Comparison of blood tests for liver fibrosis specific or not to NAFLD

doi:10.1016/j.jhep.2008.07.035

Journal of Hepatology

Volume 50, Issue 1, January 2009, Pages 165-173

https://doi.org/10.1016/j.jhep.2008.07.035 Get rights and content

Background/Aims

To compare blood tests of liver fibrosis specific for NAFLD: the FibroMeter NAFLD and the NAFLD fibrosis score (NFSA) with a non-specific test, APRI.

Methods

Two hundred and thirty-five NAFLD patients with liver Metavir staging and blood markers from two independent centres were randomly assigned to a test (n = 121) or a validation population (n = 114).

Results

The highest accuracy – 91% – for significant fibrosis was obtained with the FibroMeter whose (i) AUROC (0.943) was significantly higher than those of NFSA (0.884, p = 0.008) and APRI (0.866, p < 10⁻³; p = 0.309 vs NFSA) in the whole population, and (ii) misclassification rate (9%) was significantly lower than those of NFSA (14%, p = 0.04) and APRI (16%, p = 0.002) and did not vary according to centre (14 vs 7%, p = 0.07), unlike those of NFSA (25 vs 9%, p = 0.001) and APRI (29 vs 11%, p < 10⁻³). By using thresholds of 90% predictive values, liver biopsy could have been avoided in most patients: FibroMeter: 97.4% vs NFSA: 86.8% (p < 10⁻³) and APRI: 80.0% (p < 10⁻³). A new classification provided three reliable diagnosis intervals: F0/1, F0/1/2, F2/3/4 with 91.4% accuracy for FibroMeter, avoiding biopsy in all patients.

Conclusions

FibroMeter NAFLD had high performance and provided reliable diagnosis for significant fibrosis, significantly outperforming NFSA and APRI.

Introduction

Several blood tests have been proposed to diagnose liver fibrosis [1]. Some tests are simple, like the aspartate aminotransferase to platelet ratio index (APRI) [2]. Others are more complex, constructed as algorithms (regression score) like the FibroMeter [3]. Most of them have been developed in chronic hepatitis C or in miscellaneous causes [4]. However, in a previous study, we observed that the cause of CLD was an independent predictor of fibrosis and thus it was preferable to develop specific tests for alcoholic or viral CLD to improve accuracy [3].

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized condition in several countries [5] that can lead to cirrhosis or liver cancer. Some simple variables [6], [7], [8], fibrosis blood markers [9], [10] and other tests [4], [11] have been evaluated in NAFLD but these studies are rare or performed in only a few patients [4] and no blood test had been specifically designed for this prevalent disease until recently. We thus designed a simple algorithm in a previous study [12]. More recently, the NAFLD fibrosis score of Angulo et al. (NFSA) has been implemented in a large cohort with excellent performance [13]. However, this test was designed for severe fibrosis whereas most tests have been designed for significant fibrosis and usually for chronic hepatitis C. Some of the latter have been validated in NAFLD [11], [14].

The main aim of the present study was to implement a blood test for significant liver fibrosis specifically designed for NAFLD with high diagnostic performance. The secondary aims were to compare this test to the only other specific test, the NFSA, and to a non-specific reference test, i.e. APRI, the simplest test. Other aims were to evaluate the factors influencing this diagnostic performance, such as diagnostic targets and fibrosis stages, as well as reproducibility.

Section snippets

Centres

Two tertiary centres, Angers and Rennes, provided, respectively, 73 and 162 patients, for a total of 235. The centres were independent for study design, patient recruitment, blood measurements, and liver interpretation. Due to differences in size and patient characteristics, especially fibrosis stages, between the two centres (Table 1), all patients were pooled then randomly divided into test (121 patients) and validation (114 patients) populations with stratification based on Metavir fibrosis

General characteristics

Mean age of patients was 51 years, 75% were male, mean BMI was 29 and 27.7% had significant fibrosis. Type II diabetes was present in 24.1% and under drug treatment in 13.1% of the patients. Present or past consumption of alcohol and/or tobacco was noted in 67.5% and 26.8% of patients, respectively. Alcohol intake (median, interquartiles) was 13.5 (4.8–23.4) g/d for 25.8 (16.0–31.1) years. Obesity (BMI ⩾ 30) was present in 31.0% of patients. Non-alcoholic steatohepatitis (NASH) was diagnosed on

Methods

Metavir staging, initially developed in chronic hepatitis C, was used in the present study. We have previously demonstrated that the Metavir system correctly staged fibrosis in alcoholic steatohepatitis [28]; it was also a histological reference in NAFLD [12]. We chose significant fibrosis (F ⩾ 2) as the main diagnostic target for the following reasons. First and importantly, this target is thought to be clinically significant in several circumstances, not only in viral hepatitis but also in

Funding

A grant was provided by the French national agency for valorisation “OSEO-ANVAR”. The sponsor had no role in study design, in data collection, analysis, and interpretation, in the writing of the report or in the decision to submit the paper for publication.

Acknowledgement

We express our thanks to Anne Laure Tropet, Dermot O’Toole, Kevin Erwin, and Gwénaëlle Soulard for their contributions.

References (45)

C.T. Wai et al.
A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C
Hepatology
(2003)
W.M. Rosenberg et al.
Serum markers detect the presence of liver fibrosis: a cohort study
Gastroenterology
(2004)
V. Ratziu et al.
Liver fibrosis in overweight patients
Gastroenterology
(2000)
J.B. Dixon et al.
Non-alcoholic fatty liver disease: predictors of non-alcoholic steatohepatitis and liver fibrosis in the severely obese
Gastroenterology
(2001)
E.M. Brunt
Alcoholic and non-alcoholic steatohepatitis
Clin Liver Dis
(2002)
A.S. Glas et al.
The diagnostic odds ratio: a single indicator of test performance
J Clin Epidemiol
(2003)
J. Parkes et al.
Performance of serum marker panels for liver fibrosis in chronic hepatitis C
J Hepatol
(2006)
P. Halfon et al.
Comparison of test performance profile for blood tests of liver fibrosis in chronic hepatitis C
J Hepatol
(2007)
C. Pilette et al.
Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores Comparison with serum markers
J Hepatol
(1998)
P. Bedossa et al.
Sampling variability of liver fibrosis in chronic hepatitis C
Hepatology
(2003)

A. Regev et al.

Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection

Am J Gastroenterol

(2002)

G. Colloredo et al.

Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease

J Hepatol

(2003)

V. Ratziu et al.

Sampling variability of liver biopsy in non-alcoholic fatty liver disease

Gastroenterology

(2005)

L.A. Adams et al.

Role of liver biopsy and serum markers of liver fibrosis in non-alcoholic fatty liver disease

Clin Liver Dis

(2007)

P. Cales et al.

Reproducibility of blood tests of liver fibrosis in clinical practice

Clin Biochem

(2008)

G. Sebastiani et al.

Non-invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy

World J Gastroenterol

(2006)

P. Cales et al.

A novel panel of blood markers to assess the degree of liver fibrosis

Hepatology

(2005)

J.M. Clark

The epidemiology of non-alcoholic fatty liver disease in adults

J Clin Gastroenterol

(2006)

P. Angulo et al.

Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis

Hepatology

(1999)

G. Musso et al.

Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with non-alcoholic steatohepatitis

Am J Gastroenterol

(2005)

I.H. Bahcecioglu et al.

Levels of serum hyaluronic acid, TNF-alpha and IL-8 in patients with non-alcoholic steatohepatitis

Hepatogastroenterology

(2005)

V. Ratziu et al.

Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease

BMC Gastroenterol

(2006)

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^☆: Paul Calès, Frédéric Oberti, Isabelle Hubert, and Françoise Lunel have mentioned potential conflict of interest due to stock ownership in a society (BioLiveScale) recently created under the auspices of University of Angers.

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Comparison of blood tests for liver fibrosis specific or not to NAFLD☆

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Centres

General characteristics

Methods

Funding

Acknowledgement

Hepatology

Gastroenterology

Gastroenterology

Gastroenterology

Clin Liver Dis

J Clin Epidemiol

J Hepatol

J Hepatol

J Hepatol

Hepatology

Am J Gastroenterol

J Hepatol

Gastroenterology

Clin Liver Dis

Clin Biochem

Non-invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy

World J Gastroenterol

A novel panel of blood markers to assess the degree of liver fibrosis

Hepatology

The epidemiology of non-alcoholic fatty liver disease in adults

J Clin Gastroenterol

Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis

Hepatology

Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with non-alcoholic steatohepatitis

Am J Gastroenterol

Levels of serum hyaluronic acid, TNF-alpha and IL-8 in patients with non-alcoholic steatohepatitis

Hepatogastroenterology

Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease

BMC Gastroenterol