The trends in healthcare utilization and costs associated with primary liver cancer: an analysis of United States hospitals between 2016 and 2019

Abstract

Background:

Primary liver cancer (PLC) has placed an increasing economic and resource burden on the healthcare system of the United States. We attempted to quantify its epidemiology and associated costs using a national inpatient database.

Methods:

Hospital discharge and insurance claims data from the National Inpatient Sample were used to conduct this analysis. Patients diagnosed with PLC (hepatocellular carcinoma or cholangiocarcinoma) were included in the study population, which was then stratified using patient demographics, comorbidities, degree of cancer spread, liver disease complications, and other descriptors. Trends were analyzed via regression curves for each of these strata from the years 2016–2019, with special attention to patterns in hospitalization incidence, inpatient mortality rate, total costs, and average per-capita costs. The resulting curves were evaluated using goodness-of-fit statistics and p-values.

Results:

Aggregate hospitalization incidence, inpatient mortality rates, and total costs were found to significantly increase throughout the study period (p=0.002, p=0.002, and p=0.02, respectively). Relative to their demographic counterparts, males, White Americans, and those older than 65 years of age contributed the largest proportions of total costs. These population segments also experienced significant increases in total expenditure (p=0.04, p=0.03, and p=0.02, respectively). Admissions deemed to have multiple comorbidities were associated with progressively higher total costs throughout the study period (p=0.01). Of the categorized underlying liver diseases, only admissions diagnosed with alcoholic liver disease or non-alcoholic fatty liver disease saw significantly increasing total costs (p=0.006 and p=0.01), although hepatitis C was found to be the largest contributor to total expenses.

Conclusion:

From 2016–2019, total costs, admission incidence, and inpatient mortality rates associated with PLC hospitalization increased. Strata-specific findings may be reflective of demographic shifts in the PLC patient populations, as well as changes in underlying chronic liver disease etiologies.

Introduction

Primary liver cancer (PLC) accounts for significant morbidity and mortality in the United States (US) and has placed increasing economic strain on its healthcare system in recent decades (12). The World Health Organization 2020 estimates of cancer incidence and mortality rank PLC 6th and 3rd worldwide, respectively, and the global burden continues to rise (3). PLC occurs most often in the setting of chronic liver disease and cirrhosis, with the most common underlying disease being viral hepatitis (4,5,6,7). PLC is also associated with heavy alcohol consumption, non-alcoholic steatohepatitis (NASH), and other factors including exposure to aflatoxin B1, microcystins, and polluted drinking water (3,4,8,9). Leading etiologies of PLC vary across demographics, regions, and countries. For instance, hepatitis B is most common in Asia and Sub-Saharan Africa, while hepatitis C and alcohol abuse are the main risk factors for PLC in the US (3). The incidence of PLC associated with non-alcoholic fatty liver disease (NAFLD) is expected to increase significantly worldwide over the next decade (10).

As the incidence and prevalence of chronic liver disease in the US continues to grow (11), a parallel increase in PLC is likely to follow. Prior research has already shown increasing hospitalization costs associated with inpatient hospitalization for hepatocellular carcinoma and cholangiocarcinoma from 2002 to 2011 and 1997 to 2012, respectively (1,2). Since then, substantial progress has been made in the prevention, diagnosis, and treatment of PLC, such as more widespread acceptance of surveillance programs in high-risk patients (12,13), the advent of direct-acting antiviral agents for the treatment of hepatitis C (14), refinement of the Liver Imaging Reporting and Data System classification of hepatic nodules (15), and improved access and utilization of surgical therapies, tumor ablation, transarterial chemo- and radioembolization, and small molecule inhibitors (16–25). Whether national healthcare utilization and costs associated with PLC have changed alongside these advancements remains to be seen. In this study, we analyzed contemporary trends in healthcare utilization and costs associated with PLC (hepatocellular carcinoma, cholangiocarcinoma, and mixed hepatic malignancy) in the US using a nationally representative dataset. Specifically, we measured annual inpatient hospitalization incidence, mortality rates, and the associated changes in total and mean hospitalization costs from 2016–2019 by patient demographics, comorbidities, degree of cancer spread, liver disease complications, socioeconomic status, and hospital characteristics. Understanding the distribution of PLC hospitalization incidence, mortality, and costs will aid in the identification of targeted strategies to reduce healthcare spending.

Methods

Data was analyzed from the National Inpatient Sample (NIS), a US-based hospital database funded by the Agency for Healthcare Research and Quality via the Healthcare Cost and Utilization Project (HCUP-AHRQ) (26). Since 2012, the NIS has been produced annually by sampling twenty percent of discharges within each State Inpatient Database (SID), rather than keeping all discharges from a sample of hospitals drawn from each SID (27). The current method of data collection allows the NIS to be generalizable across all regions of the US. There are no unique patient identifiers associated with an indexed hospitalization; therefore, each hospitalization is treated independently. Patient demographics and discharge diagnoses for each hospitalization were coded according to the ICD-10 classification system.

This study includes all inpatient admissions from January 1, 2016 to December 31, 2019, which was the most current data available at the time of the analysis. This period was chosen specifically to minimize potential data irregularities caused by the change from ICD-9 to ICD-10 coding systems in 2015. Cost trends were evaluated for hospitalizations that carried a diagnosis of PLC (hepatocellular carcinoma, cholangiocarcinoma, and mixed hepatic cancer diagnoses). The ICD-10 diagnosis and procedure codes used in the analysis are presented in Supplementary Table 1. Variables pertaining to demographics (age, gender, race), comorbidities, liver disease complications, cancer type, degree of cancer spread, oncologic surgery, etiology of liver disease, hospital characteristics and region, and payer information were used to stratify the cohort and further examine cost trends in specific patient populations with PLC. Continuous variables were grouped into ranges to create categories for cohort stratification (e.g., age cohorts included 18 to 34 year olds, 35 to 49 year olds, 50 to 64 year olds, and those older than 65). For simplification, certain variables were associated with multiple ICD-10 codes. Specifically, the autoimmune liver disease variable includes primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis. The metabolic liver disease variable includes hemochromatosis, alpha 1-antitrypsin deficiency, and Wilson’s disease. The variable pertaining to lymphatic spread includes ICD-10 codes associated with prior receipt of chemotherapy or chemotherapy received during the indexed hospitalization.

The costs for each hospitalization were calculated by using a charge-to-cost ratio conversion and then adjusting for inflation based on the Consumer Price Index ratio for a given year. National total and per-capita mean and median costs were then estimated using hospital and stratum-specific weighted data provided by the NIS. Interquartile per-capita cost ranges were also derived. Each stratum was graphed on a regression curve to analyze the cost trends over the study period. These curves were assessed using goodness-of-fit (R2) and p-values. In addition to costs, trends in PLC hospitalization incidence and in-hospital mortality rates were also examined. The number of events in the weighted PLC hospitalization incidence and in-hospital mortality analyses were denoted as the number of cases per 100,000 hospitalizations. The annual percent differences in PLC hospitalization incidence, as well as total, mean, and median PLC hospitalization costs, were calculated. For in-hospital mortality, the annual proportion percentage was calculated by dividing the in-hospital mortality incidence by the hospital admission incidence for the given year. The multiple imputation by chained equations method was implemented to account for random-type missing data (28). A p-value of less than 0.05 was considered statistically significant, and corresponding 95% confidence intervals were constructed for all analyses except for median cost data. R2 and p-values are denoted in the form (R2, p). R version 4.1.2 was used for all analyses.

Results

PLC-related hospitalizations

Annualized incidence of PLC hospitalizations was calculated from 2016 through 2019. The estimated annual incidence of PLC hospitalizations was 172.32, 187.58, 199.14, and 215.08 for the years 2016 through 2019, which represented a significant increase (1.00, 0.002).

The following groups constituted the majority of PLC hospitalizations during the years 2016 through 2019 as demonstrated by the incidence rates and stratum percentages: those aged 50–64 and greater than 65, White Americans, men; those with a diagnosis of hepatocellular carcinoma, multiple comorbidities, and hepatitis C; non-surgical hospitalizations; those without PLC spread; those who received care at large-sized hospitals, teaching hospitals, and in the Southern region of the US; as well as Medicare beneficiaries. As far as trends, the number of PLC hospitalizations among those age greater than 65 significantly increased over the study period. The male, female, white, Hispanic, black, and Asian/Pacific islander groups also saw a significant increase in the annual incidence of PLC hospitalizations, as well as Medicare and private insurance beneficiaries, those who received care at teaching hospitals, and those who were hospitalized in the Midwestern, Southern, and Western regions of the US. There were increasing rates of PLC hospitalizations among those with hepatocellular carcinoma and cholangiocarcinoma.

Additional trends that reached significance included a growing incidence of PLC hospitalizations among those with diabetes, hypertension, and multiple comorbidities. There was a general rise in PLC hospitalizations among those with congestive heart failure, although this was not statistically significant. There were increasing PLC hospitalizations among those with no cancer spread, spread to non-gastrointestinal organs, spread to lymph nodes (not statistically significant), and those with cancer spread requiring chemotherapy. Furthermore, PLC hospitalizations for non-surgical care, lobectomy, and partial hepatectomy increased significantly. An increasing incidence of PLC hospitalizations among those without liver disease complications, encephalopathy, hepatorenal syndrome, and 2 or 3 combined liver complications was also observed. Notably, an increasing trend in PLC hospitalizations was observed among those with a diagnosis of NAFLD and alcoholic liver disease (ALD).

When considering hospitalization rates relative to the general PLC cohort (as opposed to total US hospitalizations), there was an increasing percentage of PLC hospitalizations with admission ages greater than 65, Asian/Pacific Islander, multiple comorbidities, chemotherapy, cholangiocarcinoma, non-surgical hospitalizations, no liver complications, hepatorenal syndrome, non-alcoholic fatty liver disease, alcoholic liver disease, small hospital bed size, teaching hospital, and Medicare beneficiary groups. Moreover, there was a corresponding, decreasing percentage of PLC hospitalizations among the following strata: ages 50–64, black, hypertension, no cancer spread, hepatocellular carcinoma, ablation procedure complication, liver transplant, hepatitis B and C, large hospital bed size, non-teaching hospital, Medicaid and private insurance beneficiary groups. It should be noted that some of these trends were not statistically significant. These patterns in annual incidence and stratum percentage trends are further detailed in Table 1.

Table 1:

Admission Rates Associated with Primary Liver Cancer in US Hospitals

Year	2016		2017			2018			2019			r2		p-value
Total Admissions	Total: 61,474.99 Total per 100,000: 172.32 (162.45 – 182.18)		Total: 67,149.97 Total per 100,000: 187.58 (177.14 – 198.01)			Total: 70,749.99 Total per 100,000: 199.14 (188.32 – 209.96)			Total: 76,179.99 Total per 100,000: 215.08 (203.87 – 226.30)			Total: 0.99 Total per 100,000: 1.00		Total: 0.003 ** Total per 100,000: 0.002 **
Demographics	Rate per 100,000 Admissions	Stratum Percentage (%)	Rate per 100,000 Admissions	Stratum Percentage (%)	Percent Difference (%)	Rate per 100,000 Admissions	Stratum Percentage (%)	Percent Difference (%)	Rate per 100,000 Admissions	Stratum Percentage (%)	Percent Difference (%)	r2 for Rate per 100,000 admissions	r2 for Stratum percentage (%)	p-value for Rate per 100,000 admissions	p-value for Stratum percentage (%)
Age
18 to 34	2.26	1.31	2.14	1.14	−5.30	2.39	1.20	11.96	2.39	1.11	−0.28	0.47	0.62	0.32	0.21
35 to 49	8.98	5.21	10.03	5.35	11.63	10.12	5.08	0.90	10.11	4.70	−0.11	0.66	0.70	0.19	0.16
50 to 64	75.54	43.84	77.06	41.08	2.00	80.60	40.47	4.60	79.08	36.77	−1.88	0.68	0.94	0.18	0.03 *
Greater than 65	85.54	49.64	98.36	52.43	14.99	106.03	53.24	7.80	123.51	57.42	16.48	0.98	0.94	0.01 *	0.03 *
Gender
Male	116.17	67.42	126.88	67.64	9.21	134.35	67.46	5.89	146.07	67.91	8.72	0.99	0.57	0.003 **	0.25
Female	56.15	32.58	60.70	32.36	8.11	64.79	32.54	6.74	69.02	32.09	6.52	1.00	0.57	< 0.001 ***	0.25
Race
White	101.09	58.67	109.52	58.38	8.33	116.99	58.75	6.83	128.17	59.59	9.55	0.99	0.61	0.004 **	0.22
Black	25.75	14.94	26.76	14.27	3.94	27.18	13.65	1.55	29.35	13.65	7.99	0.91	0.89	0.05 *	0.06
Hispanic	25.98	15.08	29.02	15.47	11.70	32.26	16.20	11.14	34.08	15.84	5.65	0.99	0.66	0.007 **	0.19
Asian or Pacific Islander	11.24	6.52	12.36	6.59	9.97	13.34	6.70	7.94	14.46	6.72	8.35	1.00	0.95	< 0.001 ***	0.03 *
Native American	1.77	1.02	1.44	0.77	−18.54	1.89	0.95	31.09	1.76	0.82	−6.43	0.09	0.23	0.70	0.52
Other	6.49	3.77	8.48	4.52	30.65	7.49	3.76	−11.69	7.27	3.38	−2.90	0.05	0.27	0.79	0.48
Comorbidities
Coronary Artery Disease	1.71	0.99	2.05	1.09	20.08	2.45	1.23	19.27	2.20	1.02	−10.07	0.61	0.08	0.22	0.72
Congestive Heart Failure	1.53	0.89	3.60	1.92	135.88	3.87	1.94	7.40	4.49	2.09	15.99	0.85	0.71	0.08	0.15
Chronic Kidney Disease	9.29	5.39	8.69	4.63	−6.51	9.22	4.63	6.11	10.86	5.05	17.76	0.52	0.13	0.28	0.64
Chronic Obstructive Pulmonary Disease	4.20	2.44	4.80	2.56	14.27	5.24	2.63	8.96	5.10	2.37	−2.66	0.77	0.03	0.12	0.84
Diabetes	9.33	5.42	10.52	5.61	12.67	11.51	5.78	9.46	11.77	5.47	2.27	0.94	0.08	0.03 *	0.72
Hypertension	33.33	19.34	34.32	18.29	2.97	35.41	17.78	3.18	37.99	17.66	7.28	0.94	0.88	0.03 *	0.06
≥ 2 Comorbidities	69.81	40.51	76.22	40.63	9.18	83.26	41.81	9.24	93.83	43.63	12.70	0.99	0.88	0.008 **	0.06
None	43.11	25.02	47.38	25.26	9.89	48.19	24.20	1.71	48.84	22.71	1.36	0.81	0.80	0.10	0.10
Spread of Cancer & Metastases
Chemotherapy	10.46	6.07	11.55	6.16	10.48	13.00	6.53	12.58	14.64	6.81	12.57	0.99	0.96	0.004 **	0.02 *
Gastrointestinal Metastasis	8.27	4.80	8.72	4.65	5.40	9.30	4.67	6.74	8.95	4.16	−3.79	0.61	0.76	0.22	0.13
Lymph Node Metastasis	2.76	1.60	2.77	1.47	0.16	3.21	1.61	16.03	4.07	1.89	26.70	0.84	0.54	0.08	0.26
Non-Gastrointestinal Metastasis	18.36	10.65	21.47	11.44	16.93	22.73	11.41	5.88	26.10	12.14	14.84	0.97	0.89	0.01 *	0.06
≥ 2 Spread Types	10.78	6.25	12.12	6.46	12.49	13.95	7.00	15.04	14.33	6.66	2.74	0.95	0.51	0.03 *	0.29
≥ 3 Spread Types	1.79	1.04	2.54	1.36	41.70	2.76	1.39	8.51	2.88	1.34	4.40	0.85	0.55	0.08	0.26
≥ 4 Spread Types	0.11	0.07	0.28	0.15	149.14	0.35	0.18	25.95	0.34	0.16	−3.71	0.78	0.64	0.12	0.20
No Spread	119.79	69.52	128.13	68.31	6.97	133.84	67.21	4.45	143.78	66.85	7.43	0.99	0.95	0.005 **	0.02 *
Type of PLC
Cholangiocarcinoma	52.42	30.42	56.92	30.34	8.58	63.16	31.72	10.98	70.54	32.80	11.68	0.99	0.88	0.006 **	0.06
Hepatocellular Carcinoma	119.09	69.11	129.67	69.13	8.89	134.92	67.75	4.05	143.17	66.57	6.11	0.98	0.89	0.008 **	0.06
Mixed Hepatic Malignancy	0.81	0.47	0.99	0.53	21.99	1.06	0.53	6.44	1.37	0.64	29.73	0.93	0.87	0.04 *	0.07
Types of Surgery
Tumor Ablation Complication	2.62	1.52	2.68	1.43	2.32	2.42	1.22	−9.73	1.99	0.93	−17.77	0.79	0.95	0.11	0.02 *
Hepatic Lobectomy	1.96	1.14	2.03	1.08	3.22	2.46	1.24	21.61	2.65	1.23	7.76	0.93	0.56	0.04 *	0.25
Liver Transplant	5.10	2.96	5.54	2.96	8.69	5.40	2.71	−2.54	5.17	2.40	−4.40	0.00	0.88	0.97	0.06
Partial Hepatectomy	5.10	2.96	5.68	3.03	11.43	5.70	2.86	0.27	6.39	2.97	12.19	0.90	0.06	0.05 *	0.76
Mixed Surgery Type	0.74	0.43	0.75	0.40	1.54	0.82	0.41	8.23	0.80	0.37	−1.42	0.77	0.80	0.12	0.11
No Surgery	156.79	90.99	170.89	91.10	8.99	182.34	91.56	6.70	198.07	92.09	8.63	1.00	0.94	0.002 **	0.03 *
Liver Complications
Ascites	5.65	3.28	5.41	2.88	−4.30	6.90	3.46	27.58	8.46	3.93	22.62	0.84	0.57	0.09	0.25
Encephalopathy	1.40	0.81	1.58	0.84	12.61	1.79	0.90	13.25	1.84	0.85	2.68	0.95	0.42	0.03 *	0.35
Hepatocellular Carcinoma	64.58	37.48	69.25	36.92	7.23	69.58	34.94	0.48	75.24	34.98	8.14	0.91	0.87	0.04 *	0.07
Hepatorenal Syndrome	0.17	0.10	0.22	0.12	32.87	0.37	0.18	63.74	0.47	0.22	27.31	0.98	0.97	0.01 *	0.02 *
Varices	0.49	0.28	0.45	0.24	−8.89	0.76	0.38	70.04	0.80	0.37	5.88	0.79	0.58	0.11	0.24
≥ 2 Liver Complications	38.57	22.38	41.09	21.91	6.54	43.92	22.06	6.89	46.23	21.50	5.26	1.00	0.78	< 0.001 ***	0.12
≥ 3 Liver Complications	15.00	8.70	17.33	9.24	15.58	19.00	9.54	9.61	19.92	9.26	4.84	0.96	0.53	0.02 *	0.27
≥ 4 Liver Complications	3.17	1.84	4.32	2.30	36.26	4.62	2.32	6.96	4.77	2.22	3.36	0.83	0.44	0.09	0.33
≥ 5 Liver Complications	0.25	0.15	0.43	0.23	71.63	0.49	0.25	13.76	0.42	0.20	−14.02	0.51	0.24	0.28	0.51
None	43.04	24.98	47.50	25.32	10.37	51.72	25.97	8.88	56.93	26.47	10.08	1.00	0.99	0.001 **	0.006 **
Liver Etiologies
Alcoholic Liver Disease	12.96	7.52	15.45	8.24	19.16	17.11	8.59	10.78	18.76	8.72	9.63	0.99	0.90	0.006 **	0.05
Autoimmune Hepatitis	1.05	0.61	1.45	0.77	38.19	1.56	0.78	7.54	2.95	1.37	88.86	0.82	0.79	0.09	0.11
Hepatitis B	6.78	3.94	7.14	3.80	5.22	6.73	3.38	−5.74	6.72	3.12	−0.11	0.15	0.97	0.61	0.02 *
Hepatitis C	40.20	23.33	41.92	22.35	4.28	39.29	19.73	−6.25	38.65	17.97	−1.63	0.44	0.97	0.34	0.01 *
Metabolic Liver Disease	0.31	0.18	0.35	0.19	13.25	0.32	0.16	−7.30	0.32	0.15	0.31	0.03	0.76	0.82	0.13
Non-Alcoholic Fatty Liver Disease	7.37	4.28	8.55	4.56	15.95	10.70	5.37	25.13	12.93	6.01	20.90	0.98	0.97	0.009 **	0.02 *
Mixed Liver Etiology	17.49	10.15	17.89	9.54	2.29	19.04	9.56	6.43	19.42	9.03	2.01	0.95	0.88	0.02 *	0.06
Other	86.15	50.00	94.84	50.56	10.08	104.38	52.42	10.07	115.32	53.62	10.48	1.00	0.97	0.001 **	0.02 *
Hospital Bed Size
Small	21.54	12.50	25.07	13.37	16.38	28.06	14.09	11.93	31.80	14.79	13.33	1.00	1.00	< 0.001 ***	0.001 **
Medium	39.80	23.10	44.85	23.91	12.67	49.98	25.10	11.43	52.08	24.21	4.20	0.97	0.50	0.02 *	0.29
Large	110.97	64.40	117.66	62.73	6.02	121.10	60.81	2.93	131.20	61.00	8.34	0.96	0.87	0.02 *	0.07
Hospital Teaching Status
Nonteaching	34.14	19.81	35.43	18.89	3.79	33.27	16.71	−6.11	34.16	15.88	2.68	0.09	0.97	0.70	0.02 *
Teaching	138.18	80.19	152.14	81.11	10.11	165.87	83.29	9.02	180.92	84.12	9.07	1.00	0.97	< 0.001 ***	0.02 *
Hospital Region
Northeast	36.47	21.16	40.36	21.52	10.69	38.66	19.41	−4.22	42.99	19.99	11.19	0.70	0.54	0.16	0.26
Midwest	33.47	19.42	36.58	19.50	9.30	40.04	20.11	9.46	42.83	19.91	6.97	1.00	0.67	< 0.001 ***	0.18
South	61.95	35.95	65.48	34.91	5.70	72.24	36.28	10.33	77.70	36.12	7.56	0.99	0.16	0.007 **	0.61
West	40.43	23.46	45.16	24.07	11.68	48.20	24.20	6.75	51.57	23.98	6.98	0.99	0.44	0.005 **	0.34
Insurance Type
Medicare	89.73	52.07	100.19	53.41	11.66	108.32	54.40	8.12	121.18	56.34	11.87	0.99	0.98	0.004 **	0.009 **
Medicaid	31.06	18.02	32.08	17.10	3.30	32.75	16.45	2.08	32.36	15.04	−1.20	0.66	0.98	0.19	0.01 *
Private	41.43	24.04	43.24	23.05	4.38	46.26	23.23	6.98	47.79	22.22	3.30	0.98	0.83	0.008 **	0.09
Other Insurance	10.11	5.86	12.07	6.43	19.42	11.81	5.93	−2.15	13.76	6.40	16.57	0.85	0.22	0.08	0.53

^*p < 0.05

^**p < 0.01

^***p < 0.001

PLC-related in-hospital mortality

Table 2 illustrates the stratum-specific PLC hospitalization mortality rates. Annual in-hospital mortality rates were the highest among those aged 50–64 and greater than 65, men, and White Americans; those with multiple comorbidities, no cancer spread, and hepatocellular carcinoma; non-surgical hospitalizations, two combined liver complications, and other liver disease etiology; those who received care at large hospitals, teaching hospitals, and in the southern region of the US, and among Medicare beneficiaries. With respect to mortality trends, the overall annual incidence of PLC hospitalization mortality increased significantly from 2016 to 2019: 14.72, 16.29, 17.37, and 18.85 (1.00, 0.002). The following groups saw significant increasing mortality rates associated with PLC hospitalization: Age >65, men, White Americans; those with congestive heart failure, chronic obstructive pulmonary disease, no cancer spread, hepatocellular carcinoma, non-surgical hospitalization, hepatorenal syndrome, 3 combined liver complications; all hospital sizes, teaching hospitals, and Medicare beneficiaries. Additionally, those with hypertension, multiple comorbidities, chemotherapy, 2–3 combined cancer spread types, cholangiocarcinoma, ascites, no liver complications, NAFLD, ALD; those who received care in the Northeast region of the US; and Medicaid beneficiaries saw increasing rates of mortality over the study period, although these trends were not statistically significant. When considering the mortality proportion percentage for each stratum, the following groups saw significantly increasing proportions of cases who died: those with chronic obstructive pulmonary disease, hepatorenal syndrome; and those who received care in medium-sized hospitals. The following groups saw significant decreasing proportions of cases who died: White Americans and those with autoimmune liver disease. Table 2 further illustrates the annual PLC hospitalization mortality trends.

Table 2.

Mortality Rates Associated with Primary Liver Cancer in US Hospitals

Year	2016		2017			2018			2019			r2		p-value
Total Deaths	Total Deaths: 5,250.00 Total Deaths per 100,000: 14.72		Total Deaths: 5,829.99 Total Deaths per 100,000: 16.29			Total Deaths: 6,170.00 Total Deaths per 100,000: 17.37			Total Deaths: 6,675.00 Total Deaths per 100,000: 18.85			Total Deaths: 0.99 Total Deaths per 100,000: 1.00		Total Deaths: 0.005 ** Total Deaths per 100,000: 0.002 **
Demographics	Mortality rate per 100,000 admissions	Proportion percentage (%)	Mortality rate per 100,000 admissions	Proportion percentage (%)	Percent Difference (%)	Mortality rate per 100,000 admissions	Proportion percentage (%)	Percent Difference (%)	Mortality rate per 100,000 admissions	Proportion percentage (%)	Percent Difference (%)	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	0.11	4.97	0.06	2.61	−50.17	0.10	4.12	76.33	0.20	8.28	100.61	0.42	0.38	0.35	0.38
35 to 49	0.74	8.27	0.87	8.64	16.58	0.80	7.93	−7.36	0.65	6.42	−19.05	0.23	0.69	0.52	0.17
50 to 64	6.83	9.04	7.19	9.33	5.39	7.16	8.89	−0.41	7.21	9.12	0.70	0.64	0.02	0.20	0.87
Greater than 65	7.04	8.23	8.17	8.31	16.13	9.30	8.77	13.85	10.79	8.73	15.94	1.00	0.82	0.002 **	0.10
Gender
Male	10.32	8.88	11.37	8.96	10.22	12.60	9.38	10.79	13.20	9.04	4.79	0.98	0.28	0.008 **	0.48
Female	4.40	7.84	4.92	8.10	11.72	4.77	7.36	−2.96	5.65	8.18	18.36	0.79	0.01	0.11	0.90
Race
White	8.42	8.33	9.06	8.28	7.62	9.63	8.23	6.20	10.43	8.14	8.37	0.99	0.98	0.003 **	0.010 **
Black	2.51	9.74	2.58	9.66	3.00	2.65	9.74	2.40	3.23	11.01	22.18	0.76	0.59	0.13	0.23
Hispanic	2.03	7.82	2.56	8.81	25.77	2.77	8.60	8.47	2.75	8.08	−0.71	0.79	0.03	0.11	0.84
Asian or Pacific Islander	1.04	9.23	1.15	9.27	10.43	1.48	11.08	29.03	1.26	8.69	−14.98	0.46	0.00	0.32	0.97
Native American	0.14	7.94	0.10	6.80	−30.24	0.20	10.45	101.53	0.28	16.00	43.29	0.72	0.77	0.15	0.12
Other	0.57	8.86	0.84	9.88	45.84	0.65	8.65	−22.75	0.89	12.23	37.38	0.42	0.49	0.35	0.30
Comorbidities
Coronary Artery Disease	0.20	11.48	0.24	11.56	21.01	0.18	7.47	−22.95	0.18	8.33	0.31	0.22	0.68	0.53	0.18
Congestive Heart Failure	0.29	19.27	0.38	10.47	28.13	0.55	14.18	45.55	0.59	13.21	8.02	0.95	0.26	0.02 *	0.49
Chronic Kidney Disease	1.14	12.22	1.28	14.79	13.19	1.48	16.03	15.00	1.37	12.61	−7.34	0.64	0.03	0.20	0.83
Chronic Obstructive Pulmonary Disease	0.43	10.33	0.53	11.05	22.16	0.59	11.29	11.37	0.65	12.74	9.86	0.98	0.91	0.008 **	0.05 *
Diabetes	0.76	8.11	1.03	9.83	36.57	0.99	8.56	−4.68	1.10	9.35	11.77	0.72	0.17	0.15	0.59
Hypertension	2.17	6.52	2.21	6.43	1.59	2.42	6.84	9.69	2.92	7.69	20.72	0.85	0.78	0.08	0.12
≥ 2 Comorbidities	5.63	8.07	5.92	7.77	5.11	6.01	7.22	1.48	7.00	7.46	16.51	0.83	0.69	0.09	0.17
None	4.09	9.49	4.69	9.91	14.67	5.15	10.69	9.76	5.03	10.29	−2.43	0.79	0.64	0.11	0.20
Spread of Cancer & Metastases
Chemotherapy	0.46	4.42	0.63	5.44	35.90	0.63	4.87	0.76	0.73	5.01	15.91	0.88	0.14	0.06	0.63
Gastrointestinal Metastasis	0.95	11.53	0.99	11.38	4.05	1.22	13.16	23.47	1.07	11.99	−12.38	0.40	0.26	0.36	0.49
Lymph Node Metastasis	0.18	6.60	0.15	5.56	−15.68	0.27	8.33	74.04	0.20	4.86	−26.09	0.18	0.04	0.57	0.79
Non-Gastrointestinal Metastasis	2.42	13.21	3.06	14.25	26.15	2.72	11.95	−11.20	3.78	14.49	39.29	0.68	0.03	0.18	0.83
≥ 2 Spread Types	1.11	10.27	1.31	10.83	18.58	1.82	13.02	38.28	1.55	10.84	−14.47	0.60	0.17	0.22	0.59
≥ 3 Spread Types	0.18	10.16	0.21	8.24	14.99	0.23	8.16	7.48	0.34	11.76	50.46	0.83	0.13	0.09	0.64
≥ 4 Spread Types	0.00	0.00	0.01	5.00	Inf	0.03	8.00	101.53	0.03	8.33	0.31	0.89	0.88	0.06	0.06
No Spread	9.40	7.85	9.92	7.74	5.45	10.46	7.81	5.45	11.14	7.75	6.52	1.00	0.33	0.002 **	0.43
Type of PLC
Cholangiocarcinoma	3.88	7.41	3.98	6.99	2.53	4.39	6.95	10.31	5.17	7.32	17.67	0.89	0.03	0.06	0.84
Hepatocellular Carcinoma	10.76	9.04	12.18	9.39	13.15	12.86	9.53	5.62	13.50	9.43	4.92	0.96	0.61	0.02 *	0.22
Mixed Hepatic Malignancy	0.07	8.62	0.13	12.68	79.38	0.11	10.67	−10.43	0.18	13.40	63.00	0.81	0.55	0.10	0.26
Types of Surgery
Tumor Ablation Complication	0.04	1.60	0.06	2.08	32.87	0.06	2.33	0.76	0.01	0.71	−74.92	0.30	0.20	0.46	0.56
Hepatic Lobectomy	0.04	2.14	0.03	1.38	−33.56	0.07	2.86	151.91	0.14	5.32	100.61	0.76	0.69	0.13	0.17
Liver Transplant	0.08	1.65	0.06	1.01	−33.56	0.13	2.34	126.72	0.04	0.82	−66.56	0.04	0.05	0.81	0.79
No Surgery	14.42	9.20	15.91	9.31	10.31	16.92	9.28	6.34	18.48	9.33	9.24	0.99	0.65	0.003 **	0.19
Partial Hepatectomy	0.08	1.65	0.20	3.44	132.53	0.17	2.96	−13.63	0.14	2.21	−16.41	0.15	0.04	0.61	0.80
Mixed Surgery Type	0.04	5.66	0.04	5.56	−0.34	0.03	3.45	−32.82	0.03	3.51	0.31	0.80	0.81	0.10	0.10
Liver Complications
Ascites	0.52	9.18	0.56	10.34	7.74	0.66	9.59	18.40	0.89	10.52	34.45	0.89	0.45	0.06	0.33
Encephalopathy	0.27	19.00	0.29	18.58	10.15	0.34	18.90	15.16	0.28	15.38	−16.41	0.15	0.62	0.61	0.21
Hepatocellular Carcinoma	4.02	6.23	4.73	6.84	17.71	4.43	6.37	−6.37	5.41	7.19	21.96	0.73	0.50	0.15	0.29
Hepatorenal Syndrome	0.06	33.33	0.08	37.50	49.48	0.14	38.46	67.94	0.20	42.42	40.43	0.98	0.95	0.01 *	0.02 *
Varices	0.06	11.43	0.04	9.38	−25.26	0.07	9.26	67.94	0.03	3.51	−59.88	0.15	0.82	0.61	0.10
≥ 2 Liver Complications	4.55	11.81	4.62	11.25	1.50	5.09	11.60	10.20	4.95	10.72	−2.74	0.69	0.63	0.17	0.21
≥ 3 Liver Complications	1.99	13.27	2.16	12.49	8.78	2.63	13.85	21.57	2.70	13.54	2.45	0.92	0.23	0.04 *	0.52
≥ 4 Liver Complications	0.52	16.37	0.91	21.04	75.07	0.99	21.34	8.51	0.90	18.93	−8.29	0.57	0.20	0.24	0.55
≥ 5 Liver Complications	0.06	22.22	0.10	22.58	74.40	0.08	17.14	−13.63	0.10	23.33	17.02	0.56	0.01	0.25	0.90
None	2.68	6.22	2.78	5.85	3.83	2.93	5.66	5.32	3.39	5.95	15.74	0.88	0.30	0.06	0.45
Liver Etiologies
Alcoholic Liver Disease	1.22	9.41	1.47	9.49	20.27	1.75	10.20	19.00	1.69	9.03	−2.93	0.83	0.01	0.09	0.89
Autoimmune Hepatitis	0.11	10.67	0.15	10.58	37.03	0.10	6.31	−35.88	0.10	3.35	0.31	0.22	0.91	0.53	0.05 *
Hepatitis B	0.76	11.16	0.63	8.81	−16.95	0.70	10.46	11.96	0.72	10.71	2.31	0.01	0.00	0.92	0.96
Hepatitis C	3.24	8.05	3.45	8.23	6.56	3.56	9.06	3.21	3.54	9.17	−0.49	0.80	0.90	0.11	0.05
Metabolic Liver Disease	0.00	0.00	0.03	8.00	Inf	0.01	4.35	−49.62	0.04	13.04	200.92	0.65	0.69	0.20	0.17
Non-Alcoholic Fatty Liver Disease	0.25	3.42	0.50	5.88	99.31	0.72	6.71	42.75	0.71	5.46	−1.66	0.87	0.41	0.07	0.36
Mixed Liver Etiology	1.50	8.57	1.75	9.76	16.42	1.80	9.46	3.18	1.84	9.45	1.87	0.82	0.34	0.10	0.41
Other	7.64	8.87	8.31	8.76	8.80	8.73	8.36	5.00	10.21	8.85	16.97	0.93	0.06	0.04 *	0.76
Hospital Bed Size
Small	1.96	9.11	2.46	9.81	25.28	2.74	9.78	11.64	3.15	9.90	14.71	0.99	0.69	0.005 **	0.17
Medium	3.52	8.84	4.01	8.94	13.95	4.56	9.12	13.75	4.91	9.43	7.74	0.99	0.95	0.004 **	0.03 *
Large	9.24	8.32	9.82	8.35	6.31	10.06	8.31	2.48	10.79	8.22	7.18	0.97	0.66	0.02 *	0.19
Hospital Teaching Status
Nonteaching	3.15	9.24	3.56	10.05	12.94	3.45	10.36	−3.19	3.05	8.93	−11.57	0.05	0.01	0.77	0.88
Teaching	11.56	8.37	12.72	8.36	10.04	13.92	8.39	9.39	15.80	8.73	13.49	0.98	0.65	0.008 **	0.19
Hospital Region
Northeast	2.90	7.96	3.51	8.69	20.84	3.56	9.21	1.57	3.88	9.03	9.03	0.89	0.76	0.06	0.13
Midwest	2.72	8.12	2.50	6.83	−8.05	3.10	7.73	23.84	3.42	7.98	10.34	0.73	0.01	0.14	0.90
South	5.42	8.76	5.85	8.94	7.90	5.67	7.85	−3.08	6.69	8.61	17.98	0.72	0.17	0.15	0.59
West	3.67	9.08	4.43	9.81	20.58	5.04	10.45	13.80	4.86	9.42	−3.62	0.78	0.13	0.12	0.64
Insurance Type
Medicare	6.98	7.78	7.56	7.54	8.26	8.56	7.90	13.24	9.73	8.03	13.67	0.98	0.47	0.01 *	0.31
Medicaid	2.70	8.71	2.88	8.97	6.37	2.90	8.85	0.76	3.28	10.12	12.97	0.87	0.67	0.07	0.18
Private	3.64	8.80	4.13	9.56	13.45	4.28	9.25	3.49	4.15	8.69	−2.99	0.59	0.04	0.23	0.80
Other Insurance	1.39	13.73	1.72	14.24	23.82	1.63	13.83	−4.97	1.69	12.31	3.77	0.51	0.52	0.29	0.28

^*p < 0.05

^**p < 0.01

^***p < 0.001

Total Annual Costs

The total annual cost of PLC hospitalizations increased significantly in the US for the years 2016 through 2019: 1,180.90, 1,307.99, 1,365.54, and 1,547.95 million US dollars, respectively (0.96, 0.02). Following stratification of the PLC cohort, the majority of annual costs were observed in the following groups: ages 50–64 and greater than 65, men, and White Americans; those with multiple comorbidities, no cancer spread, hepatocellular carcinoma, hepatitis C, and two and three combined liver complications; large-sized hospitals, teaching hospitals, as well as those with non-surgical hospitalization (followed by hospitalization for liver transplant); Medicare beneficiaries, and those who received care in the Southern and Western regions of the US. With respect to the annual trends, rising costs were observed among those aged >65 (0.95, 0.03), white race (0.96, 0.02), Hispanics (0.92, 0.04), and Asian/Pacific Islanders (0.99, 0.007); those with congestive heart failure (0.97, 0.02), chronic obstructive pulmonary disease (0.92, 0.04), diabetes (0.96, 0.02), and multiple comorbidities (0.98, 0.01); those without cancer spread (0.90, 0.05), spread requiring chemotherapy (0.99, 0.003), two (0.90, 0.05), and three (0.91, 0.04) combined spread types; cholangiocarcinoma (0.97, 0.01) and hepatocellular carcinoma (0.93. 0.04); those who underwent lobectomy (0.95, 0.02), partial hepatectomy (0.99, 0.004) and did not undergo surgery (0.96, 0.02); those with ascites (0.92, 0.04), hepatic encephalopathy (0.97, 0.01), two (0.99, 0.006), three (0.91, 0.04), and four (0.91, 0.04) combined liver complications, and those without liver complications (0.98, 0.008); those with ALD (0.99, 0.006) and NAFLD (0.98, 0.01); those who received care in small-sized hospitals (0.99, 0.004), teaching hospitals (0.98, 0.01), and in the Midwestern (0.99, 0.005), Southern (0.92, 0.04), and Western (0.91, 0.05) regions of the US; as well as Medicare beneficiaries (0.95, 0.02). All of these trends coincided with an increasing annual incidence of PLC hospitalizations within each group except for those with chronic obstructive pulmonary disease, 2 and 3 combined cancer spread types, and ascites; these groups were associated with increasing PLC hospitalization costs despite no increasing hospitalization incidence. It should also be noted that increasing costs were not observed among Black Americans, those with lymphatic spread, nor for large-sized hospitals despite increasing PLC hospitalization incidence within these groups. Furthermore, there was a general increase in PLC hospitalization cost among those without any comorbidities, with non-gastrointestinal spread, medium-sized hospitals, and private insurance beneficiaries, although these trends did not reach statistical significance. PLC hospitalization costs associated with liver transplantation and hepatitis B and C, both relatively significant cost contributors, remained steady. Table 3 further illustrates the trends in annual PLC hospitalization costs, and Figures 1 through 5 demonstrate total cost data for select strata as bar charts. Mean Costs

Table 3.

Total Cost Associated with Primary Liver Cancer in US Hospitals

Year	2016		2017			2018			2019			r2	p-value
Total Cost (in million dollars)	1,180.90		1,307.99			1,365.54			1,547.95			0.96	0.02 *
Demographics	Total Cost (in million dollars)	(95% confidence interval)	Total Cost (in million dollars)	(95% confidence interval)	Percent Difference (%)	Total Cost (in million dollars)	(95% confidence interval)	Percent Difference (%)	Total Cost (in million dollars)	(95% confidence interval)	Percent Difference (%)	r2 for Total (in million dollars)	p-value for Total (in million dollars)
Age
18 to 34	19.24	(13.73 – 24.75)	25.05	(10.59 – 39.50)	30.17	31.11	(9.40 – 52.82)	24.20	24.68	(15.84 – 33.52)	−20.66	0.35	0.40
35 to 49	65.17	(54.08 – 76.26)	78.67	(66.20 – 91.14)	20.72	79.34	(66.65 – 92.04)	0.85	75.58	(63.88 – 87.28)	−4.74	0.39	0.37
50 to 64	549.45	(483.54 – 615.36)	553.36	(494.07 – 612.65)	0.71	564.45	(506.06 – 622.84)	2.00	597.08	(532.10 – 662.05)	5.78	0.85	0.08
Greater than 65	547.05	(498.35 – 595.74)	650.91	(589.52 – 712.31)	18.99	690.64	(630.27 – 751.01)	6.10	850.62	(773.93 – 927.30)	23.16	0.95	0.03 *
Gender
Male	813.56	(728.29 – 898.84)	891.50	(806.70 – 976.30)	9.58	923.90	(834.83 – 1,012.98)	3.63	1,067.21	(969.05 – 1,165.36)	15.51	0.93	0.04 *
Female	367.34	(329.56 – 405.11)	416.49	(369.16 – 463.81)	13.38	441.63	(395.24 – 488.03)	6.04	480.75	(430.29 – 531.21)	8.86	0.99	0.007 **
Race
White	663.34	(595.84 – 730.83)	727.26	(654.06 – 800.46)	9.64	769.05	(691.47 – 846.64)	5.75	879.20	(798.49 – 959.92)	14.32	0.96	0.02 *
Black	167.28	(146.09 – 188.48)	177.52	(155.14 – 199.90)	6.12	176.91	(156.55 – 197.27)	−0.34	181.41	(162.68 – 200.15)	2.55	0.81	0.10
Hispanic	200.40	(166.44 – 234.37)	222.21	(190.85 – 253.57)	10.88	233.25	(200.69 – 265.81)	4.97	281.34	(233.83 – 328.85)	20.62	0.92	0.04 *
Asian or Pacific Islander	89.95	(66.99 – 112.91)	101.86	(80.06 – 123.65)	13.24	114.15	(92.93 – 135.37)	12.07	121.11	(100.90 – 141.32)	6.10	0.99	0.007 **
Native American	11.06	(8.32 – 13.81)	10.16	(7.10 – 13.21)	−8.20	15.38	(9.51 – 21.25)	51.43	12.25	(8.00 – 16.50)	−20.34	0.25	0.50
Other	48.87	(36.18 – 61.56)	68.99	(45.93 – 92.04)	41.16	56.80	(41.40 – 72.20)	−17.67	72.63	(54.96 – 90.31)	27.88	0.48	0.30
Comorbidities
Coronary Artery Disease	11.32	(8.29 – 14.36)	13.80	(10.38 – 17.22)	21.86	21.84	(16.08 – 27.61)	58.30	15.86	(12.08 – 19.65)	−27.39	0.39	0.38
Congestive Heart Failure	19.99	(12.45 – 27.52)	27.01	(22.94 – 31.07)	35.12	31.92	(26.73 – 37.12)	18.21	43.50	(35.27 – 51.73)	36.27	0.97	0.02 *
Chronic Kidney Disease	91.23	(70.22 – 112.24)	79.52	(64.28 – 94.76)	−12.84	72.66	(57.50 – 87.82)	−8.62	101.45	(79.23 – 123.67)	39.62	0.06	0.76
Chronic Obstructive Pulmonary Disease	26.40	(22.66 – 30.13)	28.72	(24.63 – 32.82)	8.80	35.22	(30.20 – 40.23)	22.61	35.89	(30.62 – 41.17)	1.93	0.92	0.04 *
Diabetes	63.89	(53.73 – 74.06)	76.25	(64.91 – 87.58)	19.34	81.04	(70.02 – 92.07)	6.29	97.04	(83.66 – 110.42)	19.74	0.96	0.02 *
Hypertension	218.73	(194.95 – 242.51)	218.79	(196.14 – 241.44)	0.03	216.62	(192.64 – 240.61)	−0.99	244.33	(219.86 – 268.80)	12.79	0.53	0.27
None	283.41	(251.24 – 315.58)	344.88	(303.15 – 386.61)	21.69	350.48	(304.71 – 396.25)	1.62	376.44	(331.26 – 421.62)	7.41	0.87	0.07
≥ 2 Comorbidities	465.93	(418.32 – 513.54)	519.03	(468.90 – 569.16)	11.40	555.75	(509.30 – 602.21)	7.08	633.44	(578.08 – 688.79)	13.98	0.98	0.01 *
Spread of Cancer & Metastases
Chemotherapy	61.55	(51.02 – 72.08)	69.69	(59.79 – 79.60)	13.23	77.38	(65.67 – 89.08)	11.02	88.00	(77.03 – 98.97)	13.73	0.99	0.003 **
Gastrointestinal Metastasis	51.06	(45.31 – 56.81)	54.02	(47.63 – 60.41)	5.80	68.72	(46.28 – 91.17)	27.21	53.37	(46.51 – 60.22)	−22.34	0.12	0.65
Lymph Node Metastasis	23.23	(17.65 – 28.81)	20.81	(17.18 – 24.43)	−10.44	23.18	(18.59 – 27.77)	11.41	32.37	(25.71 – 39.04)	39.67	0.57	0.25
No Spread	869.52	(776.49 – 962.55)	949.87	(852.63 – 1,047.12)	9.24	962.12	(867.11 – 1,057.13)	1.29	1,095.99	(985.96 – 1,206.01)	13.91	0.90	0.05 *
Non-Gastrointestinal Metastasis	102.63	(93.09 – 112.16)	116.65	(105.82 – 127.49)	13.67	123.54	(112.87 – 134.21)	5.90	163.06	(148.46 – 177.67)	31.99	0.88	0.06
≥ 2 Spread Types	61.05	(52.94 – 69.17)	79.16	(62.19 – 96.13)	29.65	91.76	(75.95 – 107.57)	15.92	93.53	(80.35 – 106.71)	1.93	0.90	0.05
≥ 3 Spread Types	11.16	(7.73 – 14.58)	15.64	(11.74 – 19.54)	40.18	15.93	(12.23 – 19.63)	1.84	19.55	(13.33 – 25.78)	22.78	0.91	0.04 *
≥ 4 Spread Types	0.71	(0.12 – 1.30)	2.14	(1.20 – 3.08)	203.05	2.91	(1.41 – 4.42)	36.04	2.08	(0.93 – 3.22)	−28.71	0.47	0.31
Type of PLC
Cholangiocarcinoma	325.98	(296.29 – 355.67)	360.76	(322.78 – 398.75)	10.67	402.03	(365.60 – 438.46)	11.44	472.39	(427.43 – 517.35)	17.50	0.97	0.01 *
Hepatocellular Carcinoma	849.82	(753.15 – 946.49)	940.90	(844.32 – 1,037.48)	10.72	954.70	(855.92 – 1,053.48)	1.47	1,065.99	(955.62 – 1,176.37)	11.66	0.93	0.04 *
Mixed Hepatic Malignancy	5.11	(2.90 – 7.32)	6.33	(4.75 – 7.90)	23.84	8.81	(6.10 – 11.51)	39.23	9.58	(7.53 – 11.62)	8.72	0.96	0.02 *
Types of Surgery
Tumor Ablation Complication	19.67	(15.65 – 23.69)	22.04	(16.38 – 27.71)	12.07	16.37	(11.93 – 20.81)	−25.76	14.02	(11.19 – 16.85)	−14.31	0.68	0.18
Hepatic Lobectomy	26.61	(21.78 – 31.44)	31.46	(21.67 – 41.26)	18.25	34.08	(28.27 – 39.90)	8.32	42.30	(33.56 – 51.03)	24.10	0.95	0.02 *
Liver Transplant	208.91	(176.07 – 241.75)	208.28	(172.92 – 243.63)	−0.30	214.94	(178.90 – 250.98)	3.20	228.80	(183.72 – 273.89)	6.45	0.81	0.10
No Surgery	861.08	(798.05 – 924.11)	975.61	(905.17 – 1,046.05)	13.30	1,020.22	(948.68 – 1,091.76)	4.57	1,171.15	(1,090.37 – 1,251.93)	14.79	0.96	0.02 *
Partial Hepatectomy	54.58	(47.31 – 61.86)	60.34	(51.97 – 68.72)	10.56	66.73	(54.98 – 78.49)	10.59	75.26	(63.97 – 86.56)	12.78	0.99	0.004 **
Mixed Surgery Type	10.06	(6.96 – 13.15)	10.25	(7.50 – 13.01)	1.94	13.20	(6.52 – 19.89)	28.78	16.42	(4.32 – 28.52)	24.37	0.90	0.05 *
Liver Complications
Ascites	40.64	(33.79 – 47.49)	45.95	(38.42 – 53.47)	13.07	54.22	(44.35 – 64.10)	18.01	73.44	(60.84 – 86.03)	35.44	0.92	0.04 *
Encephalopathy	8.75	(6.74 – 10.77)	10.03	(7.52 – 12.55)	14.64	13.34	(10.40 – 16.27)	32.92	15.14	(11.56 – 18.72)	13.51	0.97	0.01 *
Hepatocellular Carcinoma	407.19	(364.68 – 449.70)	464.07	(418.71 – 509.44)	13.97	442.88	(396.02 – 489.74)	−4.57	493.55	(449.57 – 537.53)	11.44	0.71	0.16
Hepatorenal Syndrome	1.14	(0.43 – 1.85)	1.85	(0.58 – 3.13)	62.61	2.58	(1.16 – 4.00)	39.08	8.60	(3.98 – 13.22)	233.63	0.76	0.13
Varices	3.05	(1.87 – 4.23)	3.86	(2.04 – 5.67)	26.40	3.61	(2.45 – 4.77)	−6.39	4.03	(3.21 – 4.84)	11.54	0.66	0.19
≥ 2 Liver Complications	279.43	(241.06 – 317.80)	305.51	(269.94 – 341.08)	9.33	327.88	(288.41 – 367.36)	7.32	365.02	(316.38 – 413.65)	11.32	0.99	0.006 **
≥ 3 Liver Complications	135.68	(112.98 – 158.37)	142.09	(122.19 – 161.99)	4.73	151.99	(131.97 – 172.02)	6.97	175.57	(150.25 – 200.88)	15.51	0.91	0.04 *
≥ 4 Liver Complications	42.92	(29.52 – 56.33)	45.93	(36.00 – 55.86)	7.01	52.91	(37.61 – 68.22)	15.20	54.91	(40.86 – 68.97)	3.78	0.96	0.02 *
≥ 5 Liver Complications	3.81	(1.34 – 6.28)	6.14	(3.37 – 8.91)	61.12	4.59	(3.21 – 5.98)	−25.21	4.51	(2.22 – 6.79)	−1.86	0.01	0.93
None	258.29	(235.98 – 280.61)	282.55	(254.68 – 310.43)	9.39	311.53	(286.62 – 336.43)	10.25	353.19	(321.69 – 384.69)	13.37	0.98	0.008 **
Liver Etiologies
Alcoholic Liver Disease	94.54	(80.91 – 108.17)	113.82	(99.92 – 127.72)	20.39	129.37	(109.82 – 148.92)	13.66	141.24	(120.62 – 161.86)	9.18	0.99	0.006 **
Autoimmune Hepatitis	9.22	(7.00 – 11.44)	10.00	(7.21 – 12.79)	8.45	14.71	(10.91 – 18.51)	47.12	30.65	(19.46 – 41.84)	108.36	0.80	0.11
Hepatitis B	56.29	(43.07 – 69.50)	60.00	(46.12 – 73.89)	6.60	55.51	(43.17 – 67.85)	−7.49	75.16	(51.20 – 99.12)	35.40	0.54	0.27
Hepatitis C	286.50	(249.96 – 323.03)	298.35	(264.52 – 332.18)	4.14	271.23	(240.63 – 301.83)	−9.09	266.50	(234.39 – 298.62)	−1.74	0.60	0.23
Metabolic Liver Disease	4.02	(1.05 – 6.98)	2.94	(1.49 – 4.39)	−26.76	4.61	(−0.27 – 9.49)	56.74	2.92	(1.40 – 4.44)	−36.70	0.06	0.75
Non-Alcoholic Fatty Liver Disease	63.92	(50.87 – 76.98)	75.63	(63.14 – 88.11)	18.31	95.74	(76.42 – 115.06)	26.60	103.98	(88.75 – 119.20)	8.60	0.98	0.01 *
Mixed Liver Etiology	130.93	(113.93 – 147.92)	131.64	(113.04 – 150.25)	0.55	126.75	(112.51 – 140.99)	−3.72	145.43	(126.15 – 164.72)	14.74	0.38	0.39
Other	535.49	(490.24 – 580.75)	615.61	(557.66 – 673.56)	14.96	667.62	(608.73 – 726.52)	8.45	782.08	(717.56 – 846.61)	17.14	0.98	0.01 *
Hospital Bed Size
Small	108.27	(95.12 – 121.43)	128.69	(111.79 – 145.60)	18.86	141.50	(125.07 – 157.93)	9.95	160.90	(144.83 – 176.97)	13.71	0.99	0.004 **
Medium	221.91	(183.31 – 260.51)	266.76	(230.09 – 303.44)	20.21	310.85	(262.15 – 359.55)	16.53	308.37	(270.49 – 346.25)	−0.80	0.87	0.07
Large	850.72	(739.85 – 961.59)	912.53	(792.98 – 1,032.08)	7.27	913.19	(797.53 – 1,028.85)	0.07	1,078.68	(941.00 – 1,216.36)	18.12	0.82	0.10
Hospital Teaching Status
Nonteaching	158.16	(146.17 – 170.15)	170.43	(155.28 – 185.58)	7.76	149.87	(135.35 – 164.40)	−12.06	162.89	(146.40 – 179.39)	8.68	0.01	0.90
Teaching	1,022.74	(905.22 – 1,140.27)	1,137.56	(1,012.28 – 1,262.83)	11.23	1,215.66	(1,089.93 – 1,341.40)	6.87	1,385.06	(1,242.32 – 1,527.81)	13.93	0.98	0.01 *
Hospital Region
Northeast	255.63	(201.65 – 309.61)	287.90	(227.76 – 348.04)	12.62	280.53	(218.98 – 342.07)	−2.56	330.86	(262.15 – 399.57)	17.94	0.81	0.10
Midwest	205.39	(164.90 – 245.88)	227.56	(178.76 – 276.36)	10.79	256.01	(197.10 – 314.92)	12.50	290.54	(227.28 – 353.80)	13.49	0.99	0.005 **
South	370.06	(313.32 – 426.80)	387.57	(333.62 – 441.53)	4.73	418.21	(360.45 – 475.97)	7.90	482.61	(413.06 – 552.15)	15.40	0.92	0.04 *
West	349.82	(271.19 – 428.45)	404.96	(321.21 – 488.70)	15.76	410.80	(337.14 – 484.46)	1.44	443.94	(359.74 – 528.14)	8.07	0.91	0.05 *
Insurance Type
Medicare	592.00	(535.86 – 648.14)	667.30	(602.30 – 732.29)	12.72	709.09	(645.99 – 772.18)	6.26	838.98	(759.46 – 918.50)	18.32	0.95	0.02 *
Medicaid	217.46	(187.81 – 247.11)	214.85	(190.12 – 239.58)	−1.20	216.33	(193.86 – 238.80)	0.69	230.55	(205.88 – 255.22)	6.57	0.53	0.27
Private	302.79	(260.40 – 345.18)	353.20	(306.21 – 400.20)	16.65	371.72	(317.15 – 426.30)	5.24	382.20	(331.58 – 432.81)	2.82	0.89	0.06
Other Insurance	68.65	(53.08 – 84.23)	72.64	(61.71 – 83.56)	5.80	68.40	(59.04 – 77.76)	−5.83	96.23	(80.14 – 112.31)	40.68	0.58	0.24

^*p < 0.05

^**p < 0.01

^***p < 0.001

Figure 1.

Inflation-adjusted total and mean costs and trends for patients undergoing liver transplantation, stratified using demographic variables.

The mean cost for each PLC hospitalization was determined for each stratified group. Hospitalizations associated with liver transplant had the highest mean hospitalization cost, followed by hospitalizations associated with mixed surgery types, lobectomy, partial hepatectomy, and four to five liver complications. In general, mean costs were stable across all groups with the exception of PLC hospitalizations associated with no comorbidities (0.91, 0.05) and encephalopathy (0.92, 0.04), which saw significantly increased mean costs. Table 4 further describes these mean values, whereas Supplementary Table 2 illustrates the median and interquartile hospitalizations costs. Pictorial representations of mean cost data are included in Figures 1, 2, 3, 4, and 5.

Table 4.

Mean Costs Associated with Primary Liver Cancer in US Hospitals

Year	2016		2017			2018			2019			r2	p-value
Demographics	Mean Cost (in dollars)	(95% confidence interval)	Mean Cost (in dollars)	(95% confidence interval)	Percent Difference (%)	Mean Cost (in dollars)	(95% confidence interval)	Percent Difference (%)	Mean Cost (in dollars)	(95% confidence interval)	Percent Difference (%)	r2 for Mean Cost (in dollars)	p-value for Mean Cost (in dollars)
Age
18 to 34	23,901.73	(17,469.61 – 30,333.85)	32,739.77	(16,021.06 – 49,458.48)	36.98	36,597.06	(11,566.46 – 61,627.65)	11.78	29,208.88	(19,486.78 – 38,930.99)	−20.19	0.22	0.53
35 to 49	20,333.24	(17,403.66 – 23,262.81)	21,914.72	(19,160.37 – 24,669.08)	7.78	22,070.06	(19,375.16 – 24,764.97)	0.71	21,111.01	(18,710.32 – 23,511.70)	−4.35	0.16	0.60
50 to 64	20,387.76	(18,819.52 – 21,956.01)	20,060.09	(18,782.64 – 21,337.55)	−1.61	19,711.87	(18,451.20 – 20,972.55)	−1.74	21,316.56	(19,783.05 – 22,850.07)	8.14	0.21	0.54
Greater than 65	17,927.08	(16,982.15 – 18,872.01)	18,486.56	(17,407.09 – 19,566.04)	3.12	18,333.98	(17,372.74 – 19,295.21)	−0.83	19,444.89	(18,335.15 – 20,554.64)	6.06	0.78	0.12
Gender
Male	19,629.99	(18,378.08 – 20,881.90)	19,627.94	(18,589.29 – 20,666.60)	−0.01	19,356.90	(18,301.09 – 20,412.71)	−1.38	20,628.33	(19,488.02 – 21,768.64)	6.57	0.39	0.37
Female	18,339.45	(17,194.70 – 19,484.19)	19,166.50	(17,656.45 – 20,676.55)	4.51	19,184.83	(17,738.21 – 20,631.46)	0.10	19,666.43	(18,347.91 – 20,984.95)	2.51	0.88	0.06
Race
White	18,392.80	(17,395.40 – 19,390.21)	18,550.20	(17,525.59 – 19,574.82)	0.86	18,502.42	(17,426.81 – 19,578.03)	−0.26	19,367.83	(18,386.66 – 20,348.99)	4.68	0.69	0.17
Black	18,212.38	(16,614.15 – 19,810.60)	18,530.18	(17,014.71 – 20,045.66)	1.75	18,323.04	(16,935.93 – 19,710.15)	−1.12	17,451.98	(16,267.04 – 18,636.91)	−4.75	0.47	0.32
Hispanic	21,618.64	(18,839.94 – 24,397.35)	21,386.89	(19,371.93 – 23,401.85)	−1.07	20,353.34	(18,477.71 – 22,228.97)	−4.83	23,309.18	(20,512.65 – 26,105.72)	14.52	0.18	0.57
Asian or Pacific Islander	22,430.85	(18,901.89 – 25,959.82)	23,018.48	(19,897.21 – 26,139.74)	2.62	24,081.96	(21,344.10 – 26,819.82)	4.62	23,654.08	(21,514.24 – 25,793.91)	−1.78	0.71	0.16
Native American	17,562.29	(13,716.29 – 21,408.28)	19,722.66	(14,817.26 – 24,628.07)	12.30	22,956.36	(16,336.59 – 29,576.12)	16.40	19,603.27	(13,861.94 – 25,344.61)	−14.61	0.29	0.46
Other	21,110.19	(18,403.14 – 23,817.24)	22,730.04	(19,803.92 – 25,656.15)	7.67	21,353.10	(18,737.84 – 23,968.36)	−6.06	28,207.40	(23,309.09 – 33,105.71)	32.10	0.60	0.22
Comorbidities
Coronary Artery Disease	18,563.27	(14,181.15 – 22,945.39)	18,773.67	(14,821.56 – 22,725.79)	1.13	25,107.80	(18,866.12 – 31,349.47)	33.74	20,335.33	(16,380.61 – 24,290.04)	−19.01	0.24	0.51
Congestive Heart Failure	36,671.23	(23,845.37 – 49,497.08)	20,934.24	(18,253.44 – 23,615.03)	−42.91	23,215.90	(19,869.74 – 26,562.07)	10.90	27,358.70	(22,608.39 – 32,109.02)	17.84	0.23	0.52
Chronic Kidney Disease	27,520.92	(22,149.81 – 32,892.03)	25,568.27	(21,068.46 – 30,068.07)	−7.10	22,186.60	(17,976.94 – 26,396.25)	−13.23	26,385.48	(20,943.27 – 31,827.69)	18.93	0.15	0.62
Chronic Obstructive Pulmonary Disease	17,599.32	(15,363.62 – 19,835.02)	16,698.96	(14,809.66 – 18,588.26)	−5.12	18,933.40	(16,577.75 – 21,289.06)	13.38	19,886.20	(17,330.85 – 22,441.55)	5.03	0.69	0.17
Diabetes	19,186.93	(16,842.61 – 21,531.26)	20,251.46	(17,980.23 – 22,522.69)	5.55	19,814.74	(17,737.62 – 21,891.87)	−2.16	23,270.88	(20,717.09 – 25,824.67)	17.44	0.71	0.16
Hypertension	18,396.20	(17,142.05 – 19,650.35)	17,809.58	(16,693.03 – 18,926.13)	−3.19	17,219.69	(15,980.82 – 18,458.56)	−3.31	18,158.87	(17,099.72 – 19,218.03)	5.45	0.11	0.67
≥ 2 Comorbidities	18,708.33	(17,424.06 – 19,992.60)	19,022.51	(17,810.65 – 20,234.38)	1.68	18,788.15	(17,898.30 – 19,678.00)	−1.23	19,059.28	(18,010.78 – 20,107.79)	1.44	0.37	0.39
None	18,427.14	(17,162.73 – 19,691.54)	20,334.87	(18,780.08 – 21,889.65)	10.35	20,471.81	(18,525.58 – 22,418.03)	0.67	21,759.62	(19,998.03 – 23,521.21)	6.29	0.91	0.05 *
Spread of Cancer & Metastases
Chemotherapy	16,501.69	(14,568.85 – 18,434.53)	16,854.35	(15,065.46 – 18,643.24)	2.14	16,748.03	(14,900.13 – 18,595.92)	−0.63	16,971.88	(15,494.39 – 18,449.36)	1.34	0.71	0.16
Gastrointestinal Metastasis	17,308.85	(15,681.76 – 18,935.94)	17,314.37	(15,668.76 – 18,959.98)	0.03	20,793.16	(14,448.62 – 27,137.70)	20.09	16,834.71	(15,071.07 – 18,598.36)	−19.04	0.02	0.86
Lymph Node Metastasis	23,584.37	(18,649.70 – 28,519.04)	21,016.37	(18,487.82 – 23,544.91)	−10.89	20,333.24	(17,058.24 – 23,608.25)	−3.25	22,482.58	(18,516.76 – 26,448.40)	10.57	0.12	0.65
Non-Gastrointestinal Metastasis	15,667.96	(14,597.15 – 16,738.76)	15,179.54	(14,153.41 – 16,205.66)	−3.12	15,299.30	(14,417.38 – 16,181.22)	0.79	17,637.96	(16,517.97 – 18,757.94)	15.29	0.46	0.32
≥ 2 Spread Types	15,878.89	(14,501.62 – 17,256.16)	18,239.64	(14,972.23 – 21,507.04)	14.87	18,519.11	(16,523.42 – 20,514.80)	1.53	18,429.93	(16,679.74 – 20,180.12)	−0.48	0.66	0.19
≥ 3 Spread Types	17,431.62	(14,155.29 – 20,707.95)	17,185.67	(14,556.55 – 19,814.80)	−1.41	16,252.10	(14,265.10 – 18,239.11)	−5.43	19,171.40	(14,736.28 – 23,606.53)	17.96	0.21	0.55
≥ 4 Spread Types	17,670.63	(7,176.81 – 28,164.46)	21,420.50	(14,195.66 – 28,645.34)	21.22	23,311.98	(12,508.53 – 34,115.44)	8.83	17,310.62	(12,210.18 – 22,411.05)	−25.74	0.00	0.96
No Spread	20,346.75	(19,009.16 – 21,684.35)	20,707.95	(19,441.50 – 21,974.40)	1.78	20,233.81	(19,025.44 – 21,442.18)	−2.29	21,521.56	(20,163.72 – 22,879.40)	6.36	0.46	0.32
Types of PLC
Cholangiocarcinoma	17,432.10	(16,559.54 – 18,304.66)	17,706.21	(16,633.06 – 18,779.37)	1.57	17,915.87	(17,075.73 – 18,756.02)	1.18	18,906.80	(17,965.26 – 19,848.34)	5.53	0.87	0.07
Hepatocellular Carcinoma	20,002.73	(18,598.98 – 21,406.48)	20,269.27	(19,055.45 – 21,483.10)	1.33	19,916.57	(18,627.48 – 21,205.66)	−1.74	21,021.32	(19,614.09 – 22,428.55)	5.55	0.48	0.31
Mixed Hepatic Malignancy	17,613.03	(10,640.13 – 24,585.94)	17,818.41	(14,141.22 – 21,495.61)	1.17	23,484.88	(16,894.25 – 30,075.51)	31.80	19,742.19	(15,896.46 – 23,587.91)	−15.94	0.33	0.43
Types of Surgery
Tumor Ablation Complication	21,037.69	(17,561.96 – 24,513.42)	22,962.08	(18,603.45 – 27,320.72)	9.15	19,029.95	(16,200.30 – 21,859.60)	−17.12	19,891.13	(16,854.71 – 22,927.54)	4.53	0.31	0.44
Hepatic Lobectomy	38,010.59	(32,671.45 – 43,349.73)	43,399.41	(31,906.60 – 54,892.23)	14.18	38,952.49	(34,641.36 – 43,263.63)	−10.25	44,998.00	(38,407.99 – 51,588.00)	15.52	0.40	0.37
Liver Transplant	114,784.64	(103,419.72 – 126,149.56)	104,924.69	(95,053.72 – 114,795.65)	−8.59	111,946.65	(100,996.97 – 122,896.33)	6.69	125,029.92	(110,284.25 – 139,775.59)	11.69	0.34	0.42
Partial Hepatectomy	29,990.51	(27,518.81 – 32,462.22)	29,653.14	(26,814.62 – 32,491.66)	−1.12	32,954.60	(29,104.28 – 36,804.92)	11.13	33,227.94	(30,004.70 – 36,451.18)	0.83	0.79	0.11
Mixed Surgery Type	37,946.04	(28,410.51 – 47,481.57)	37,966.92	(29,592.32 – 46,341.51)	0.06	45,522.24	(23,918.43 – 67,126.06)	19.90	57,609.05	(15,485.61 – 99,732.49)	26.55	0.86	0.07
No Surgery	15,394.29	(14,827.69 – 15,960.90)	15,947.86	(15,329.47 – 16,566.24)	3.60	15,748.97	(15,158.38 – 16,339.56)	−1.25	16,693.70	(16,069.10 – 17,318.30)	6.00	0.76	0.13
Liver Complications
Ascites	20,167.02	(17,508.59 – 22,825.45)	23,746.22	(20,641.87 – 26,850.58)	17.75	22,131.92	(19,096.02 – 25,167.83)	−6.80	24,520.48	(21,010.26 – 28,030.70)	10.79	0.59	0.23
Encephalopathy	17,506.54	(13,696.17 – 21,316.91)	17,760.20	(13,805.39 – 21,715.01)	1.45	21,005.04	(16,942.16 – 25,067.92)	18.27	23,292.89	(18,013.38 – 28,572.40)	10.89	0.92	0.04 *
Hepatocellular Carcinoma	17,673.15	(16,521.09 – 18,825.20)	18,720.15	(17,548.15 – 19,892.15)	5.92	17,915.82	(16,602.58 – 19,229.06)	−4.30	18,519.81	(17,445.79 – 19,593.82)	3.37	0.21	0.55
Hepatorenal Syndrome	18,997.98	(10,564.13 – 27,431.83)	23,169.27	(12,275.69 – 34,062.84)	21.96	19,829.96	(11,859.97 – 27,799.96)	−14.41	52,125.49	(26,348.46 – 77,902.52)	162.86	0.61	0.22
Varices	17,433.70	(11,218.19 – 23,649.21)	24,101.92	(14,865.61 – 33,338.23)	38.25	13,370.36	(10,078.18 – 16,662.55)	−44.53	14,128.56	(11,921.47 – 16,335.64)	5.67	0.30	0.46
≥ 2 Liver Complications	20,307.54	(18,332.83 – 22,282.25)	20,768.74	(19,134.88 – 22,402.60)	2.27	21,011.51	(19,238.51 – 22,784.50)	1.17	22,291.06	(20,013.90 – 24,568.22)	6.09	0.89	0.06
≥ 3 Liver Complications	25,360.13	(22,163.00 – 28,557.26)	22,899.53	(20,601.64 – 25,197.43)	−9.70	22,517.56	(20,227.54 – 24,807.57)	−1.67	24,885.62	(22,145.17 – 27,626.07)	10.52	0.03	0.84
≥ 4 Liver Complications	37,983.80	(27,529.01 – 48,438.58)	29,728.34	(24,583.11 – 34,873.57)	−21.73	32,264.54	(24,193.16 – 40,335.92)	8.53	32,493.80	(25,387.52 – 39,600.07)	0.71	0.27	0.48
≥ 5 Liver Complications	42,346.69	(19,379.20 – 65,314.18)	39,617.62	(26,764.70 – 52,470.54)	−6.44	26,242.55	(20,297.84 – 32,187.25)	−33.76	30,046.23	(18,622.36 – 41,470.10)	14.49	0.72	0.15
None	16,821.41	(15,978.66 – 17,664.16)	16,615.87	(15,691.66 – 17,540.07)	−1.22	16,953.86	(16,277.55 – 17,630.16)	2.03	17,514.88	(16,728.33 – 18,301.44)	3.31	0.66	0.19
Liver Etiologies
Alcoholic Liver Disease	20,441.40	(18,081.55 – 22,801.25)	20,582.37	(18,574.68 – 22,590.06)	0.69	21,277.62	(18,719.95 – 23,835.28)	3.38	21,254.76	(18,650.86 – 23,858.66)	−0.11	0.85	0.08
Autoimmune Hepatitis	24,584.17	(19,435.88 – 29,732.45)	19,227.33	(14,874.68 – 23,579.98)	−21.79	26,502.77	(20,510.69 – 32,494.85)	37.84	29,327.87	(20,980.39 – 37,675.36)	10.66	0.42	0.35
Hepatitis B	23,259.67	(19,317.79 – 27,201.56)	23,484.41	(19,902.85 – 27,065.98)	0.97	23,225.10	(19,851.76 – 26,598.44)	−1.10	31,579.58	(23,550.40 – 39,608.76)	35.97	0.60	0.23
Hepatitis C	19,978.88	(18,337.23 – 21,620.54)	19,883.16	(18,500.95 – 21,265.38)	−0.48	19,428.88	(17,990.84 – 20,866.92)	−2.28	19,466.92	(17,736.59 – 21,197.25)	0.20	0.83	0.09
Metabolic Liver Disease	36,510.83	(12,026.89 – 60,994.77)	23,531.82	(13,481.10 – 33,582.54)	−35.55	40,090.28	(−1,053.96 – 81,234.52)	70.37	25,378.09	(15,172.39 – 35,583.79)	−36.70	0.07	0.73
Non-Alcoholic Fatty Liver Disease	24,305.35	(20,394.91 – 28,215.78)	24,714.97	(21,841.75 – 27,588.19)	1.69	25,195.78	(21,121.79 – 29,269.77)	1.95	22,701.96	(20,590.82 – 24,813.10)	−9.90	0.27	0.48
Mixed Liver Etiology	20,981.58	(18,987.92 – 22,975.25)	20,552.85	(18,443.97 – 22,661.72)	−2.04	18,736.13	(17,190.25 – 20,282.01)	−8.84	21,138.14	(19,061.99 – 23,214.28)	12.82	0.02	0.84
Other	17,422.92	(16,548.06 – 18,297.79)	18,132.87	(17,058.97 – 19,206.76)	4.07	18,002.52	(17,053.57 – 18,951.47)	−0.72	19,147.55	(18,227.52 – 20,067.58)	6.36	0.82	0.09
Hospital Bed Size
Small	14,088.63	(13,052.27 – 15,125.00)	14,338.99	(13,059.75 – 15,618.23)	1.78	14,192.86	(13,145.83 – 15,239.89)	−1.02	14,283.41	(13,473.71 – 15,093.12)	0.64	0.27	0.48
Medium	15,627.48	(14,035.63 – 17,219.33)	16,615.68	(15,368.11 – 17,863.24)	6.32	17,507.64	(15,805.95 – 19,209.32)	5.37	16,718.21	(15,585.22 – 17,851.20)	−4.51	0.49	0.30
Large	21,488.32	(19,947.15 – 23,029.49)	21,665.05	(20,146.45 – 23,183.66)	0.82	21,224.61	(19,825.25 – 22,623.97)	−2.03	23,212.45	(21,584.52 – 24,840.37)	9.37	0.47	0.32
Hospital Location/Teaching Status
Nonteaching	12,985.21	(12,291.81 – 13,678.60)	13,435.58	(12,747.78 – 14,123.39)	3.47	12,679.73	(11,987.52 – 13,371.94)	−5.63	13,462.01	(12,722.47 – 14,201.56)	6.17	0.05	0.77
Teaching	20,747.42	(19,432.01 – 22,062.82)	20,886.05	(19,638.44 – 22,133.67)	0.67	20,628.98	(19,478.73 – 21,779.22)	−1.23	21,614.58	(20,349.22 – 22,879.93)	4.78	0.47	0.32
Hospital Region
Northeast	19,648.90	(17,852.62 – 21,445.18)	19,923.83	(18,111.98 – 21,735.68)	1.40	20,424.23	(18,454.11 – 22,394.34)	2.51	21,731.51	(19,363.76 – 24,099.27)	6.40	0.89	0.06
Midwest	17,202.04	(15,726.49 – 18,677.59)	17,377.66	(15,708.91 – 19,046.42)	1.02	17,996.91	(15,761.92 – 20,231.91)	3.56	19,152.37	(17,070.79 – 21,233.96)	6.42	0.90	0.05
South	16,744.74	(15,230.98 – 18,258.51)	16,534.67	(15,304.03 – 17,765.30)	−1.25	16,294.93	(14,998.69 – 17,591.17)	−1.45	17,536.55	(15,967.30 – 19,105.79)	7.62	0.26	0.49
West	24,250.99	(20,926.93 – 27,575.05)	25,051.47	(21,879.54 – 28,223.40)	3.30	23,988.19	(21,453.79 – 26,522.59)	−4.24	24,305.67	(21,488.34 – 27,123.00)	1.32	0.06	0.75
Insurance Type
Medicare	18,494.25	(17,425.88 – 19,562.62)	18,605.83	(17,480.17 – 19,731.48)	0.60	18,425.02	(17,451.31 – 19,398.74)	−0.97	19,547.49	(18,369.55 – 20,725.44)	6.09	0.54	0.27
Medicaid	19,626.23	(17,612.75 – 21,639.72)	18,707.08	(17,387.08 – 20,027.08)	−4.68	18,592.85	(17,208.38 – 19,977.31)	−0.61	20,117.67	(18,514.74 – 21,720.60)	8.20	0.06	0.76
Private	20,486.56	(18,716.31 – 22,256.81)	22,816.79	(21,042.18 – 24,591.40)	11.37	22,617.79	(20,557.72 – 24,677.85)	−0.87	22,581.86	(20,714.21 – 24,449.51)	−0.16	0.51	0.28
Other Insurance	19,043.87	(16,034.17 – 22,053.57)	16,814.03	(15,141.99 – 18,486.06)	−11.71	16,305.53	(14,674.06 – 17,937.01)	−3.02	19,739.02	(17,168.17 – 22,309.87)	21.06	0.01	0.88

^*p < 0.05

^**p < 0.01

^***p < 0.001

Figure 2.

Inflation-adjusted total and mean costs and trends for patients undergoing liver transplantation, stratified using hospital-related and socioeconomic variables.

Figure 3.

Inflation-adjusted total and mean costs and trends for patients undergoing in-hospital liver transplantation, stratified using liver complications.

Figure 4.

Inflation-adjusted total and mean costs and trends for patients undergoing in-hospital liver transplantation, stratified using liver etiologies.

Figure 5.

Inflation-adjusted total and mean costs and trends for patients undergoing in-hospital liver transplantation, stratified using primary liver cancer subtypes.

Discussion

This study examined incidence rates, mortality, and costs of PLC using a nationwide inpatient database from 2016–2019. Total costs associated with PLC hospitalization rose in parallel with increasing hospitalization rates, representing a continuation of prior trends in hospitalization seen individually with cholangiocarcinoma and hepatocellular carcinoma, and despite average hospitalization costs that appear to have stabilized in this study compared to prior increasing trends (1,2). Moreover, in-hospital mortality rates were increased, which deviates from prior studies that reported decreasing in-hospital mortality rates associated with PLC (1,2). Our findings appear to be in line with previously reported national trends in PLC incidence from global and national cancer-specific epidemiologic registries (29,30). While there was a plateauing of PLC incidence during the period of 2006–2011 (29), more recent data from a global registry shows increasing PLC incidence in North America owing to the transition from viral hepatitis to metabolic syndrome, NAFLD, and ever increasing alcohol use as the major risk factors for this disease (30).

After stratifying the PLC cohort, increasing hospitalization costs were found among those age >65; men and women; white, hispanic, and asian/pacific islander races; those with a concomitant diagnosis of congestive heart failure, chronic obstructive pulmonary disease, diabetes, and multiple comorbidities; those with hepatocellular carcinoma and cholangiocarcinoma; early and later stages of disease; those who underwent lobectomy/partial hepatectomy and did not undergo surgery; those with no hepatic complications, ascites, encephalopathy, and multiple hepatic complications; ALD and NAFLD; those with Medicare; and among small and medium-sized hospitals, teaching hospitals, and hospitals in the midwest, south, and western regions of the US. These findings highlight the need for targeted public health strategies to mitigate PLC’s increasing economic burden.

The increased healthcare utilization and costs of PLC may be attributed to greater complexity of care in an aging population with a larger number of comorbidities. Not surprisingly, the overall economic burden of PLC was seen predominantly in male patients aged 50–64 and over 65. These findings are consistent with the typical age of presentation and sex distribution for PLC (3). The increased incidence and costs among those older than 65 and with multiple comorbidities could be a testament to improved access, utilization, and effectiveness of the various screening and treatment modalities for PLC, prolonging patient survival (16–22) and shifting the demographic of patients hospitalized for PLC into an older age category. Simultaneously, older ages at admission may also explain the observed increases in inpatient mortality rates associated with PLC hospitalizations.

Notably, the vast majority of patients hospitalized for PLC in this study, and the correlative costs, were either for non-surgical management or liver transplantation. This observation is likely representative of a PLC cohort with concomitant decompensated cirrhosis. A significant proportion of these costs are presumably related to readmissions for complications of cirrhosis. Though we weren’t able to determine the number of readmissions within our PLC cohort, prior research using population-level data suggests that approximately 20% of patients with cirrhosis are readmitted to the hospital within 90 days of discharge from initial hospitalization. The most common reason for readmission was acute complications of cirrhosis and hepatic encephalopathy was most strongly associated with readmission (31). This is important to note because the progression of PLC is usually characterized by liver failure as opposed to complications related to metastasis, potentially leading to growing healthcare usage and expenditure for inpatient management of ascites, encephalopathy, and variceal bleeding (32). The observed rise in the incidence and cost related to non-surgical management of PLC, in conjunction with increased incidence and costs associated with hepatic decompensation and stable incidence and costs of liver transplant, is worrisome and may suggest a growing gap of available donor livers and PLC patients on the liver transplant waitlist. The use of marginal grafts and living donor liver transplant can help close this gap and further contain costs as it can be performed prior to the development of decompensated cirrhosis (33–35).

There was also an increase in the incidence and cost of PLC hospitalizations for lobectomy and partial hepatectomy in this study. We postulate that this finding is an indication of better targeted screening programs in high-risk patient populations and thus improved identification of early-stage PLC amenable to surgical resection (12,13,36). As mentioned previously, these higher costs could also be due to an aging patient demographic with multiple comorbidities and hence an increased risk of postoperative complications (37). Early identification and referral of high-risk surgical patients to rehabilitation and skilled nursing facilities may help decrease costs (1,2).

There were also statistically significant rising temporal trends of PLC hospitalizations across all racial and ethnic groups over the study period, except for Native Americans/Alaska Natives. Costs also increased within these groups, except for Black Americans. Interestingly, White Americans had the highest rate of hospital admissions for PLC and associated costs over the study period despite prior population-based studies in the United States suggesting Asian/Pacific Islanders having significantly higher incidence of PLC, followed by Black Americans, Hispanic Americans, Native Americans/Alaska Natives, and White Americans (38–40). This finding may highlight difficulties with access to healthcare for PLC among non-White Americans. The available treatment strategies for PLC, especially resection and transplant, are highly complex and are typically performed at tertiary medical centers. Barriers in obtaining care at these centers perpetuate disparities among different races and ethnicities and can affect patient survival (41). Therefore, further investigation is required to determine the factors responsible for these disparities within the PLC population.

With respect to liver disease etiologies, hepatitis C-associated PLC hospitalization incidence and costs were stable over the study period, although it continued to be the highest overall contributor to resource utilization and costs for PLC. This is not surprising, as hepatitis C has been, and continues to be, the leading cause of PLC in the US (3). Nonetheless, this observation is encouraging and may be linked to more focused screening programs and the introduction of direct-acting antiviral therapy in 2011, which has significantly reduced the incidence and prevalence of chronic hepatitis C (42). Hepatitis B-associated PLC hospitalizations and costs also were steady. Overall, hepatitis B represented a comparatively low-cost contributor, pointing to continued effectiveness of the hepatitis B vaccination and other measures on risk mitigation (43). Despite improvements in the prevention, screening, and treatment of hepatitis B and C, chronic liver disease due to ALD and NAFLD is rising (44,45). Our analysis corroborates this trend, showing that PLC hospitalization incidence and costs for these etiologies increased, and in combination, are comparable to the incidence rates and costs of hepatitis C-associated PLC as of 2019. This finding calls for increased attention towards improving outpatient management and coordination of care in patients with ALD and NAFLD, focusing on prevention, and providing patient-centered counseling related to diet and exercise, abstinence from alcohol, smoking cessation, medication-assisted therapies, and other resources (46–49). Although PLC typically arises in the setting of cirrhosis, it is possible for PLC to develop in NAFLD patients without cirrhosis (50–52). While the absolute risk of PLC in NAFLD patients is low, there is a higher risk for developing PLC in non-cirrhotic NAFLD specifically in men over 65 with a history of smoking, diabetes, and elevated aminotransferases (51). Future prospective studies are needed to establish methods of identifying NAFLD patients at increased risk of PLC and to determine the utility of surveillance programs in this population.

Limitations

There may be an element of selection bias in the present study given that the NIS database primarily consists of ICD diagnosis codes. As such, the NIS does not account for the possible mislabeling or under-coding of diagnoses. Additionally, each hospitalization recorded in the NIS is unique and therefore is likely to include readmissions. As mentioned previously, we were unable to determine the proportion of PLC hospitalizations that were considered readmissions and their impact on costs. The ICD diagnosis code for cholangiocarcinoma was inclusive of both intrahepatic and extrahepatic subtypes; therefore, we were unable to study their respective trends. The NIS does not contain data on specific tumor stage at the time of hospitalization. Instead, we relied on surrogate ICD codes related to tumor spread. Additionally, we were unable to analyze utilization, costs, and trends associated with tumor ablation therapy relative to resection for early stage PLC, as ablation is typically performed in the outpatient setting. The NIS only captures instances of post-procedural complications of ablation therapy that require inpatient hospitalization.

Conclusion

The incidence and costs associated with PLC hospitalization is rising. This finding may be attributed to an aging population with multiple comorbidities, availability of donor livers in a predominantly cirrhotic population, and the increasing rates of ALD and NAFLD. Targeted public health strategies for these groups must be developed to improve the utilization of inpatient resources and cost of PLC.