Biological markers of liver fibrosis and activity as non-invasive alternatives to liver biopsy in patients with chronic hepatitis C and associated mixed cryoglobulinemia vasculitis

doi:10.1016/j.clinbiochem.2006.04.019

Clinical Biochemistry

Volume 39, Issue 7, July 2006, Pages 715-721

https://doi.org/10.1016/j.clinbiochem.2006.04.019 Get rights and content

Abstract

Objective and methods:

We assessed the reliability of non-invasive biological scoring indexes (Fibrotest–Actitest [FT–AT], Forns, APRI, age–platelet, platelet, hyaluronic acid) as non-invasive alternatives to liver biopsy (LB) in 138 HCV-infected patients.

Results:

Thirty-six of 138 (26%) patients had systemic vasculitis, 27% significant serum inflammation, 47% fibrosis (F2F3F4) on LB. The diagnostic value of FT (F2F3F4 vs. F0F1) was assessed by an AUC of 0.83, without difference regarding to systemic vasculitis or serum inflammation. A discordance between FT–AT and the Metavir scoring indexes, present in 29% of patients, was associated with serum hemolysis and male but not with systemic vasculitis or serum inflammation. The other non-invasive biological tests were not influenced by serum inflammation or systemic vasculitis but were less reliable than FT (P ≤ 0.05).

Conclusion:

The FT–AT is a reliable non-invasive biochemical alternative to LB in HCV-infected patients with systemic vasculitis and is more reliable than other non-invasive biological indexes.

Introduction

Hepatitis C virus (HCV) infection is a worldwide disease that affects more than 170 million people, 80% of whom will develop chronic hepatitis which may lead to cirrhosis and hepatocarcinoma [1]. For evaluation of the severity of the liver disease and decision-making for treatment, liver biopsy, to date, remains the golden standard [2], [3]. Nevertheless, this examination is burdened by inter-examiner variability and high sampling error [4], [5], [6], [7]. In addition, liver biopsy is complicated by several side effects, such as pain, under-capsular or peritoneal hemorrhage and death, though fortunately rare [8].

Therefore, studies investigating non-invasive alternatives to liver biopsy using biochemical markers (Fibrotest–Actitest, FT–AT) have been performed. In 2001, Imbert-Bismuth et al. [9] published a scoring algorithm using a panel of five biochemical markers: α₂-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl-transpeptidase (GGT) and total bilirubin for liver fibrosis (Fibrotest) plus alanine aminotransferase (ALT) for liver inflammatory activity (Actitest). This non-invasive test allows, with great accuracy, the distinction between non-clinically significant (F0F1 on the Metavir scale) and clinically significant fibrosis (F2F3F4) and between minor (A0A1) and relevant (A2A3) necroinflammatory activity. Other studies have confirmed these results among HCV-infected [10], [11], [12], [13], [14], HBV-infected [15] and HIV-HCV co-infected patients [16]. Other biological scoring indexes for the appraisal of HCV-related liver fibrosis have been developed with variable accuracy, including the APRI [aspartate aminotransferase (AST) to Platelet Ratio Index] scoring index [17], the serum hyaluronic acid level [18], [19], [20], the platelet and age–platelet scoring indexes [21] and the Forns index [22].

The HCV infection is also associated with the occurrence of numerous extra-hepatic manifestations, among which the most severe is mixed cryoglobulinemia systemic vasculitis [23]. Even though HCV-associated systemic vasculitis is by itself an indication for antiviral therapy, whatever the liver disease severity, it remains interesting to know the liver fibrosis stage. The liver fibrosis stage is known to influence the rate of virological response, and it is crucial for the follow-up as cirrhosis can be complicated by liver cancer. Two important serum parameters included in FT–AT, haptoglobin [24] and α₂-macroglobulin, may be influenced by the presence of serum inflammation markers, mostly in cases of HCV-associated systemic vasculitis.

The aim of this study was to assess the reliability of FT–AT in predicting liver fibrosis and activity among HCV-infected patients with systemic vasculitis and those with serum inflammation. In addition, other biochemical non-invasive liver fibrosis indexes (i.e. APRI, Forns, age–platelet, platelet and hyaluronic acid) in such HCV-infected populations were examined.

Section snippets

Patients

One hundred and thirty-eight consecutive HCV-infected patients (positive HCV RNA) who had been followed in the same department of Internal Medicine were included. HCV-induced systemic vasculitis was defined by the presence of serum mixed cryoglobulin, associated with asthenia, skin purpura, arthralgia or arthritis, peripheral neuropathy and in some cases membranoproliferative glomerulonephritis [25]. The peripheral neuropathy was always confirmed by electromyogram and in some cases by nerve

Study population

Our study population included 138 HCV-infected patients (positive HCV RNA) with a mean age of 57.9 ± 15.6 years and a sex ratio of 1. Seventy-two out of 138 (52%) patients had serum cryoglobulin, 37 (27%) had serum inflammation and 11 (8%) serum hemolysis (Table 1). The characteristics of HCV-infected patients with serum inflammation markers are reported in Table 2. HCV-associated systemic vasculitis was present in 26% (36/138) of patients, and main features are reported in Table 3.

All included

Discussion

Several non-invasive scoring indexes using biological markers for the appraisal of the liver fibrosis in HCV-infected patients have recently been developed. Among these, FT–AT has previously demonstrated high accuracy in distinguishing significant from non-significant liver fibrosis and necroinflammatory activity [9], [11], [12], [13]. The question remains, however, concerning the impact of serum inflammation markers, some of which are included in FT–AT scores (such as haptoglobin and α₂

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FibroTest (FT) is a biomarker of liver fibrosis initially validated in patients with chronic hepatitis C (CHC) and subsequently assessed in other frequent liver diseases, including chronic hepatitis B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). The primary aim of the present study was to update a previous meta-analysis of FT diagnostic value, and to summarize its advantages and limitations. The secondary aim was to provide an overview of the prognostic value of FT in CHC, CHB and ALD. For diagnostic value, the main endpoint was the FT area under the ROC curves (AUROCs) for the diagnosis of bridging fibrosis (F2/F3/F4 vs F0/F1), standardized for the spectrum of fibrosis. Sensitivity analysis integrated the non-standardized observed AUROCs, the independency of authors, size (length) of biopsy, prospective design, correctness of procedures, co-morbidities, and timelag between biopsy and serum sampling. For prognostic value, the main endpoint was the FT AUROC for the prognostic value of liver complications or death related to liver disease.
A total of 38 diagnostic studies were included, which pooled 7985 subjects who had undergone both FT and biopsy (4600 HCV, 1580 HBV, 267 NAFLD, 524 ALD and 1014 mixed). The mean standardized AUROC was 0.84 (95% CI, 0.83-0.86), with no differences in terms of causes of liver disease: HCV 0.84 (0.82-0.87); HBV 0.81 (0.78-0.83); NAFLD 0.84 (0.76-0.92); ALD 0.87 (0.82-0.92); and mixed 0.85 (0.81-0.89). Three prognostic studies were also included. FT was found to have higher or similar prognostic value compared with biopsy in patients with CHC, CHB or ALD.
FibroTest is an effective alternative to biopsy in patients with chronic hepatitis C or B, ALD or NAFLD. Indeed, the prognostic performance of FibroTest was at least as accurate as that of biopsy in patients with chronic hepatitis C or B, or ALD.
Le FibroTest (FT) est un marqueur biologique de fibrose hépatique initialement validé au cours de l’hépatite C puis au cours de l’hépatite B, de la maladie alcoolique du foie et de la stéatopathie métabolique.
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Un total de 38 études diagnostiques ont été évaluées permettant l’inclusion de 7985 sujets avec à la fois FT et biopsie (4600 hépatites C, 1580 hépatites B, 267 stéatopathies métaboliques, 524 maladies alcooliques du foie, et 1014 étiologies multiples). L’AUROC moyenne standardisée était de 0,84 (intervalle de confiance à 95%, 0,83-0,86), sans différence entre les différentes étiologies: hépatite C 0,84 (0,82-0,87), hépatite B 0,81 (0,78-0,83), stéatopathie métabolique 0,84 (0,76-0,92), maladie alcoolique du foie 0,87 (0,82-0,92), étiologies multiples 0,85 (0,81-0,89). Trois études pronostiques ont été incluses. Le FT avait une valeur pronostique meilleure ou identique à celle de la biopsie chez les malades avec hépatite C, hépatite B et maladie alcoolique du foie.
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Citation Excerpt :
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Biological markers of liver fibrosis and activity as non-invasive alternatives to liver biopsy in patients with chronic hepatitis C and associated mixed cryoglobulinemia vasculitis

Abstract

Objective and methods:

Results:

Conclusion:

Introduction

Section snippets

Patients

Study population

Discussion

Lancet

Hepatology

Am J Gastroenterol

J Hepatol

Hepatology

Lancet

Hepatology

Am J Gastroenterol

J Hepatol

Hepatology

Hepatology

Am J Med

Hepatology

Rev Med Intern

Role of liver biopsy in management of chronic hepatitis C: a systematic review

Hepatology

Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group

Hepatology

Appropriateness of liver biopsy

Can J Gastroenterol