185,012 patients with a diagnostic code for NAFLD or NASH between 1st January 2006 and 31st July 2018 were eligible for study inclusion. Of these, each NAFLD, LC, and HCC cohort included 123,379, 205, and 96 patients, respectively (Fig. 1).
The mean age of patients across all the severity stages ranged between 46 and 50 years (Table 1). Majority of patients were male (70.0–71.7%). The mean follow-up time were 1,192 ± 915.2 days, 895 ± 690.0 days and 967 ± 728.4 days for the NAFLD/NASH, LC and HCC patients respectfully. Patients who were diagnosed by specialist ranged from 32.0% with NAFLD/NASH to 64.6% with HCC. The comorbidity burden was high across all liver disease severity stages, with significantly higher prevalence of comorbid conditions in each increasing severity stage compared to NAFLD/NASH. The most prevalent comorbidities included hyperlipidaemia (50.2–61.5%), diabetes mellitus (40.0–60.4%), and hypertension (27.9 % to 42.7%). T2DM was also statistically significantly higher for LC (33.2%) and HCC (35.4%) compared to that in NAFLD/NASH (10.6%), whereas renal impairment was only significantly higher in LC patients (26.3%) compared to NAFLD/NASH (18.1%). All types of infections were similar across all 3 liver diseases severities ranging from 27.4–30.2%. More than two-thirds of the patients across all severity stages including those with NAFLD/NASH had at least 1 comorbidity out of hypertension, hyperlipidaemia, and T2DM. In addition, the proportion of patients with all 3 of these conditions was significantly higher among patients with advanced liver diseases (13.1–20.8%) compared with NAFLD/NASH (3.9%) (all p < 0.0001).
Table 1
Demographic and clinical characteristics of NAFLD/NASH, LC, and HCC patients.
| NAFLD/NASH | LC | HCC |
| (n = 123,379) | (n = 205) | (n = 96) |
Age in years at index date; (Mean ± SD) | 46 ± 11.5 | 46 ± 12.2 | 50 ± 11.5* |
Age group in years at index date, n (%) | | | |
18–34 years | 20,531 (16.6%) | 39 (19.0%) | 9 (9.4%)* |
35–44 years | 32,084 (26.0%) | 47 (22.9%) | 23 (24.0%) |
45–54 years | 38,225 (31.0%) | 69 (33.7%) | 25 (26.0%) |
55–64 years | 26,569 (21.5%) | 35 (17.1%) | 30 (31.3%) |
≥ 65 years | 5,969 (4.8%) | 15 (7.3%) | 9 (9.4%) |
Length of follow-up, days; (Mean ± SD) | 1,192 ± 915.2 | 895 ± 690.0*** | 967 ± 728.4* |
Gender: Males (%) | 86,365 (70.0%) | 147 (71.7%) | 68 (70.8%) |
Comorbidity at baseline, n (%) |
Diabetes mellitus | 49,391 (40.0%) | 145 (70.7%)* | 58 (60.4%)*** |
T2DM | 13,016 (10.6%) | 68 (33.2%)*** | 34 (35.4%)*** |
Hyperlipidaemia | 61,882 (50.2%) | 121 (59.0%)* | 59 (61.5%)* |
Hypertension | 34,456 (27.9%) | 80 (39.0%)** | 41 (42.7%)** |
CVD | 14,040 (11.4%) | 45 (22.0%)*** | 24 (25.0%)*** |
Renal impairment | 22,283 (18.1%) | 54 (26.3%)** | 16 (16.7%) |
Anaemia | 13,674 (11.1%) | 86 (42.0%)*** | 25 (26.0%)*** |
Abdominal pain | 6,685 (5.4%) | 7 (3.4%) | 10 (10.4%)* |
Infection | 33,834 (27.4%) | 61 (29.8%) | 29 (30.2%) |
Combination of “Type 2 diabetes mellitus” or “Hypertension” or “Hyperlipidaemia” |
3 comorbidities, n (%) | 4,853 (3.9%) | 27 (13.1%)*** | 20 (20.8%)*** |
2 comorbidities, n (%) | 24,522 (19.9%) | 53 (25.7%) | 20 (20.8%) |
1 comorbidity, n (%) | 45,917 (37.2%) | 82 (39.8%) | 35 (36.5%) |
No comorbidities, n (%) | 48,086 (39.0%) | 44 (21,4%) | 21 (21.9%) |
NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; LC: liver cirrhosis; HCC: hepatocellular carcinoma; SD: standard deviation; T2DM: type 2 diabetes mellitus; CVD: cardiovascular disease. *p < 0.05 for comparison of LC or HCC cohort versus NAFLD/NASH; **p < 0.01 for comparison of LC or HCC cohort versus NAFLD/NASH; ***p < 0.0001 for comparison of LC or HCC cohort versus NAFLD/NASH. |
Overall, the mean annual number of HCRU across all service categories (inpatient admission, outpatient services, and prescription fills) increased from pre-index to post-index period (all p < 0.0001), (Table 2). The mean annual admissions per patient increased from pre-index to post-index periods (all p < 0.0001). Post-index HCRU across all service categories was significantly higher among patients with advanced liver diseases compared with NAFLD/NASH. The percentage of patients with an inpatient admission was significantly higher among HCC patients versus NAFLD/NASH patients (all p < 0.0001). Mean annual number of admissions per patient were significantly higher among advanced liver diseases compared with NAFLD/NASH (all p < 0.0001). This trend held when comparing mean annual outpatient services and prescription fills. patients, respectively (p < 0.0001).
Table 2
Annual all-cause healthcare resource utilization among NAFLD/NASH, LC, and HCC patients.
| NAFLD/NASH | LC | HCC |
| (n = 123,379) | (n = 205) | (n = 96) |
Healthcare Resource Utilization Parameters | Pre-Index | Post-Index | Pre-Index | Post-Index | Pre-Index | Post-Index |
Inpatient hospitalizations | | | | | | |
Patients with hospitalization [n (%)] | 3,393 (3%) | 8,391 (7%)* | 18 (9%) | 35 (17%) | 6 (6%) | 34 (35%)* |
Annual admissions per patient [mean (SD)] | 0.04 (0.27) | 0.10 (0.42)* | 0.17 (0.70) | 0.31 (0.79) | 0.10 | 0.68* |
% change from pre-index to post-index period | 150% | 82% | 580% |
Length of stay [mean (SD)] | 0.34 (2.38) | 0.83 (3.48)* | 1.66 (4.85) | 2.88 (6.12)* | 0.83 (2.80) | 6.00 (7.89)* |
Outpatient services | | | | | | |
Patients with service [n (%)] | 99,125 (80%) | 123,329 (99%) | 179 (87%) | 205 (100%)* | 88 (92%) | 96 (100%)* |
Annual services per patient [mean (SD)] | 5.7 (8.1) | 8.4 (8.6)* | 10.8 (14.3) | 13.2 (14.4) | 10.4 (11.8) | 13.1 (9.8) |
% change from pre-index to post-index period | 46% | 22% | 26% |
Prescription fills | | | | | | |
Patients with fills [n (%)] | 76,738 (62%) | 91,642 (74%)* | 151 (74%) | 166 (81%) | 70 (73%) | 79 (83%) |
Annual prescriptions per patient [mean (SD)] | 2.4 (3.0) | 3.1 (3.2)* | 4.0 (5.0) | 4.6 (4.8) | 3.54 (3.3) | 3.84 (3.0) |
% change from pre-index to post-index period | 30% | 17% | 8% |
NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; LC: liver cirrhosis; HCC: hepatocellular carcinoma; SD: standard deviation. *P < 0.05 for comparison of pre-index versus post-index period. |
The mean total all-cause healthcare annual cost after diagnosis was significantly lower in patients with NAFLD/NASH at ¥146,096 compared to those with more advanced liver diseases at ¥399,425 for LC patients, and ¥842,875 for HCC patients (Fig. 2). Overall, the mean total annual healthcare cost increased at the post-index from pre-index (p < 0.0001), with an increase of 75% in NAFLD/NASH, 50% in LC, and 312% in HCC patients from pre-index to post-index. Inpatient costs were the largest contributor in both LC and HCC patients, whereas outpatient costs were the major contributor among NAFLD/NASH patients.
After adjusting for potential confounders, the adjusted annual all-cause post-index costs increased with liver disease severity (Table 3). Compared to NAFLD/NASH patients, the increased cost ratio was 1.61 and 3.01 for LC and HCC respectively (all p < 0.0001). Age group cost ratio values increased with age, with the 65 years and over group having the highest cost ratio of 1.16 (p < 0.0001) compared to the 18–34 years group. All comorbidities had an increased cost ratio except hyperlipidemia which had a cost ratio of 0.91 (p < 0.0001). Patients with CVD had the highest cost ratio value of 1.77 (p < 0.0001), which was followed by T2DM, abdominal pain, anemia and hypertension, with cost ratios of 1.45, 1.43, 1.42, and 1.32 respectfully (all p < 0.0001). Significantly high risk of disease progression within the NAFLD/NASH cohort were those of ≥ 65 years (HR: 2.65, p = 0.0198) and comorbid T2DM (HR: 1.74, p = 0.0353), while those associated with significantly slower disease progression with comorbid hyperlipidemia (HR: 0.65, p < 0.05) (Fig. 3).
Table 3
Total annual all-cause healthcare post- index costs adjusted by demographics and clinical characteristics – Multivariable analysis
Independent Variables | Cost Ratio | 95% CI (Lower-Upper) |
Liver disease severity stage | | |
NAFLD/NASH | Reference | ---- |
LC | 1.61* | (1.46, 1.76) |
HCC | 3.01* | (2.99, 3.04) |
Age groups | | |
18–34 years | Reference | ---- |
35–44 years | 1.02* | (0.95, 1.09) |
45–54 years | 1.05* | (0.98, 1.12) |
55–64 years | 1.09* | (1.02, 1.16) |
≥65 years | 1.16* | (1.09, 1.24) |
Comorbidities | | |
Diabetes mellitus | 1.27* | (1.24, 1.30) |
T2DM | 1.45* | (1.43, 1.46) |
Hyperlipidaemia | 0.91* | (0.89, 0.93) |
Hypertension | 1.32* | (1.30, 1.35) |
CVD | 1.77* | (1.75, 1.78) |
Renal impairment | 1.16* | (1.14, 1.18) |
Abdominal pain | 1.43* | (1.41, 1.45) |
Anaemia | 1.41* | (1.38, 1.44) |
Infections | 1.25* | (1.22, 1.27) |
CI: confidence interval; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; LC: liver cirrhosis; HCC: hepatocellular carcinoma; T2DM: type 2 diabetes mellitus; CVD: cardiovascular disease. *p < 0.05 for comparison of independent variable versus reference |