Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL

doi:10.1016/j.jhep.2022.04.009

Journal of Hepatology

Volume 77, Issue 3, September 2022, Pages 695-701

https://doi.org/10.1016/j.jhep.2022.04.009 Get rights and content

Highlights

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The detection of patients with early cirrhosis is important to improve prognosis.
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The SEAL algorithm evaluates the utility of population-based screening to detect cirrhosis as early as possible.
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Excluding patients with decompensated cirrhosis at initial diagnosis, SEAL was associated with a 60% higher chance of early cirrhosis detection.
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Only 50% of the patients identified by SEAL in primary care utilized specialist assessment.

Background & Aims

Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible.

Methods

SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 (“Check-up 35”) at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care.

Results

A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰).

Conclusions

The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program.

Registration

DRKS00013460

Lay summary

Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the ‘SEAL’ pathway represents a feasible and potentially cost-effective screening program.

Graphical abstract

Introduction

Globally, cirrhosis as a common consequence of end-stage liver diseases accounts for more than 1.3 million deaths every year.¹ The incidence of deaths caused by cirrhosis as a proportion of all deaths increased from 1.9% in 1990 to 2.4% in 2017.¹ In general, cirrhosis can be stratified into compensated and decompensated cirrhosis. Decompensated cirrhosis is defined by the occurrence of ascites, hepatic encephalopathy, variceal bleeding or jaundice and is associated with a very poor prognosis.² In contrast, compensated cirrhosis is more benign as life expectancy is comparable to healthy individuals if cirrhosis remains compensated.² In routine care, it is challenging to differentiate between patients with advanced fibrosis and early cirrhosis. Additionally, patients with advanced fibrosis are also at risk of disease progression and may as well qualify for hepatocellular carcinoma surveillance.³ For this reason, the term compensated advanced chronic liver disease has been introduced as an umbrella term for those 2 disease stages.⁴

Whereas the treatment of patients with decompensated cirrhosis focuses on the management of complications and frequently results in the need for liver transplantation, patients with advanced fibrosis and asymptomatic cirrhosis can benefit from causal treatment of their underlying liver disease.⁵ In this context, recent studies indicated that causal treatment may not only result in fibrosis regression, but also in an amelioration of portal hypertension, which is one of the best predictors of future decompensation.[6], [7], [8] Unfortunately, the minority of patients with cirrhosis are diagnosed at an early stage, and about 3 out of 4 show decompensation at initial diagnosis.⁹ Therefore, the development of screening pathways for the detection of patients with advanced fibrosis and early cirrhosis appears of pivotal importance to improve prognosis, disease burden, and reduce healthcare expenditures. For this reason, the aim of the SEAL (Structured Early Detection of Asymptomatic Liver Cirrhosis) program was to evaluate the feasibility and usefulness of a systematic screening program to detect patients with cirrhosis at early stage in the general population.

Section snippets

SEAL cohort and algorithm

SEAL was a prospective cohort study conducted in 2 federal states in Germany, Rhineland-Palatinate and Saarland, between 01/2018 and 02/2021. Fig. 1 outlines the SEAL algorithm for the detection of patients with advanced fibrosis and cirrhosis. In total, 201 practices of general practitioners in Rhineland-Palatinate (n = 141) and Saarland (n = 60) joined the study by signing a special contract (§ 140a SGB V Besondere Versorgung) with the major social health insurance AOK Rhineland-Palatinate

Implementation of the SEAL pathway

In total, 12,093 patients were registered and screened in the SEAL program. Of these, 234 (1.94%) patients did not fully meet the inclusion criteria and were excluded, resulting in the analysis cohort of 11,859 patients with available data (Fig. 2). Most patients were recruited in 2019 during the pre-COVID-19 era (Fig. S1). Of 11,859 patients included into SEAL, 488 patients (4.12%) met the criteria of elevated aminotransferase activities and APRI >0.5. The number of patients with elevated AST

Discussion

In this study, we report the results of the SEAL project – a prospective study to evaluate the usefulness of structured screening to detect cirrhosis in the general population. To the best of our knowledge, this study represents the largest reported trial using a predefined pathway primarily designed for the early detection of cirrhosis. SEAL not only provides a robust overview of the incidence of chronic liver diseases in patients with suspected advanced liver disease in 2 German territorial

Financial support

This project was funded by the Innovationsausschuss beim Gemeinsamen Bundesausschuss from 2016 to 2021 (G-BA 01NVF16026).

Authors’ contributions

Performed research: C.L., A.A., M.N.T., M.N., E.G., D.S., J.O., F.L., P.R.G. Contributed to acquisition of data: C.L., A.A., M.N.T., M.N., M.A.W., M.R., F.J.H., D.M., G.Z., B.R., F.L., P.R.G. Designed the experiments and analyzed the data: C.L., A.A., M.N.T., M.N., M.A.W., H.B., E.F.G., U.F., E.G., D.S., R.V.E., J.U., L.V., F.L., P.R.G. Wrote the manuscript: C.L., P.R.G. Critical revision of the manuscript: all authors. Statistical analysis: H.B., D.S., E.G., E.F.G, U.F. All authors approved

Data availability statement

The datasets generated and analyzed during the current study are not publicly available due to ethical restrictions but are available from the corresponding author on reasonable request.

Conflict of interest

The authors disclose no potential financial or non-financial conflict of interests regarding this study.

Please refer to the accompanying ICMJE disclosure forms for further details.

Acknowledgments

We are grateful for continuous support of this project from the AOK RLP Health insurance, in particular to Martin Giesen, Jutta Bartmann, Alexandra Schanzenbach and Inge Bearzatto, Felix Strobel, Jörg Eppers, and Monika Behrendts.

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Cited by (28)

FIB-4 and APRI for cirrhosis detection in a privately insured national cohort
2024, JHEP Reports
Non-invasive laboratory-based fibrosis indices have been proposed as a tool for population-based screening for advanced fibrosis. We aimed to examine the performance of fibrosis indices at the time of and prior to cirrhosis diagnosis.
We included adult patients with cirrhosis diagnosis codes in a privately insured database (Optum) from 2010-2018 with 1:4 birth year-matched controls without cirrhosis diagnosis codes. We analyzed aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) up to 30 months prior to the entry of cirrhosis diagnosis codes. Cut-offs of <1 and ≥2 were used for APRI and <1.3 and ≥2.67 were used for FIB-4.
We included 10,650 patients with cirrhosis (median age 62 years), who were predominantly white (57.8%) and male (51.9%). The most common etiologies of cirrhosis were non-alcoholic steatohepatitis (23.8%), hepatitis C (23.0%), and alcohol-related liver disease (20.5%). At the time of cirrhosis diagnosis (±3 months), 9.3% of patients with cirrhosis had APRI ≥2 and 41.3% had a FIB-4 ≥2.67 compared to 1.2% and 8.9% in control patients, respectively. In the periods spanning 3-12, 12-21, and 21-30 months prior to cirrhosis diagnosis, APRI was ≥2 in 9.4%, 6.6%, and 6.5% of patients, respectively; FIB-4 was ≥2.67 in 42.1%, 37.1%, and 34.3% of patients, respectively. The sensitivity and specificity of APRI at the time of cirrhosis diagnosis were 9.3% and 98.8%, respectively, while the sensitivity and specificity of FIB-4 were 41.3% and 91.0%, respectively. Lower cut-off values for APRI and FIB-4 showed similar performance.
Existing non-invasive fibrosis makers are suboptimal when used for advanced fibrosis identification, missing over half of patients with cirrhosis at the time of and prior to clinical diagnosis.
Commonly available laboratory-based indices, including APRI and FIB-4, have been proposed to rule in or rule out advanced fibrosis in the general population. In a study of a large privately insured cohort from the US, FIB-4 and APRI were not sufficient for screening for advanced fibrosis at the time of or prior to clinical diagnosis. While performance for screening out advanced fibrosis was better, a significant percentage of patients with cirrhosis have lab indices below threshold values. Future studies to develop laboratory-based algorithms to help stratify liver fibrosis for population-based screening are warranted.
Noninvasive Assessment of Liver Fibrosis in NAFLD
2023, Clinical Gastroenterology and Hepatology
Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of liver-related morbidity and mortality worldwide, afflicting approximately a billion individuals. NAFLD is a slowly progressive disease that may evolve in a subset of patients toward cirrhosis, hepatocellular carcinoma, and end-stage liver disease. Liver fibrosis severity is the strongest predictor of clinical outcomes. The emergence of effective therapeutics on the horizon highlights the need to identify among patients with NAFLD, those with severe fibrosis or cirrhosis, who are the most at risk of developing complications and target them for therapy. Liver biopsy has been the reference standard for this purpose. However, it is not suitable for large-scale population evaluation, given its well-known limitations (invasiveness, rare but severe complications, and sampling variability). Thus, there have been major efforts to develop simple noninvasive tools that can be used in routine clinical settings and in drug development. Noninvasive approaches are based on the quantification of biomarkers in serum samples or on the measurement of liver stiffness, using either ultrasound- or magnetic resonance–based elastography techniques. This review provides a roadmap for future development and integration of noninvasive tools in clinical practice and in drug development in NAFLD. We discuss herein the principles for their development and validation, their use in clinical practice, including for diagnosis of NAFLD, risk stratification in primary care and hepatology settings, prediction of long-term liver-related and non–liver-related outcomes, monitoring of fibrosis progression and regression, and response to future treatment.
Prediction of liver-related mortality in a community setting
2023, Journal of Hepatology
Time to focus on chronic liver diseases in the community: A review of primary care hepatology tools, pathways of care and reimbursement mechanisms
2023, Journal of Hepatology
Citation Excerpt :
A study in Germany suggests a structured population screening programme, using simple blood tests such as aspartate aminotransferase/alanine aminotransferase, could be feasible. The detection of advanced fibrosis/cirrhosis in the screening programme was slightly higher than in controls (3.83% vs. 3.36%).27 The effectiveness may be improved by refining the initial “screening “population and diagnostic tools.
Addressing primary care’s low confidence in detecting and managing chronic liver disease is becoming increasingly important owing to the escalating prevalence of its common lifestyle-related metabolic risk factors – obesity, physical inactivity, smoking and alcohol consumption. Whilst liver blood testing is frequently carried out in the management of long-term conditions, its interpretation is not typically focused on specific liver disease risk. Educational steps for primary care should outline how liver fibrosis is the flag of pathological concern, encourage use of pragmatic algorithms such as fibrosis-4 index to differentiate between those requiring referral for further fibrosis risk assessment and those who can be managed in the community, and emphasise that isolated minor liver function test abnormalities are unreliable for estimating the risk of fibrosis progression. Measures to increase primary care’s interest and engagement should make use of existing frameworks for the management of long-term conditions, so that liver disease is considered alongside other metabolic disorders, including type 2 diabetes, cardiovascular disease, chronic kidney disease etc. Selling points when considering the required investment in developing local fibrosis assessment pathways include reduced repeat testing of minor abnormalities and improved secondary care referrals, plus improvements in the patient’s journey through long-term multimorbidity care. A focus on improving chronic liver disease is likely to have wide-ranging benefits across co-existing metabolic disorders, particularly when pathways are aligned with community lifestyle support services. The important message for primary care is to increase the value of existing monitoring rather than to generate more work.
Reply to: “SEAL: Why was this approach not effective?”
2023, Journal of Hepatology
SEAL: Why was this approach not effective?
2023, Journal of Hepatology

Research ArticleStructured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL

Highlights

Background & Aims

Methods

Results

Conclusions

Registration

Lay summary

Graphical abstract

Introduction

Section snippets

SEAL cohort and algorithm

Implementation of the SEAL pathway

Discussion

Financial support

Authors’ contributions

Data availability statement

Conflict of interest

Acknowledgments

J Hepatol

Lancet

J Hepatol

Gastroenterology

Hepatology

J Hepatol

Lancet Reg Health Eur

Lancet Gastroenterol Hepatol

J Hepatol

Lancet

J Hepatol

Research Article
Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL