Marie Christine Rousselet

Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis

BACKGROUND/AIMS Evaluation of the degree of hepatic fibrosis is especially important in patients with chronic liver disease. Our aim was to study the diagnostic accuracy of abdominal ultrasonography for cirrhosis or fibrosis. METHODS Twenty-three clinical (n=12) and Doppler ultrasonic (n=11) variables were recorded in 243 patients with chronic (alcoholic and viral) liver disease under conditions close to those of clinical practice. Fibrosis was classified into six grades by two pathologists. Diagnostic accuracy was evaluated by discriminant analysis, first globally using all variables, then by stepwise analysis. RESULTS A) Diagnosis of cirrhosis: 1) whole group (n=243): diagnostic accuracy was globally 84%, and 84% with two variables: spleen length, portal velocity; 2) compensated chronic liver disease (n=191): diagnostic accuracy was globally 85%, and 82% with two variables: liver surface, liver length (right kidney); 3) alcoholic compensated chronic liver disease (n=109): diagnostic accuracy was globally 86%, and 88% with two variables: spleen length, liver length (middle clavicle); 4) viral compensated chronic liver disease (n= 83): diagnostic accuracy was globally 86% and 86% with one variable: liver surface. By subtracting the proportion of patients who could not be investigated due to anatomical limitations, the highest calculated univariate diagnostic accuracy decreased by 7%. B) Diagnosis of fibrosis: diagnostic accuracy was globally 84% for extensive fibrosis. CONCLUSIONS Cirrhosis can be correctly diagnosed in 82-88% of patients with chronic liver disease using a few ultrasonographic signs. However, the diagnostic accuracy of ultrasound is decreased by the anatomical limitations of this technique.

Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores: Comparison with serum markers

BACKGROUND/AIMS Liver fibrosis is mainly evaluated by qualitative histological examination. Although histological semi-quantitative scores and quantitative determination with image analysis are now possible, these methods have not been fully validated and compared. Therefore, we evaluated these two methods prospectively in 243 patients with chronic liver disease. METHODS The semi-quantitative fibrosis score was evaluated by two independent pathologists, using the Knodell fibrosis score and a 6-grade score derived from the Metavir score; the area of fibrosis was measured by image analysis. The serum levels of hyaluronate, N-terminal peptide of procollagen III, laminin, transforming growth factor-beta1, alpha2-macroglobulin, apolipoprotein A1, PGA score and prothrombin index were measured. RESULTS There was a good correlation between the semi-quantitative fibrosis score and the area of fibrosis (r=0.84, p<10(-4)). Using multiple regression analysis, the semi-quantitative score was predicted by the 8 serum markers with R2=0.69 (R2=0.59 for hyaluronate at the 1st step) while the area of fibrosis was predicted with R2=0.79 (R2=0.76 for hyaluronate at the 1st step), and the Knodell fibrosis score was predicted with R2=0.65 (R2=0.31 for hyaluronate at the 1st step). CONCLUSIONS The area of fibrosis, as determined by image analysis, and the semi-quantitative score are well correlated. However, for serum markers the correlation is higher with the area of fibrosis than with the semi-quantitative score. Other characteristics such as reproducibility, rapidity, simplicity, adaptability, and exhaustiveness also favor image analysis.

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

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.

Non-invasive diagnosis of esophageal varices in chronic liver diseases

BACKGROUND/AIMS The primary prevention of bleeding from esophageal varices is a major therapeutic issue requiring early screening of esophageal varices. Our aim was to study the diagnostic accuracy of non-endoscopic means for the diagnosis of esophageal varices. METHODS Sixty-three clinical, biochemical, endoscopic and Doppler ultrasound variables were prospectively recorded in 207 consecutive patients with chronic liver disease. Diagnostic accuracy was evaluated by discriminant analysis, first globally using all variables with diagnostic accuracy > or = 65% in univariate analysis, then by stepwise regression. RESULTS A) whole group (n=207), 1) diagnosis of esophageal varices: diagnostic accuracy was globally 81%, and 81% with 1 variable: irregular liver surface at ultrasound, 2) Diagnosis of large esophageal varices (grades 2+3): diagnostic accuracy was globally 80%, and 79% with 2 variables: prothrombin index, gamma-globulins. B) patients with cirrhosis (n=116), 1) diagnosis of esophageal varices: diagnostic accuracy was globally 71%, and 72% with 2 variables: platelet count, prothrombin index, 2) diagnosis of large esophageal varices (grades 2+3): diagnostic accuracy was globally 71%, and 72% with 3 variables: platelet count, prothrombin index, spider naevi. The ROC curve showed that the best threshold for the diagnostic accuracy of platelet count was 160 G/l providing a sensitivity of 80% and a specificity of 58%. Platelet count > or = 260 G/l has a negative predictive value > or = 91%. CONCLUSIONS Using a few non-endoscopic criteria, esophageal varices can be correctly diagnosed in 81% of patients with chronic liver disease and in 71% of patients with cirrhosis. These results show that the non-invasive screening of patients who are candidates for the primary prevention of variceal bleeding is possible, but should be improved before being used in a clinical setting.

The combination of a blood test and Fibroscan improves the non‐invasive diagnosis of liver fibrosis

Background and aims: Blood tests and liver stiffness evaluation (LSE) by ultrasonographic elastometry are accurate tools for diagnosing liver fibrosis. We evaluated whether their synchronous combination in new scores could improve the diagnostic accuracy and reduce liver biopsy requirement in algorithm.

Prothrombin index is an indirect marker of severe liver fibrosis

Objective The non-invasive diagnosis of liver fibrosis is based mainly on biochemical markers. The main aim was to validate whether the prothrombin index is an indirect marker of the severity of liver fibrosis. Patients and methods The predictive value of the prothrombin index for liver fibrosis was first assessed in 243 patients with chronic liver disease, then validated in 193 other patients with chronic liver disease. The reproducibility of measurement of the prothrombin index in different laboratories was evaluated in 82 other patients. Results In the first group, the prothrombin index was predicted accurately by serum hyaluronate (R2 = 0.67 at the first step by multiple regression). The relationship between the prothrombin index and the area of fibrosis was not influenced significantly by non-fibrotic pathological lesions. The prothrombin index began to decrease when the Metavir fibrosis score was 2 versus 3 for albumin. In the second group, the prothrombin index and the histological fibrosis score were well correlated (r =− 0.70, P < 10–4). Prothrombin index ⩽80% or ⩽70% diagnosed severe fibrosis or cirrhosis, respectively, and prothrombin index ⩾105% or ⩾100% excluded a diagnosis of severe fibrosis or cirrhosis, respectively, at the 95% probability level. The prothrombin indices measured in different laboratories were similar (78 ± 18%v. 78 ± 14%) and well correlated (r = 0.91, P < 10–4). Conclusions The prothrombin index was well correlated with pathological liver fibrosis score, had a high diagnostic accuracy for severe fibrosis or cirrhosis especially due to alcohol, and was not influenced by other pathological lesions. The prothrombin index was reproducible. Thus, the prothrombin index expressed as a percentage is an accurate, reproducible, inexpensive and easily available marker of severe liver fibrosis.

Diagnostic accuracy, reproducibility and robustness of fibrosis blood tests in chronic hepatitis C: A meta-analysis with individual data

OBJECTIVES To evaluate the diagnostic accuracy of liver fibrosis tests and its influencing factors in a meta-analysis with individual data. DESIGN AND METHODS Four independent centers provided four blood tests and Metavir staging from 825 patients with chronic hepatitis C. RESULTS FibroMeter AUROC (0.840) for significant fibrosis was superior to those of Fibrotest (0.803, p=0.049), APRI (0.789, p=0.001) and Hepascore (0.781, p<0.001). The misclassification rate was lower for FibroMeter (23%) than for Fibrotest and Hepascore (both 28%, p<0.001). The variation in the diagnostic cut-offs of tests among centers, reflecting the overall reproducibility, was: FibroMeter: 4.2%, APRI: 24.0%, Fibrotest: 24.2%, Hepascore: 35.0%. Accordingly, the proportion of patients diagnosed with significant fibrosis changed: FibroMeter: 0.8%, Hepascore: 2.4% (p=0.02 vs FibroMeter), Fibrotest: 5.8% (p<10(-3)), APRI: 18.2% (p<10(-3)). CONCLUSIONS This study on clinical applicability shows significant differences in diagnostic accuracy, inter-center reproducibility, and robustness of biomarkers to changes in population characteristics between blood tests.

Improved diagnostic accuracy of blood tests for severe fibrosis and cirrhosis in chronic hepatitis C.

Objective Blood tests are usually designed to identify significant fibrosis. We evaluated their diagnostic accuracy, and how to increase it, for the clinically important targets of severe fibrosis and cirrhosis. Methods The accuracy for severe fibrosis or cirrhosis of four blood tests was evaluated based on Metavir staging in 1056 patients with chronic hepatitis C recruited in five independent hospitals. Results Using original scores, an original diagnostic target (significant fibrosis) and best diagnostic cutoff, the correct classification rates in severe fibrosis and cirrhosis stages were, respectively: FibroMeter: 90.1, 100%, Fibrotest: 78.2, 95.1%, Hepascore: 73.8, 94.9%, aspartate aminotransferase to platelet ratio index (APRI): 71.4, 88.0% (P<0.003, P=0.004, respectively, between tests). The corresponding area under the receiver operating characteristics were FibroMeter: 0.885, 0.907, Fibrotest: 0.837, 0.882, Hepascore: 0.834, 0.896, APRI: 0.822, 0.841 (P<0.003, respectively). Observed 100% negative predictive values for severe fibrosis and cirrhosis were, respectively, FibroMeter: 15.4, 47.5%, Fibrotest: 3.6, 31.9%, Hepascore: 0.3, 24.6%, APRI: 1.4, 5.3% of patients (P<0.003, respectively, between tests). By calculating a specific test for cirrhosis, including the FibroMeter markers, the correct classification (93.0%) was significantly higher for the cirrhosis diagnosis compared with the original FibroMeter (90.9%, P=0.005). This specific test provided a 100% positive predictive value for cirrhosis diagnosis versus 88% for original FibroMeter. Conclusion Using the most accurate original test, cirrhosis can be excluded in 47.5% of patients and is correctly diagnosed, as significant fibrosis, in 100% of patients. A specific test for cirrhosis provides a significant gain in diagnostic accuracy to 93% and in positive predictive value to 100% compared with the original test.

A non-randomised dose-escalating phase II study of thalidomide for the treatment of patients with low-risk myelodysplastic syndromes : the Thal-SMD-2000 trial of the Groupe Français des Myélodysplasies

Patients (n = 47) with low‐risk myelodysplastic syndrome were treated with thalidomide [200 mg/d, increased by 200 mg/d/4 weeks up to week 16]. Responses were evaluated according to the International Working Group criteria at week 16 for 39 patients who received at least 8 weeks of treatment. Twenty‐three (59%) patients showed haematological improvement (HI): four major erythroid response (HI‐EM), 15 minor erythroid response, six major neutrophil response, two major platelet response. Side effects caused 22/39 to stop thalidomide before week 16. Nine of 23 responders continued thalidomide after week 16 [19% of trial patients] with sustained response in eight of nine. Six reached week 56, including the four HI‐EM patients [13% of trial patients]. Nineteen of 36 red blood cell transfusion‐dependent patients (53%) showed erythroid response, but only four became transfusion‐independent. Among the 23 responders, the median duration of response was 260 d (range 30–650). Responses were sustained in all patients except one, and were observed between week 4 and week 8 in 85% of patients, at doses ranging from 200 to 400 mg. Only two patients responded at 600 mg/d and none at 800 mg/d. No clinical characteristics of responding versus non‐responding patients were identified. The erythroid response rate was identical in all cytogenetic subgroups, including 5q31.1 deletions. Pretreatment vascular endothelial growth factor levels were lower in responders compared with non‐responders (P = 0·004). Microvessel density (MVD) increased and apoptosis decreased in four of six and in all six responders studied respectively whereas MVD and apoptosis were unchanged in three non‐responders.

Diagnosis of different liver fibrosis characteristics by blood tests in non-alcoholic fatty liver disease.

Aims: Our aim was to develop an accurate, non‐invasive, blood‐test‐based method for identifying the main characteristics of liver fibrosis in non‐alcoholic fatty liver disease (NAFLD).