ABSTRACT
Background/Aims
Epidemiological data on mortality in autoimmune liver diseases (AILDs) are scarce. We examined all‐cause and cancer‐related mortality in individuals with AILD from Sweden.
Methods
We identified 9654 individuals with AILD (3342 with autoimmune hepatitis (AIH), 3751 with primary biliary cholangitis (PBC), and 2561 with primary sclerosing cholangitis (PSC)) using national Swedish registries between 2001 and 2020. These were matched with 80 685 comparators from the general population at a ratio of 1:10 on age, sex, year of diagnosis and municipality. Rates of outcomes were estimated using Cox regression models, adjusted for matching factors and cardiovascular disease, diabetes, inflammatory bowel disease, chronic obstructive pulmonary disease, and education.
Results
Individuals with AILD had higher mortality than comparators (adjusted hazard ratio (aHR) = 2.3, 95% CI = 2.2–2.4) and higher rates of cancer‐related death (aHR = 2.1, 95% CI = 1.9–2.3). The presence of liver cirrhosis in AILD was related to even higher mortality, with aHR 5.8 (95% CI = 5.1–6.6). Both males and females with AILD had increased mortality (males aHR = 2.6, 95% CI = 2.4–3.0, and females aHR = 2.2, 95% CI = 2.1–2.3). The mortality was higher in individuals aged 18–50 years (aHR = 4.6, 95% CI = 3.6–5.8), than in individuals above 50 years (aHR = 2.2, 95% CI = 2.1–2.3). Overall mortality rates and cancer‐related death were particularly high in individuals with PSC compared to their matched comparators, with aHR = 4.1 (95% CI = 3.2–5.2) and aHR = 6.4 (95% CI = 4.0–10.3), respectively.
Conclusions
Patients with AILDs have increased rates of overall and cancer‐related mortality compared to matched comparators, and relative risks are highest in cirrhosis, younger age and PSC.
Keywords: autoimmune liver disease, cancer‐related mortality, death, epidemiology
Summary.
A population‐based study of 9654 individuals with autoimmune liver diseases and 80 685 matched controls shows that overall and cancer‐related mortality is more than two times higher in autoimmune liver diseases.
Among all autoimmune liver diseases, mortality was the highest in individuals with primary sclerosing cholangitis.
Abbreviations
- aHR
adjusted hazard ratio
- AIH
autoimmune hepatitis
- AILD
autoimmune liver disease
- CI
confidence interval
- COPD
chronic obstructive lung disease
- CVD
cardiovascular disease
- HR
hazard ratio
- IBD
inflammatory bowel disease
- ICD
International Classification of Diseases
- IQR
Interquartile range
- IR
Incidence rate
- LT
liver transplantation
- NPR
National Patient Register
- PBC
primary biliary cholangitis
- PIN
personal identification number
- PSC
primary sclerosing cholangitis
- PY
persons‐years
1. Introduction
Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and autoimmune hepatitis (AIH) constitute classic autoimmune liver diseases (AILDs). Each disease has a distinct pathogenetic mechanism causing liver damage [1, 2]. In AIH, inflammation primarily targets hepatocytes, leading to interface hepatitis, which can progress to fibrosis if not promptly diagnosed or treated. PBC involves inflammation of small intrahepatic biliary ducts, resulting in non‐suppurative cholangitis, whereas PSC is characterised by fibrotic obliterative inflammation affecting both intra‐ and extrahepatic biliary ducts, leading to multifocal bile duct stricturing [1].
The risk of developing AILDs varies by sex. AIH and PBC are more prevalent in females, with approximately two‐thirds of patients with AIH and up to 90% of patients with PBC being female. In contrast, PSC predominantly affects males, with approximately two‐thirds of PSC patients being male. Notably, around 80% of patients with PSC also have a concomitant diagnosis of inflammatory bowel disease (IBD) [3].
Persistent liver inflammation associated with chronic AILD may progress to cirrhosis. Patients with liver cirrhosis are at increased risk of liver‐related complications, including portal hypertension, ascites, hepatic encephalopathy, as well as liver‐related malignancies and mortality [4, 5]. While AIH and PBC typically have established successful treatment regimens, PSC currently lacks effective treatment options [3, 6, 7]. Liver transplantation (LT) remains the only therapeutic option if conventional treatment fails, particularly for PSC patients who progress to end‐stage liver disease. Notably, over the past decade, there has been a 50% decrease in the number of PBC patients undergoing LT, while PSC has emerged as the leading indication for LT among AILD patients [8].
Epidemiological data on AILDs vary considerably, including incidence and prevalence rates [1, 9]. Mortality data for AILDs are even more dispersed and scarce, making prognostication challenging [9, 10, 11, 12]. Our study aimed to investigate the prognosis of AILDs in Sweden using population‐based data, with all‐cause mortality, transplant‐free survival, and cancer‐related mortality as outcomes.
2. Materials and Methods
2.1. Study Setting
Study individuals and their matched references were identified using the DELIVER (Decoding the Epidemiology of Liver Disease in Sweden) cohort, encompassing over 300 000 patients with various chronic liver diseases in Sweden dating back to 1964 [13]. This cohort was established by integrating data from multiple Swedish healthcare registries, including the National Patient Register (NPR), the National Cancer Register, the Causes of Death Register, and the Prescribed Drug Register [13]. The linkage of these registries is facilitated by a unique personal identity number (PIN) assigned to every resident in Sweden.
Within the DELIVER cohort, patients with chronic liver diseases are matched with up to 10 reference individuals from the general population on sex, age, municipality, and calendar year when the first liver disease diagnosis was recorded [13]. The NPR, established in 1987, provides nationwide inpatient data and has included outpatient contact data since 2001 [14]. The National Cancer Register, established in 1958, records data on malignant tumour cases across the country with approximately 96% completeness [15]. The Cause of Death register, created in 1952, contains information on all deaths in Sweden, including the underlying cause and contributing conditions, with around 96% of registered cases having an underlying cause of death reported [16].
In Sweden, physicians are mandated to utilise International Classification of Disease (ICD) codes during healthcare visits to classify primary and secondary diagnoses, with this information being regularly transmitted to healthcare registers.
2.2. Study Cohort
The study population comprised all individuals diagnosed with AILD, including AIH, PBC and PSC, at any time between January 1st, 2001, and December 31st, 2020. Diagnoses were identified based on 10th edition coding, whether listed as the main or contributing diagnoses, in the Swedish inpatient and outpatient registries (see Table S1). Patients with several AILD diagnoses were categorised into one of the cohorts depending on the first received diagnosis in the registries (AIH, PBC or PSC) to avoid the risk of the same patient being included in two different groups. If more than one AILD diagnosis was registered the same day, individuals were categorised into one of the cohorts based on the following priority: PSC, PBC and AIH. This selection order was chosen based on perceived disease severity, with PSC associated with the poorest outcomes, followed by PBC and AIH. Additionally, individuals with a pre‐existing diagnosis of AILD who survived until at least January 1st, 2001, were included.
Up to 10 matched comparators were selected from the general population, matched for age, municipality, and calendar year of first liver disease diagnosis.
2.3. Exclusion Criteria
To enhance the precision of patient selection and diagnosis, we systematically excluded all study subjects and comparators with re‐used personal identity numbers and other inconsistencies. This involved excluding individuals who were younger than 18 years old, emigrated from Sweden, died, underwent LT, or had prevalent or pre‐existing cancer or chronic liver diseases other than AILDs before or at the time of diagnosis/baseline, such as alcohol‐related liver disease, metabolic dysfunction‐associated fatty liver disease, viral hepatitis, alfa antitrypsin deficiency, Budd‐Chiari syndrome, and hemochromatosis (Table S2). Additionally, individuals, with unknown educational level, were excluded (Tables S2 and S4). Lastly, patients with AILD without matched controls at baseline or after the exclusion process were also omitted (Figure 1). Both ICD 9th and 10th editions were used to identify exclusion criteria.
FIGURE 1.
Flowchart of inclusion of study population individuals and their comparators. AILD, autoimmune liver disease; ICD, international coding of diseases.
2.4. Outcomes
The primary outcome assessed was time to overall mortality, defined as the date individuals were listed as “dead” in the National Population Registry (NPR). Secondary outcomes included time to 1) death or LT (identified by ICD‐codes, see Table S3), accounting for only the first LT after baseline, and 2) cancer‐related death (defined by any cancer ICD‐code, Table S4), which were selected from NPR, the Cause of Death Register and Cancer Register. All cancer deaths, irrespective of whether they were the primary or contributing cause of death, were considered.
In addition to the matching factors, several covariates were collected. These included cardiovascular disease (CVD); diabetes (both types as one variable); inflammatory bowel disease (IBD); chronic obstructive pulmonary disease (COPD) as a proxy for smoking for those with a first diagnosis at 40 or above; and education level (< 10 years, 10–12 years, and > 12 years), based on the Swedish educational system, where more than 12 years equates to university studies. Comorbidities were defined as an ICD code (9th and 10th edition) for the respective diseases at or before baseline in the inpatient or outpatient registries (Table S5).
2.5. Statistical Analyses
Incidence rates (IR) for all outcomes were defined as total events per person‐time and are presented as events per 1000 person‐years (PY). Cox proportional hazard regression was utilised to estimate hazard ratios (HR) with their corresponding 95% CI for comparing outcomes between patients with AILDs and their matched reference individuals. These models were conditioned on the matching factors (age, sex, year of first diagnosis and municipality). Additionally, adjusted hazard ratios (aHR) were calculated, including the covariates: CVD, diabetes, IBD, COPD and education. Subgroup analyses were conducted by sex, age groups (18–50, ≥ 51), and disease severity (cirrhosis or no cirrhosis at baseline). Interaction analysis was performed to compare the overall mortality between sexes, with a significance level set at p < 0.05.
Cumulative incidence curves (Stata: stcompet) were calculated where death in other causes were considered as the competing risk.
Analyses were performed using Stata version 16.1 and R version 4.3.1.
3. Results
3.1. Baseline Characteristics
We identified 14 702 patients with AILDs in the NPR Register between 2001 and 2020, along with 140 470 matched comparators from the general population. After applying exclusion criteria, the total study population comprised 9654 individuals with AILDs (3342 with AIH, 3751 with PBC, and 2561 with PSC) and 80 685 matched comparators (Figure 1).
The median age at baseline for AILD was 56 years (IQR 39–67) and 67.8% of the population (N = 6546) were female. As anticipated, the AIH and PBC groups were predominantly composed of females, while PSC demonstrated a male predominance. At baseline, compensated liver cirrhosis was diagnosed in 6.1% of the population with AILD (N = 586), and liver decompensation was observed in 3.8% (N = 369). Most PSC patients had concomitant IBD diagnosis (84.8%) It was noted that 42.1% of PSC individuals had attained the highest level of education (> 12 years) whereas individuals with AIH and PBC had 34.4% and 22.7% respectively. A statistically significant difference was noted between different AILDs and education levels (p < 0.001). Baseline characteristics are summarised in Table 1.
TABLE 1.
Baseline characteristics of study individuals with autoimmune liver disease (AIH, PBC, PSC) and their matched comparators.
| Characteristic | Comparators b (N = 80 685) | Any AILD (N = 9645) | AIH (N = 3342) | PBC (N = 3751) | PSC (N = 2561) |
|---|---|---|---|---|---|
| Sex N (%) | |||||
| Male | 26 803 (33.2%) | 3108 (32.2%) | 894 (26.8%) | 546 (14.6%) | 1668 (65.1%) |
| Age at baseline, years | |||||
| Median | 55 | 57 | 58 | 63 | 39 |
| IQR | (39–67) | (41–69) | (41–69) | (55–72) | (28–55) |
| Age categories N (%) | |||||
| 18–50 years | 32 564 (40.3%) | 3579 (37.1%) | 1229 (36.8%) | 614 (16.4%) | 1736 (67.8%) |
| ≥ 51 | 48 139 (59.7%) | 6075 (62.9%) | 2113 (63.2%) | 3137 (83.6%) | 825 (32.2%) |
| Education level a | |||||
| < 10 years | 18 825 (23.3%) | 2380 (24.7%) | 744 (22.3%) | 1289 (34.4%) | 347 (13.5%) |
| 10–12 years | 34 837 (43.2%) | 4198 (43.5%) | 1449 (43.4%) | 1612 (43.0%) | 1137 (44.4%) |
| 12+ years | 27 023 (33.5%) | 3076 (31.9%) | 1149 (34.4%) | 850 (22.7%) | 1077 (42.1%) |
| Start year of follow‐up N (%) | |||||
| 2001–2005 | 24 263 (30.1%) | 2798 (29.0%) | 435 (13.0%) | 1531 (40.8%) | 832 (32.5%) |
| 2006–2010 | 17 545 (21.7%) | 2076 (21.5%) | 895 (26.8%) | 666 (17.8%) | 515 (20.1%) |
| 2011–2015 | 19 181 (23.8%) | 2315 (24.0%) | 1002 (30.0%) | 742 (19.8%) | 571 (22.3%) |
| 2016–2020 | 19 696 (24.4%) | 2465 (25.5%) | 1010 (30.2%) | 812 (21.6%) | 643 (25.1%) |
| Comorbidities/severity at inclusion | |||||
| IBD | 754 (0.9%) | 2513 (26.0%) | 242 (7.2%) | 99 (2.6%) | 2172 (84.8%) |
| CVD | 6078 (7.5%) | 1198 (12.4%) | 429 (12.8%) | 610 (16.3%) | 159 (6.2%) |
| COPD/proxy for smoking | 1151 (1.4%) | 318 (3.3%) | 115 (3.4%) | 171 (4.6%) | 32 (1.2%) |
| Diabetes | 3097 (3.8%) | 876 (9.1%) | 386 (11.5%) | 335 (8.9%) | 155 (6.1%) |
| Cirrhosis, compensated | 8 (0.0%) | 586 (6.1%) | 288 (8.6%) | 221 (5.9%) | 77 (3%) |
| Cirrhosis, decompensated | 9 (0.0%) | 369 (3.8%) | 152 (4.5%) | 158 (4.2%) | 59 (2.3%) |
Abbreviations: AIH, autoimmune hepatitis; AILD, autoimmune liver disease; COPD, chronic obstructive lung disease; CVD, cardiovascular disease; IBD, inflammatory bowel disease; IQR, interquartile range; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
Significant difference (p < 0.001, Pearson's Chi‐square test) between different AILDs and education levels.
Up to 10 matched comparators were selected from the general population, matched for age, municipality, and calendar year of first liver disease diagnosis.
3.2. Overall Mortality
During the follow‐up period, 2485 patients with AILD (25.7%) and 11 030 (13.7%) comparators died; 1357 (36.2%) with PBC vs. 6902 (22.6%) comparators, 650 (19.4%) with AIH vs. 2657 (9.7%) comparators and 478 (18.7%) with PSC vs. 1471 (6.5%) comparators.
The IR for overall mortality for all AILDs was 31.13 (95% CI 29.93–32.37) per 1000 PY compared with 14.391 (95% CI = 14.13–14.66) per 1000 PY in comparators. Patients with AILD had more than two times higher mortality than the comparators with HR 2.6 (95% CI = 2.5–2.7) which was only slightly attenuated after adjusting for confounders, (aHR = 2.3, 95% CI = 2.2–2.4). Similar estimates were found for individuals with PBC and AIH. PSC was linked to around 4‐fold higher rate for all‐cause mortality than comparators (HR = 4.1, 95% CI = 3.2–5.2), with overall mortality IR being 20.35 (95% CI = 18.60–22.25) per 1000 PY compared with 6.340 (95% CI = 6.02–6.67) per 1000 PY in comparators (Table 2, Figure 2).
TABLE 2.
Rates of overall mortality presented as crude and adjusted hazard ratios (HR) and incidence rate (IR) of study individuals with autoimmune liver disease and their comparators.
| AILD | Comparators b | AIH | Comparators b | PBC | Comparators b | PSC | Comparators b | |
|---|---|---|---|---|---|---|---|---|
| Death N (%) | 2485 (25.7%) | 11 030 (13.7%) | 650 (19.4%) | 2657 (9.7%) | 1357 (36.2%) | 6902 (22.5%) | 478 (18.7%) | 1471 (6.5%) |
| IR (95% CI) per 1000 PY | 31.13 (29.93–33.37) | 14.39 (14.13–14.66) | 26.99 (25.00–29.15) | 12.12 (11.66–12.59) | 42.06 (39.89–44.36) | 21.90 (21.39–22.42) | 20.35 (118.60–22.25) | 6.340 (6.02–6.67) |
| HR (95% CI) | 2.6 (2.5–2.7) | 2.4 (2.2–2.6) | 2.4 (2.2–2.5) | 3.8 (3.4–4.2) | ||||
| aHR a (95% CI) | 2.3 (2.2–2.4) | 2.2 (2.0–2.4) | 2.2 (2.1–2.4) | 4.1 (3.2–5.2) | ||||
| Cirrhosis N (%) | 503 (52.7%) | 1605 (21.6%) | 184 (41.8%) | 481 (14.1%) | 262 (69.1%) | 956 (33.0%) | 57 (41.9%) | 168 (14.9%) |
| IR (95% CI) per 1000 PY | 94.04 (86.17–102.63) | 24.48 (23.31–25.70) | 75.87 (65.67–87.67) | 18.11 (16.56–19.80) | 138.03 (122.29–155.80) | 34.47 (32.35–36.72) | 55.57 (42.86–72.04) | 14.90 (12.81–17.33) |
| HR (95% CI) | 6.2 (5.5–7.0) | 5.8 (4.7–7.1) | 6.5 (5.5–7.7) | 6.4 (4.4–9.2) | ||||
| aHR a (95% CI) | 5.8 (5.1–6.6) | 5.2 (4.2–6.4) | 6.3 (5.2–7.5) | 8.1 (4.9–13.3) | ||||
| No cirrhosis N (%) | 1982 (22.8%) | 9425 (12.9%) | 466 (16.1%) | 2176 (9.1%) | 1095 (32.5%) | 5946 (21.4%) | 421 (17.4%) | 1303 (6.0%) |
| IR (95% CI) per 1000 PY | 26.61 (25.46–27.81) | 13.45 (13.18–13.77) | 21.52 (19.65–23.56) | 11.29 (10.83–11.78) | 36.07 (33.99–38.27) | 20.69 (20.17–21.22) | 18.74 (17.03–20.62) | 5.90 (5.59–6.23) |
| HR (95% CI) | 2.2 (2.1–2.4) | 1.9 (1.7–2.2) | 2.1 (1.9–2.2) | 3.6 (3.2–4.0) | ||||
| aHR a (95% CI) | 1.9 (1.8–2.1) | 1.8 (1.6–2.0) | 1.9 (1.8–2.1) | 3.3 (2.5–4.5) | ||||
| Female N (%) | 1762 (26.9%) | 8240 (15.3%) | 493 (20.1%) | 2044 (10.3%) | 1098 (34.3%) | 5637 (21.4%) | 171 (19.1%) | 559 (7.3%) |
| IR (95% CI) per 1000 PY | 32.80 (31.30–34.37) | 16.20 (15.85–16.55) | 27.51 (25.19–30.05) | 12.61 (12.08–13.17) | 38.66 (36.44–41.02) | 20.54 (20.01–21.08) | 23.11 (19.89–26.85) | 7.74 (7.12–8.41) |
| HR (95% CI) | 2.4 (2.3–2.6) | 2.4 (2.2–2.7) | 2.3 (2.2–2.5) | 3.9 (3.2–4.7) | ||||
| aHR a (95% CI) | 2.2 (2.1–2.3) | 2.2 (1.9–2.4) | 2.1 (2.0–2.3) | 4.5 (3.0–6.7) | ||||
| Male N (%) | 723 (23.3%) | 2790 (10.4%) | 157 (17.6%) | 613 (78.3%) | 259 (47.4%) | 1265 (29.0%) | 307 (18.4%) | 912 (6.1%) |
| IR (95% CI) per 1000 PY | 27.68 (25.74–29.78) | 10.83 (10.44–11.24) | 25.47 (21.79–29.79) | 10.72 (9.90–11.60) | 67.11 (59.42–75.80) | 31.10 (29.44–32.87) | 19.07 (17.06–21.33) | 5.71 (5.35–6.09) |
| HR (95% CI) | 3.0 (2.8–3.3) | 2.4 (2.0–2.9) | 2.8 (2.4–3.2) | 3.7 (3.2–4.3) | ||||
| aHR a (95% CI) | 2.6 (2.4–3.0) | 2.3 (1.9–2.8) | 2.6 (2.2–3.0) | 3.9 (2.8–5.4) | ||||
| 18–50 years N (%) | 270 (7.5%) | 420 (1.3%) | 55 (4.5%) | 89 (0.8%) | 38 (6.2%) | 112 (2.0%) | 177 (10.2%) | 219 (1.4%) |
| IR (95% CI) per 1000 PY | 7.97 (7.08–8.98) | 1.30 (1.18–1.43) | 5.26 (4.04–6.85) | 0.91 (0.74–1.12) | 6.19 (4.51–8.51) | 1.96 (1.63–2.356) | 10.25 (8.84–11.87) | 1.29 (1.13–1.47) |
| HR (95% CI) | 6.3 (5.4–7.4) | 5.7 (4.1–8.0) | 3.3 (2.3–4.8) | 8.1 (6.6–9.9) | ||||
| aHR a (95% CI) | 4.6 (3.6–5.8) | 5.9 (4.0–8.5) | 3.0 (2.0–4.4) | 8.7 (4.5–16.9) | ||||
| ≥ 51 years N (%) | 2215 (36.5%) | 10 610 (22.0%) | 595 (28.2%) | 2568 (15.8%) | 1319 (42.0%) | 6790 (26.9%) | 301 (36.5%) | 1252 (18.8%) |
| IR (95% CI) per 1000 PY | 48.18 (46.22–50.23) | 24.00 (23.55–24.46) | 43.66 (40.29–47.32) | 21.08 (20.28–21.91) | 50.49 (47.84–53.29) | 26.32 (25.70–26.96) | 48.40 (43.23–54.19) | 20.10 (19.02–21.25) |
| HR (95% CI) | 2.4 (2.3–2.5) | 2.3 (2.1–2.5) | 2.4 (2.2–2.5) | 2.8 (2.4–3.2) | ||||
| aHR a (95% CI) | 2.2 (2.1–2.3) | 2.1 (1.9–2.3) | 2.2 (2.1–2.3) | 3.5 (2.6–4.6) | ||||
Note: IR for all outcomes presented as events per 1000 PY. Level of significance: p < 0.05 (Cox proportional hazard regression for HR).
Abbreviations: aHR, adjusted hazard ratio; AIH, autoimmune hepatitis; AILD, autoimmune liver disease; CI, confidence interval; HR, hazard ratio; IR, incidence ratio; LT, liver transplantation; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PY, person‐year.
Adjusted for baseline comorbidities: cardiovascular disease (CVD), diabetes, inflammatory bowel disease (IBD), chronic obstructive lung disease (COPD)/proxy for smoking and education.
Up to 10 matched comparators were selected from the general population, matched for age, municipality and calendar year of first liver disease diagnosis.
FIGURE 2.
Cumulative incidence for overall mortality of study participants and their comparators. Comparators were selected based on the matching factors (age, sex, year of first diagnosis and municipality). (A) AILD and comparators, (B) AIH and their comparators, (C) PBC and their comparators, (D) PSC and their comparators. AILD, autoimmune liver disease; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
3.3. Death or LT
When the composite endpoint of all‐cause mortality or LT was investigated, incidence rates were even higher for patients with AILD (IR = 37.38, 95% CI = 36.03–38.77) per 1000 PY, while incidence rates in comparators were the same as for overall mortality (IR = 14.40, 95% CI = 14.13–14.67 per 1000 PY). Individuals with PSC had more than six times increased rate (aHR 6.7 = 95% CI = 5.3–8.4) for death or LT than comparators with an IR of 32.77 (95% CI = 30.43–35.29) per 1000 PY. Individuals with AIH and PBC had similar estimates for death or LT, with aHR = 2.4, 95% CI = 2.2–2.7, and aHR = 2.4, 95% CI = 2.3–2.6, respectively. (Table 3, Figure 3).
TABLE 3.
Rates of death or liver transplantation presented as crude and adjusted hazard ratios (HR) and incidence rate (IR) of study individuals with autoimmune liver disease and their comparators.
| AILD | Comparators b | AIH | Comparators b | PBC | Comparators b | PSC | Comparators b | |
|---|---|---|---|---|---|---|---|---|
| Death or LT N (%) | 2854 (29.6%) | 11 035 (13.7%) | 708 (21.2%) | 2658 (9.7%) | 1444 (38.5%) | 6904 (22.5%) | 702 (27.4%) | 1473 (6.5%) |
| IR (95% CI) per 1000 PY | 37.38 (36.03–38.77) | 14.34 (14.13–14.67) | 29.94 (27.82–32.23) | 12.12 (11.67–12.59) | 46.15 (43.83–48.59) | 21.91 (21.40–22.43) | 32.77 (30.43–35.29) | 6.35 (6.03–6.68) |
| HR (95% CI) | 3.1 (3.0–3.2) | 2.7 (2.4–2.9) | 2.6 (2.5–2.8) | 6.2 (5.6–6.9) | ||||
| aHR a (95% CI) | 2.6 (2.5–2.7) | 2.4 (2.2–2.7) | 2.4 (2.3–2.6) | 6.7 (5.3–8.4) | ||||
| Cirrhosis N (%) | 575 (60.2%) | 1605 (21.6%) | 206 (46.8%) | 481 (14.1%) | 286 (75.5%) | 956 (33.0%) | 83 (61.0%) | 168 (14.9%) |
| IR (95% CI) per 1000 PY | 128.70 (118.60–139.66) | 24.48 (23.31–25.70) | 92.99 (81.12–106.59) | 18.11 (16.56–19.80) | 181.73 (161.84–204.06) | 34.47 (32.35–36.72) | 122.29 (98.62–151.64) | 14.90 (12.81–17.33) |
| HR (95% CI) | 7.9 (6.9–8.8) | 6.7 (5.5–8.1) | 8.1 (6.8–9.6) | 11.5 (8.1–16.3) | ||||
| aHR a (95% CI) | 7.2 (6.4–8.2) | 6.0 (4.9–7.3) | 7.8 (6.5–9.4) | 13.2 (8.1–21.3) | ||||
| No cirrhosis N (%) | 2279 (26.2%) | 9430 (12.9%) | 502 (17.3%) | 2177 (9.1%) | 1158 (34.3%) | 5948 (21.4%) | 619 (25.5%) | 1305 (6.1%) |
| IR (95% CI) per 1000 PY | 31.70 (30.43–33.03) | 13.46 (13.29–13.73) | 23.43 (21.46–25.57) | 11.30 (10.83–11.78) | 38.97 (36.79–41.28) | 20.70 (20.18–21.23) | 29.84 (27.58–32.29) | 5.91 (5.60–6.24) |
| HR (95% CI) | 2.7 (2.5–2.8) | 2.1 (1.9–2.3) | 2.2 (2.1–2.4) | 5.9 (5.3–6.5) | ||||
| aHR a (95% CI) | 2.2 (2.1–2.3) | 1.9 (1.7–2.2) | 2.1 (1.9–2.2) | 5.7 (4.3–7.4) | ||||
| Female N (%) | 1925 (29.4%) | 8242 (15.3%) | 526 (21.5%) | 2045 (10.3%) | 1173 (36.6%) | 5638 (21.4%) | 226 (25.3%) | 559 (7.3%) |
| IR (95% CI) per 1000 PY | 36.96 (35.34–38.65) | 16.20 (15.85–16.55) | 29.75 (27.31–32.40) | 12.62 (12.08–13.18) | 42.58 (40.21–45.08) | 20.54 (20.01–21.09) | 32.98 (28.95–37.58) | 7.74 (7.12–8.41) |
| HR (95% CI) | 2.7 (2.6–2.9) | 2.6 (2.3–2.9) | 2.6 (2.4–2.7) | 5.6 (4.7–6.7) | ||||
| aHR a (95% CI) | 2.4 (2.3–2.6) | 2.3 (2.1–2.6) | 2.4 (2.2–2.5) | 6.9 (4.8–10.0) | ||||
| Male N (%) | 929 (29.9%) | 2793 (10.4%) | 182 (120.4%) | 613 (8.3%) | 271 (49.6%) | 1266 (29.0%) | 476 (28.5%) | 914 (6.1%) |
| IR (95% CI) per 1000 PY | 38.28 (35.89–40.82) | 10.84 (10.45–11.25) | 30.53 (26.41–35.30) | 10.72 (9.90–11.60) | 72.47 (64.34–81.63) | 31.13 (29.46–32.89) | 32.67 (29.86–35.74) | 5.72 (5.36–6.11) |
| HR (95% CI) | 4.2 (3.9–4.6) | 2.9 (2.4–3.5) | 3.0 (2.6–3.4) | 6.6 (5.8–7.5) | ||||
| aHR a (95% CI) | 3.2 (2.9–3.5) | 2.8 (2.3–3.3) | 2.8 (2.4–3.2) | 6.8 (5.0–9.2) | ||||
| 18–50 years N (%) | 533 (14.9%) | 424 (1.3%) | 93 (7.6%) | 90 (0.8%) | 70 (11.4%) | 113 (2.1%) | 370 (21.3%) | 221 (1.4%) |
| IR (95% CI) per 1000 PY | 16.92 (15.55–18.42) | 1.31 (1.19–1.44) | 9.17 (7.48–11.23) | 0.92 (0.75–1.14) | 12.01 (9.50–15.17) | 1.976 (1.64–2.38) | 23.84 (21.53–26.40) | 1.30 (1.14–1.49) |
| HR (95% CI) | 14.1 (12.3–16.2) | 10.2 (7.5–13.7) | 6.7 (4.9–9.1) | 20.3 (16.9–24.4) | ||||
| aHR a (95% CI) | 9.9 (8.1–12.1) | 10. 7 (7.7–14.9) | 6.3 (4.6–8.7) | 26.7 (15.3–46.6) | ||||
| ≥ 51 years N (%) | 2321 (38.2%) | 10 611 (22.0%) | 615 (29.1%) | 2568 (15.8%) | 1374 (43.8%) | 6791 (26.9%) | 332 (40.2%) | 1252 (18.8%) |
| IR (95% CI) per 1000 PY | 51.74 (49.67–53.88) | 24.01 (23.55–24.47) | 45.55 (42.09–49.30) | 21.08 (20.28–21.91) | 53.97 (51.19–56.90) | 26.33 (25.71–26.96) | 56.25 (50.51–62.64) | 20.11 (19.03–21.26) |
| HR (95% CI) | 2.6 (2.4–2.7) | 2.4 (2.1–2.6) | 2.5 (2.4–2.7) | 3.2 (2.8–3.7) | ||||
| aHR a (95% CI) | 2.3 (2.2–2.5) | 2.1 (1.9–2.4) | 2.3 (2.2–2.5) | 4.3 (3.2–5.6) | ||||
Note: IR for all outcomes presented as events per 1000 PY. Level of significance: p < 0.05 (Cox proportional hazard regression for HR).
Abbreviations: aHR, adjusted hazard ratio; AIH, autoimmune hepatitis; AILD, autoimmune liver disease; CI, confidence interval; HR, hazard ratio; IR, incidence ratio; LT, liver transplantation; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PY, person‐year.
Adjusted for baseline comorbidities: cardiovascular disease (CVD), diabetes, inflammatory bowel disease (IBD), chronic obstructive lung disease (COPD)/proxy for smoking and education.
Up to 10 matched comparators were selected from the general population, matched for age, municipality and calendar year of first liver disease diagnosis.
FIGURE 3.
Cumulative incidence for death or LT of study participants and their comparators. Comparators were selected based on the matching factors (age, sex, year of first diagnosis and municipality). (A) AILD and comparators, (B) AIH and their comparators, (C) PBC and their comparators, (D) PSC and their comparators. AILD, autoimmune liver disease; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
3.4. Cancer‐Related Mortality
Patients with AILD had a higher rate of cancer‐related death than comparators. The IR for cancer‐related death was 8.69 per 1000 PY (95% CI = 8.07–9.36) for individuals with AILDs compared to 3.80 (95% CI = 3.67–3.94) per 1000 PY in comparators, with aHR 2.1 (95% CI = 1.9–2.4). Individuals with PBC and AIH had similar hazard ratios compared to their comparators. Individuals with PSC had an IR of 9.70 (95% CI = 8.52–11.05) per 1000 PY while for comparators it was 1.80 (95% CI = 1.64–1.98). Patients with PSC had the highest rate of cancer‐related death compared to comparators with aHR 6.4 (95% CI = 4.0–10.3) (Table 4, Figure 4).
TABLE 4.
Rates of cancer‐related mortality presented as crude and adjusted hazard ratios (HR) and incidence rates (IR) of study individuals with autoimmune liver disease and their comparators.
| AILD | Comparators b | AIH | Comparators b | PBC | Comparators b | PSC | Comparators b | |
|---|---|---|---|---|---|---|---|---|
| Cancer‐related death N (%) | 694 (7.2%) | 2915 (3.6%) | 164 (4.9%) | 699 (2.6%) | 302 (8.1%) | 1798 (5.9%) | 228 (8.9%) | 418 (1.8%) |
| IR (95% CI) per 1000 PY | 8.69 (8.07–9.36) | 3.80 (3.67–3.94) | 6.81 (5.84–7.94) | 3.19 (2.96–3.43) | 9.36 (8.36–10.48) | 5.71 (5.45–5.98) | 9.70 (78.52–11.05) | 1.80 (1.64–1.98) |
| HR (95% CI) | 2.6 (2.4–2.8) | 2.3 (1.9–2.7) | 1.9 (1.7–2.1) | 6.4 (5.4–7.6) | ||||
| aHR a (95% CI) | 2.1 (1.9–2.4) | 2.1 (1.7–2.5) | 1.8 (1.6–2.1) | 6.4 (4.0–10.3) | ||||
| Cirrhosis N (%) | 88 (9.2%) | 375 (5.0%) | 33 (7.5%) | 129 (3.8%) | 37 (9.8%) | 211 (7.3%) | 18 (13.2%) | 35 (3.1%) |
| IR (95% CI) per 1000 PY | 16.45 (13.35–20.28) | 5.72 (5.16–6.33) | 13.61 (9.67–19.14) | 4.86 (4.09–5.77) | 19.49 (14.12–26.90) | 7.61 (6.45–8.71) | 17.55 (11.06–27.85) | 3.10 (2.23–4.32) |
| HR (95% CI) | 4.0 (3.0–5.2) | 3.7 (2.5–5.7) | 3.3 (2.2–4.9) | 8.6 (4.4–17.0) | ||||
| aHR a (95% CI) | 3.6 (2.8–4.8) | 3.2 (2.1–5.0) | 3.1 (2.1–4.7) | 14.4 (5.4–38.4) | ||||
| No cirrhosis N (%) | 606 (7.0%) | 2540 (3.5%) | 131 (4.5%) | 570 (2.4%) | 265 (7.9%) | 1587 (5.7%) | 210 (8.7%) | 383 (1.8%) |
| IR (95% CI) per 1000 PY | 7.14 (7.61–8.81) | 3.62 (3.49–3.77) | 6.05 (5.10–7.18) | 2.96 (2.72–3.21) | 8.73 (7.74–9.85) | 5.52 (5.26–5.80) | 9.35 (8.16–10.70) | 1.74 (1.57–1.92) |
| HR (95% CI) | 2.5 (2.3–2.7) | 2.0 (1.7–2.5) | 1.8 (1.6–2.0) | 6.3 (5.2–7.5) | ||||
| aHR a (95% CI) | 2.0 (1.8–2.2) | 1.9 (1.6–2.4) | 1.7 (1.5–2.0) | 5.0 (2.9–8.8) | ||||
| Female N (%) | 447 (6.8%) | 2142 (4.0%) | 127 (5.2%) | 527 (2.7%) | 251 (7.8%) | 1471 (5.6%) | 69 (7.7%) | 144 (1.9%) |
| IR (95% CI) per 1000 PY | 8.32 (7.58–9.13) | 4.21 (4.04–4.39) | 7.09 (5.96–8.43) | 3.25 (2.99–3.54) | 8.84 (7.81–10.00) | 5.36 (5.09–5.64) | 9.33 (7.37–11.81) | 1.99 (1.69–2.35) |
| HR (95% CI) | 2.2 (2.0–2.5) | 2.3 (1.9–2.8) | 1.8 (1.6–2.1) | 5.7 (4.2–7.8) | ||||
| aHR a (95% CI) | 2.0 (1.8–2.3) | 2.2 (1.7–2.7) | 1.8 (1.5–2.0) | 10.4 (4.9–22.2) | ||||
| Male N (%) | 247 (7.9%) | 773 (2.9%) | 37 (4.1%) | 172 (2.3%) | 51 (9.3%) | 327 (7.5%) | 159 (9.5%) | 274 (1.8%) |
| IR (95% CI) per 1000 PY | 9.46 (8.35–10.71) | 3.00 (2.80–3.22) | 6.00 (4.35–8.29) | 3.01 (2.59–3.49) | 13.22 (10.04–17.39) | 8.04 (7.21–8.96) | 8.878 (8.46–11.54) | 1.72 (1.52–1.93) |
| HR (95% CI) | 3.9 (3.3–4.5) | 2.1 (1.4–3.0) | 2.1 (1.5–2.9) | 6.8 (5.4–8.4) | ||||
| aHR a (95% CI) | 2.3 (1.9–2.9) | 1.8 (1.2–2.6) | 2.1 (1.5–2.9) | 5.1 (2.7–9.7) | ||||
| 18–50 years N (%) | 148 (4.1%) | 161 (0.5%) | 14 (1.1%) | 38 (0.3%) | 11 (1.8%) | 65 (1.2%) | 123 (7.1%) | 58 (0.4%) |
| IR (95% CI) per 1000 PY | 4.37 (3.72–5.13) | 0.50 (0.43–0.58) | 1.34 (0.79–2.26) | 0.39 (0.28–0.54) | 1.79 (0.99–3.24) | 1.14 (0.89–1.45) | 7.12 (5.97–8.50) | 0.34 (0.26–0.44) |
| HR (95% CI) | 8.8 (7.0–11.0) | 3.3 (1.1–6.1) | 1.6 (0.8–3.1) | 20.18 (15.1–28.8) | ||||
| aHR a (95% CI) | 3.3 (2.2–4.7) | 2.5 (1.2–4.9) | 1.6 (0.9–3.1) | 37.5 (9.6–146.1) | ||||
| ≥ 51 years N (%) | 546 (9.0%) | 2754 (5.7%) | 150 (7.1%) | 661 (4.1%) | 291 (9.3%) | 1733 (6.9%) | 105 (12.7%) | 360 (5.4%) |
| IR (95% CI) per 1000 PY | 11.88 (10.92–12.92) | 6.23 (6.00–6.47) | 11.01 (9.38–12.92) | 5.43 (5.03–5.86) | 11.14 (9.93–12.50) | 6.72 (6.41–7.04) | 16.88 (13.94–20.44) | 5.78 (5.21–6.41) |
| HR (95% CI) | 2.2 (2.0–2.4) | 2.2 (1.8–2.6) | 1.9 (1.7–2.2) | 3.3 (2.6–4.2) | ||||
| aHR a (95% CI) | 2.0 (1.8–2.2) | 2.0 (1.7–2.4) | 1.8 (1.6–2.1) | 4.4 (2.5–7.6) | ||||
Note: IR for all outcomes presented as events per 1000 PY. Level of significance: p < 0.05 (Cox proportional hazard regression for HR).
Abbreviations: aHR, adjusted hazard ratio; AIH, autoimmune hepatitis; AILD, autoimmune liver disease; CI, confidence interval; HR, hazard ratio; IR, incidence ratio; LT, liver transplantation; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PY, person‐year.
Adjusted for baseline comorbidities: cardiovascular disease (CVD), diabetes, inflammatory bowel disease (IBD), chronic obstructive lung disease (COPD)/proxy for smoking and education.
Up to 10 matched comparators were selected from the general population, matched for age, municipality and calendar year of first liver disease diagnosis.
FIGURE 4.
Cumulative incidence for cancer‐related mortality of study participants and their comparators. Comparators were selected based on the matching factors (age, sex, year of first diagnosis and municipality). (A) AILD and comparators, (B) AIH and their comparators, (C) PBC and their comparators, (D) PSC and their comparators. AILD, autoimmune liver disease; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
3.5. Subgroup Analyses
3.5.1. Liver Cirrhosis
A subgroup analysis of individuals with and without liver cirrhosis (compensated and decompensated) was performed. If liver cirrhosis was present, the rates of all‐cause mortality and cancer‐related death increased to aHR 5.8 (95% CI = 5.1–6.6) and aHR 3.6 (95% CI = 2.8–4.8) respectively. Detailed information on the rates for death, death or LT and cancer‐related death in AIH, PBC and PSC respectively is shown in Tables 2 and 4.
3.5.2. Sex
In both males and females with AILDs, crude and adjusted models showed higher mortality, with aHR 2.6 (95% CI = 2.4–2.9) for males, and aHR 2.2 (95% CI = 2.1–2.3) for females. Similar estimates were found for death or LT and cancer‐related death (Tables 2, 3, 4).
In AIH, overall mortality and cancer‐related death rates did not differ much between both sexes (p interaction > 0.05) in crude and adjusted models. Both sexes had around two‐fold increased rate for overall mortality and cancer‐related death, with aHR 2.2 (95% CI = 1.9–2.4) for females and 2.3 (95% CI = 1.9–2.8) for males, and aHR 2.2 (95% CI = 1.7–2.7) for females and aHR 1.8 (95% CI = 1.2–2.6) for males respectively (Tables 2 and 4).
In the PSC group, both sexes had higher rates for all‐cause mortality than their comparators, with aHR 3.9 (95% CI = 2.8–5.4) in males and 4.5 (95% CI = 3.0–6.7) in females, with no differences between sexes (p interaction > 0.05) in crude and adjusted models. Males had a higher crude cancer‐related death rate than females with HR 6.8 (95% CI = 5.4–8.4) and HR 5.7 (95% CI = 4.2–7.8) respectively, however, in the adjusted, model, aHR decreased to 5.1 (95% CI = 2.7–9.8) for males and increased to 10.4 (95% CI = 4.8–22.2) for females (Tables 2 and 4). However, no significant difference was observed between the sexes (p interaction > 0.05) in crude and adjusted models.
In PBC, male sex was predominant in overall mortality in a crude model (p interaction = 0.034), but it did not differ significantly (p interaction > 0.05) in an adjusted model. For PBC, the aHR for overall mortality was 2.6 (95% CI = 2.2–3.0) in males and 2.1 (95% CI = 2.0–2.3) in females. No sex difference was observed in cancer‐related death, with aHR 2.1 (95% CI = 1.5–2.9) for males and aHR 1.8 (95% CI = 1.5–2.0) for females, (p interaction > 0.05) in crude and adjusted models.
3.5.3. Age
Higher relative risk of death for individuals with AILD compared to their matched comparators was found in younger people (18–50 years old), with aHR 4.6 (95% CI = 3.6–5.8). In the same age group, the cancer‐related mortality rate was almost 9 times higher than in comparators (HR = 8.8, 95% CI = 7.0–11.0) in the crude model but decreased to around 3 times higher in the adjusted model (aHR = 3.2, 95% CI = 2.2–4.7) (Tables 2 and 4).
Patients with PBC in the 18–50 years old group had around three‐fold higher rate of death than comparators (aHR = 3.0, 95% CI = 2.0–4.4). A slightly higher rate of cancer‐related death was observed in the PBC age group ≥ 51 compared to comparators (aHR = 1.8, 95% CI = 1.6–2.1), however 18–50‐year‐old individuals with PBC had basically the same relative cancer‐related death risk as their matched comparators (Tables 2 and 4).
Younger individuals with AIH (18–50 years) had substantially higher overall mortality compared to comparators, with aHR 5.9 (95% CI = 4.0–8.5). Cancer‐related death in AIH was similarly increased in both age groups (18–50 and ≥ 51) compared to their matched comparators, with aHR 2.6 (95% CI = 1.4–5.1) for 18–50‐year‐olds and 2.0 (95% CI = 1.7–2.4) for ≥ 51‐year‐olds (Tables 2 and 4).
In PSC, a higher all‐cause mortality rate was observed in individuals aged 18–50, with aHR 8.7 (95% CI = 4.5–16.8). In the same age group, the rate of mortality or requiring LT was almost 27 times higher (aHR = 26.7, 95% CI = 15.3–46.6) and cancer‐related mortality increased by 37.5 times (aHR = 37.5, 95% CI 9.6–146.0) compared to comparators (Tables 2, 3, 4).
4. Discussion
4.1. Summary of the Main Results
In this population‐based cohort study, we show two to three times increased mortality rates in AILDs compared to matched population‐based comparators, with PSC being linked to the highest mortality. Moreover, we observed that AILDs have around two times higher risk of dying from cancer compared with their comparators. Notably, PSC exhibits the highest rates of all‐cause mortality, cancer‐related mortality and LT or death.
Patients with liver cirrhosis had significantly higher mortality rates, while sex appears to have a minimal impact. Younger patients with AILDs had higher relative mortality rates compared with their population‐based comparators, than older patients. However, the highest incidence rates were found in older patients with AILDs. This is likely explained by the higher risk for mortality in both older patients with AILD and their comparators, caused by older age itself.
4.2. PSC
In concordance with previous studies, the all‐cause mortality in PSC was significantly higher when compared to population‐based comparators, especially when liver cirrhosis was present [17, 18, 19, 20, 21]. Contrary to a Finnish population‐based study, we found that both males and females with PSC have similar overall mortality rates [20].
The overall mortality in the PSC group was four times higher than in their matched comparators. Furthermore, the rates of death or LT in individuals with PSC were six times higher than those of their population‐based comparators. Rates for overall mortality and death or LT in AIH and PBC were, in contrast, very similar. These findings suggest that patients with PSC undergo LT more often than other AILDs, although a direct comparison cannot be made between different AILDs in our study design (since individuals with each disease are compared to their matched comparators). This aligns with the findings of Webb et al., who reported that in their 20‐year analysis of AILDs on the UK and US liver transplant waitlist PSC has become the leading indication for LT since 2014 [8].
Consistent with other large‐scale studies, we found that PSC patients face significantly elevated rates of cancer‐related death [10, 21].
4.3. AIH
Our findings corroborate the results reported by Sharma et al., demonstrating that Swedish patients with AIH experience around two times higher all‐cause mortality rates, and align with studies conducted in other countries [9, 12, 22, 23]. Contrary to a large national cohort study from the Netherlands, showing that only AIH with cirrhosis has a higher relative risk for overall mortality, we found that even individuals with AIH without concomitant cirrhosis have significantly higher all‐cause mortality [24]. AIH had an around two‐fold higher relative risk for cancer‐related mortality in line with a Finnish population‐based study, where the malign neoplasm‐related standardised mortality rate was 1.7 [22]. The influence of sex on AIH mortality appears to be conflicting. Population‐based studies from Finland and Denmark indicate that males exhibit a higher overall mortality rate than females, whereas our study found that both men and women demonstrated similarly increased rates for all‐cause mortality, consistent also with findings from other studies [12, 22, 25, 26].
At the baseline, 13.2% of patients with AIH had cirrhosis (compensated and decompensated). Although some of these patients could have had AIH for some time before the inclusion, it is still lower than reported by Grønbæk et al., in a Danish population‐based study with 28.3% of individuals with AIH having cirrhosis at diagnosis [12].
4.4. PBC
Previously, it has been noted that patients with PBC are at a heightened risk for overall mortality [9]. However, it is believed that advancements in diagnostics and early disease detection, along with ursodeoxycholic acid treatment, have altered the disease prognosis, minimising adverse outcomes for most patients. Nevertheless, current population‐based data on this matter are lacking [27]. Despite the relatively high IR observed in our study, which can be partly attributed to the older age of PBC patients, we still report that PBC patients continue to experience over a 2‐fold increase in overall mortality compared to their matched comparators. Furthermore, our study revealed that PBC patients face elevated cancer‐related mortality, consistent with the findings of a meta‐analysis conducted by Liang et al. [11].
Contrary to some other studies, we did not find male gender to be an inherent determinant for poorer prognosis in PBC [28, 29, 30]. After performing interaction analysis between sexes for overall and cancer‐related mortality rates as well as transplant‐free survival, no significant difference was observed.
4.5. Education Level
It has been previously observed that chronic liver diseases are closely associated with a lower than college‐degree educational attainment [31, 32]. It is hypothesized that individuals with higher education tend to lead healthier lifestyles and are more conscious of factors contributing to the development or progression of chronic liver diseases, such as smoking, alcohol consumption, and obesity. However, data regarding AILD is limited. Here, we found that over 40% of individuals with PSC patients had completed more than 12 years of education. Despite this higher education level, PSC patients experienced the highest risk of death or LT, reflecting the lack of treatment to halt disease progression in PSC. Whether lifestyle factors affect disease course in PSC remains to be studied.
4.6. Strengths and Weaknesses
Sweden among other Nordic countries is known to have one of the highest prevalence of patients with AILDs globally, presenting a significant opportunity for researchers to investigate the prognosis of these individuals [33, 34]. Our nationwide population‐based study of all AILDs diagnosed in specialised care represents the largest study to date, examining mortality, death or LT and cancer‐related death in patients with AIH, PBC and PSC during the same observation period. Importantly, our study was not influenced by referrals or selection biases, thus enabling generalisation to the Swedish population. Additionally, the DELIVER cohort facilitated longitudinal long‐term follow‐up of patients through Swedish registries with minimal loss of follow‐up and comparison of findings with up to 10 controls, enabling comparison of mortality estimates to the general population. We adjusted the results for several potential confounders to bolster the reliability of our findings.
Our study has some limitations. Firstly, we lacked access to detailed clinical and biochemistry results to further describe patients or verify the accuracy of the diagnosis, as our patient identification relied solely on ICD coding and its validity. Furthermore, the causes of death were not manually adjudicated, but relied on registry information. This however does not compromise the overall mortality estimates, since Ludvigsson et al., report high Swedish inpatient registers' validity, with an 85%–95% positive predictive value [14].
Secondly, we chose not to analyse overlap syndrome patients as a separate group to avoid introducing potentially significant bias, as the registry data did not allow us to confirm whether patients received both diagnoses (indicating overlap) or if one diagnosis was revised during follow‐up. Patients with several AILD diagnoses were categorised into one of the cohorts depending on the first received diagnosis in the registries (AIH, PBC or PSC). This may however risk misclassifying some patients with an initial erroneous diagnosis which may affect the risk estimates both in positive and negative directions, depending on the misclassification.
If more than one AILD diagnosis was registered the same day, individuals were categorised into one of the cohorts based on the following priority: PSC, PBC and AIH. In our study, 54 patients were identified with AIH + PBC, receiving both diagnoses on the same date, and 26 patients had PSC + AIH/PBC diagnoses at the same date, which may be a reasonable group to have both diseases and little risk for misclassification bias of either disease. However, the total of 80 patients was insufficient to provide robust information regarding overlap syndrome prognosis.
Lastly, individuals in the < 18 years old group were excluded from our study due to the very small sample size in both the AILD and the matched comparators' groups to avoid potentially hyperinflated estimations.
5. Conclusion
In this population‐based study of 9654 individuals with autoimmune liver disease and 80 685 matched controls, mortality was more than two‐fold higher in patients with AILDs. Mortality estimates were highest in PSC, but did not significantly differ between men and women. Patients with cirrhosis at first diagnosis have the worst prognosis. The risk for cancer‐related death was particularly high. These estimates can be valuable for clinicians caring for patients with AILDs to better quantify risks and estimate prognosis.
Author Contributions
Study conception and design: A.B., H.H. Acquisition of data: L.W., H.H. Statistical analysis: L.W. Analysis and interpretation of data: I.L. Drafting of manuscript: I.L. Critical revision: All. Guarantor of article: I.L. All authors approved the article's final version, including the authorship list. Writing Assistance: Grammarly for grammar.
Ethics Statement
Study approval was obtained from the Regional Swedish Ethical Review Authority, No 2017/1019–31/1.
Consent
The authors have nothing to report.
Conflicts of Interest
HH: institutions have received research funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. He has served as consultant or on advisory boards for Astra Zeneca, Bristol Myers‐Squibb, MSD and Novo Nordisk and has been part of hepatic events adjudication committees for Boehringer Ingelheim, KOWA and GW Pharma.
Supporting information
Data S1.
Table S1. ICD‐codes used to define AILD—(PSC, AIH, PBC).
Table S2. Other chronic liver diagnoses’ codes ICD (9th and 10th edition) codes used as exclusion criteria before or at the baseline of inclusion for the study population and comparators.
Table S3. Liver transplantation ICD (9th and 10th edition) codes.
Table S4. ICD (9th and 10th edition) codes for causes of death (main or contributing causes) from the inpatient and outpatient registries, The Cause of Death Register and Cancer Register.
Table S5. ICD (9th and 10th edition) codes for comorbidities at the baseline.
Funding: This work was supported by Region Värmland.
Annika Bergquist and Hannes Hagström share senior authors.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Table S1. ICD‐codes used to define AILD—(PSC, AIH, PBC).
Table S2. Other chronic liver diagnoses’ codes ICD (9th and 10th edition) codes used as exclusion criteria before or at the baseline of inclusion for the study population and comparators.
Table S3. Liver transplantation ICD (9th and 10th edition) codes.
Table S4. ICD (9th and 10th edition) codes for causes of death (main or contributing causes) from the inpatient and outpatient registries, The Cause of Death Register and Cancer Register.
Table S5. ICD (9th and 10th edition) codes for comorbidities at the baseline.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.