key: cord-0278643-j1orwd2s
authors: Chang, W. H.; Mueller, S.; Chung, S.-C.; Foster, G. R.; Lai, A. G.
title: Increased burden of cardiovascular disease in people with liver disease: unequal geographical variations, risk factors and excess years of life lost
date: 2021-10-11
journal: nan
DOI: 10.1101/2021.10.07.21264705
sha: 4d30d69149a3531e136c9377b1195730a5a043e8
doc_id: 278643
cord_uid: j1orwd2s

Background People with liver disease are at increased risk of developing cardiovascular disease (CVD), however, there has yet been an investigation of incidence burden, risk, and premature mortality across a wide range of liver conditions and cardiovascular outcomes. Methods We employed population-wide electronic health records (EHRs; from 1998-2020) consisting of almost 4 million adults to assess regional variations in disease burden of five liver conditions, alcoholic liver disease (ALD), autoimmune liver disease, chronic hepatitis B infection (HBV), chronic hepatitis C infection (HCV) and NAFLD, in England. We analysed regional differences in incidence rates for 17 manifestations of CVD in people with or without liver disease. The associations between biomarkers and comorbidities and risk of CVD in patients with liver disease were estimated using Cox models. For each liver condition, we estimated excess years of life lost (YLL) attributable to CVD (i.e., difference in YLL between people with or without CVD). Results The age-standardised incidence rate for any liver disease was 114.5 per 100,000 person years. The highest incidence was observed in NAFLD (85.5), followed by ALD (24.7), HCV (6.0), HBV (4.1) and autoimmune liver disease (3.7). Regionally, the North West and North East regions consistently exhibited high incidence burden. Age-specific incidence rate analyses revealed that the peak incidence for liver disease of non-viral aetiology is reached in individuals aged 50-59 years. Patients with liver disease had a 2-fold higher incidence burden of CVD (2,634.6 per 100,000 persons) compared to individuals without liver disease (1,339.7 per 100,000 persons). When comparing across liver diseases, atrial fibrillation was the most common initial CVD presentation while hypertrophic cardiomyopathy was the least common. We noted strong positive associations between body mass index and current smoking and risk of CVD. Patients who also had diabetes, hypertension, proteinuric kidney disease, chronic kidney disease, diverticular disease and gastro-oesophageal reflex disorders had a higher risk of CVD, as do patients with low albumin, raised C-reactive protein and raised International Normalized Ratio levels. All types of CVD were associated with shorter life expectancies. When evaluating excess YLLs by age of CVD onset and by liver disease type, differences in YLLs, when comparing across CVD types, were more pronounced at younger ages. Conclusions We developed a public online app (https://lailab.shinyapps.io/cvd_in_liver_disease/) to showcase results interactively. We provide a blueprint that revealed previously underappreciated clinical factors related to the risk of CVD, which differed in the magnitude of effects across liver diseases. We found significant geographical variations in the burden of liver disease and CVD, highlighting the need to devise local solutions. Targeted policies and regional initiatives addressing underserved communities might help improve equity of access to CVD screening and treatment.

Although cardiovascular disease (CVD) prevention policies have had some success, for the past two 72 decades, they have remained limited in reducing the number of deaths globally with CVD still ranked 73 as the leading cause of death. A large proportion of deaths are attributable to preventable illnesses 74 -most premature deaths from CVD in people younger than 75 are avoidable 1,2 . As major risk factors 75 for CVD, type 2 diabetes and obesity have received the most attention in policy, public awareness 76 and guidelines. However, despite reported associations between liver disease and cardiovascular 77 risk, liver conditions other than non-alcoholic fatty liver disease (NAFLD) have mostly been 78 overlooked.

Liver disease encompasses a spectrum of conditions including viral hepatitis, NAFLD, steatosis to 81 end-stage cirrhosis. Other causes of liver cirrhosis include autoimmune liver disease and alcoholic 82 liver disease (ALD). The heart has been implicated in the progression of aggravating liver disease, 83 with the liver-heart axis more extensively explored in patients with NAFLD 3 . With a global prevalence 

Current guidelines from the American Association for the Study of Liver Diseases recommended the 100 modification of CVD risk factors in these individuals and the screening of CVD during liver transplant 101 evaluation 13 . Furthermore, since CVD is the most common cause of death in patients with NAFLD, 102 the European Association for the Study of Liver recommends mandatory screening for CVD in 103 individuals with NAFLD 14 . As liver disease progresses, liver-specific risk factors (e.g., raised 104 International Normalised Ratio) and prevalent comorbidities that are independently associated with 105 increased CVD risk may come into play and could result in more severe illness in these individuals.

Yet, CVD is often underdiagnosed in patients with liver disease and there are no policies on 107 screening patients with chronic liver disease.

Harnessing an emerging data science opportunity from population-based electronic health records 110 (EHRs), we sought to identify population groups, among patients with liver disease, who might be at 111 high risk for CVD. Employing linked EHRs from primary and secondary care on 4 million individuals, 112 our study aims to address the value, or futility, of targeted monitoring of CVD risk in patients with 113 liver disease. We characterised clinical features of patients with any of the five liver conditions, ALD, 114 autoimmune liver disease, HBV, HCV and NAFLD and explored the associations between risk 115 factors and future risk of 17 of the most common initial cardiovascular presentations. A report on the 116 atlas of variation in risk factors and healthcare for liver disease by the Public Health England found 117 that for the past three decades, there have been limited improvements in mortality rates and 118 incidence of liver disease 15 . Deaths from liver disease have increased by fourfold and progress on 119 earlier diagnosis and better treatment have been slow 16, 17 . For these reasons, we investigated 120 regional variations in liver disease burden and CVD burden to highlight potential gaps in the provision 121 of services, inequality of access and prevention initiatives, drawing attention to regions where 122 improvements are most needed. Specific objectives of this study were: (i) to estimate the regional 123 variations in incidence rates for liver disease in England, (ii) to estimate regional variations in 124 incidence rates for CVD in patients with and without liver disease, (iii) to estimate the associations 125 of age, clinical biomarkers, pre-existing comorbidities and smoking with risk of initial presentation of 126 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.07.21264705 doi: medRxiv preprint age of CVD onset by comparing patients with liver disease who subsequently developed CVD to 128 those who did not.

We provide an open-access online app, with implications for clinical risk assessment and targeted 131 policy on CVD prevention, that shows incidence rates, years of life lost estimations and cause-132 specific hazard ratios for associations between clinical features and initial presentation of CVD.

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Estimations of age-standardised and age-specific incidence rates

Age-standardised incidence rates were estimated per 100,000 person-years and based on a five-

year study period from 01.01.2015 till 31.12.2019. We analysed geographical variations in incidence 177 rates based on CPRD practice region definitions. We retrieved the 2019 population estimates 178 (overall and by age groups) from the Office for National Statistics 24 for age-standardisation of 179 incidence rates. Additionally, we estimated incidence rates by age groups (i.e., age-specific 180 incidence rates) to explore differences across the age groups. Patient years were calculated by age package in R (version 3.2.10). Confidence intervals for incidence rates were calculated based on 183 the central limit theorem given dichotomous outcome in a single population. For event numbers 184 smaller than five, age-standardised incidence rate was not reported. Using these approaches, we 185 estimated both age-standardised and age-specific incidence rates for liver disease and incidence 186 rates for CVD in patients with and without liver disease.

190 191

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The copyright holder for this this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.07.21264705 doi: medRxiv preprint on the specific age of onset of CVD and compared the average of these individuals to the patients 194 without CVD of the same age. We also examined excess YLL by the type of first CVD presentation 195 within age groups.

Cox proportional hazards models were fitted. Hazard ratios (HRs) from the fully adjusted models 201 were reported with 95% confidence intervals (CI). All P values were two-sided. Models were also 202 refitted with age group as a categorical variable to return HRs by age group. Proportional hazards 203 assumption violations were tested for a zero slope in the scaled Schoenfeld residuals. Biomarker 204 and BMI measurements were indicated as the presence or absence of a particular measurement 205 above or below the stated threshold. In the primary analysis, those with missing BMI information 206 were assumed to be non-obese. Those with missing biomarker information were assumed to be 207 within the normal threshold on the assumption that abnormal blood test results were likely to be 208 recorded if present. Additionally, sensitivity analyses were conducted on complete records to 209 demonstrate that the estimates were robust to our assumptions around missing data.

Data were analysed using R (3.6.3) with the following packages: survival, tidyverse, tableone, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The study cohort included 3,929,596 individuals, of whom 12,845, 2,210, 1,753, 3,112 and 20,928 219 individuals were newly diagnosed with ALD, autoimmune liver disease, HBV, HCV and NAFLD, 220 respectively (Additional file 4). The median age of diagnosis for each liver disease was ALD (54.8; 

The age-standardised incidence rate for any of the five liver diseases in England was 114.5 per 232 100,000 person years (95% confidence interval (CI): 112.5-116.6) ( Figure 1A , Additional file 5). For 233 specific liver diseases, the age-standardised incidence rates per 100,000 person years were as 

To ascertain whether patients with liver disease had a higher incidence of CVD, we considered 17 244 cardiovascular conditions (see methods). The age-standardised incidence rate for CVD in patients 245 with any liver disease was two-fold higher than in people without liver disease. Incidence rate was 

The age-specific incidence rates of CVD in patients with any liver disease exhibited an upward trend 254 with increasing age, peaking at ages 70 to 79 (766 per 100,000 person years). Similarly, in people 255 without liver disease, this upward trend was maintained, albeit at a lower magnitude (highest CVD 256 incidence was observed in individuals aged 80 and above; 562 per 100,000 person years) (Additional 257 file 9, Additional file 10). Unlike the incidence rates of CVD which increased with age peaking in the 258 highest age groups, the incidence rates of liver disease peaked in middle-aged individuals as shown 259 earlier ( Figure 1B ). Geographical variations of liver disease burden and CVD burden (in people with 260 or without liver disease) were further explored and presented in the supplementary appendix.

We analysed the first presentation of 17 types of incident CVD. When considering the first 266 presentation of CVD, the number of incident CVD events for patients with liver disease were as is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.07.21264705 doi: medRxiv preprint angina, myocardial infarction, heart failure and coronary heart disease unspecified, was the most common, followed by arrhythmia, stroke/TIA, peripheral vascular disease and cardiomyopathy ( Figure 3B ). When delving into specific liver conditions, coronary heart disease was the first presentation in 53% of patients with NAFLD who had cardiovascular events, while cardiomyopathy was the first presentation in only 3% of patients. By contrast, 44% of patients with autoimmune liver (Additional file 2). In men, 5%, 5%, 6% and 19% of these events account for peripheral vascular 284 disease, stroke/TIA, arrhythmia and coronary heart disease respectively. While in women, the 285 proportion differs with 4%, 15% and 24% events accounting for stroke/TIA, arrhythmia and coronary 286 heart disease respectively (Additional file 2).

The associations between patient-level factors (i.e., prevalent comorbidities, biomarkers and 292 smoking) and the risk of incident CVD were shown in Figure 4 and Additional file 11. We noted strong 

We observed a consistent pattern of increased risk for a body mass index (BMI; kg/m 2 ) of over 30; 

We observed that albumin levels of < 35 g/L were associated with a higher risk of CVD in patients is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.07.21264705 doi: medRxiv preprint ALT levels and CVD risk also revealed inverse associations where patients with raised ALT (≥ 35 329 U/L) had a lower risk of CVD (reasons for this are explored in the discussion section).

Among patients with liver disease, we estimated excess years life lost (YLL), which was calculated 335 as the average number of years that individuals with a specific CVD condition lose in excess of that 336 found in people without CVD of the same sex and age. We estimated excess YLL based on the age 337 of CVD onset at ages 30, 40, 50, 60, 70 and 80 ( Figure 5A ). Overall, individuals with NAFLD 338 experienced the highest excess YLL upon CVD diagnosis, a pattern that was most pronounced at 339 younger ages. Patients with NAFLD who developed CVD at the age of 40 years experienced an 340 excess YLL of 18.2 years (CI: 16.5 -20.2) compared to those without CVD. In contrast, at the same 341 age of CVD onset, patients with HBV experienced excess YLL of only 9.5 years (CI: 7.1 -12.1) 342 ( Figure 5A ).

When investigating sex differences, the difference in excess YLL between men and women 345 appeared to be marginal in patients with ALD, autoimmune liver disease and NAFLD (Additional file 

We also evaluated excess YLL by age of CVD onset for each of the five liver diseases stratified by 354 the five CVD categories. In the interest of maintaining conciseness and to aid comparison across 355 liver diseases, we graphically displayed results as radar plots ( Figure 5B ). Each radar showed 356 excess YLL estimates for a specific age of CVD onset, with each spoke representing excess YLL for 

(as represented by a larger surface area connecting the CVD categories) that was consistent across 362 the five liver conditions. Conversely, as the age of onset increased, excess YLL decreased. The 363 radar plots also facilitate the visualisation of the differences by liver disease and CVD category.

Notably, when comparing across the five liver conditions, the differences in excess YLL by CVD 365 category were more pronounced at younger ages ( Figure 5B ). At age 40, patients with autoimmune 366 liver disease, compared to other liver diseases, experience the highest excess YLL when diagnosed 367 with peripheral vascular disease (25.7 years; CI: 12.7 -41.6) compared to other CVD categories. In 368 contrast, patients with autoimmune liver disease who are diagnosed with incident arrythmia at age 369 40 lost only 6.7 years (9.5% CI: 4.5 -9.5) ( Figure 5B ).

We developed a public online tool to share results interactively 372 (https://lailab.shinyapps.io/cvd_in_liver_disease/).

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have an enhanced incidence burden of CVD compared to the general population. Coronary heart disease and arrhythmia are two of the most common first presentation of CVD, which show similar disease did not impact upon CVD presentation, perhaps suggesting that the liver disease drives 384 CVD rather than the causative aetiology (i.e., viral infection or alcoholism). We provide the public, 385 researchers and policymakers with an interactive online tool for exploration and visualisation of the 386 incidence rates of liver disease, incidence rates of CVD in patients with and without liver disease 

Our observation that incidence rates for liver disease (except for HBV) were the highest in North

East and North West regions was corroborated by the Public Health England's (PHE's) second atlas 396 of variation for liver disease 30 . The PHE atlas revealed that Northern regions had a high rate of 397 expenditure for hepatobiliary problems, liver disease admissions rates, liver disease mortality and 398 rate of years of life lost. We observed that the incidence rate for HBV was the highest in London.

This result was consistent with the PHE atlas which found that the percentage of women who tested 

When examining the regional variations of CVD in patients with or without liver disease, we found 405 that variation in incidence rates is ubiquitous across England. Our results draw attention to the need 406 to coordinate CVD and liver disease services across regions to maintain equity in service access at 407 a local level by helping commissioners, service providers and clinicians to compare the disease 408 burden of their region with the national figure to ensure that care pathways are planned optimally.

Regional variations signify that a one-size-fits-all approach is less likely to be effective. Services 

Our population-wide study of nearly 4 million individuals provides evidence that associations 416 between clinical factors and 17 cardiovascular disease outcomes differ in terms of magnitude of 417 effects when comparing across the five liver diseases. Raised BMI and current and former smoking 418 were associated with an increased risk of CVD. Similarly, diabetes mellitus, hypertension, 419 dyslipidaemia and chronic kidney disease are comorbidities associated with a higher risk. CVD risk 420 is increased by at least two times in patients with impaired renal function 12 . We also observed that 421 proteinuria, which is an indication of kidney damage, is associated with a higher risk of CVD. C-422 reactive protein is a marker of systemic inflammation, where it is found to be a predictor of mortality 423 in patients with liver disease 31 . We found that patients with raised C-reactive protein have an 424 increased risk of CVD, which corroborates previous findings that inflammation may serve as a 425 pathogenic mechanism for triggering atherothrombotic CVD events 32 . Low albumin levels were 426 associated with a higher risk. An inverse association between albumin and CVD may be explained is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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We found that markers of liver function (i.e., bilirubin, aspartate transaminase and 431 gamma−glutamyltransferase) do not appear to be associated with CVD risk. Evidence on the 432 association between these measurements and CVD risk has been mixed 34 . When analysing the 433 effects of alanine aminotransferase (ALT) levels, we observed an inverse relationship between ALT 434 and CVD risk. A systematic review and meta-analysis of 29 cohort studies demonstrated that there 435 was limited evidence for association between ALT and CVD events 35 . In contrast, stratified analysis 436 on cause-specific CVD endpoints demonstrated that ALT was inversely associated with coronary 437 heart disease but positively associated with stroke 35 . A study on three large prospective cohorts 438 (West of Scotland Coronary Prevention Study, the Prospective Study of Pravastatin in the Elderly at 439 Risk, and the Leiden 85-plus Study) with ages ranging from 45 to 85 years, also described an inverse 440 association between ALT and cardiovascular outcomes, even after adjusting for confounders 36 

Our results confirm that patients with liver disease experience premature mortality attributable to 456 CVD. These findings are consistent with a report from the Centers for Disease Control and 457 Prevention stating that CVD ranks third in YLL prior to age 65 41 along with other studies 458 demonstrating that premature death due to CVD continues to increase globally 42,43 . Although each 459 type of CVD is associated with excess YLL, we observed that women lost more years of life 460 compared to men at a younger age of CVD onset among patients with HCV and at an older age of 461 CVD onset among patients with HBV.

A major strength of this study is the ability to differentiate 17 cardiovascular outcomes using a real-467 world population cohort, which is larger, contemporary and more representative of the general 468 population compared with investigator-led cohorts. Given that we have analysed records from both 469 primary and secondary care, we are able to capture conditions that are treated by general 470 practitioners and specialist clinicians in hospitals. Primary care records also provide more detailed 471 data than those recorded on admission to hospital, where the former account for the total population is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.07.21264705 doi: medRxiv preprint 

An exploration of regional variations revealed that the patterns of incidence burden differed across 

Regionally, the maximum incidence for any liver disease was reached in individuals aged 50-59 for 745 all regions except the West Midlands (where incidence peaked in individuals age 60-69) (Additional 746 file 6). Additional age-specific incidence rates by specific liver disease type and geographical regions 747 were provided in Additional file 6. 748 749 750 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.07.21264705 doi: medRxiv preprint people without liver disease (1,537 per 100,000 person years) ( Figure 2B, Additional file 8) . In 758 individuals with liver disease, the lowest CVD incidence was observed in the South East region 759 (2,420 per 100,000 person years, CI: 2,098-2,742) (Figure 2A, Additional file 7) . However, in people 760 without liver disease, East of England had the lowest CVD incidence rate (1,226 per 100,000 person 761 years) ( Figure 2B , Additional file 8).

Variation rates were more striking when comparing liver disease types. Regions with the highest 764 incidence burdens of CVD by liver disease type were as follow: ALD (North East; 3,827 per 100,000 

When investigating regional variations in age-specific incidence rates, the highest CVD incidence in 770 people with and without liver disease was observed in individuals aged 70 and above across all 771 regions (Additional file 9, Additional file 10).

Comorbidity patterns in patients with liver disease

We analysed comorbidity patterns for 14 prevalent conditions stratified by liver disease type, age is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Age-standardised incidence rate (per 100,000 person years) Figure 1 . Variations in incidence rates for liver disease. (A) Age-standardised incidence rates by geographical regions. (B) Age-specific incidence rates of liver disease to demonstrate changes in incidence rates across age-groups. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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New metrics for the Lancet Standing Commission 611 on Liver Disease in the UK

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