EASL-ALEH 2015 Algorithm for the Use of Transient Elastography in Treatment-naive Patients With Hepatitis B

An Independent Validation

Jean Nana; Kristina Skaare; Jean Luc Bosson; Vincent Leroy; Tarik Asselah; Michael Adler; Nathalie Sturm; Jean-Pierre Zarski

Disclosures

J Viral Hepat. 2021;28(8):1169-1176. 

In This Article

Results

Patients' Characteristics

Among the 709 patients included, 95 patients were duplicates and only the first complete measure was retained. Among the 614 potentially eligible patients, 201 (32.7%) were not included mostly because their LSM was not available or because the time between LSM and liver biopsy exceeded 3 months (Figure 1). Four hundred and thirteen (413) consecutive patients met the inclusion criteria and were included in the analysis. METAVIR fibrosis stages were distributed as follows: F0: n = 80 (19.4%), F1: n = 181 (43.8%), F2: n = 96 (23.2%), F3: n = 30 (7.3%), F4: n = 26 (6.3%). Main demographic, laboratory and histological features of patients are summarized in Table 1. Seventy-five per cent of patients were male with a median age of 39 years. They were mainly HBeAg negative (81.8%) with HBV-DNA levels above 20 000 IU/ml in 54% of cases. ALT serum levels were elevated in 84% of patients. The median length of biopsy samples was 20 mm (16−27), with pathological examination showing significant fibrosis (F ≥ 2) and cirrhosis (F4) in 36.8% and 6.3%, respectively. One hundred and fifty-four (154) biopsies showed <11 portal tracts. One hundred and fifteen (115) biopsies had <9 portal tracts (27.8%). The accuracy of liver stiffness measurement for the diagnosis of significant fibrosis was comparable in the two groups (<10 vs ≥10 portal tracts) of our cohort (p = .11).

Figure 1.

Flow chart

Diagnostic Accuracy of Transient Elastography in the Whole Population

Results of TE according to fibrosis stages are given in Figure 2. The distribution of LSM differed significantly according to METAVIR stages in patients with significant fibrosis versus no or minimal fibrosis (p < .00001). LSM values were significantly different in patients with mild liver fibrosis (F = 1) depending on the level of activity (p < .0021). Overall diagnostic accuracy estimated by AUROC was 0.79 (0.75–0.84), 0.82 (0.76–0.88) and 0.92 (0.88–0.96) for F ≥ 2, F ≥ 3 and F4, respectively (Table 2). For the same diagnostic targets, optimal calculated cut-offs were 6.2, 8.3 and 10 kPa, respectively. Based on ROC curve, a cut-off at 20.5 kPa had a PPV at 78% and an NPV at 95% for the diagnosis of cirrhosis.

Figure 2.

Box plots of LSM according to fibrosis stage

Diagnostic Accuracy of TE in Subgroups According to ALT and HBV-DNA Serum Levels

EASL 2012 guidelines[20] stated that TE more than liver biopsy should be performed in patients with normal ALT and HBV-DNA serum levels below 20 000 UI/ml. In our study population, 40 patients belonged to this class. The prevalence of significant liver fibrosis was 23%. In this subgroup, the performance of TE estimated by AUROC was 0.82 (0.66–0.99). The optimal calculated cut-off of 6.1 kPa gave a NPV of 96% and a PPV of 44%, with a percentage of well-classified patients of 75%. According to EASL 2012 guidelines, the second group of patients to be evaluated by TE are those with ALT levels above 2 times ULN and serum HBV-DNA above 20,000 IU/ml. This group represented 118 patients in our study population. Significant liver fibrosis was present in 57% of patients in this subgroup, and extensive fibrosis (F ≥ 3) was present in 22% of patients. In this subgroup, AUROCs of TE were 0.82 (0.74–0.89) and 0.86 (0.78–0.93) for F ≥ 2 and F ≥ 3 diagnostic targets. Respective optimal cut-offs were 7.3 for F ≥ 2 and 10.5 kPa for F ≥ 3. According to these cut-offs, the percentages of well-classified patients were 79% for F ≥ 2, 86% for F ≥ 3 and 84% for F = 4 patients.

Diagnostic Accuracy of TE in Subgroups According to ALT Serum Levels (EASL 2015 Algorithm)

EASL 2015 guidelines[21] stated that TE should be performed and interpreted according to ALT serum levels without the need of HBV-DNA serum level, with two separated groups of patients: ALT<N, ALT>N but <5N. First population: ALT<N: in this group (n = 65), AUROCs of TE were 0.75 (0.62–0.88) and 0.85 (0.65–1) for F ≥ 2 and F = 4 diagnostic targets. Respective optimal cut-offs were 5.9 for F ≥ 2 and 6.7 kPa for F = 4. According to these cut-offs, the percentages of well-classified patients were 72% for F2 and 68% for F4 patients. Second population: ALT serum levels >ULN but ≤5 ULN, in our study population, 306 patients belonged to this class. AUROCs of TE were 0.79 (0.73–0.84), 0.84 (0.75–0.92) and 0.95 (0.91–0.98) for F ≥ 2, F ≥ 3 and F = 4 diagnostic targets. Respective optimal cut-offs were 6.2 for F ≥ 2, 8.3 for F ≥ 3 and 10.2 kPa for F = 4. According to these cut-offs, the percentages of well-classified patients were 73% for F ≥ 2, 82% for F ≥ 3 and 91% for F ≥ 4 patients (Table 3).

Prevalence of Fibrosis Stages According to ALT Serum Levels and LSM: Validation of EASL 2015 Guidelines

In this group of patients with normal ALT serum levels, the prevalence of significant lesions was, respectively, 9% (3/35), 38% (8/21) and 67% (6/9) when LSM was <6kPa, between 6 and 9 kPa or more than 9 kPa. Patients with elevated ALT serum levels but <5 times ULN values, the prevalence of significant fibrosis was, respectively, 15% (23/152), 52% (67/128) and 85% (22/26) when LSM was <6kPa, between 6 and 12 kPa or more than 12 kPa (Figure 3).

Figure 3.

Prevalence of fibrosis according to liver stiffness and ALT value. A: ALT<N; B: ALT>N but <5N

Significant Discrepancies (≥2 Points) Between Liver Histology and LSM

In the first group, (patients with normal ALT serum levels; n = 65), one patient with LSM < 6 kPa had significant fibrosis. He was F = 3 with a LSM of 4.7 kPa. Three patients with LSM > 9 KPa did not have severe fibrosis (2 were F = 1 and one F = 0).

In the second population (ALT>ULN but ≤5<ULN), 306 patients belonged to this class. Five patients with LSM < 6 kPa had significant fibrosis. They were all F = 3. In these patients, mean HBV-DNA serum level was 7 441 852 UI/mL (161,909, 1 400, 9152, 536,800, 36,500,000 UI/mL) and LSM was 4.1, 4.3, 4.8, 5.1 and 5.3 kPa. Four patients with LSM > 12 kPa did not have severe fibrosis (4 were F = 1).

Significant discrepancies between LSM and histological assessment were observed in 13 patients. Mean age (37 ± 3 years), sex (92% male) ALT serum level (44 ± 6 IU/L), HBV-DNA serum level (6.5 ± 6.4 logUI/L), quality criteria of TE especially number of measurements per patient for (10 ± 0 measures) and LSM success rate (96.7 ± 2), and mean length of LB(23.2 ± 1.7) were not significantly different between patients with and those without discrepancies.

Diagnostic Accuracy of Zeng Score in Our Cohort

In the EASL-ALEH 2015 guidelines, two other non-invasive fibrosis staging scores were mentioned especially addressing HBV-infected patients, the one by Zeng et al[22] and the other by Hui et al.[23] Data of our cohort allowed to calculate only the Zeng score on 119 patients. The optimal cut-off values were 15.68 for F ≥ 2 determined according to the Youden method. According to this cut-off, the percentage of well-classified patients were 72%. Overall diagnostic accuracy estimated by AUROC was 0.74 (0.65–0.84).

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