الفهرس 
Introduction
The biology of liver fibrosisOnly 14 pages are availabe for public view
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Abstract
Hepatitis C constitutes a significant problem particularly in Egypt as one of the highest prevalence countries. As morbidity and mortality in chronic HCV patients depend on the rate of development of liver fibrosis, percutaneous liver biopsy has been set as a gold standard both for assessment of the stage of fibrosis and allocation into antiviral therapy. Despite the increasing interest and numerous publications on the use of blood markers as non-invasive tests of fibrosis (including indirect markers that reflect a change in liver function, and direct markers that reflect extracellular matrix remodeling), there are no conclusive data supporting the use of a particular test, with no available formulae for some tests (patented and paid). This study was designed to investigate the discriminant value of various direct and indirect tests of fibrosis in HCV patients aiming at identifying the most appropriate test(s) for possible application in our initial patients’ assessment schemes. The study included 78 chronic HCV adult male patients attending the Viral Hepatitis Clinic, Assiut University Hospital for initial assessment for antiviral therapy (including clinical, abdominal ultrasonographic, and laboratory). Exclusion criteria included presence of hepatitis B co-infection, clinical or ultrasound evidence of cirrhosis or hepatocellular failure, chronic illnesses (cardiac, renal, or systemic), or any contraindications of liver biopsy. According to their liver biopsy METAVIR scoring, the distribution of fibrosis stages was: F0 in 12 (15.4%), F1 in 32 (41%), F2 in 18 (23.1%), F3 in 9 (11.5%), and F4 in 7 (9%) patients; significant fibrosis (F≥2) in 43.6% and advanced fibrosis (F≥3) in 20.5%, with a highly significant positive correlation between fibrosis stages and activity grades (p= 0.000; r=0.87). After statistical exclusion of fibrosis non discriminating markers at the level of ANOVA testing (including prothrombin time, prothrombin concentration, INR, cholesterol), the final stepwise performance analysis was done for 8 markers (5 routine indirect markers; platelet count, AST, ALT, GGT, albumin, and 3 direct markers; hyaluronic acid, TIMP-1, and alpha-2 macroglobulin), and 13 panels (AAR, APRI, GAPRI, HAPRI, FIB-4, Forns index, Lok score, Hepacore, Pohl score, AP index, CDS, Fibrometer, and SHASTA index). On step1 sequential analysis for discrimination of adjacent stages of fibrosis (between F0 and F1, F1 and F2, etc.), none of the blood markers (indirect or direct) show any discriminant value. On step 2 analysis for discrimination of significant fibrosis (F≥2), the best performance was shown by hyaluronic acid at a cut-off value of >100 ng/ml (AUROC 0.74, sensitivity 52.9%, specificity 95.4%, PPV 90%, +LR 11.6, accuracy 76.9%, and DO 23.8) and its derived panel HAPRI at a cut-off value of >111 (AUROC 0.75, sensitivity 52.9%, specificity 97.7%, PPV 94.7%, +LR 23.3, accuracy 82%, and DO 48.5). On step 3 analysis for discrimination of advanced fibrosis (F≥3), the best performance was shown by the platelet count at a cut-off point of <150 x109/L (AUROC 0.76, sensitivity 56.2%, specificity 95.2%, PPV 75%, +LR 11.6, accuracy 78.2%, and DO 25.3) and its derived panel Forns index at a cut-off value of >6.9 (AUROC 0.70, sensitivity 43.7%, specificity 96.8%, PPV 77.8%, +LR 13.6, accuracy 85.9%, and DO 23.4). Among the three direct markers tested in this study, hyaluronic acid showed the best performance in comparison to TIMP-1 and alpha-2 macroglobulin. Interestingly, alpha-2 macroglobulin was the only direct marker that showed early rise before any detectable histopathological fibrosis, with a statistically significantly difference between F0 and controls (3.6±1.1vs.1.8±0.6; p <0.0001) maintaining a high statistical difference between controls and all stages of fibrosis. Despite showing good correlation with fibrosis, several published panels of fibrosis showed either poor performance for discrimination of significant or advanced fibrosis (F≥2 or F≥3) as the hepascore, failure of discrimination as the AAR (AST/ALT ratio), or non valid calculations as the fibrometer and SHASTA index (giving negative values or values >1 in some patients, although originally designed to give 0-1 values).
In conclusion:
● None of the blood markers, tested in this study (indirect or direct), could discriminate the close adjacent stages of liver fibrosis (between F0 and F1, F1 and F2, etc.) or perform in concordance with the hitopathologic METAVIR liver biopsy system.
● The direct marker hyaluronic acid (and its HAPRI derived panel) provided the best performance characteristics for discrimination of significant fibrosis (F≥2) at a cut-off of 100 ng/ml (AUROC 0.74, sensitivity 52.9%, specificity 95.4%, PPV 90%, +LR 11.6, accuracy 76.9%, and DO 23.8).
● The indirect marker platelet count (and its Forns derived panels) provided the best performance characteristics for discrimination of advanced fibrosis (F≥3) at a cut-off point of <150x109/L (AUROC 0.76, sensitivity 56.2%, specificity 95.2%, PPV 75%, +LR 11.6, accuracy 78.2%, and DO 25.3).
● Of the 3 direct markers components of the fibrospect pateneted paid test, hyaluronic acid showed the best performance characteristics, in comparison to TIMP-1 and alpha-2 macroglobulin, and thus could be used singly in assessment of fibrosis to reduce the costs.
● Many of the panels available in the literature showed either poor performance for discrimination of significant or advanced fibrosis as the hepascore, failure of discrimination as the AAR (AST/ALT ratio), invalid calculations as the fibrometer and SHASTA index, or invalid cut-off point as the CDS, particularly in the context of a patient population having a high prevalence of normal AST, ALT, GGT and albumin values.
● With the available data in this study, it would be appropriate to follow the following simple sequential approach for the overall initial discrimination of fibrosis (when the strategy is to avoid or at least reduce liver biopsy for improving the cost-effectiveness and risk benefit in management of chronic C): if patient’s platelet count is <150x109/L, then at least significant fibrosis is present (F≥2) reducing biopsy in a third of patients; if >150, then hyaluronic acid measurement can be done, if the latter is >100 ng/ml, then at least significant fibrosis is present (F≥2) reducing biopsy in a half of patients; if <100 then liver biopsy would be the remaining choice for identifying the stage of fibrosis. This approach is simple, not necessitating complex calculations and logarithmic values, based on a routinely performed indirect marker (platelet count) in its first step, adding only one direct marker (hyaluronic acid) in its second step for the purpose of limiting the added cots as much as possible.
● Hyaluronic acid could be a possible candidate for follow up measurements for assessment of progression of fibrosis and response to therapy.
● In view of its early rise in chronic HCV patients, even before the detection of histopathologic fibrosis (at F0), alpha-2 macroglobulin changing levels may be used as a predictor of progression to fibrosis. Future cohort studies can examine whether patients having high initial levels would be fast fibrosers