Practical diagnosis of cirrhosis in non-alcoholic fatty liver disease using currently available non-invasive fibrosis tests

Abstract

Unlike for advanced liver fibrosis, the practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD remain not well defined. Here, we report the derivation and validation of a stepwise diagnostic algorithm in 1568 patients with NAFLD and liver biopsy coming from four independent cohorts. The study algorithm, using first the elastography-based tests Agile3+ and Agile4 and then the specialized blood tests FibroMeter^V3G and CirrhoMeter^V3G, provides stratification in four groups, the last of which is enriched in cirrhosis (71% prevalence in the validation set). A risk prediction chart is also derived to allow estimation of the individual probability of cirrhosis. The predicted risk shows excellent calibration in the validation set, and mean difference with perfect prediction is only -2.9%. These tools improve the personalized non-invasive diagnosis of cirrhosis in NAFLD.

Fig. 1. Agile3 + /4 and FibroMeter^V3G/CirrhoMeter^V3G (FM/CM) classifications in the derivation set.

a Fibrosis stages as a function of subgroups defined by the F34 thresholds of Agile3+ and F4 thresholds of Agile4. b Fibrosis stage as a function of the four groups of the Agile3 + /4 classification. The four groups of the Agile3 + /4 classification result from the crossing of Agile3+ and Agile4 results as follows: (i) Agile3 + < 0.451; (ii) Agile3+ between 0.451-0.678; (iii) Agile 3 + ≥ 0.679 with Agile4 ≤ 0.474; and (iv) Agile3 + ≥0.679 with Agile4 > 0.474. c Fibrosis stages as a function of subgroups defined by the F34 thresholds of FibroMeter^V3G (FMV3G) and F4 thresholds of CirrhoMeter^V3G (CMV3G). d Fibrosis stage as a function of the four groups of the FM/CM classification. The four groups of the FM/CM classification result from the crossing of FMV3G and CMV3G results as follows: (i) FMV3G < 0.31; (ii) FMV3G between 0.31-0.76; (iii) FMV3G > 0.76 with CMV3G ≤ 0.40; and (iv) FMV3G > 0.76 with CMV3G > 0.40. Source data are provided as a Source Data file.

Fig. 2. Agile3+/4 and FibroMeter^V3G/CirrhoMeter^V3G (FM/CM) classifications in the validation set.

Fibrosis stages as a function of the four groups of the Agile3+/4 classification (a) and the four groups of the FM/CM classification (b) in the validation set. Source data are provided as a Source Data file.

Fig. 3. Study algorithm.

a Algorithm description. The sequence of use of non-invasive tests is the same than recently recommended by the European Association for the Study of the Liver: first VCTE and second specialized blood test. Specialized blood testing is performed after VCTE only if Agile3 + ≥0.451 to confirm the diagnosis in case of suspicion of advanced fibrosis/cirrhosis. The study algorithm stratifies patients in four diagnostic groups: F0-2 (no/mild fibrosis), Biopsy (i.e. undetermined diagnosis with liver biopsy required), F34 (advanced fibrosis), and F4 (cirrhosis). b Fibrosis stages as a function of the four groups defined by the study algorithm in the derivation set. c Fibrosis stages as a function of the four groups defined by the study algorithm in the validation set. CMV3G: CirrhoMeter^V3G; FMV3G: FibroMeter^V3G; FM/CM classification: FibroMeter^V3G/CirrhoMeter^V3G classification; VCTE: vibration controlled transient elastography. Source data are provided as a Source Data file.

Fig. 4. Risk prediction charts.

Risk charts for the prediction of cirrhosis (a) and advanced fibrosis (b). When Agile3 + >0.678, move to the Agile4 scale; when FibroMeter^V3G > 0.76, move to the CirrhoMeter^V3G scale.

Fig. 5. Calibration of the predicted risk by the study risk charts in the validation set.

a Calibration plot of the predicted risk of cirrhosis by the risk chart presented in Fig. 4a. The blue dotted line represents perfect prediction (predicted risk of cirrhosis = observed prevalence of cirrhosis). The black solid line represents the observed prevalence of cirrhosis as a function of the predicted risk by the cirrhosis risk chart. b Calibration plot of the predicted risk of advanced fibrosis by the risk chart presented in Fig. 4b. c Patients were spitted into the 7 groups delineated by the cirrhosis risk chart, and the observed prevalence of cirrhosis is presented for each of these 7 groups. d Patients were spitted into the 10 groups delineated by the advanced fibrosis risk chart, and the observed prevalence of advanced fibrosis is presented for each of these 10 groups. Source data are provided as a Source Data file.