Background.
Prevalence of concurrent liver diseases among liver transplant recipients and impact on posttransplant outcomes are unknown.
Methods.
This retrospective study included adult liver transplants between January 1‚ 1985‚ and December 31‚ 2019‚ from the Australian and New Zealand Liver and Intestinal Transplant Registry. Up to 4 liver disease causes were recorded for each transplant; concurrent liver diseases were defined as >1 liver disease indication for transplantation, excluding hepatocellular carcinoma. Impact on posttransplant survival was determined using Cox regression.
Results.
A total of 840 (15%) of 5101 adult liver transplant recipients had concurrent liver diseases. Recipients with concurrent liver diseases were more likely male (78% versus 64%) and older (mean age 52 versus 50 y). A higher proportion of liver transplants for hepatitis B (12% versus 6%), hepatitis C (33% versus 20%), alcohol liver disease (23% versus 13%), and metabolic-associated fatty liver disease (11% versus 8%, all P < 0.001) were identified when all indications were included than with primary diagnosis only. The number and proportion of liver transplants performed for concurrent liver diseases have increased from 8 (6%) during Era 1 (1985–1989) to 302 (20%) during Era 7 (2015–2019; P < 0.001). Concurrent liver diseases were not associated with increased posttransplant mortality (adjusted hazard ratio, 0.98, 95% confidence interval, 0.84-1.14).
Conclusions.
Concurrent liver diseases are increasing among adult liver transplant recipients in Australia and New Zealand; however, they do not appear to impact posttransplant survival. Reporting all liver disease causes in the transplant registry reports provides more accurate estimates of liver disease burden.
INTRODUCTION
Chronic liver diseases and related hepatocellular carcinoma (HCC) cause significant morbidity and mortality and are major threats to global health because of rising prevalence.1,2 Liver transplantation remains the only curative option for many patients with advanced chronic liver disease3,4 but remains a scarce resource.5 The relative contributions of individual liver diseases and liver disease cofactors to national liver transplantation rates reflect underlying community prevalence of advanced chronic liver disease and HCC causes and the impact of national strategies to prevent chronic liver diseases.6-8 These data are, therefore, vital for policymakers and public health stakeholders to guide the planning and evaluation of liver disease prevention programs and investment in hepatology services and transplantation programs. They also inform investment to achieve WHO disease elimination targets, such as for hepatitis B (HBV) and hepatitis C (HCV) elimination.9-11
The Australia and New Zealand Liver and Intestinal Transplant Registry (ANZLITR)12 captures data for up to 4 underlying liver disease causes for each liver transplant; however, in line with many international liver transplant registries,7,13,14 the data presented in the annual ANZLITR report focus predominantly on the primary liver disease that is listed as the main indication for each liver transplant.12 This approach to reporting liver transplant data by primary diagnosis has been adopted worldwide to facilitate meaningful comparisons in outcome data for the primary liver disease; however, this reporting method potentially underestimates the relative disease burden from specific causes where >1 liver disease or liver cofactor is present concurrently or where a previous liver disease or cofactor has contributed substantially to the development of cirrhosis or HCC but is inactive at the time of transplantation. This is particularly relevant to alcohol-related liver disease (ALD)15 and metabolic-associated fatty liver disease (MAFLD)‚ which frequently coexist with other chronic liver diseases such as viral hepatitis and may not be the dominant liver disease at the time of transplantation but remain important cofactors for liver disease progression and contribute to the public health burden of advanced liver disease.16 The second issue with this method of data reporting is that it does not capture the prevalence and impact on clinical outcomes of a single liver disease compared with multiple liver disease causes in adult liver transplant recipients.
Concurrent liver disease, defined as having >1 chronic liver disease or liver disease cofactor contemporaneously, is increasingly reported worldwide, driven by increasing prevalence of ALD and MAFLD.1,17-20 In 1 statewide data linkage study from Australia, concurrent liver diseases were reported in 27% of people with cirrhosis requiring hospitalization.20 Synergistic inflammation, fibrogenesis, and carcinogenesis pathway activation by viral hepatitis, ALD‚ and MAFLD have been shown to adversely impact progression to cirrhosis and HCC risk in people with >1 liver disease21-25; however, the prevalence of concurrent liver diseases and their effect on liver transplant outcomes are less certain, in part, because of concurrent liver diseases not being adequately captured in liver transplant registry databases.
In this study, we report the difference in the number and proportion of adult liver transplants performed for different liver disease causes when all causes of liver disease listed as the indication for liver transplantation in the ANZLITR are included, compared with inclusion of only the listed primary liver disease cause. We also determined trends in the number and proportion of liver transplants performed for concurrent liver diseases over time. Finally, we explored the impact of concurrent liver diseases on posttransplant survival.
MATERIALS AND METHODS
This was a retrospective longitudinal registry study. The primary study aims were (1) to determine whether including all liver disease causes significantly increased the number of liver transplants recorded for each liver disease indication‚ (2) to determine whether there has been a change in the proportion of liver transplants performed for concurrent liver diseases over time‚ and (3) to determine whether liver transplant recipients with multiple liver disease causes listed as an indication for liver transplantation have inferior survival outcomes compared with liver recipients listed as having only 1 liver disease cause.
Complete deidentified data for all liver transplants (excluding liver-kidney transplants) performed in adults aged 16 y and older within Australia and New Zealand between January 1 1985‚ and December 31‚ 2019‚ from the ANZLITR database were used for this study.12 For this analysis, only first liver transplants were included. Variables included liver transplant type, date of transplantation, age, biological gender, and liver disease cause. Liver diseases associated with disorders of metabolism, such as hemachromatosis and Wilson disease, were combined into 1 metabolic liver disease category, which did not include MAFLD. In the ANZLITR, up to 4 liver disease causes are recorded as an indication for each liver transplant; all liver disease causes listed for each liver transplant recipient were included to determine the number of liver transplants performed for each specific liver disease. Concurrent liver diseases was defined as the presence of >1 chronic liver disease cause listed within the ANZLITR database, for example‚ HBV and MAFLD. In recognition of the fact that most HCC cases in the ANZLITR data set occurred in patients with underlying liver disease, for the purposes of this analysis‚ HCC was not counted as a liver disease cause when determining the presence of concurrent liver diseases; however, the number of transplant recipients with >1 liver disease who also had HCC was reported. Similarly, cholangiocarcinoma was not classed as a concurrent liver disease if patients also had primary sclerosing cholangitis (PSC). Because of recognition that the majority of historical cryptogenic liver disease diagnoses would now be recognized as MAFLD, MAFLD and cryptogenic liver disease were combined as 1 liver disease cause category for the purposes of this analysis.
Categorical data were described using number (proportion) and continuous data by mean and SD (normally distributed) or median (interquartile range [IQR]) for nonparametric data as appropriate. Year of transplant was separated into 5-y eras (Era 1: 1985–1989, Era 2: 1990–1994, Era 3: 1995–1999, Era 4: 2000–2004, Era 5: 2005–2009, Era 6: 2010–2014, and Era 7: 2015–2019). Comparison of the proportion of liver transplants performed for different liver diseases identified when primary diagnosis compared with all diagnostic categories were used was performed using 2 sample test of proportions. Change in the proportion of liver transplants performed for concurrent liver diseases by era was assessed using the χ2 test. Change in the rate of the number of liver transplants for individual liver disease causes and for concurrent liver diseases per year was determined using linear regression modeling. Bivariate associations between concurrent liver diseases and posttransplant overall survival were determined, stratified by potential confounders available in the ANZLITR data set (age, gender, era, and underlying liver disease). Multivariable Cox proportional hazards modeling was used to determine the association between survival posttransplant and concurrent liver diseases, adjusted for a priori variables age category, era‚ and gender and confounding variables identified on bivariate analysis (HCV, HBV, and HCC). A sensitivity analysis was performed excluding all patients who had fulminant and subfulminant hepatic failure as an indication for transplantation from the posttransplant survival analysis to control for the early mortality seen in these patients (included in Supplemental Results, SDC, http://links.lww.com/TXD/A430). Within a subset of patients, a further sensitivity analysis was performed including metabolic risk factors (diabetes, hypertension, history of ischemic heart disease at time of listing, as entered by the clinician in the ANZLITR), previous history of malignancy other than HCC, functional status at transplant listing (defined by the treating clinician as independent, requiring some assistance, needing considerable assistance with activities of daily living, in hospital)‚ and model for end-stage liver disease score at listing and transplantation where available. Body mass index (BMI) was available for a subset of patients at listing and at transplant; this was subcategorized into healthy weight range (BMI 18.5–25 kg/m2), overweight (>25 kg/m2), obese (>30 kg/m2), and morbidly obese (>40 kg/m2); underweight was defined as BMI <18.5 kg/m2.
This project was approved by the ANZLITR steering committee and institutional ethics committee (Austin HREC 64438/2020) with a waiver of consent.
RESULTS
A total of 6627 liver transplants were performed in 6121 individuals between January 1‚ 1985‚ and December 31‚ 2019‚ in Australia and New Zealand. A total of 5460 (82%) liver transplants were performed in 5102 adults, including 358 (7%) repeat liver transplants, which were excluded from this analysis. One adult liver transplant did not have any cause listed in the ANZLITR database and was, therefore, excluded from the analysis, leaving a total of 5101 liver transplant recipients included in this analysis. Across Australia and New Zealand, the number of liver transplants performed per year has steadily increased over time, with a mean increase of 9.4 liver transplants per year (95% confidence interval [CI], 9.33-9.48, adjusted R2 0.92, P < 0.0001) from 4 in 1985 to 311 transplants in 2019.
Revised Prevalence of Liver Disease Causes Among Adult Liver Transplant Recipients in Australia and New Zealand
Table 1 shows the number of additional adult liver transplants performed for each liver disease cause that was captured when all recorded liver disease causes were counted, compared with only the primary liver disease category. A significantly higher number of adult liver transplants were performed for most causes when all diagnostic categories were included compared with only the primary diagnosis; this difference was most striking for HBV and HCV, ALD‚ and MAFLD/cryptogenic cirrhosis. An additional 309 liver transplants for HBV were identified when all diagnostic categories were included, doubling the proportion of transplants performed for HBV from 6% to 12% when using primary diagnosis only. Similarly, an additional 411 liver transplants for HCV were identified when all cause categories were included; the proportion of adult liver transplants performed for HCV increased to almost one third compared with one fifth using primary cause category only. An additional 534 liver transplants were due to ALD (23% compared with 13%)‚ and similarly, an additional 118 liver transplants were due to MAFLD (11% compared with 8%) when all diagnostic categories were used. Other liver disease categories including autoimmune hepatitis (AIH), metabolic liver disease, and PSC also had smaller numbers of additional cases identified when all diagnostic categories were included.
TABLE 1.
Adult liver transplant numbers by liver disease cause: comparing all recorded liver disease diagnoses to primary liver disease cause (n = 5101)
| Cause | Liver transplants: all causes | Liver transplants: primary cause | Comparison proportions, P |
|---|---|---|---|
| HBV | 600 (12%) | 300 (6%) | <0.001 |
| HCV | 1496 (29%) | 1094 (21%) | <0.001 |
| HDV | 55 (1%) | 42 (0.8%) | 0.185 |
| ALD | 1205 (24%) | 676 (13%) | <0.001 |
| MAFLD/cryptogenic | 561 (11%) | 445 (9%) | <0.001 |
| PBC | 280 (6%) | 276 (5%) | 0.862 |
| PSC | 534 (10%) | 516 (10%) | 0.558 |
| AIH | 264 (5%) | 226 (4%) | 0.079 |
| Biliary atresia | 55 (1%) | 55 (1%) | 1.00 |
| Metabolic liver diseasea | 298 (6%) | 249 (5%) | 0.031 |
aMetabolic liver diseases include disorders of metabolism, such as hemachromatosis, Wilson disease, and so on.
AIH, autoimmune hepatitis; ALD, alcohol-related liver disease; HBV, hepatitis B; HCV, hepatitis C; HDV, hepatitis D virus; MAFLD, metabolic-associated fatty liver disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
Table S1 (SDC, http://links.lww.com/TXD/A430) outlines the relative breakdown of different liver disease causes for patients with multiple liver diseases listed as indications for transplantation, including where HCC was listed as the primary indication for liver transplantation. The 3 most common secondary, tertiary‚ or quaternary diagnoses were ALD, HCV, and MAFLD; the most common concurrent liver diseases combination was HCV and ALD (451, 30% of HCV transplants and 37% of ALD transplants).
Figure 1 and Table S2 (SDC, http://links.lww.com/TXD/A430) show the difference in number of liver transplants by cause per year, comparing numbers by primary liver disease category to numbers including all liver disease categories. There was a significant increase in the number of liver transplants performed per year for HBV (17%), HCV (29%), ALD (89%), and MAFLD (73%) when all diagnostic categories were included compared with primary liver disease category only, as shown in Table 2. Figure 1 shows that the trajectory of number of adult liver transplants per year for HBV, HCV, ALD, and MAFLD was similar whether primary diagnosis only or all liver disease diagnoses are used for case ascertainment. HCV-related liver transplantation has declined since 2017, HBV-related transplantation has remained stable since 2015, ALD-related transplantation has steadily increased over time‚ and MAFLD-related transplantation has rapidly increased since 2012. Importantly, since 2017‚ ALD has surpassed HBV as the most common indication for adult liver transplantation in Australia and New Zealand when cases are ascertained by primary diagnosis only or by all diagnosis categories. In 2019, MAFLD overtook HCV as the second leading indication for adult liver transplantation for the first time when determined by primary diagnosis only; however, MAFLD remains the third most common indication when determined by all diagnostic categories (Figure 1).
FIGURE 1.
Number of adult liver transplants performed for different liver disease causes per year: comparison between all listed diagnoses (solid lines) and primary diagnosis (dashed lines; n = 5101). ALD, alcohol-related liver disease; HBV, hepatitis B; HCV, hepatitis C; MAFLD, metabolic-associated fatty liver disease.
TABLE 2.
Rate ratio of adult liver transplants per year for the most common liver disease indications for liver transplantation in the ANZLITR, determined by all listed disease diagnoses compared with primary liver disease diagnosis only (n = 5101)
| Variable | Rate ratio | 95% CI | P |
|---|---|---|---|
| HBV | 1.17 | 1.01-1.36 | <0.001 |
| HCV | 1.29 | 1.24-1.33 | <0.001 |
| ALD | 1.89 | 1.84-1.93 | <0.001 |
| MAFLD | 1.73 | 1.70-1.76 | <0.001 |
ALD, alcohol-related liver disease; ANZLITR, Australia and New Zealand Liver and Intestinal Transplant Registry; CI, confidence interval; HBV, hepatitis B; HCV, hepatitis C; MAFLD, metabolic-associated fatty liver disease.
Prevalence of Concurrent Liver Diseases Among Adult Liver Transplant Recipients in Australia and New Zealand
Overall, 820 of 5101 (16%) individuals received liver transplants for multiple liver disease causes (concurrent liver diseases). A higher proportion of adult liver transplant recipients with concurrent liver diseases was male (78% versus 64%, P < 0.001) and was older than liver transplant recipients with a single liver disease indication (mean age 52 ± 9 versus 50 ± 12 y, respectively, P < 0.001). The most common causes in patients with concurrent liver diseases were ALD (68%), HCV (64%), HBV (16%), and MAFLD (13.5%), and all of these liver diseases were significantly more frequent among adults with concurrent liver diseases than among those with a single liver disease indication for liver transplantation (Table 3 and Table S1, SDC, http://links.lww.com/TXD/A430). A higher proportion of adult liver transplant recipients with concurrent liver diseases had diabetes and hypertension and a previous history of malignancy; however, people with concurrent liver diseases also had a higher functional status and lower model for end-stage liver disease score both at the time of listing for transplant and time of transplantation (Table 3). Interestingly, the proportion with obesity was not significantly different between the 2 groups (68% in the concurrent liver disease group, 65% in the single liver disease group), including the proportion with morbid obesity (3% in both groups). The number and proportion of adult liver transplants performed for concurrent liver diseases has steadily risen over time, from 8 (6%) during Era 1 (1985–1989) to 302 (20%) during Era 7 (2015–2019) (P < 0.0001) (Figure 2).
TABLE 3.
Demographic and clinical factors of adult liver transplant recipients with multiple liver diseases compared with a single liver disease (n = 5101)
| Variable | Single liver disease, N = 4281(86%) | Multiple liver diseases, N = 820 (16%) | χ2 P |
|---|---|---|---|
| Age at transplant | <0.001 | ||
| 16–29 y | 391 (9%) | 18 (2%) | |
| 30–39 y | 414 (10%) | 52 (6%) | |
| 40–49 y | 967 (23%) | 228 (28%) | |
| 50–59 y | 1592 (37%) | 367 (45%) | |
| 60–69 y | 899 (21%) | 154 (19%) | |
| >70 y | 16 (0.4%) | 1 (0.1%) | |
| Male | 2757 (64%) | 644 (78%) | <0.001 |
| HBV | 472 (11%) | 128 (16%) | <0.001 |
| HCV | 972 (22.7%) | 524 (64%) | <0.001 |
| ALD | 642 (15%) | 563 (68%) | <0.001 |
| MAFLD | 449 (10%) | 112 (14%) | 0.008 |
| HCC | 1045 (24%) | 268 (33%) | <0.001 |
| Median MELD score at listing (IQR)a (n = 3621) | 18 (14–23) | 11 (8–15) | <0.001 |
| Median MELD score at transplant (IQR)a (n = 3622) | 19 (14–25) | 12 (9–17) | <0.001 |
| Transplant BMI (n = 2040) | 0.34 | ||
| Underweight | 37 (2%) | 8 (2%) | |
| Normal (BMI <25) | 502 (33%) | 151 (30%) | |
| Overweight (BMI 25–29) | 366 (24%) | 50 (10%) | |
| Obese (BMI ≥30) | 637 (41%) | 289 (58%) | |
| Diabetes (n = 3199) | 475 (20%) | 219 (28%) | <0.001 |
| IHD (n = 2931) | 107 (5%) | 41 (6%) | 0.25 |
| Hypertension (n = 3765) | 192 (8%) | 103 (14%) | <0.001 |
| Dialysis at listing (n = 3174) | 99 (4%) | 4 (0.5%) | <0.001 |
| Previous malignancy (excluding HCC) (n = 2492) | 145 (8%) | 216 (36%) | <0.001 |
| Functional status at time of listing (n = 3119) | <0.001 | ||
| Independent | 412 (15%) | 295 (36%) | |
| Needs some assistance with ADLs | 1244 (46%) | 394 (48%) | |
| Needs assistance with most ADLs | 265 (10%) | 82 (10%) | |
| In hospital, dependent | 764 (28%) | 57 (7%) |
aMELD score only available for transplants from 2012.
ADL, activity of daily living; ALD, alcohol-related liver disease; BMI, body mass index; HBV, hepatitis B; HCC, hepatocellular carcinoma; HCV, hepatitis C; IHD, ischemic heart disease; IQR, interquartile range; MAFLD, metabolic-associated fatty liver disease; MELD, model for end stage liver disease.
FIGURE 2.
Proportion of adult liver transplants performed for concurrent liver diseases, stratified by era (n = 5101). Era 1: 7 of 130 (5%); Era 2: 30 of 411 (7%); Era 3: 45 of 580 (8%); Era 4: 118 of 748 (16%); Era 5: 130 of 809 (16%); Era 6: 196 of 1031 (19%); and Era 7: 294 of 1390 (21%). χ2 P < 0.001.
Outcomes in Patients With Concurrent Liver Diseases
A higher proportion of adult liver transplant recipients with concurrent liver diseases had HCC as an indication for liver transplantation than liver transplant recipients with only 1 liver disease cause (33% versus 24%; odds ratio, 1.56; 95% CI, 1.33-1.84; P < 0.001; Table 3). The association between concurrent liver diseases and HCC as an indication for liver transplantation remained significant after adjusting for age at transplant, gender‚ and era (Table 4).
TABLE 4.
Association between concurrent liver diseases and HCC at time of liver transplantation: logistic regression multivariable analysis (n = 5101)
| OR | 95% CI | P | |
|---|---|---|---|
| Univariable analysis | |||
| Concurrent liver diseases (crude) | 1.56 | 1.33-1.84 | <0.001 |
| Multivariable analysis | |||
| Concurrent liver diseases (adjusted) | 1.21 | 1.01-1.44 | 0.034 |
| Age at transplant | 1.07 | 1.07-1.08 | <0.001 |
| Male | 3.20 | 2.69-3.80 | <0.001 |
| Era | 1.25 | 1.19-1.31 | <0.001 |
CI, confidence interval; HCC, hepatocellular carcinoma; OR, odds ratio.
Median follow-up of the adult liver transplant cohort was 7.3 y (IQR, 2.9, 14.0 y), a total of 46 839.6 person-years at risk. Of the 5101 liver transplant recipients, 1598 (31%) died‚ including 42 (0.8%) who died on the day of transplantation. There was no difference in posttransplant survival for transplant recipients with concurrent liver diseases compared with those with only 1 liver disease cause on Kaplan-Meier analysis (Figure 3), including when stratified by era (Table S4, SDC, http://links.lww.com/TXD/A430). Median survival time posttransplant was 21.2 y (IQR, 9.3, no upper bound) for those with concurrent liver diseases and 21.7 y (IQR, 9.8, no upper bound) for those with a single liver disease cause. Concurrent liver diseases were not associated with mortality on adjusted multivariable Cox regression modeling (Table 5). Moreover, there was no significant change in the association between concurrent liver diseases and posttransplant survival in sensitivity analysis where patients transplanted for fulminant hepatic failure were excluded (Table S3, SDC, http://links.lww.com/TXD/A430). We also did not find a significant difference in survival between those with concurrent liver diseases, with or without HCC (adjusted hazard ratio [aHR], 0.94; 95% CI, 0.81-1.09; P = 0.434). We also found no difference in survival comparing those with concurrent liver disease and HCC and those with a single liver disease and HCC (aHR, 0.34; 95% CI, 0.05-2.49; P = 0.286).
FIGURE 3.
Overall survival in adults postliver transplantation, stratified by concurrent liver diseases status (n = 5059*). Log-rank P = 0.368. Survival time (years) measured from date of first liver transplant. Note that total number of patients is 5059 because 42 patients died on the day of transplantation and therefore did not contribute survival time to the analysis.
TABLE 5.
Impact of concurrent liver diseases on overall survival posttransplant in adults: Cox proportional hazards analysis (n = 5059a)
| Crude HR | 95% CI | P | Adjusted HR | 95% CI | P | |
|---|---|---|---|---|---|---|
| Concurrent liver diseases | 0.93 | 0.81-1.08 | 0.368 | 0.98 | 0.83-1.14 | 0.757 |
| Age at transplant | ||||||
| 16–29 y | Ref | |||||
| 30–39 y | 1.06 | 0.84-1.34 | 0.636 | 1.11 | 0.87-1.42 | 0.386 |
| 40–49 y | 1.27 | 1.05-1.55 | 0.015 | 1.29 | 1.05-1.59 | 0.017 |
| 50–59 y | 1.52 | 1.26-1.84 | <0.001 | 1.69 | 1.38-2.07 | <0.001 |
| 60–69 y | 1.76 | 1.43-2.17 | <0.001 | 2.24 | 1.80-2.80 | <0.001 |
| >70 y | 0.94 | 0.23-3.79 | 0.926 | 1.55 | 0.38-6.30 | 0.539 |
| Male | 3.26 | 2.75-3.87 | <0.001 | 1.10 | 0.98-1.22 | 0.101 |
| HBV | 0.80 | 0.68-0.94 | 0.007 | 0.81 | 0.68-0.96 | 0.014 |
| HCV | 1.16 | 1.05-1.29 | 0.005 | 1.18 | 1.04-1.34 | 0.010 |
| ALD | 1.03 | 0.92-1.17 | 0.581 | |||
| MAFLD | 0.93 | 0.78-1.10 | 0.392 | |||
| AIH | 0.92 | 0.74-1.14 | 0.438 | |||
| PSC | 0.94 | 0.80-1.10 | 0.428 | |||
| HCC | 1.10 | 0.98-1.25 | 0.101 | 1.13 | 0.99-1.30 | 0.076 |
| Era | 0.85 | 0.82-0.87 | <0.001 | 0.81 | 0.78-0.84 | <0.001 |
aNote survival analysis included 5059 individuals because 42 died on the same day of transplantation and, therefore, did not contribute survival time to the analysis.
Survival time measured from date of first liver transplant.
AIH, autoimmune hepatitis; ALD, alcohol-related liver disease; CI, confidence interval; HBV, hepatitis B; HCC, hepatocellular carcinoma; HCV, hepatitis C; HR, hazard ratio; MAFLD, metabolic-associated fatty liver disease; PSC, primary sclerosing cholangitis.
In a subset of 2880 patients, data were available for metabolic risk factors (ischemic heart disease, diabetes, hypertension, obesity) and other recipient factors that may confound or interact with any association between concurrent liver diseases and survival posttransplant. In this subset, we performed a further sensitivity analysis to control for additional variables that might impact posttransplant survival, shown in Table S5 (SDC, http://links.lww.com/TXD/A430). In this adjusted analysis, concurrent liver disease was associated with a 21% reduction in mortality risk compared with transplantation for a single liver disease (aHR, 0.79; 95% CI, 0.62–0.99; P = 0.04). Older age at transplant, HCV, diabetes, and era of transplant were all significantly associated with worse survival posttransplant, whereas HBV was associated with improved survival on adjusted analysis (Table S5, SDC, http://links.lww.com/TXD/A430).
DISCUSSION
In this study, we have shown that reporting only the primary diagnosis for each liver transplant leads to significant under reporting of the liver transplant burden from chronic liver diseases, particularly ALD, MAFLD, and chronic viral hepatitis. Currently, other international liver transplant registries‚ including United Network for Organ Sharing and European Liver Transplant Registry, report primary diagnosis only when describing the proportional contribution of liver diseases to liver transplant indication.7,13,14 Our data show that, when all liver disease causes listed as an indication for liver transplant were included, diseases such as viral hepatitis and ALD accounted for almost double the proportion of liver transplants compared with when only primary diagnosis was used. Liver transplant recipients are often not representative of the overall population with end-stage liver disease because of the strict clinical and psychosocial criteria they must fulfill to undergo transplantation; however, in the absence of a national cirrhosis registry, national and regional transplantation databases and reports are an important source of epidemiological data that reflects trends in prevalence of liver diseases. Under reporting of liver diseases within liver transplant registries may lead to underestimation of the true burden of liver diseases requiring transplantation among policymakers and governments, leading to inadequate investment to improve liver disease outcomes on a national level.10,11,16,26 The widespread use of economic modeling to inform governments on the most cost-effective interventions for investment relies heavily on the accuracy of disease prevalence and outcome data.
We also showed that the proportion of adult liver transplants performed in Australia and New Zealand for concurrent liver diseases has increased significantly over time, predominantly driven by an increase in MAFLD and ALD as coindications for liver transplantation. The prevalence of ALD and MAFLD is rising globally, with a shift from high-income countries to increasing prevalence in low-middle income countries with increasing urbanization.1 Although recognition and reporting of MAFLD and ALD has certainly improved over time in the ANZLITR database,27 the rapid increase in MAFLD in our data set mirrors what has been described overseas among other liver transplant populations.28-30 Notably, risk factors, such as diabetes and obesity, were common within our cohort. Prevalence of HBV-related liver transplantation has been declining in many high-income countries because of the generational effect of successful infant vaccination programs and availability of effective antiviral treatment.12-14,31 Similarly, reductions in rates of HCV-related liver transplantation are widely reported in countries with access to highly effective direct acting antiviral therapy15-20,25,26; however, reductions in viral hepatitis as an indication for liver transplantation have been slower than the increase in ALD- and MAFLD-related liver transplantation in Australia and New Zealand (Figure 1).
In our study population, a higher proportion of patients with concurrent liver diseases also had HCC as an indication for transplantation than those with a single liver disease cause. This finding was independent of the confounding factors of age at time of transplant, biological sex, and era. These data have not previously been reported to our knowledge in the liver transplantation literature‚ and our findings are supported by other publications highlighting an increased HCC risk in patients with concurrent liver diseases.17,18,21,24 Metabolic risk factors and excessive alcohol consumption have been shown to be important cofactors for development of HCC in patients with HCV who have achieved sustained virological response.19,20 HCC prevalence is increasing in Australia12,34 and in many countries worldwide,35,36 reflecting the dynamics of the viral hepatitis, ALD, and MAFLD epidemics.1,31 Our data suggest but do not prove that the presence of multiple liver diseases may enhance HCC risk, highlighting the urgent need for public health interventions to improve prevention and timely management of liver diseases, such as ALD and MAFLD. Further large prospective cohort studies that address this important observation are warranted.
Importantly, we also showed that having multiple liver disease causes listed as an indication for liver transplantation does not negatively impact posttransplant survival, including when adjusted for era. Moreover, in a sensitivity analysis performed within a large subset of adult liver transplant recipients with data on metabolic risk factors and other determinants of posttransplant survival, there was a small reduction in relative risk of mortality in those with concurrent liver diseases compared with single liver disease. In the sensitivity analysis, the apparent significant association between concurrent liver diseases and posttransplant survival should be interpreted in the context of the 95% CI being close to 1 and bias in the sample with available metabolic data. The apparent improvement in outcomes among those with concurrent liver diseases may be driven by the fact that more untreatable liver diseases that affect posttransplant outcomes are present in the single liver disease group, such as autoimmune liver disease and PSC. Concurrent liver diseases were more likely to be viral hepatitis, ALD, and MAFLD, which are likely to have been optimized pretransplant. Over time, there may be further separation of the survival curves between those with MAFLD as a concurrent liver disease compared with those without, as MAFLD carries greater risk of cardiovascular mortality.
When key drivers of posttransplant outcome, such as age, presence of HCC, and diabetes, are accounted for in the multivariate model, disease cause may become more important. It is also possible that the apparent difference is confounded by some unmeasured factor; however, the lack of association between concurrent liver diseases and mortality with adjustment for key risk factors for mortality posttransplant is reassuring that concurrent liver diseases do not increase mortality posttransplantation per se. When cardiovascular and metabolic factors were controlled for in multivariable analysis, having >1 liver disease is not an independent risk for adverse outcomes posttransplant. This highlights the importance of aggressive control of cardiovascular risk factors in people undergoing liver transplantation from any cause. It also should reassure clinicians of the safety and appropriateness of referring people with >1 liver disease for transplantation.
The presence of concurrent liver diseases is increasingly recognized as an important determinant of clinical outcomes in liver disease because of the synergistic progression of liver fibrogenesis and carcinogenesis17,21,24,33; however, this is the first study to our knowledge that reports the impact on survival postliver transplantation. Presence of >1 liver disease concurrently should prompt more individualized approaches to comorbidity risk assessment and prevention of liver disease recurrence posttransplantation.
The availability of effective curative treatment for HCV and suppressive treatment for HBV and the requirement for alcohol abstinence when listed for transplantation in Australia and New Zealand are likely to have minimized the recurrence of these diseases after transplantation. Hence, recipients with concurrent liver diseases pretransplant may not have multiple active liver diseases after transplantation.37 MAFLD is without an effective cure and, therefore, may continue to influence clinical outcomes after liver transplantation, particularly given the high prevalence of an adverse metabolic profile posttransplantation.38 We did not show an adverse effect of MAFLD on postliver transplant survival, consistent with data from other international studies.39 This may reflect careful candidate selection and changes in lifestyle before and after liver transplantation, such as improved diabetic control, improved nutrition, and weight loss. These variables were not captured in the ANZLITR data set. Furthermore, MAFLD as an indication for liver transplantation has been a recent phenomenon in Australia and New Zealand, and we had fewer MAFLD recipients with shorter duration of follow-up than recipients transplanted for HBV, HCV, and ALD (Figure 1).
There are several limitations to our study. Similar to international practices,7,13,14 in the ANZLITR, listing of primary disease cause was at the discretion of the transplant center. It can be challenging to determine the relative contributions of multiple liver diseases and cofactors toward liver disease severity in an individual without examining explant histology. Secondary liver disease causes listed in the ANZLITR may have been codominant liver diseases driving progression or merely cofactors, which is not well captured within our data set. As such, our data cannot be interpreted as providing disease attributable risks for liver transplantation but do capture prevalence of different liver diseases within the adult liver transplant recipient population of Australia and New Zealand. The recognition of MAFLD as a liver disease cause has improved over time, leading to better recognition and recording within the ANZLITR. It is, therefore, possible that MAFLD was under recognized as an important coexisting liver disease in our data set. Metabolic risk factors, such as BMI and type 2 diabetes, have not been routinely collected in the ANZLITR, although coverage has increased in recent years. BMI may also be affected by ascites (weight) if not using a dry weight, which we assume was used for the registry but cannot verify. Moreover, the subset with metabolic risk factor data may not be representative of the total ANZLITR cohort. Our national data reflect disease prevalence within Australia and New Zealand; however, similar trends in ALD and MAFLD have also been reported in other countries, making our data relevant to the wider international community.8,14,40 Donor factors were not included in this analysis and are an area of interest for future studies.
Our data are for transplanted patients only; therefore, we have not captured differences in patients delisted, which may have impacted on the posttransplant survival through selection bias. Finally, the lack of survival difference post liver transplant between patients with and without concurrent liver diseases must be interpreted in the context of the study limitations, namely, that this was a retrospective registry database analysis that did not include data on other potential confounders on survival, such as liver disease treatment, donor factors, and socioeconomic determinants of health.
Our study has several key strengths, including that it is based on a detailed, complete data set from 6 liver transplant centers across 2 countries over 35 y. The registry data allowed us to uniquely explore concurrent liver diseases, as it captures all liver disease diagnoses for liver transplant recipients, a feature that is not well reported by many liver transplant registries. Finally, the study accurately reflects the liver disease prevalence and diversity of the Australian and New Zealand populations. Our data support the proposal to capture all liver disease diagnoses that are listed as indications in liver transplantation registry databases.
CONCLUSIONS
Concurrent liver diseases are increasing among adult liver transplant recipients in Australia and New Zealand, although it does not appear to have a negative impact on posttransplant survival. Capturing and reporting data for all liver disease causes in addition to primary liver disease cause in liver transplant registries will provide more accurate estimates of liver disease prevalence among transplant recipients than documenting primary liver disease alone. Such data are essential additions to guide public health policy for the prevention of chronic liver disease and related liver cancer. Further studies on clinical outcomes in liver transplantation for concurrent liver diseases are warranted.
ACKNOWLEDGMENTS
We would like to acknowledge the generous contributions of all liver transplant center staff, patients, and their families in Australia and New Zealand who have indirectly contributed to this work.
Supplementary Material
Footnotes
J.H. conceived and designed the study, performed the analyses, and wrote the manuscript. P.G. designed and mentored the study and contributed to manuscript drafting. M.B. provided the data set on behalf of the Australia and New Zealand Liver and Intestinal Transplant Registry (ANZLITR). A.M., M.F., G.M., S.I.S., M.C., P.H., K.A.S., C.T., J.C., A.W., R.J., B.J., G.J., L.A., M.C.W., E.G., and A.T. all contributed to manuscript drafting. All authors approved the final manuscript.
The authors declare no conflicts of interest.
J.H. is supported by an NHMRC Program grant and a University of Melbourne Faculty Fellowship.
Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantationdirect.com).
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