Review
Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review

https://doi.org/10.1016/S2468-1253(16)30205-9Get rights and content

Summary

As of 2016, there is no evidence-based pathway to stratify the risk of chronic liver disease in a general population setting. Non-invasive tests of liver fibrosis might provide a mechanism for earlier diagnosis. These tests have been extensively validated in the hospital setting but their performance in a general population setting is unclear. We did a systematic review of non-invasive tests used to stratify patients at risk of clinically significant liver disease in a general population setting and report the prevalence of chronic liver disease as defined by these tests. We systematically searched Embase, MEDLINE, Web of Science, reference lists from the original studies identified, and recent conference proceedings. All study designs were considered. 19 studies were identified, in which 11 non-invasive tests were used. Only transient elastography and FibroTest were compared with histological endpoints. The prevalence of liver fibrosis varied between 0·7% and 25·7%. More focused stratification for advanced liver fibrosis (0·9–2·0%) or cirrhosis (0·1–1·7%) narrowed the estimates of prevalence. Investigators from studies targeting patients with risk factors of liver disease, such as non-alcoholic fatty liver disease, hazardous alcohol use, or type 2 diabetes, reported higher prevalence of advanced liver fibrosis (0–27·9%) and cirrhosis (2·4–4·0%) than those in the general population. Validated non-invasive tests for liver fibrosis consistently detected otherwise unrecognised liver disease in the general population. Reliance on abnormal liver function tests will miss most patients with significant liver injury. New pathways to stratify chronic liver disease, with the use of non-invasive markers of liver fibrosis, are needed in the general population setting.

Introduction

Chronic liver disease has become an increasing health burden worldwide. In 2015, cirrhosis and chronic liver diseases accounted for 2% of deaths worldwide, with a relative increase of 10·3% from 2005.1 Mortality varies substantially in different regions of the world, with Mokdad and colleagues2 reporting liver cirrhosis as a health priority in central Asia, central Europe, eastern Europe, and Central America. Increasing mortality is attributable to viral hepatitis but also driven by the increasing prevalence of alcoholic liver disease and non-alcoholic fatty liver disease, which are now the most common causes of chronic liver disease in developed countries.3, 4, 5

Because of the increasing morbidity and mortality of chronic liver disease, there is a necessity for urgent action to be taken to prioritise the earlier identification and treatment of patients, particularly in the community setting.6, 7 Commonly used diagnostic tests have poor sensitivity and specificity, are completed on an ad-hoc basis, or are not appropriate to be used within a community setting, therefore limiting the opportunities for intervening at an earlier stage of the disease. These limitations result in nearly 50% of patients receiving their diagnosis of cirrhosis following an emergency admission to hospital with a decompensating liver event.8 Liver biochemistry panels, often referred to as liver function tests, are inappropriately relied upon in the community setting to identify patients with asymptomatic chronic liver disease.9, 10, 11 Fracanzani and colleagues12 showed that 59% of patients with a histological diagnosis of non-alcoholic fatty liver disease had a normal serum concentration of alanine aminotransferase (ALT) and would not have been identified by current diagnostic algorithms.

As of 2016, an evidenced-based risk stratification pathway does not exist in a community setting to screen the general or a targeted population who are at risk of chronic liver disease. One of the barriers has been the absence of a robust and reproducible screening tool. Non-invasive tests for liver fibrosis represent such a tool, and their use in hospital practice has been supported by several international organisations, including the recent guidelines by the European Association for the Study of the Liver (EASL).13 However, most evidence has been derived and validated from populations in secondary care,14, 15, 16 and therefore extrapolation of these tests to a cohort in a community setting might not be valid because of a reliance on abnormal liver function tests instigating referral for specialist advice, a different prevalence of disease, and spectrum bias (which describes the effect of a change of patient case mix might have on the performance of a test).

To facilitate the emergence of strategies that aim to stratify patients at risk in a general population or community setting, we have systematically reviewed the available evidence. From this evidence, the prevalence of undiagnosed chronic liver disease can be estimated, the inadequacy of current referral pathways can be highlighted, and an optimal risk stratification strategy potentially proposed. Because the commonest causes of chronic liver disease are alcoholic liver disease and non-alcoholic fatty liver disease, we have focused on the non-invasive tests that have been used to stratify patients at risk of these causes.

The primary aim of this systematic review was to assess the proportion of the studied populations found to have clinically significant liver disease as defined by the non-invasive tests used in the individual studies. The secondary aims were: to identify the proportion of patients with liver fibrosis or cirrhosis, as defined by the non-invasive test, who had normal ALT results; to assess the difference in the proportion of patients identified as having liver disease with use of non-invasive tests between unselected or targeted populations within a community setting; and to determine the patient variables that are important in identifying patients with liver fibrosis.

Section snippets

Search strategy

This systematic review was done in accordance with the Cochrane Handbook for Systematic Reviews of Interventions17 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.18

Two reviewers (RH and DJH) defined the key MeSH headings and free text search terms relevant to the participants involved in the studies, the two causes of chronic liver disease, the community setting, and the non-invasive tests used to stratify for liver fibrosis. Subsequently, a search

Findings

Our systematic search of the databases identified 813 citations. An additional seven studies were identified from the grey literature. After screening of the titles and abstracts, 779 studies were excluded. The full text of 41 studies was assessed against the inclusion and exclusion criteria, resulting in a further 22 studies being excluded from the final analysis. 19 studies (17 full journal articles and two abstracts) were included in this systematic review. The overall results of the search

Discussion

We have shown in this systematic review that several non-invasive tests have the ability to stratify for the severity of liver disease within a community setting. Moreover, when compared with the uptake of other screening programmes, the participation of those invited suggests that as screening tests for the use in the community, non-invasive tests are more acceptable to patients. The prevalence estimates of cirrhosis (0·1–1·7%) are greater than previously reported (0·07–0·13%),41, 42

References (50)

  • P Nahon et al.

    Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease

    J Hepatol

    (2008)
  • KM Fleming et al.

    Incidence and prevalence of cirrhosis in the United Kingdom, 1992–2001: a general population-based study

    J Hepatol

    (2008)
  • D Roulot et al.

    Liver stiffness values in apparently healthy subjects: influence of gender and metabolic syndrome

    J Hepatol

    (2008)
  • F Conti et al.

    Transient elastography in healthy subjects and factors influencing liver stiffness in non-alcoholic fatty liver disease: an Italian community-based population study

    Dig Liver Dis

    (2016)
  • F Imbert-Bismut et al.

    Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study

    Lancet

    (2001)
  • V Ratziu et al.

    Sampling variability of liver biopsy in nonalcoholic fatty liver disease

    Gastroenterology

    (2005)
  • J Boursier et al.

    Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by Fibroscan in non-alcoholic fatty liver disease

    J Hepatol

    (2016)
  • Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015

    Lancet

    (2016)
  • AA Mokdad et al.

    Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis

    BMC Med

    (2014)
  • N Bhala et al.

    How to tackle rising rates of liver disease in the UK

    BMJ

    (2013)
  • DJ McLernon et al.

    Health outcomes following liver function testing in primary care: a retrospective cohort study

    Fam Pract

    (2009)
  • AL Fracanzani et al.

    Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes

    Hepatology

    (2008)
  • EASL-ALEH clinical practice guidelines: non-invasive tests for evaluation of liver disease severity and prognosis

    J Hepatol

    (2015)
  • M Friedrich-Rust et al.

    Performance of transient elastography for the staging of liver fibrosis: a meta-analysis

    Gastroenterology

    (2008)
  • P Angulo et al.

    The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD

    Hepatology

    (2007)
  • Cited by (0)

    *

    Joint first authors

    Joint senior authors

    View full text