Mortality and the risk of malignancy in autoimmune liver diseases: A population-based study in Canterbury, New Zealand

Authors

  • Jing Hieng Ngu,

    1. Department of Gastroenterology, Christchurch Hospital, Christchurch, Canterbury, New Zealand
    2. University of Otago, Christchurch, Canterbury, New Zealand
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  • Richard Blair Gearry,

    1. Department of Gastroenterology, Christchurch Hospital, Christchurch, Canterbury, New Zealand
    2. University of Otago, Christchurch, Canterbury, New Zealand
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  • Chris Miles Frampton,

    1. University of Otago, Christchurch, Canterbury, New Zealand
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  • Catherine Ann Malcolm Stedman

    Corresponding author
    1. Department of Gastroenterology, Christchurch Hospital, Christchurch, Canterbury, New Zealand
    2. University of Otago, Christchurch, Canterbury, New Zealand
    • Gastroenterologist/Clinical Pharmacologist, Clinical Senior Lecturer in Medicine, Gastroenterology Department, Christchurch Hospital, Private bag 4710, Christchurch, New Zealand
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    • fax: 64 3 3640304


  • Potential conflict of interest: Nothing to report.

  • Dr. Ngu's stipend is supported by Clinical Research Training Fellowship from the Health Research Council of New Zealand (2011-2013), Ferring/New Zealand Society of Gastroenterology Fellowship and Canterbury Medical Research Foundation Fellowship (2010). Research related expenses were supported by grant from the Royal Australasia College of Physicians.

Abstract

Population-based quantitative data on the mortality and cancer incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are scarce. Our aim was to systematically investigate the survival and risk of malignancy on population-based cohorts of AIH, PBC, and PSC in Canterbury, New Zealand. Multiple case-finding methods were employed, including searches of all public and private, adult and pediatric outpatient clinics, hospital notes, laboratory, radiology, and pathology reports. Cases that fulfilled standardized diagnostic criteria were included. Kaplan-Meier survival estimates, standardized mortality ratios (SMR), and standard incidence ratios (SIR) for malignancy were calculated. A total of 130 AIH, 70 PBC, and 81 PSC patients were included contributing to 1,156, 625, and 613 person-years at risk, respectively. For AIH, PBC, and PSC cohorts, SMRs for all-cause mortality were 2.1 (95% confidence interval [CI] 1.4-3.1), 2.7 (95% CI 1.7-4.0), and 4.1 (95% CI 2.6-6.3), SMRs for hepatobiliary mortality were 42.3 (95% CI 20.3-77.9), 71.2 (95% CI 30.7-140.3), and 116.9 (95% CI 66.8-189.8), SIRs for all cancers were 3.0 (95% CI 2.0-4.3), 1.6 (95% CI 0.8-2.9), and 5.2 (95% CI 3.3-7.8), and SIRs for extrahepatic malignancy were 2.7 (95% CI 1.8-3.9), 1.6 (95% CI 0.8-2.9), and 3.0 (95% CI 1.6-5.1), respectively. Conclusion: This is the first population-based study to examine and compare the survival and cancer incidence in AIH, PBC, and PSC in the same population. The mortality for all three cohorts was significantly increased due to liver-related death, demonstrating the inadequacy of current management strategies. The risk of hepatic and extrahepatic malignancy was significantly increased in AIH and PSC patients. (HEPATOLOGY 2012)

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are chronic progressive liver diseases of presumed autoimmune etiology. These autoimmune liver diseases (AiLD) can lead to complications such as cirrhosis of the liver, hepatic and extrahepatic malignancies, liver failure, and death. However, population-based quantitative data on the mortality and cancer incidence of these conditions remains scarce, and in some areas current reports show conflicting results.

Traditionally, it was believed that the survival of treated AIH patients is good and similar to that of the general population1-3; however, this was disputed by a recent study that showed increased mortality.4 For PBC patients, earlier reports suggested an increased incidence of breast, respiratory, renal, and hematological cancers as well as melanoma,5-8 although these associations were not confirmed in subsequent studies.9, 10 There was also a discrepancy between reports on the survival of PBC patients, with one study suggesting a median survival not significantly different from that of the general population,11 yet others reported a significant increase in mortality.10, 12, 13 The risk of malignancy in patients with AIH has hitherto been examined in only one study that employed standardized diagnostic criteria14 and, therefore, their results have yet to be independently verified. Information on prognosis of AiLD is of immense importance in patient education as well as in devising management and surveillance plans. Therefore, studies from unselected population-based cohorts are desperately needed to systematically examine the survival and risk of malignancy in patients with AiLD.

Canterbury lies on the east coast of the South Island of New Zealand. It is New Zealand's largest province by area and second largest by population. Population-based cohorts of AIH, PBC, and PSC in Canterbury were identified when exhaustive population-based epidemiology studies of AiLD in Canterbury were performed.15-17 The aim of the present study was to systematically investigate the survival and risk of malignancy on the population-based cohorts of AIH, PBC, and PSC in Canterbury, New Zealand.

Abbreviations

AIH, autoimmune hepatitis; AiLD, autoimmune liver disease; CRC, colorectal carcinoma; HCC, hepatocellular carcinoma; IBD inflammatory bowel disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SIR, standard incidence ratio; SMR, standardized mortality ratio.

Patients and Methods

Study Population.

This study was conducted in the geographically defined region of Canterbury, New Zealand (Fig. 1). It has defined boundaries that correlate with the National Census boundaries and is relatively geographically isolated. Therefore, reliable demographic information of the study population can be obtained from the Department of Statistics New Zealand based on data from National Census. The estimated population for this region in 2008 was 494,170.

Figure 1.

Geographic boundaries of Canterbury as defined by Canterbury District Health Board.

Case Identification.

Christchurch Hospital is a tertiary teaching hospital and is the only public hospital in this region that provides gastroenterology and hepatology services. There are nine adult gastroenterologists and one pediatric gastroenterologist providing services to this region, and all private gastroenterologists in Canterbury also work at Christchurch Hospital. The public health system is used by the majority of New Zealand residents, although 32% of the population were covered by private health insurance.18 Therefore, in order to ensure that all diagnosed AiLD cases in the region were included in the study, patients from both public and private clinics and hospitals would need to be identified.

Cases were recruited both prospectively and retrospectively using multiple case-finding strategies. All private and public gastroenterology clinic notes, inpatient discharge codes, laboratory, and pathology and radiology reports were searched to identify retrospectively all known cases of AIH, PBC, or PSC in Canterbury diagnosed from January 1 1980 to December 31 2006. All gastroenterologists that serve the region also provided a list of their patients with these diseases. These methods have been shown in studies of inflammatory bowel disease (IBD) to reliably recruit more than 92% of all cases as determined by a capture-recapture methodology.19 From 2007 to 2008, cases were recruited prospectively.

Case Ascertainment.

Demographic, clinical data, laboratory, and radiology and histology results were extracted from paper and computer case notes. Cases that fulfilled standardized and widely accepted diagnostic criteria were included in the study. The revised original scoring system20 was used for AIH, and cases were included in the study if they had definite or probable AIH as determined by the score. The date of diagnosis was taken as the date that the liver biopsy was performed. There were three patients who did not undergo a liver biopsy. For these cases date of diagnosis was taken as the date that treatment was initiated. PBC cases were defined by the presence of at least two of the three criteria: (1) cholestatic liver function tests for greater than 6 months; (2) positive serum antimitochondrial antibody with titer of at least 1:40; (3) compatible liver histology.21 The date of diagnosis was taken as the date when two of the three criteria were fulfilled. PSC cases were defined using the Mayo criteria.22 Cases were included if they had endoscopic retrograde cholangiography, magnetic resonance cholangiography, or liver biopsy-proven PSC and the date of diagnosis was taken as that on which one of these definitive procedure was performed. End of follow-up was at death, liver transplantation, last outpatient clinic consultation for those who were lost to follow-up, or the end of study (December 31 2010).

Statistical Analysis.

Kaplan-Meier curves were used to present survival data and to estimate the cumulative survival probabilities for up to 15 years after diagnosis of AIH, PBC, or PSC. Patients who survived were censored on the date of their last follow-up or at the time of liver transplantation. Statistical software IBM SPSS for Windows v. 19.0.0 was used for this analysis.

The standardized mortality ratio (SMR) was calculated to compare the mortality of the AiLD cohorts with the age- and gender-matched Canterbury population. SMR is defined as SMR = O/E, where O is the observed number of deaths within the cohort and E is the expected number of deaths. Expected number of deaths was calculated using the prospective model as described by Hartz et al.,23 where the probability of death for each individual case during the period of follow-up was calculated using age, gender, and calendar year-specific mortality data of the Canterbury population provided by the Department of Statistics New Zealand. Expected number of deaths is defined as the sum of the individual mortality probabilities.

Standard incidence ratios (SIR) for all and specific malignancies were calculated to assess the risk of malignancy. Following the procedure outlined above for assessing expected mortality, the expected number of cancer cases was calculated using age, gender, and calendar year-specific cancer incidence data provided by Cancer Registry New Zealand, which has an underreporting rate of less than 2% based on internal audits. Subjects not diagnosed with a malignancy of interest were censored at the diagnosis of first cancer, death, liver transplantation, or last follow-up. When calculating the SIR for colorectal cancer, subjects were also censored when colectomy was performed.

Results

Characteristics of the Study Cohorts.

These population-based cohorts included a total of 130 patients with AIH, 71 patients with PBC, and 79 patients with PSC, contributing to a total of 1,156, 625, and 613 person-years at risk, respectively. Median follow-up times were 7, 9, and 7 years for AIH, PBC, and PSC cohorts, respectively. There was a female predominance in AIH (71%) and PBC (92%) cohorts, whereas the PSC cohort had more male subjects (62%). PBC patients on average were diagnosed about 10 years later than AIH and PSC patients. There were a total of 31, 24, and 22 deaths within the AIH, PBC, and PSC cohorts, respectively, during the follow-up period. Seven PSC patients and two AIH patients underwent liver transplantation. Seven AIH, four PBC, and two PSC patients were lost to follow-up mostly due to migration away from the region. Characteristics of these cohorts are summarized in Table 1.

Table 1. Characteristics of AIH, PBC, and PSC Cohorts
 AIHPBCPSC
Total number of cases1307179
 Female92 (71%)65 (92%)30 (38%)
 Male38 (29%)6 (8%)49 (62%)
 Male:female1: 2.41: 111: 0.6
Mean age at diagnosis (years)506150
Median age at diagnosis (years, range)54 (14-82)60 (34-91)49 (17-82)
Total follow-up (years)1156652613
Median follow-up (years, range)7 (1-29)9 (1-25)7 (1-28)
Mean follow-up (years)997
Total number of deaths31 (24%)24 (34%)22 (28%)
Total liver transplantation207
Total patients with malignancy31 (24%)11 (15%)23 (29%)

Mortality of the AIH, PBC, and PSC Cohorts Was Significantly Increased.

Figure 2A-C shows the Kaplan-Meier estimates of survival of AIH, PBC, and PSC patients from the date of diagnosis showing increased transplant-free mortality for all three cohorts when compared with the age- and gender-matched Canterbury population. Figure 2D presents the estimated cumulative survival probabilities of all three AiLD cohorts showing that 5 years after diagnosis, survival probabilities were similar for all three AiLD cohorts at about 90%. However, 15 years from diagnosis, survival probabilities were markedly reduced at 74% (95% confidence interval [CI] 62%-86%) for AIH, 58% (95% CI 43%-73%) for PBC, and only 45% (95% CI 26%-64%) for PSC.

Figure 2.

(A) Cumulative survival probabilities of the AIH cohort. Survival was significantly decreased in the AIH cohort (P < 0.001) compared with the age- and gender-matched Canterbury population. (B) Cumulative survival probabilities of the PBC cohort. Survival was significantly decreased in the PBC cohort (P < 0.0001) compared with the age- and gender-matched Canterbury population. (C) Cumulative survival probabilities of the PSC cohort. Survival was significantly decreased in the PSC cohort (P < 0.00001) compared with the age- and gender-matched Canterbury population. (D) Cumulative survival probabilities of the autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis cohorts in Canterbury.

SMRs for all-cause and cause-specific mortality in the AIH, PBC, and PSC cohorts are presented in Table 2. These data show that the mortality of all three AiLD cohorts was significantly increased when compared to the age- and gender-matched Canterbury population. PSC had the poorest outcome, with more than a 4-fold increased risk of death and SMR for all-cause mortality was 4.1 (95% CI 2.6-6.3; P < 0.0001). For AIH and PBC cohorts, SMRs for all-cause mortality were 2.1 (95% CI 1.4-3.1; P < 0.001) and 2.7 (95% CI 1.7-4.0; P < 0.0001), respectively. When the composite endpoint of death and liver transplantation was used, SMRs for all-cause mortality were 2.3 (95% CI 1.5-3.3; P < 0.001) for AIH, 2.7 (95% CI 1.7-4.0; P < 0.0001) for PBC, and 6.1 (95% CI 4.2-8.7; P < 0.0001) for PSC.

Table 2. Standardized Mortality Ratio (SMR) for All-Cause and Cause-Specific Mortality for AIH, PBC, and PSC Cohorts
Cause of DeathSMR95% CIP
AIH   
 All cause2.11.4-3.1<0.001
 Hepatobiliary42.320.3-77.9<0.00001
 Nonhepatobiliary1.40.8-2.2NS
 Extrahepatic cancer1.40.6-2.9NS
 Cardiovascular1.20.4-2.7NS
PBC   
 All cause2.71.7-4.1<0.0001
 Hepatobiliary71.230.7-140.3<0.00001
 Nonhepatobiliary1.81.0-3.0NS
 Extrahepatic cancer1.50.5-3.6NS
 Cardiovascular0.90.2-2.6NS
PSC   
 All cause4.12.6-6.3<0.00001
 Hepatobiliary116.966.8-189.8<0.00001
 Nonhepatobiliary1.50.7-3.0NS
 Extrahepatic cancer1.50.3-4.3NS
 Cardiovascular0.5<0.1-2.9NS

SMRs were also calculated for cause-specific mortality, and it is notable that hepatobiliary mortality, including death as a result of liver failure, hepatobiliary cancers, and biliary sepsis, was markedly increased for all three AiLD cohorts. However, SMRs for mortality as a result of extrahepatic malignancy and cardiovascular diseases were not increased, and SMRs for nonhepatobiliary mortality were close to unity, demonstrating that excess mortality in AIH, PBC, and PSC cohorts was due to liver-related death.

Risk of Malignancy in the AIH, PBC, and PSC Cohorts.

SIRs for all and specific malignancies in the AIH, PBC, and PSC cohorts are summarized in Table 3. A total of 31 AIH patients, 11 PBC patients, and 23 PSC patients developed at least one malignancy after the diagnosis of AiLD. Four AIH patients and two PSC patients had two malignancies, and one AIH patient developed three malignancies. There was no statistically significant increased risk of malignancy in the PBC cohort. However, the risk of malignancy was significantly increased in patients with AIH and PSC compared to the age- and gender-matched Canterbury population, with SIR for all cancer of 3.0 (95% CI 2.0-4.3) in AIH and 5.2 (95% CI 3.3-7.8) in PSC cohorts, respectively.

Table 3. Standard Incidence Ratio (SIR) for All and Specific Malignancy in AIH, PBC, and PSC Cohorts
Site of CancerObservedExpectedSIR95% CIP
  1. Subjects were censored at the diagnosis of malignancy of interest, death, liver transplantation, or last follow-up. When calculating SIR of cancers at all sites, subjects were censored at the diagnosis of first malignancy. Subjects were also censored when colectomy was performed when calculating SIR of colorectal cancer.

AIH     
All sites3111.43.02.0-4.3<0.0001
Hepatobiliary30.215.13.1-44.3<0.01
Extrahepatic2810.42.71.8-3.9<0.0001
 Colorectal61.93.11.1-6.80.03
 Skin (nonmelanoma)7<0.1157.163.1-323.6<0.0001
 Breast11.70.6<0.1-3.3NS
 Hematological50.95.21.7-12.2<0.001
 Lung21.21.60.2-6.3NS
 Prostate31.61.90.4-5.6NS
 Melanoma11.10.9<0.1-4.9NS
 Renal22.90.70.1-2.5NS
 Gynecological15.10.2<0.1-1.1NS
 Other1
PBC     
All sites116.81.60.8-2.9NS
Hepatobiliary0
Extrahepatic116.71.60.8-2.9NS
 Colorectal11.40.7<0.1-3.8NS
 Skin (nonmelanoma)10.729.60.7-165.8NS
 Breast11.70.6<0.1-3.3NS
 Hematological20.63.50.4-12.5NS
 Lung30.83.90.8-11.3NS
 Prostate0
 Melanoma0
 Renal0
 Gynecological15.60.2<0.1-1.0NS
 Other2
PSC     
All sites234.55.23.3-7.8<0.0001
Hepatobiliary110.1105.250.5-193.5<0.0001
Extrahepatic124.43.01.6-5.1<0.001
 Colorectal50.77.02.3-16.3<0.001
 Skin (nonmelanoma)3<0.1117.624.2-343.6<0.0001
 Breast20.54.10.5-14.8NS
 Hematological0
 Lung20.54.30.5-15.4NS
 Prostate10.81.2<0.1-6.7NS
 Melanoma0
 Renal11.20.8<0.1-4.6NS
 Gynecological0
 Other0

The incidence of hepatobiliary cancers, including hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, was significantly increased by 15-fold in the AIH cohort and greater than 100-fold in the PSC cohort when compared to the age- and gender-matched Canterbury population. All hepatobiliary cancers in AIH were hepatocellular carcinoma (HCC) and were found in subjects with established cirrhosis. For the PSC cohort, the majority (64%) of the hepatobiliary cancers were cholangiocarcinoma, with the remainder HCC (18%) and gallbladder carcinoma (18%). In addition, the incidence of extrahepatic malignancy was also significantly raised by more than 2-fold in the AIH cohort and by 3-fold in the PSC cohort, showing that the excess of malignancy incidence were not only due to hepatobiliary cancers.

In the PSC cohort, colorectal carcinoma (CRC) and nonmelanoma skin cancer were extrahepatic cancers with significantly raised SIRs (Table 3). The majority of the PSC cohort (76%) had concurrent IBD, which would have contributed to the risk of CRC. All five cases of CRC were found in PSC patients with concurrent IBD. Twenty percent of the PSC patients were immunosuppressed with thiopurine and/or corticosteroids for IBD at the time a malignancy was diagnosed.

In the AIH cohort, nonmelanoma skin cancer and hematological cancer were extrahepatic cancers with significantly raised SIRs. There was almost a 5-fold increased risk of hematological cancer, including two cases of acute myeloid leukemia, one case of chronic lymphocytic leukemia, and two cases of non-Hodgkin's B cell lymphoma. All of these patients were immunosuppressed with either thiopurine or corticosteroids when hematological cancer was diagnosed. In total, 90% of the AIH patients were immunosuppressed when a malignancy was diagnosed.

Ursodeoxycholic Acid and Mortality in the PBC Cohort.

The use of ursodeoxycholic acid in Canterbury for PBC patients has not been as universal as other centers despite the availability of the drug since the 1990s. In total, 59% of our PBC cohorts were treated with ursodeoxycholic acid. SMR for PBC patients treated and not treated with ursodeoxycholic acid were 2.6 (95% CI 1.2-4.7) and 2.9 (95% CI 1.6-4.8), respectively. However, these results need to be interpreted with care, as ursodeoxycholic acid tends to be started on patients in the early stages of disease and, hence, those with a better prognosis.

Overlap Syndrome.

There were nine patients who fulfilled the inclusion criteria for both AIH and PBC and five patients fulfilled the criteria for both AIH and PSC. These patients with overlap syndromes were included in both of the study cohorts of their overlap conditions. To ensure that our findings were not skewed as a result of patients with overlap syndromes, analysis of SMRs and cancer SIRs were reperformed excluding all overlap patients. The results show that the trend of statistical significance remains unchanged for all categories, with only one exception. The SIR for CRC in the AIH cohort that was raised with borderline statistical significant would no longer be significant when a patient with AIH and PSC overlap was excluded.

Discussion

This is the first study to systematically examine and compare the survival and cancer incidence in unselected population-based AIH, PBC, and PSC cohorts on the same population during the same study period. We have shown that PSC patients had the poorest outcome, whereas AIH, the only AiLD with effective treatment available, had the best outcome. However, when compared to the age- and gender-matched general population, the mortality for all three cohorts was significantly increased, indicating that patients with AIH, PBC, and PSC are dying prematurely under current management strategies.

AIH is generally considered to have a good prognosis, with earlier reports implying that mortality in the AIH cohorts was similar to that in the general population.1-3 Our study contradicts these findings, showing that the mortality of our AIH cohort was significantly increased compared to age- and gender-matched Canterbury population with an SMR for all-cause mortality at 2.1. This finding supports a recent report4 that suggested the long-term outcome of AIH is less benign than commonly supposed. This result also confirms the inadequacy of current AIH management, as only about 40% of AIH patients were achieving complete remission, defined as normal liver test results and immunoglobulin G level.24, 25 Mortality of our PBC and PSC cohorts was also increased by 3-fold and 4-fold, respectively, compared to the Canterbury population, results comparable to previous reports from the United Kingdom10, 12, 13, 26 and Canada,27 but not agreed upon by one other study.28 Given the retrospective nature of the study, one potential limitation could be missing some older cases who died early, leading to an underestimation of mortality. Even if this was the case, it would further strengthen our conclusion that standardized mortality ratios in patients with AIH, PBC, and PSC are higher when compared to the general population. Our study is also the first study to present cause-specific SMRs and demonstrate convincingly that the excess mortality for all three cohorts of AiLD was due to liver-related death. Therefore, better treatment strategies are desperately needed to improve the outcome of these patients.

We have shown that both hepatic and extrahepatic cancer incidence was significantly raised in the PSC and AIH cohorts. Although an association between PSC and hepatic malignancy and CRC is well established,26, 29 our study has demonstrated for the first time that nonmelanoma skin cancer risk is also significantly increased in these patients. The current study is also only the second study to examine the risk of malignancy in AIH patients, demonstrating that the risk of hepatobiliary, skin (nonmelanoma), and hematological cancers were significantly raised, confirming that these are real risks that should not be ignored.

Several studies have examined the risk of malignancy in PBC patients, producing a range of very diverse results, with some suggesting an increased overall cancer risk,9, 30, 31 whereas others disagreed.10, 32, 33 Our study showed only a trend toward increased overall cancer risk, with an SIR of 1.6, and this was not statistically significant. Surprisingly, HCC was not found in our PBC patients and this may be explained by the small number of male patients (n = 6), the highest risk group for HCC,34, 35 in our PBC cohort, although some previous studies have also not shown an excess risk of HCC.30, 36 Compared to the AIH and PSC cohorts, the PBC cohort was the only group without a significantly increased cancer risk when compared to the age- and gender-matched Canterbury population.

In AIH and PSC patients, a trend was observed for an increase in extrahepatic malignancy related mortality; however, these results were not statistically significant. Although this could be due to a lack of power for this study to demonstrate a significant difference, it may also be explained by the effect of surveillance, as these patients were under regular hospital follow-up, maximizing the possibility of early cancer diagnosis, and early treatment. For example, two renal cell cancers were first diagnosed during surveillance liver ultrasound scan for HCC as incidental findings, and so were surgically curable with a better prognosis than their counterparts in the community. A previous study has also described excellent long-term survival after cancer detection in patients with chronic active hepatitis.37

Our usual management strategy for AIH patients is to induce remission with prednisone 40 mg per day and to maintain remission with azathioprine up to 2 mg per kg. Therefore, nearly all of our AIH patients were treated with thiopurine at some stage of their disease, although duration of exposure varies depending on tolerability and response to therapy. Ninety percent of the AIH patients and 20% of the PSC patients were immunosuppressed at the time when a malignancy was diagnosed, raising the possibility that immunosuppressive therapy may have contributed to the risk of extrahepatic malignancy such as skin (nonmelanoma) and hematological cancers. Immunosuppressive therapy has been well documented to increase the risk of malignancy in organ transplant recipients, possibly by impairing cancer surveillance, facilitating the action of oncogenic viruses as well as having a direct pro-oncogenic action. Interestingly, the PBC cohort is the only group of patients in this study who were not immunosuppressed, and the observation that PBC patients did not have a significantly increased risk of malignancy does seem to support the hypothesis that immunosuppressive therapy is an important contributor toward increased risk of extrahepatic malignancy in patients with AiLD. However, it is beyond the scope of the current study to determine the risk of immunosuppression in inducing malignancy, and this will need to be addressed by future studies.

Nevertheless, it is also possible that autoimmune or inflammatory diseases themselves may increase the risk of malignancy. For example, an association between hematological cancer and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, Sjogren's syndrome, celiac disease, and chronic thyroiditis has been well documented.38, 39 Proposed mechanisms have included common genetic and environmental factors for autoimmunity and malignancy, chronic inflammation, and infection. This increased risk of malignancy may then be amplified by the use of immunosuppressive therapies required for these autoimmune conditions.

It is essential for physicians managing patients with AiLD to be vigilant in view of this increased risk of malignancy. Sun protection advice on minimizing ultraviolet radiation to skin should be routinely provided to patients with AIH and PSC. Future studies should investigate ways to improve the management of AiLD. For example, effective targeted cellular and molecular interventions may be a way forward to improve the survival of AIH patients without exposing them to the potential complications related to current immunosuppression therapy.40

In conclusion, this is the first population-based study to examine and compare the survival and cancer incidence in AIH, PBC, and PSC cohorts on the same population. The mortality for all three cohorts was significantly increased when compared to the age- and gender-matched population due to liver-related death. The risk of both hepatic and extrahepatic malignancy was significantly increased in AIH and PSC patients. These results demonstrate the inadequacy of current management strategies and the need for new effective treatments.

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