across 2016–2019 to derive goodness-of-fit for each trend from which R2 and p-values were calculated.

Results:

Annual total hospital admissions per 100,000 hospitalizations due to WD were 1,075, 1,180, 1,140, 1,330 (R2 = 0.75, p = 0.13) from 2016 to 2019 respectively. Within the demographics, there was a significant increase in admissions among patients greater than 65 years of age (R2 = 0.90, p = 0.05) and White patients (R2 = 0.97, p = 0.02). Assessing WD-related mortality rates, there was a significant increase in the mortality rate among those in the first quartile of income (R2 = 1.00, p < 0.001). The total cost for WD-related hospitalizations was $20.90, $27.23, $24.20, and $27.25 million US dollars for the years 2016, 2017, 2018, and 2019 respectively (R2 = 0.47, p = 0.32). There was a significantly increasing total cost trend for Asian or Pacific Islander patients (R2 = 0.90, p = 0.05), those with a diagnosis of bipolar disorder (R2 = 0.99, p = 0.003) and those with a diagnosis of schizophrenia (R2 = 0.92, p = 0.04). Interestingly, patients with a liver complication of cirrhosis demonstrated a decreased total cost (R2 = 0.97, p = 0.02).

Conclusion:

Our study showed there were no significant increases in hospital admissions, mortality, or overall cost of WD. However, it demonstrated that certain ethnicity groups, income classes, and comorbidities had increased admissions or costs. Implementing screening and management of the vulnerable cohorts will improve WD-related admission, mortality, and costs.

Keywords: Wilson’s Disease, WD, weighted analysis of national data, inflation-adjusted admission costs, regression trends, liver decompensation

Introduction

The pathophysiology of Wilson’s Disease (WD) is copper overload and deposition in the liver, causing parenchymal damage (1,2). Ceruloplasmin deficiency inhibits the hepatobiliary system’s copper excretion functions, resulting in increased hepatic concentrations and oxidative stress (3,4). The end result of this mineral overload is a distortion of the hepatic cytoarchitecture and inflammation, eliciting fibrosis and ultimately cirrhosis (5–7). In select cases, WD-driven liver inflammation can evolve into fulminant liver failure and a cascade of complications including portal hypertension, ascites, jaundice, variceal hemorrhage, and multi-organ failure (8,9). In dire cases, immediate therapies are warranted to remediate the ensuing liver failure (7, 10–12). These therapies often require focalized inpatient care with a multidisciplinary perspective, not excluding surgical consults to discuss liver transplant therapy as a life-saving option (13,14).

WD is accompanied by neurological and psychiatric symptoms, often serving as the initial indicators of WD. Neurological manifestations of WD include both bulbar (drooling, dysphagia, and dysarthria) and non-bulbar abnormalities (dystonia, Parkinsonism, and ataxia). These symptoms typically appear about a decade after the onset of liver disease and vary in severity, which can permanently limit functional ability even if appropriate treatment is initiated (15,16). Parkinson-like symptoms of tremor, dystonia, and chorea can potentially impact gait leading to immobility thereby necessitating the need for prolonged hospitalization (17). While WD is known primarily by its liver and neurologic manifestations, most patients eventually develop significant psychiatric disease as well, further diminishing functional status and overall quality of life.

The multimodal aspect of care required in these admitted WD patients with complications often translates into hospital costs. However, due to the rarity of WD, the US national expenditure on these conditions is difficult to quantify. Nonetheless, it is important to evaluate the epidemiological aspects of recent WD care and to isolate aspects of WD-related admissions that impose a higher-than-expected cost burden on the hospital system (18). Identifying segments of the WD population with increased hospitalization costs will be pivotal to understanding the current landscape of resource utilization in WD care, the cost implications of these therapies, and potential measures to mitigate the growth of expenditures.

In this study, we use a US-based hospital cohort to isolate patients admitted with WD in order to investigate the pattern of admissions, mortality rates, and costs over the captured period and to identify subpopulations with higher burdens of cost and mortality rates.

Methods

Study data was drawn from the National Inpatient Sample (NIS), an annually-released, US-based, inpatient database supported by the Healthcare Cost and Utilization Project (HCUP) from the Agency for Healthcare Research and Quality (AHRQ) (19). This database is composed of 20% of samples randomly drawn from State Inpatient Databases (SIDs), each covering a specific state or region within the US. Data in the SIDs, and consequently the NIS, consists of discharge diagnoses and insurance claims information. As of 2015, the NIS codes all information using the International Classification of Diseases 10th Revision (ICD-10) (20).

Because cost data within the NIS represents charges made by the hospital, a charge-to-cost ratio (CCR) was used to estimate per-capita and aggregate expenses related to WD hospitalizations. The NIS releases from 2016 to 2019 were used in this analysis. All admissions with a WD diagnosis were included and stratified into several categories of variables, including patient demographics, patient household income, liver complications, comorbidities, and hospital characteristics. Data from the NIS was weighted via survey-weighting methodology and specific NIS-distributed hospital identifiers, which include Census division, urban or rural location, teaching status, and bed size, as described by the NIS-HCUP (21). To conduct weighted analyses, variables were turned into categorical data with continuous data converted into ranges (e.g., age was divided into 18 to 34-year-olds, 35–49 year-olds, etc.). Other data within a given category were entered as binary inputs (i.e., yes/no), having multiple variables of the same category (e.g., > 2 comorbidities), or having none of the variables (e.g., having none of the queried comorbidities).

We calculated the total, median, 25 percentile (quartile 1), and 75 percentile (quartile 3) costs for each weighted strata. The resulting data points were analyzed via polynomial regression curves, revealing trends from 2016 to 2019. The goodness-of-fit (R2) and p-values were reported from the regression curves. Furthermore, we derived hospitalization incidence and mortality rate data with a denominator of every 100,000 hospitalizations in the United States. Mortality data was also reported as a proportion of admissions. In order to account for missing data, we employed the multiple imputation by chained equation (MICE) method, which inputs any missing-at-random type data (22). All statistical calculations were made with R version 4.1.2.

Results

WD-related hospitalizations

Table 1 details US hospital admission data per 100,000 US hospitalizations for those with WD between the years 2016 to 2019. From 2016 to 2019, there was a non-significant increase in hospitalizations with total yearly admissions of 1075, 1180, 1140, and 1330, respectively (R2 = 0.75, p = 0.13). There was a significant increase in admissions among patients greater than 65 years of age (R2 = 0.90, p = 0.05) and White patients (R2 = 0.97, p = 0.02). There was also an increasing admission trend seen among those in the first quartile of income (R2 = 0.97, p = 0.02), as well as those covered by Medicare (R2 = 0.93, p = 0.04). Small hospitals in terms of beds also experienced an increase in WD admissions (R2 = 0.93, p = 0.04). Another strata demonstrating admission incidence growth, though not statistically significant, was admissions of an Asian or Pacific Islander ethnicity (R2 = 0.89, p = 0.06). There was no association with increased hospital admission rates in patients with the presence of either bulbar or non-bulbar neurologic symptoms.

Table 1:

Admission Rates Associated with Wilson Disease in US Hospitals

Year 2016 2017 2018 2019 r2 p-value
Total admissions 1,075.00 1,180.00 1,140.00 1,330.00 0.75 0.13
Demographics Rate per 100,000 Admissions Stratum Percentage Rate per 100,000 Admissions Stratum Percentage Rate per 100,000 Admissions Stratum Percentage Rate per 100,000 Admissions Stratum Percentage r2 for Rate per 100,000 Admissions Stratum Percentage p-value for Rate per 100,000 Admissions Stratum Percentage
Age
 18 to 34 0.95 31.63 1.15 34.75 0.82 25.44 1.16 30.83 0.05 0.15 0.78 0.61
 35 to 49 0.87 28.84 0.84 25.42 0.97 30.26 1.27 33.83 0.77 0.54 0.12 0.26
 50 to 64 0.81 26.98 0.88 26.69 0.97 30.26 0.76 20.30 0.01 0.26 0.91 0.49
 greater than 65 0.38 12.56 0.43 13.14 0.45 14.04 0.56 15.04 0.90 0.99 0.05 * 0.007 **
Sex
 Male 1.44 47.91 1.59 48.31 1.52 47.37 1.88 50.00 0.70 0.37 0.16 0.39
 Female 1.57 52.09 1.70 51.69 1.69 52.63 1.88 50.00 0.86 0.37 0.08 0.39
Race
 White 2.17 72.09 2.23 67.80 2.42 75.44 2.53 67.29 0.97 0.05 0.02 * 0.77
 Black 0.25 8.37 0.31 9.32 0.20 6.14 0.27 7.14 0.03 0.41 0.82 0.36
 Hispanic 0.32 10.70 0.45 13.56 0.28 8.77 0.49 13.16 0.20 0.02 0.55 0.85
 Asian or Pacific Islander 0.11 3.72 0.13 3.81 0.15 4.82 0.23 6.02 0.89 0.90 0.06 0.05
 Other 0.15 5.12 0.18 5.51 0.15 4.82 0.24 6.39 0.55 0.35 0.26 0.40
Length of Stay
 0 to 9 days 2.52 83.72 2.57 77.97 2.43 75.88 3.05 81.20 0.46 0.13 0.32 0.64
 10 to 19 days 0.39 13.02 0.43 13.14 0.52 16.23 0.45 12.03 0.41 0.00 0.36 0.99
 20 to 29 days 0.06 1.86 0.17 5.08 0.17 5.26 0.17 4.51 0.61 0.44 0.22 0.34
 30 days and greater 0.04 1.40 0.13 3.81 0.08 2.63 0.08 2.26 0.11 0.03 0.67 0.82
Comorbidities
Congestive Heart Failure 0.04 1.40 0.01 0.42 0.11 3.51 0.06 1.50 0.19 0.12 0.56 0.66
Chronic Kidney Disease 0.13 4.19 0.18 5.51 0.21 6.58 0.40 10.53 0.86 0.90 0.07 0.05
Chronic Obstructive Pulmonary Disease 0.10 3.26 0.11 3.39 0.11 3.51 0.08 2.26 0.15 0.42 0.61 0.35
Diabetes 0.14 4.65 0.11 3.39 0.15 4.82 0.17 4.51 0.47 0.04 0.31 0.80
Hypertension 0.38 12.56 0.46 13.98 0.42 13.16 0.51 13.53 0.67 0.20 0.18 0.55
≥ 2 Comorbidities 0.55 18.14 0.66 19.92 0.61 18.86 0.68 18.05 0.57 0.04 0.25 0.80
None 1.68 55.81 1.76 53.39 1.59 49.56 1.86 49.62 0.17 0.89 0.58 0.05
Psychological Etiologies
Bipolar Disorder 0.14 4.65 0.07 2.12 0.07 2.19 0.06 1.50 0.73 0.76 0.15 0.13
Depression Complications 0.22 7.44 0.32 9.75 0.28 8.77 0.35 9.40 0.65 0.39 0.19 0.38
Anxiety 0.29 9.77 0.31 9.32 0.15 4.82 0.28 7.52 0.12 0.42 0.66 0.35
Schizophrenia 0.04 1.40 0.07 2.12 0.07 2.19 0.11 3.01 0.89 0.92 0.06 0.04 *
≥ 2 Etiologies 0.35 11.63 0.32 9.75 0.42 13.16 0.58 15.41 0.78 0.63 0.12 0.21
None 1.96 65.12 2.21 66.95 2.21 68.86 2.37 63.16 0.89 0.04 0.06 0.79
Bulbar Symptoms
 Absent 2.83 93.95 3.03 91.95 3.04 94.74 3.49 92.86 0.85 0.00 0.08 0.95
 Present 0.18 6.05 0.27 8.05 0.17 5.26 0.27 7.14 0.16 0.00 0.61 0.95
Nonbulbar Movements
 Absent 2.93 97.21 3.13 94.92 3.17 98.68 3.56 94.74 0.89 0.06 0.06 0.75
 Present 0.08 2.79 0.17 5.08 0.04 1.32 0.20 5.26 0.15 0.06 0.61 0.75
Liver Complications
Ascites 0.10 3.26 0.14 4.24 0.14 4.39 0.10 2.63 0.00 0.07 0.98 0.73
Cirrhosis 0.55 18.14 0.54 16.53 0.58 17.98 0.52 13.91 0.05 0.55 0.77 0.26
Encephalopathy 0.08 2.79 0.06 1.69 0.04 1.32 0.04 1.13 0.83 0.87 0.09 0.07
≥ 2 Complications 0.38 12.56 0.67 20.34 0.59 18.42 0.69 18.42 0.60 0.36 0.22 0.40
None 1.91 63.26 1.89 57.20 1.86 57.89 2.40 63.91 0.52 0.01 0.28 0.90
Median Household Income
 Quartile 1 0.77 25.58 0.82 25.00 0.90 28.07 1.02 27.07 0.97 0.48 0.02 * 0.30
 Quartile 2 0.74 24.65 0.94 28.39 0.72 22.37 1.13 30.08 0.40 0.14 0.37 0.62
 Quartile 3 0.74 24.65 0.84 25.42 0.79 24.56 0.89 23.68 0.63 0.47 0.20 0.32
 Quartile 4 0.76 25.12 0.70 21.19 0.80 25.00 0.72 19.17 0.00 0.38 0.98 0.38
Hospital Bed Size
 Small 0.41 13.49 0.43 13.14 0.56 17.54 0.72 19.17 0.93 0.86 0.04 * 0.07
 Medium 0.76 25.12 0.70 21.19 0.89 27.63 0.95 25.19 0.73 0.10 0.15 0.68
 Large 1.85 61.40 2.16 65.68 1.76 54.82 2.09 55.64 0.04 0.50 0.79 0.29
Hospital Location/Teaching Status
 Rural 0.25 8.37 0.15 4.66 0.27 8.33 0.24 6.39 0.04 0.03 0.81 0.84
 Urban Nonteaching 0.63 20.93 0.52 15.68 0.35 10.96 0.38 10.15 0.84 0.93 0.09 0.04 *
 Urban Teaching 2.13 70.70 2.63 79.66 2.59 80.70 3.13 83.46 0.88 0.84 0.06 0.08
Hospital Region
 Northeast 0.52 17.21 0.73 22.03 0.69 21.49 0.66 17.67 0.32 0.00 0.44 0.96
 Midwest 0.76 25.12 0.66 19.92 0.72 22.37 0.78 20.68 0.09 0.37 0.71 0.39
 South 1.12 37.21 1.17 35.59 1.17 36.40 1.68 44.74 0.67 0.51 0.18 0.28
 West 0.62 20.47 0.74 22.46 0.63 19.74 0.64 16.92 0.01 0.57 0.88 0.25
Insurance Type
 Medicare 0.83 27.44 0.95 28.81 0.99 30.70 1.19 31.58 0.93 0.98 0.04 * 0.009 **
 Medicaid 0.85 28.37 0.91 27.54 0.84 26.32 1.00 26.69 0.46 0.78 0.32 0.12
 Private Insurance 1.02 33.95 1.22 36.86 1.18 36.84 1.20 31.95 0.52 0.11 0.28 0.68
 Other Insurance 0.31 10.23 0.22 6.78 0.20 6.14 0.37 9.77 0.06 0.02 0.75 0.87
Open in a new tab
*

p < 0.05,

**

p < 0.01,

***

p < 0.001

WD-related mortality

Table 2 details Wilson’s disease-related mortality rates per 100,000 US hospitalizations and the proportion of mortality among each stratum. Those in the first quartile of income (R2 = 1.00, p < 0.001) and large hospital bed size (R2 = 0.98, p = 0.01) were associated with an increasing mortality rate. Additionally, the absence of non-bulbar neurologic complications was associated with an increase in mortality (R2 = 0.91, p = 0.04).

Table 2:

Mortality Rates Associated with Wilson Disease in US Hospitals

Year 2016 2017 2018 2019 r2 p-value
Total admissions 30.00 35.00 35.00 40.00 0.90 0.05
Demographics Mortality rate per 100,000 Admissions Proportion Percentage Mortality rate per 100,000 Admissions Proportion Percentage Mortality rate per 100,000 Admissions Proportion Percentage Mortality rate per 100,000 Admissions Proportion Percentage r2 for Mortality rate per 100,000 Admissions r2 for Proportion Percentage p-value for Mortality rate per 100,000 Admissions p-value for Proportion Percentage
Age
 18 to 34 0.04 4.41 0.01 1.22 0.01 1.72 0.04 3.66 0.00 0.02 0.99 0.85
 35 to 49 0.01 1.61 0.03 3.33 0.04 4.35 0.03 2.22 0.41 0.09 0.36 0.70
 50 to 64 0.00 0.00 0.03 3.17 0.03 2.90 0.03 3.70 0.61 0.71 0.22 0.16
 greater than 65 0.03 7.41 0.03 6.45 0.01 3.13 0.01 2.50 0.80 0.93 0.10 0.04 *
Sex
 Male 0.04 2.91 0.04 2.63 0.06 3.70 0.06 3.01 0.80 0.15 0.11 0.62
 Female 0.04 2.68 0.06 3.28 0.04 2.50 0.06 3.01 0.22 0.01 0.53 0.92
Race
 White 0.07 3.23 0.06 2.50 0.08 3.49 0.08 3.35 0.46 0.16 0.32 0.60
 Black 0.00 0.00 0.03 9.09 0.00 0.00 0.00 0.00 0.07 0.07 0.74 0.74
 Hispanic 0.01 4.35 0.01 3.12 0.01 5.00 0.01 2.86 0.65 0.11 0.19 0.67
 Asian or Pacific Islander 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NaN NaN NaN NaN
 Other 0.00 0.00 0.00 0.00 0.00 0.00 0.01 5.88 0.60 0.60 0.23 0.23
Length of Stay
 0 to 9 days 0.06 2.22 0.06 2.17 0.04 1.73 0.06 1.85 0.05 0.70 0.77 0.16
 10 to 19 days 0.01 3.57 0.01 3.23 0.03 5.41 0.04 9.37 0.89 0.80 0.06 0.10
 20 to 29 days 0.00 0.00 0.01 8.33 0.03 16.67 0.01 8.33 0.40 0.40 0.36 0.37
 30 days and greater 0.01 33.33 0.01 11.11 0.00 0.00 0.00 0.00 0.80 0.83 0.10 0.09
Comorbidities
Congestive Heart Failure 0.00 0.00 0.00 0.00 0.00 0.00 0.01 25.00 0.60 0.60 0.23 0.23
Chronic Kidney Disease 0.00 0.00 0.03 15.38 0.04 20.00 0.01 3.57 0.16 0.04 0.60 0.79
Chronic Obstructive Pulmonary Disease 0.01 14.29 0.00 0.00 0.00 0.00 0.01 16.67 0.00 0.01 1.00 0.90
Diabetes 0.01 10.00 0.00 0.00 0.01 9.09 0.00 0.00 0.20 0.24 0.55 0.51
Hypertension 0.01 3.70 0.00 0.00 0.00 0.00 0.01 2.78 0.00 0.04 1.00 0.81
≥ 2 Comorbidities 0.00 0.00 0.04 6.38 0.00 0.00 0.03 4.17 0.07 0.06 0.74 0.75
None 0.04 2.50 0.03 1.59 0.04 2.65 0.03 1.52 0.19 0.17 0.57 0.59
Psychological Etiologies
Bipolar Disorder 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NaN NaN NaN NaN
Depression Complications 0.00 0.00 0.01 4.35 0.01 5.00 0.01 4.00 0.61 0.52 0.22 0.28
Anxiety 0.03 9.52 0.00 0.00 0.00 0.00 0.01 5.00 0.16 0.15 0.60 0.62
Schizophrenia 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NaN NaN NaN NaN
≥ 2 Etiologies 0.00 0.00 0.00 0.00 0.03 6.67 0.00 0.00 0.07 0.07 0.74 0.74
None 0.06 2.86 0.08 3.80 0.06 2.55 0.08 3.57 0.22 0.04 0.53 0.80
Bulbar Symptoms
 Absent 0.08 2.97 0.08 2.76 0.10 3.24 0.11 3.24 0.89 0.51 0.06 0.28
 Present 0.00 0.00 0.01 5.26 0.00 0.00 0.00 0.00 0.07 0.07 0.74 0.74
Nonbulbar Movements
 Absent 0.08 2.87 0.10 3.13 0.10 3.11 0.11 3.17 0.91 0.73 0.04 * 0.15
 Present 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NaN NaN NaN NaN
Liver Complications
Ascites 0.01 14.29 0.03 20.00 0.01 10.00 0.00 0.00 0.40 0.65 0.37 0.19
Cirrhosis 0.01 2.56 0.01 2.56 0.03 4.88 0.03 5.41 0.80 0.87 0.10 0.07
Encephalopathy 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NaN NaN NaN NaN
≥ 2 Complications 0.01 3.70 0.01 2.08 0.03 4.76 0.04 6.12 0.89 0.57 0.06 0.25
None 0.04 2.21 0.04 2.22 0.03 1.52 0.04 1.76 0.06 0.57 0.76 0.24
Median Household Income
 Quartile 1 0.01 1.82 0.03 3.39 0.04 4.69 0.06 5.56 1.00 0.98 < 0.001 *** 0.008 **
 Quartile 2 0.00 0.00 0.04 4.48 0.00 0.00 0.01 1.25 0.00 0.00 1.00 0.96
 Quartile 3 0.03 3.77 0.01 1.67 0.03 3.57 0.00 0.00 0.45 0.47 0.33 0.32
 Quartile 4 0.04 5.56 0.01 2.00 0.03 3.51 0.04 5.88 0.02 0.03 0.86 0.82
Hospital Bed Size
 Small 0.01 3.45 0.03 6.45 0.03 5.00 0.01 1.96 0.00 0.15 0.99 0.61
 Medium 0.06 7.41 0.04 6.00 0.01 1.59 0.03 2.99 0.64 0.73 0.20 0.15
 Large 0.01 0.76 0.03 1.29 0.06 3.20 0.07 3.38 0.98 0.90 0.01 * 0.05
Hospital Location/Teaching Status
 Rural 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NaN NaN NaN NaN
 Urban Nonteaching 0.01 2.22 0.00 0.00 0.00 0.00 0.00 0.00 0.60 0.60 0.23 0.23
 Urban Teaching 0.07 3.29 0.10 3.72 0.10 3.80 0.11 3.60 0.87 0.34 0.07 0.42
Hospital Region
 Northeast 0.03 5.41 0.03 3.85 0.00 0.00 0.01 2.13 0.45 0.58 0.33 0.24
 Midwest 0.03 3.70 0.04 6.38 0.01 1.96 0.00 0.00 0.64 0.55 0.20 0.26
 South 0.03 2.50 0.00 0.00 0.06 4.82 0.08 5.04 0.64 0.46 0.20 0.32
 West 0.00 0.00 0.03 3.77 0.03 4.44 0.01 2.22 0.17 0.23 0.59 0.52
Insurance Type
 Medicare 0.04 5.08 0.04 4.41 0.01 1.43 0.04 3.57 0.06 0.37 0.75 0.39
 Medicaid 0.00 0.00 0.04 4.62 0.01 1.67 0.03 2.82 0.17 0.13 0.59 0.63
 Private Insurance 0.01 1.37 0.01 1.15 0.06 4.76 0.03 2.35 0.30 0.26 0.45 0.49
 Other Insurance 0.03 9.09 0.00 0.00 0.01 7.14 0.01 3.85 0.10 0.08 0.69 0.72
Open in a new tab
*

p < 0.05,

**

p < 0.01,

***

p < 0.001

WD-related total annual cost

Table 3 details the total cost related to the treatment of Wilson’s disease expressed in millions of dollars. In combining all strata, there was no significant trend in Wilson’s disease-related cost (R2 = 0.47, p = 0.32). Upon strata-specific analyses, Asian or Pacific Islander patients (R2 = 0.90, p = 0.05) and patients with a household income in the 2nd quartile (R2 = 0.97, p = 0.01) were associated with a significantly increasing total cost. Patients with a diagnosis of bipolar disorder (R2 = 0.99, p = 0.003) or schizophrenia (R2 = 0.92, p = 0.04) were also associated with increased cost. However, patients with a liver complication of cirrhosis demonstrated a decreased total cost (R2 = 0.97, p = 0.02). Furthermore, Figures 1a, 2a, and 3a depict Table 3 in graphical format as a barchart.

Table 3:

Total Costs Associated with Wilson Disease in US Hospitals

Year 2016 2017 2018 2019 r2 p-value
Total Cost (in million dollars) 20.9 27.23 24.2 27.25 0.47 0.32
Demographics Total (in million dollars) Total (in million dollars) Total (in million dollars) Total (in million dollars) r2 for Total (in million dollars) p-value for Total (in million dollars)
Age
 18 to 34 8.98 10.82 6.86 9.22 0.07 0.74
 35 to 49 6.22 7.37 9.95 8.45 0.57 0.25
 50 to 64 3.53 6.27 5.37 4.40 0.03 0.81
 greater than 65 2.17 2.77 2.02 5.17 0.53 0.27
Sex
 Male 7.74 15.93 12.63 13.36 0.26 0.49
 Female 13.16 11.30 11.56 13.89 0.06 0.75
Race
 White 13.19 17.04 14.30 16.78 0.30 0.45
 Black 1.54 2.81 1.86 2.72 0.28 0.47
 Hispanic 1.61 4.60 2.86 2.36 0.00 0.95
 Asian or Pacific Islander 0.96 1.03 1.90 3.02 0.90 0.05 *
 Other 3.61 1.75 3.27 2.37 0.11 0.67
Length of Stay
 0 to 9 days 10.31 10.43 9.17 11.59 0.11 0.66
 10 to 19 days 4.13 7.13 5.37 6.79 0.34 0.42
 20 to 29 days 0.79 5.34 3.97 4.57 0.41 0.36
 30 days and greater 5.67 4.33 5.69 4.30 0.20 0.55
Comorbidities
 Congestive Heart Failure 2.82 0.05 1.49 0.39 0.37 0.40
 Chronic Kidney Disease 0.71 2.58 1.71 3.51 0.66 0.19
 Chronic Obstructive Pulmonary Disease 0.55 0.95 0.26 0.43 0.22 0.53
 Diabetes 1.46 0.90 1.64 0.93 0.09 0.70
 Hypertension 2.12 2.76 2.75 2.47 0.20 0.55
 ≥ 2 Comorbidities 2.22 3.85 4.75 3.55 0.36 0.40
 None 11.01 16.13 11.61 15.96 0.24 0.51
Psychological Etiologies
 Bipolar Disorder 0.34 0.37 0.40 0.44 0.99 0.003 **
 Depression Complications 1.40 1.86 1.25 1.32 0.16 0.60
 Anxiety 1.16 1.38 0.66 1.82 0.11 0.66
 Schizophrenia 0.20 0.34 0.98 1.84 0.92 0.04 *
 ≥ 2 Etiologies 1.35 3.64 2.60 2.76 0.19 0.56
 None 16.46 19.65 18.30 19.07 0.36 0.40
Bulbar Symptoms
 Absent 20.02 23.98 22.66 25.38 0.70 0.16
 Present 0.88 3.25 1.53 1.87 0.03 0.84
Nonbulbar Movements
 Absent 20.45 25.15 24.06 26.01 0.68 0.18
 Present 0.45 2.08 0.14 1.24 0.00 0.94
Liver Complications
 Ascites 0.49 2.13 1.22 3.26 0.64 0.20
 Cirrhosis 4.84 4.21 3.70 2.57 0.97 0.02 *
 Encephalopathy 0.40 1.13 0.11 0.12 0.25 0.50
 ≥ 2 Complications 6.68 7.71 7.41 8.61 0.78 0.11
 None 8.50 12.05 11.76 12.69 0.72 0.15
Median Household Income
 Quartile 1 3.41 5.53 5.30 4.25 0.09 0.70
 Quartile 2 3.17 5.82 6.81 9.34 0.97 0.01 *
 Quartile 3 10.32 8.15 5.50 6.34 0.78 0.12
 Quartile 4 4.01 7.73 6.59 7.32 0.46 0.32
Hospital Bed Size
 Small 2.58 2.54 1.96 3.84 0.27 0.48
 Medium 3.68 3.74 4.96 5.23 0.88 0.06
 Large 14.64 20.95 17.27 18.17 0.12 0.66
Hospital Location/Teaching Status
 Rural 0.70 0.51 0.90 1.02 0.60 0.23
 Urban Nonteaching 2.43 1.90 1.44 1.65 0.72 0.15
 Urban Teaching 17.77 24.82 21.86 24.58 0.47 0.31
Hospital Region
 Northeast 4.74 6.17 5.49 3.74 0.21 0.55
 Midwest 4.92 4.96 4.51 5.60 0.21 0.54
 South 7.61 6.65 6.24 9.69 0.24 0.51
 West 3.64 9.45 7.96 8.22 0.39 0.38
Insurance Type
 Medicare 3.54 6.79 5.03 7.31 0.51 0.28
 Medicaid 4.38 6.77 4.88 10.12 0.58 0.24
 Private Insurance 9.33 12.46 13.16 7.57 0.05 0.77
 Other Insurance 3.65 1.21 1.13 2.25 0.22 0.53
Open in a new tab
*

p < 0.05,

**

p < 0.01,

***

p < 0.001

Figure 1.

Figure 1.

Open in a new tab

This figure represents the annualized total and median costs of WD-related admissions stratified using patient age, sex, and race.

Figure 2.

Figure 2.

Open in a new tab

This figure represents the annualized total and median costs of WD-related admissions stratified using income quartiles, hospital region, and insurance types.

Figure 3.

Figure 3.

Open in a new tab

This figure represents the annualized total and median costs of WD-related admissions stratified using comorbidities and liver complications.

WD-related median annual cost

Table 4 details the median, per-capita admission cost for patients with WD expressed in millions of dollars. No significant findings were shown except an increased median cost in hospitals located in a rural area (R2 = 0.99, p = 0.004). Furthermore, Figures 1b, 2b, and 3b depict Table 4 in graphical format as a barchart.

Table 4:

Median Costs Associated with Wilson Disease in US Hospitals

Year 2016 2017 2018 2019 r2 p-value
Total Cost (in million dollars) 20.9 27.23 24.2 27.25 0.47 0.32
Demographics Median (in dollars) Q1 - Q3 Median (in dollars) Q1 - Q3 Median (in dollars) Q1 - Q3 Median (in dollars) Q1 - Q3 r2 for Median (in dollars) p-value for Median (in dollars)
Age
 18 to 34 7,828.05 (4,206.58 – 15,792.60) 9,242.84 (5,782.60 – 23,003.95) 12,089.71 (5,759.85 – 27,389.86) 8,605.94 (4,762.21 – 16,910.96) 0.13 0.64
 35 to 49 9,737.99 (4,472.90 – 22,906.93) 8,999.18 (4,295.23 – 29,425.44) 10,835.33 (6,154.58 – 22,716.62) 8,190.54 (5,406.99 – 19,096.28) 0.10 0.68
 50 to 64 8,664.32 (5,882.72 – 17,116.32) 8,102.36 (5,407.34 – 19,281.18) 8,998.87 (5,411.26 – 15,135.71) 9,245.25 (5,401.47 – 18,986.03) 0.47 0.31
 greater than 65 12,288.96 (7,389.59 – 19,916.65) 9,313.59 (7,271.26 – 18,321.41) 11,896.63 (4,659.63 – 16,815.29) 9,945.51 (6,594.91 – 18,114.73) 0.16 0.61
Sex
 Male 8,890.56 (4,860.72 – 15,792.60) 8,102.36 (4,823.53 – 31,933.39) 11,586.06 (5,731.47 – 19,973.63) 9,809.81 (5,406.99 – 19,096.28) 0.29 0.46
 Female 9,058.23 (4,743.42 – 19,916.65) 9,935.26 (5,800.36 – 19,281.18) 9,920.92 (5,507.90 – 17,440.35) 7,884.43 (5,213.74 – 15,254.43) 0.22 0.53
Race
 White 8,510.10 (4,743.42 – 17,965.07) 8,445.03 (4,903.05 – 16,918.93) 9,920.92 (5,507.90 – 16,815.29) 9,032.16 (5,129.40 – 17,381.00) 0.33 0.42
 Black 9,271.31 (6,075.50 – 17,117.27) 18,062.19 (11,183.66 – 33,313.71) 16,421.12 (5,559.77 – 22,716.62) 9,809.81 (5,492.10 – 18,202.34) 0.00 1.00
 Hispanic 10,803.62 (4,624.54 – 17,741.72) 11,951.68 (5,086.41 – 27,182.91) 14,285.56 (6,770.28 – 19,973.63) 7,279.67 (4,694.48 – 16,457.86) 0.13 0.64
 Asian or Pacific Islander 10,714.66 (8,598.69 – 32,494.59) 7,190.22 (5,944.60 – 8,663.57) 8,406.30 (5,315.74 – 24,140.87) 16,611.84 (9,718.28 – 47,426.29) 0.34 0.42
 Other 10,709.23 (8,415.15 – 19,140.00) 7,022.00 (5,326.99 – 32,133.14) 15,544.10 (5,408.52 – 47,460.06) 8,787.78 (6,534.55 – 22,015.81) 0.01 0.90
Length of Stay
 0 to 9 days 8,051.52 (4,449.14 – 13,296.52) 7,248.14 (4,484.28 – 12,221.41) 8,062.41 (4,730.03 – 12,850.51) 7,353.72 (4,713.57 – 11,980.21) 0.14 0.62
 10 to 19 days 22,906.93 (17,117.27 – 35,643.82) 29,425.44 (19,238.01 – 73,179.25) 26,245.64 (16,432.58 – 35,182.25) 30,668.51 (16,457.86 – 43,482.32) 0.56 0.25
 20 to 29 days 42,547.68 (28,823.72 – 42,547.68) 86,703.55 (59,544.16 – 129,603.06) 60,145.39 (38,490.36 – 104,946.93) 64,320.07 (31,489.58 – 126,931.24) 0.08 0.72
 30 days and greater 332,777.11 (332,777.11 – 553,633.22) 93,481.73 (76,454.07 – 116,083.96) 190,752.44 (49,834.74 – 264,022.82) 168,040.75 (63,682.26 – 223,345.05) 0.26 0.49
Comorbidities
 Congestive Heart Failure 8,543.79 (8,543.79 – 553,633.22) 9,935.26 (9,935.26 – 9,935.26) 12,443.99 (10,067.45 – 16,760.92) 19,704.53 (16,611.84 – 30,822.56) 0.87 0.07
 Chronic Kidney Disease 7,155.41 (5,800.88 – 8,296.47) 25,570.68 (9,313.59 – 73,179.25) 14,006.80 (9,625.13 – 27,768.08) 9,884.90 (6,113.35 – 19,482.34) 0.00 0.95
 Chronic Obstructive Pulmonary Disease 10,774.87 (4,268.60 – 20,910.68) 19,281.18 (13,455.77 – 43,048.10) 5,507.90 (2,443.34 – 9,669.96) 18,180.75 (9,395.81 – 18,986.03) 0.03 0.83
 Diabetes 16,271.05 (4,860.72 – 52,376.08) 5,759.73 (2,409.75 – 31,933.39) 4,897.51 (2,770.11 – 10,974.57) 7,884.43 (5,722.31 – 18,114.73) 0.42 0.35
 Hypertension 10,470.24 (5,341.35 – 17,741.72) 7,248.14 (4,356.19 – 12,270.91) 9,303.58 (5,745.78 – 19,589.06) 7,140.28 (4,125.40 – 20,536.20) 0.40 0.37
 ≥ 2 Comorbidities 8,738.02 (4,542.08 – 16,970.42) 8,763.75 (5,835.01 – 16,433.14) 11,586.06 (6,154.58 – 17,266.08) 9,794.55 (5,492.10 – 14,325.01) 0.33 0.42
 None 9,271.31 (4,624.54 – 18,672.03) 8,991.45 (5,782.60 – 23,725.25) 11,896.63 (5,544.13 – 19,949.04) 8,304.44 (4,867.41 – 17,318.80) 0.00 1.00
Psychological Etiologies
 Bipolar Disorder 4,123.20 (3,024.05 – 6,340.03) 3,499.56 (3,169.19 – 6,924.17) 9,669.96 (9,303.58 – 15,764.00) 11,138.85 (6,365.29 – 66,613.48) 0.83 0.09
 Depression Complications 8,240.46 (6,075.50 – 17,741.72) 8,619.40 (4,356.19 – 23,003.95) 8,062.41 (5,052.60 – 14,823.93) 7,268.92 (4,134.84 – 14,517.57) 0.62 0.21
 Anxiety 10,714.66 (5,274.39 – 15,792.60) 11,449.34 (5,835.01 – 15,538.63) 10,331.90 (4,730.03 – 20,370.03) 11,980.21 (6,764.95 – 21,061.13) 0.22 0.53
 Schizophrenia 13,753.19 (13,753.19 – 18,956.29) 6,798.81 (3,504.00 – 26,219.26) 24,140.87 (16,652.08 – 25,281.02) 15,319.13 (11,005.22 – 49,975.50) 0.16 0.60
 ≥ 2 Etiologies 8,415.15 (4,294.79 – 16,840.10) 16,118.80 (5,785.33 – 32,133.14) 9,920.92 (6,674.12 – 15,361.39) 9,246.63 (5,406.99 – 19,041.87) 0.02 0.86
 None 9,917.10 (5,250.25 – 20,140.12) 8,991.45 (5,782.60 – 21,244.54) 10,974.57 (5,381.07 – 19,296.80) 9,110.31 (5,337.46 – 18,869.96) 0.00 0.94
Bulbar Symptoms
 Absent 8,664.32 (4,743.42 – 17,652.33) 8,991.45 (5,427.21 – 19,153.33) 10,225.66 (5,559.77 – 17,440.35) 9,066.49 (5,129.40 – 18,202.34) 0.21 0.54
 Present 13,753.19 (10,714.66 – 17,965.07) 19,238.01 (7,102.80 – 49,399.13) 17,266.08 (5,759.85 – 31,420.12) 13,055.93 (6,594.91 – 31,404.74) 0.03 0.82
Nonbulbar Movements
 Absent 8,669.04 (4,797.40 – 17,652.33) 9,215.01 (5,511.92 – 21,244.54) 10,580.96 (5,630.51 – 18,454.96) 8,787.78 (5,129.40 – 18,862.82) 0.06 0.75
 Present 15,792.60 (10,803.62 – 19,004.86) 9,000.78 (3,496.75 – 47,844.26) 11,364.09 (11,364.09 – 12,178.14) 11,005.22 (8,687.58 – 17,381.00) 0.29 0.46
Liver Complications
 Ascites 6,320.03 (5,499.12 – 16,271.05) 12,787.90 (6,891.13 – 23,725.25) 11,586.06 (6,701.12 – 27,389.86) 32,906.65 (7,059.33 – 212,460.65) 0.75 0.13
 Cirrhosis 9,985.25 (5,747.74 – 19,426.83) 8,537.54 (4,356.19 – 29,425.44) 13,052.94 (4,897.51 – 19,589.06) 7,761.64 (4,694.48 – 13,270.29) 0.01 0.88
 Encephalopathy 5,882.72 (2,529.12 – 13,753.19) 17,034.34 (17,034.34 – 83,432.92) 8,210.48 (8,210.48 – 10,881.44) 8,787.78 (8,787.78 – 11,789.64) 0.00 1.00
 ≥ 2 Complications 11,754.60 (5,800.88 – 35,254.32) 9,895.16 (5,785.33 – 36,546.01) 13,652.16 (6,871.23 – 31,937.49) 10,102.13 (6,764.68 – 26,630.28) 0.01 0.91
 None 8,625.42 (4,624.54 – 17,117.27) 9,313.59 (5,533.42 – 16,918.93) 9,669.96 (5,381.07 – 15,764.00) 8,687.58 (4,905.10 – 16,866.36) 0.02 0.86
Median Household Income
 Quartile 1 8,491.94 (4,542.08 – 13,753.19) 8,307.80 (5,533.42 – 16,118.80) 10,974.57 (5,507.90 – 16,815.29) 7,077.34 (4,125.40 – 14,549.68) 0.02 0.88
 Quartile 2 8,664.32 (4,955.03 – 17,607.10) 9,215.01 (4,318.03 – 16,006.90) 8,210.48 (3,703.07 – 17,299.86) 7,905.24 (4,773.54 – 18,862.82) 0.55 0.26
 Quartile 3 10,008.46 (5,747.74 – 28,823.72) 12,027.76 (5,427.21 – 36,508.58) 12,428.57 (6,701.12 – 22,307.68) 9,718.28 (6,296.69 – 17,318.80) 0.00 0.96
 Quartile 4 11,146.35 (4,541.59 – 17,965.07) 9,097.55 (6,769.50 – 31,933.39) 10,073.47 (6,855.23 – 17,440.35) 13,297.18 (7,650.11 – 30,668.51) 0.28 0.47
Hospital Bed Size
 Small 13,459.79 (8,240.46 – 24,232.70) 9,969.05 (6,300.26 – 19,281.18) 7,799.28 (4,241.80 – 12,443.99) 9,794.55 (5,192.06 – 19,041.87) 0.52 0.28
 Medium 7,986.98 (4,955.03 – 16,970.42) 7,148.27 (4,356.19 – 12,221.41) 9,273.81 (5,630.51 – 14,855.35) 7,905.24 (3,632.19 – 14,990.23) 0.08 0.72
 Large 8,625.42 (4,624.54 – 16,840.10) 10,725.20 (5,474.65 – 27,854.67) 13,009.53 (6,602.44 – 26,245.64) 9,322.58 (5,656.45 – 19,096.28) 0.09 0.71
Hospital Location/Teaching Status
 Rural 6,320.03 (4,624.54 – 8,625.42) 7,353.40 (5,326.99 – 15,538.63) 8,070.38 (4,069.03 – 13,052.94) 9,245.25 (5,932.13 – 11,943.75) 0.99 0.004 **
 Urban Nonteaching 8,100.30 (4,261.84 – 15,551.34) 6,935.47 (4,024.45 – 12,221.41) 10,225.66 (5,731.47 – 14,855.35) 6,594.91 (3,632.19 – 12,494.27) 0.01 0.90
 Urban Teaching 10,629.63 (5,341.35 – 19,482.72) 9,976.19 (5,808.93 – 27,854.67) 11,364.09 (5,899.10 – 19,973.63) 9,246.63 (5,406.99 – 19,041.87) 0.16 0.61
Hospital Region
 Northeast 9,737.99 (4,757.15 – 22,849.00) 10,673.28 (5,876.17 – 24,504.24) 13,150.50 (6,932.36 – 18,911.82) 9,395.81 (6,594.91 – 18,862.82) 0.01 0.89
 Midwest 8,240.46 (4,261.84 – 16,089.83) 6,798.81 (3,998.73 – 25,570.68) 10,067.45 (4,423.45 – 21,498.36) 9,110.31 (5,129.40 – 15,319.13) 0.30 0.45
 South 8,625.42 (4,682.98 – 16,696.23) 7,972.07 (4,484.28 – 12,437.85) 9,303.58 (5,411.26 – 16,474.82) 7,798.90 (4,396.32 – 16,399.38) 0.05 0.78
 West 12,280.20 (7,766.78 – 22,906.93) 13,401.04 (8,619.40 – 36,546.01) 13,009.53 (6,750.94 – 23,861.00) 14,549.68 (7,140.28 – 30,427.60) 0.76 0.13
Insurance Type
 Medicare 8,669.04 (4,542.08 – 16,970.42) 9,895.16 (5,988.70 – 24,362.52) 8,896.53 (4,423.45 – 16,421.12) 9,794.55 (5,492.10 – 16,866.36) 0.24 0.51
 Medicaid 8,625.42 (4,743.42 – 17,652.33) 8,854.86 (4,356.19 – 19,281.18) 10,067.45 (5,544.13 – 21,498.36) 8,605.94 (5,213.74 – 22,404.39) 0.05 0.79
 Private Insurance 9,737.99 (4,797.40 – 17,607.10) 10,458.70 (5,808.93 – 30,237.06) 12,041.20 (6,855.23 – 24,140.87) 8,304.44 (5,192.06 – 19,041.87) 0.05 0.77
 Other Insurance 10,709.23 (8,100.30 – 28,015.77) 6,924.17 (3,499.56 – 14,799.24) 12,089.71 (4,555.61 – 14,159.81) 9,809.81 (4,762.21 – 18,862.82) 0.02 0.85
Open in a new tab
*

p < 0.05,

**

p < 0.01,

***

p < 0.001

Discussion

In this study, we investigated hospitalization data and cost burden among WD patients in the United States from 2016 to 2019 through analysis of the NIS. In particular, we examined the trends in WD-related hospital admissions, mortality rates, total hospitalization costs, and median hospitalization costs during this time period. There was a non-significant rise in total hospital admissions, with significant increases seen in patients >65, White patients, patients in the first income quartile, patients utilizing Medicare, and hospitals with a small number of beds. With regard to mortality, an increase in WD-related deaths was seen in those in the first income quartile and those admitted to large hospitals. In terms of cost burden, total hospitalization costs were shown to be significantly increased in the Asian or Pacific Islander cohort and in patients in the second income quartile. Median hospitalization costs were significantly increased in hospitals located in a rural area.

Multiple studies corroborate the increase in hospital utilization and costs among WD patients despite the scarcity of hospitalization data on WD (23,24). Undetected disease or non-adherence to treatment following diagnosis, both common occurrences due to inherent difficulties in screening and the demanding nature of the outpatient treatment, may lead to fulminant hepatic failure in the setting of underlying chronic liver disease, requiring emergent liver transplant (25). Awaiting transplant, patients must often undergo costly copper-reducing interventions such as hemofiltration, plasmapheresis, and dialysis (26). Interestingly, WD patients with cirrhosis depicted a significant decrease in total cost. This may be in part to the improvements and advancement of outpatient care and surveillance methods for WD-related cirrhosis and fibrosis. This enhanced outpatient care likely inversely affected the cohort selection of admitted patients with severe and end-stage liver disease, which in effect likely influenced the increased mortality rates observed in the mortality analysis.

Another important comorbidity/etiology that can lead to increased hospital utilization by WD patients are neuropsychiatric disorders (24,27,28). Both schizophrenia and bipolar disorder were found to be linked with increased annual cost. WD presents a broad range of psychiatric symptoms, complicating treatment and contributing to higher expenses for several reasons. Firstly, individuals with mental health disorders may struggle with adherence to WD treatment, given the frequent dosing and associated side effects of typical treatments (29). Furthermore, the presence of psychiatric symptoms alone is concordant with delayed diagnosis. According to European practice guidelines, the average time to WD diagnosis when hepatic symptoms are the initial sign is six months, while neurological symptoms is 18 months, and psychiatric symptoms is 26 months (30). A retrospective study involving 229 WD cases revealed that the strongest predictor of mortality was the development of cirrhosis from longstanding disease (31).

The increase in hospital admissions among different cohorts can be reflective of multiple factors. Increased admission rates may be reflective of undetected or uncontrolled disease, given that early detection and initiation of outpatient treatment create a favorable prognosis and can prevent severe manifestations in adherent individuals (32). Interestingly, the absence of non-bulbar neurologic disease was associated with higher mortality, which may reflect that non-classic manifestations of WD were associated with a delayed diagnosis. It is not surprising that those in the lowest income quartile may have a higher rate of missed diagnosis, as financial barriers to access to care render them less likely to utilize primary care services and undergo screening (33–36). The rising hospitalization burden among this cohort may also explain the increase in admissions in smaller hospitals, as these institutions often serve as the first point of contact in remote, lower-income regions. Furthermore, the chronic nature of WD may be related to low treatment persistence rates, with a retrospective study of 170 patients reporting only 74.1% adherence during a mean follow-up of 11.7 years (37). This investigation found higher education and a supportive family environment to predict better rates of adherence. It is not known if low socioeconomic status (SES) in turn predicts low treatment persistence in the context of WD; however, associations between low SES and medication adherence have been proposed for other chronic liver conditions (38,39).

Our study also found a rise in admissions among Medicare users and those who are 65 years of age or older. This may, in part, reflect the successful implementation of copper-reducing therapies in prior decades, which have enabled symptomatic control and longevity in more WD patients (40–43). Given that diagnostic tools and treatment modalities are constantly developing over time, it is logical that we would observe a heavier disease burden in the older population who would have had less opportunity for early initiation of treatment.

It is unclear why there is an increase in admissions among White patients. However, what is notable is that while the number of admissions increases non-significantly in the overall population and significantly in Whites, hospitalization costs are shown to increase only in the Asian/Pacific Islander cohort. It is unclear what is driving heightened costs; albeit speculative, they may be reflective of prolonged admission lengths, slower control of disease, and additional treatments secondary to adverse clinical outcomes.

For improvement of clinical outcomes and cost control in WD patients, early detection of disease is critical, as the efficacy of treatment is contingent on early initiation. Diagnosis has traditionally been challenging due to the complexity, high expense, and timeliness of molecular sequencing techniques and the lack of biomarkers to accurately identify disease (44,45). However, recent advancements in diagnostic modalities are likely to enhance detection and screening in the near future, such as mass spectrometry for quantifying proteins in dried blood, the measurement of relatively exchangeable copper, optical tomography for sensitive detection of Kayser Fleischer rings, and dynamic PET analysis for detecting copper accumulation in the liver of mice models (46–50).

Limitations

Our study included limitations related to the retrospective design of the study including potential confounding bias and difficulty in assessing causality. Data regarding diagnostic testing, progression of time from diagnosis, and level of care required were also lacking for this particular study. Also, on initial admission, the stage of liver injury and the advancement of WD were indeterminable. Specific neurologic manifestations, which are common presenting symptoms of WD, were not available in this study. Conversely, we were unable to extrapolate cases diagnosed on asymptomatic screening alone i.e. family screening. Additionally, this study aimed to evaluate hospital admission rates and their associated costs, however, we were unable to differentiate re-admissions from new case admissions.

Conclusion

Our study showed there were no significant increases in hospital admissions, mortality, or overall cost of WD. However, it demonstrated that certain ethnicity groups, income classes, and comorbidities had increased admissions or costs. Implementing screening and management of the vulnerable cohorts will improve WD-related admission, mortality, and costs.

Footnotes

Conflict of Interest Statement:

The authors of this manuscript certify they share no affiliation or involvement with any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. None declared.

References

  • 1.Yavuz S, Pişkin FC, Oktay C, Soyupak S, Tümgör G. Evaluation of the Liver and Pancreas by 2D Shear Wave Elastography in Pediatric Wilson’s Disease. Turk J Gastroenterol. 2022;33(2):161–167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Vargas O, Faraoun SA, Dautry R, et al. MR imaging features of liver involvement by Wilson disease in adult patients. Radiol Med. 2016;121(7):546–556. [DOI] [PubMed] [Google Scholar]
  • 3.El-Karaksy H, Fahmy M, El-Raziky MS, et al. A clinical study of Wilson’s disease: The experience of a single Egyptian Paediatric Hepatology Unit. Arab J Gastroenterol. 2011;12(3):125–130. [DOI] [PubMed] [Google Scholar]
  • 4.Lu ZK, Cheng J, Li SM, et al. [Phenotypes and ATP7B gene variants in 316 children with Wilson disease]. Zhonghua Er Ke Za Zhi. 2022;60(4):317–322. [DOI] [PubMed] [Google Scholar]
  • 5.Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut. 2007;56(1):115–120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Ferenci P, Stremmel W, Członkowska A, et al. Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease. Hepatology. 2019;69(4):1464–1476. [DOI] [PubMed] [Google Scholar]
  • 7.Eisenbach C, Sieg O, Stremmel W, Encke J, Merle U. Diagnostic criteria for acute liver failure due to Wilson disease. World J Gastroenterol. 2007;13(11):1711–1714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Durand F, Bernuau J, Giostra E, et al. Wilson’s disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine. Gut. 2001;48(6):849–852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Stremmel W, Meyerrose KW, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115(9):720–726. [DOI] [PubMed] [Google Scholar]
  • 10.Tian Y, Gong GZ, Yang X, Peng F. Diagnosis and management of fulminant Wilson’s disease: a single center’s experience. World J Pediatr. 2016;12(2):209–214. [DOI] [PubMed] [Google Scholar]
  • 11.Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369(26):2525–2534. [DOI] [PubMed] [Google Scholar]
  • 12.Ripamonti R, Ferral H, Alonzo M, Patel NH. Transjugular intrahepatic portosystemic shunt-related complications and practical solutions. Semin Intervent Radiol. 2006;23(2):165–176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Marin C, Robles R, Parrilla G, Ramírez P, Bueno FS, Parrilla P. Liver transplantation in Wilson’s disease: are its indications established? Transplant Proc. 2007;39(7):2300–2301. [DOI] [PubMed] [Google Scholar]
  • 14.Peedikayil MC, Al Ashgar HI, Al Mousa A, Al Sebayel M, Al Kahtani K, Alkhail FA. Liver transplantation in Wilson’s disease: Single center experience from Saudi Arabia. World J Hepatol. 2013;5(3):127–132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Litwin T, Dušek P, Członkowska A. Symptomatic treatment of neurologic symptoms in Wilson disease. Handb Clin Neurol. 2017;142:211–223. [DOI] [PubMed] [Google Scholar]
  • 16.Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015;14(1):103–113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Wang G, Jin P, Ma X, et al. Cognitive and gait in Wilson’s disease: a cognitive and motor dual-task study. Front Neurol. 2023;14:1243122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Rustgi VK, Gupta K, Tait C, et al. Wilson’s Disease: An Analysis of Health Care Use and Cost Burden of Commercially Insured Adults in the United States. Hepatol Commun. 2022;6(2):389–398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.HCUP-US NIS overview. [Google Scholar]
  • 20.Cost H, Project U, Others. NIS description of data elements. Rockville, MD: Agency for Healthcare Research and Quality. Published online 2008. [DOI] [PubMed] [Google Scholar]
  • 21.Cost H, (hcup) UP, Others. Producing National HCUP Estimates-Accessible Version. Published online 2020. [Google Scholar]
  • 22.Zhang Z Multiple imputation with multivariate imputation by chained equation (MICE) package. Ann Transl Med. 2016;4(2):30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Sandahl TD, Laursen TL, Munk DE, Vilstrup H, Weiss KH, Ott P. The Prevalence of Wilson’s Disease: An Update. Hepatology. 2020;71(2):722–732. [DOI] [PubMed] [Google Scholar]
  • 24.Li N, Krishna SG, Hinton A, Conwell DL, Mumtaz K. Characteristics and outcomes of hospitalized patients with Wilson’s disease in the United States: A national survey. Ann Hepatol. 2021;25:100362. [DOI] [PubMed] [Google Scholar]
  • 25.Yu M, Ren L, Zheng M, Hong M, Wei Z. Delayed Diagnosis of Wilson’s Disease Report From 179 Newly Diagnosed Cases in China. Front Neurol. 2022;13:884840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Leung M, Aronowitz PB, Medici V. The Present and Future Challenges of Wilson’s Disease Diagnosis and Treatment. Clin Liver Dis. 2021;17(4):267–270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264(19):2511–2518. [PubMed] [Google Scholar]
  • 28.Spyridi S, Diakogiannis I, Michaelides M, Sokolaki S, Iacovides A, Kaprinis G. Delusional disorder and alcohol abuse in a patient with Wilson’s disease. Gen Hosp Psychiatry. 2008;30(6):585–586. [DOI] [PubMed] [Google Scholar]
  • 29.Mazhar A, Piper MS. Updates on Wilson disease. Clin Liver Dis. 2023;22(4):117–121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671–685. [DOI] [PubMed] [Google Scholar]
  • 31.Beinhardt S, Leiss W, Stättermayer AF, et al. Long-term outcomes of patients with Wilson disease in a large Austrian cohort. Clin Gastroenterol Hepatol. 2014;12(4):683–689. [DOI] [PubMed] [Google Scholar]
  • 32.Walshe JM, Dixon AK. Dangers of non-compliance in Wilson’s disease. Lancet. 1986;1(8485):845–847. [DOI] [PubMed] [Google Scholar]
  • 33.Begley C, Basu R, Lairson D, et al. Socioeconomic status, health care use, and outcomes: persistence of disparities over time. Epilepsia. 2011;52(5):957–964. [DOI] [PubMed] [Google Scholar]
  • 34.Devoe JE, Baez A, Angier H, Krois L, Edlund C, Carney PA. Insurance + access not equal to health care: typology of barriers to health care access for low-income families. Ann Fam Med. 2007;5(6):511–518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hong R, Baumann BM, Boudreaux ED. The emergency department for routine healthcare: race/ethnicity, socioeconomic status, and perceptual factors. J Emerg Med. 2007;32(2):149–158. [DOI] [PubMed] [Google Scholar]
  • 36.Clancy CM, Eisenberg JM. Emergency medicine in population-based systems of care. Ann Emerg Med. 1997;30(6):800–803. [DOI] [PubMed] [Google Scholar]
  • 37.Masełbas W, Członkowska A, Litwin T, Niewada M. Persistence with treatment for Wilson disease: a retrospective study. BMC Neurol. 2019;19(1):278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Kardashian A, Wilder J, Terrault NA, Price JC. Addressing Social Determinants of Liver Disease During the COVID-19 Pandemic and Beyond: A Call to Action. Hepatology. 2021;73(2):811–820. [DOI] [PubMed] [Google Scholar]
  • 39.Gruttadauria S, Grosso G, Mistretta A, et al. Impact of recipients’ socio-economic status on patient and graft survival after liver transplantation: The IsMeTT experience. Dig Liver Dis. 2011;43(11):893–898. [DOI] [PubMed] [Google Scholar]
  • 40.Huster D Wilson disease. Best Pract Res Clin Gastroenterol. 2010;24(5):531–539. [DOI] [PubMed] [Google Scholar]
  • 41.Brewer GJ, Askari FK. Wilson’s disease: clinical management and therapy. J Hepatol. 2005;42 Suppl(1):S13–S21. [DOI] [PubMed] [Google Scholar]
  • 42.Dzieżyc K, Karliński M, Litwin T, Członkowska A. Compliant treatment with anti-copper agents prevents clinically overt Wilson’s disease in pre-symptomatic patients. Eur J Neurol. 2014;21(2):332–337. [DOI] [PubMed] [Google Scholar]
  • 43.Schaefer M, Gotthardt DN, Ganion N, et al. Wilson disease: Health-related quality of life and risk for depression. Clin Res Hepatol Gastroenterol. 2016;40(3):349–356. [DOI] [PubMed] [Google Scholar]
  • 44.Chang IJ, Hahn SH. Chapter 3 - The genetics of Wilson disease. In: Członkowska A, Schilsky ML, eds. Handbook of Clinical Neurology. Vol 142. Elsevier; 2017:19–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Hahn SH. Population screening for Wilson’s disease. Ann N Y Acad Sci. 2014;1315:64–69. [DOI] [PubMed] [Google Scholar]
  • 46.Moini M, To U, Schilsky ML. Recent advances in Wilson disease. Transl Gastroenterol Hepatol. 2021;6:21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Broniek-Kowalik K, Dzieżyc K, Litwin T, Członkowska A, Szaflik JP. Anterior segment optical coherence tomography (AS-OCT) as a new method of detecting copper deposits forming the Kayser-Fleischer ring in patients with Wilson disease. Acta Ophthalmol. 2019;97(5):e757–e760. [DOI] [PubMed] [Google Scholar]
  • 48.Peng F, Lutsenko S, Sun X, Muzik O. Imaging copper metabolism imbalance in Atp7b (−/−) knockout mouse model of Wilson’s disease with PET-CT and orally administered 64CuCl2. Mol Imaging Biol. 2012;14(5):600–607. [DOI] [PubMed] [Google Scholar]
  • 49.Jung S, Whiteaker JR, Zhao L, Yoo HW, Paulovich AG, Hahn SH. Quantification of ATP7B Protein in Dried Blood Spots by Peptide Immuno-SRM as a Potential Screen for Wilson’s Disease. J Proteome Res. 2017;16(2):862–871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.El Balkhi S, Trocello JM, Poupon J, et al. Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson’s disease diagnosis. Clin Chim Acta. 2011;412(23–24):2254–2260. [DOI] [PubMed] [Google Scholar]

RESOURCES