The Fibrosis-Cirrhosis Index ( FCI ) for Staging of Liver Fibrosis in Chronic Hepatitis C

Background and study aim : Chronic hepatitis C (CHC) is a major global health problem with its consequences of liver fibrosis and cirrhosis. Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment can help determine therapy. Several indices are available to predict cirrhosis. The fibrosis – cirrhosis index (FCI) was proposed  to be efficient for none invasive staging of liver fibrosis besides being simple and inexpensive. This study is designed to assess  the accuracy of the fibrosis-cirrhosis index (FCI) for non-invasive staging of liver fibrosis in patients with chronic hepatitis C compared to the liver biopsy findings. Patients and methods: This study was conducted on 150 chronic hepatitis C patients who attended the Hepatology, Gastroenterology and Infectious Diseases Department at Benha University Hospital and El Mansoura Health-Insurance Hospital. Another group of 30 healthy subjects (with negative hepatitis viral markers) represented the control group. Results: FCI was a relatively sensitive, specific and accurate marker of fibrosis. At a cutoff value of 0.19 it had a PPV of 82.5% for the diagnosis of advanced fibrosis. Conclusion: FCI is a simple index that integrates ALP, bilirubin, albumin and platelet count for staging fibrosis from absent up to cirrhosis.


INTRODUCTION
Chronic hepatitis C (CHC) is a major global health problem with its consequences of liver fibrosis and cirrhosis up to hepatocellular carcinoma [1].
In Egypt, Being a developing country, CHC represents a real medical and financial problem as it affects about 14.7 % of the Egyptian population making it one of the countries with highest prevalence worldwide [2].
Liver fibrosis is the main predictor of the progression of CHC, and its assessment can help determine therapy [3].
Liver biopsy is still considered the gold standard for staging fibrosis, however it is invasive, expensive and not suitable for all patients who may get severe side effects that may lead to death [4].There is a need for a simple, safe, noninvasive and inexpensive test to assess fibrosis and cirrhosis [5].
Several indices are available to predict cirrhosis but no method or score is available on exclusive basis to diagnose earlier fibrosis stages [6].
Several scoring systems like AST to ALT ratio (AAR), AST-Platelet ratio (APRI), Fibrotest (FT), Fibrosis Index (FI) and FIB-4 with different thresholds to predict presence or absence of fibrosis or cirrhosis in patients infected with HCV had been proposed.However, mild fibrosis (F0) to end stage cirrhosis cannot be predicted accurately using a single system [7].
The fibrosis-cirrhosis index (FCI) was proposed and comprised serum alkaline phosphatase (ALP), bilirubin, albumin and platelet count, where FCI =[(ALP × Bilirubin)/(Albumin × Platelet count)].It was supposed to be efficient for none invasive staging of liver fibrosis besides being simple and inexpensive [8].

PATIENTS AND METHODS
Study design: Cross-sectional study.

This study:
Was carried out on 150 patients with evidence of CHC (positive HCV-Ab and HCV-RNA-PCR with elevated ALT level for more than 6 months).They were 94 males (62.7%) and 56 females (37.3%), and their ages ranged between 18 and 60 years.
All cases were selected from the department of Hepatology, Gastroenterology and Infectious Diseases, Benha University Hospitals, and Mansoura Health Insurance Hospital, within the period between October 2013 to October 2014.
The criteria for exclusion were; any contraindication to percutaneous liver biopsy, hepatitis with causes other than HCV, age under 18 years, severe systemic illness and pregnancy.
Patients were sex and age matched with 30 healthy subjects who were volunteer blood donors visiting Benha University Hospitals-blood bank within the same period of the study and who were having normal liver profile with absence of HCV-Ab, HBsAg and HBc Ab (total) in their sera.
Patients were subjected to the following: Full history taking, thorough clinical examination.Routine laboratory investigations, that included: Complete blood picture.Liver profile tests: prothrombin time and concentration, serum albumin, AST, ALT, Alkaline phosphatase, γ-GT and serum bilirubin (total and conjugated).Hepatitis viral markers; that included: Detection of HCV-Ab by ELISA technique using Biochem Kit., Detection of HCV-RNA-PCR.Detection of HBsAg by ELISA technique using Sorin Biomedic Kit (for exclusion of +ve cases).
Liver biopsy and histopathological examination for necro Inflammatory grading and fibrosis staging applying the METAVIR scoring system [13,14].

Samples collection, preparation and handling:
A sample of 8-10 ml of venous blood was withdrawn under aseptic condition.One ml of blood was added to an anticoagulant-(EDTA) containing tube for complete blood count.The rest of the blood sample was left to clot in a sterile, clean and dry tube.After clotting, samples were thoroughly separated from all cellular material by centrifugation.Multiple freeze-thaw procedures were avoided.Any precipitates in specimens were removed by centrifugation before testing, and specimens with obvious hemolysis were excluded.

Abdominal Ultrasonography:
Liver was assessed for: size (span), echogenicity, surface, thickening of portal tracts, portal vein diameter, hepatic veins, inferior vena cava and presence or absence of focal lesions.
Spleen was assessed for: size, echogenicity, splenic vein diameter and presence or absence of collaterals.Other data concerning the gall bladder, both kidneys, pancreas, para aortic region as well as detection of ascites all were fulfilled.

Biopsy of the liver:
N.B: Patients with ascites were excluded from this study.

Histopathological examination:
The stained sections were examined for: Evidence of etiology: HCV, Schistosomiasis.Assessment of necro inflammatory grading and fibrosis staging applying the METAVIR scoring system of [15].Where Activity was graded according to the intensity of necro inflammatory lesions: A0=no histological activity, A1=mild activity, A2= moderate activity, A3=severe activity.The stage of fibrosis (F) was assessed on a five Point scale: F0= no fibrosis, F1=Portal fibrosis without septa, F2=Few septa, F3=numerous septa without cirrhosis, F4=cirrhosis.

Statistical Analysis
Data were tabulated, coded then analyzed using the computer program SPSS (Statistical package for social science) version 17.0to obtain Descriptive statistics were calculated in the form of: A-Mean ± Standard deviation (SD) for quantitative parametric data.B-Median and range (Minimum-maximum) for quantitative nonparametric data.C-Frequency (Number-percent) for qualitative data.

Analytical statistics:
In the statistical comparison between the different groups, the significance of difference was tested using one of the following tests:-A-Student's t-test:-Used to compare between mean of two groups of numerical (parametric) data.B-Mann Whitney U test: Used to compare between two groups of numerical (non-parametric) data.C-Kruskal Wallis test: Used to compare between more than two groups of numerical (non-parametric) data followed by Mann-Whitney for multiple comparisons.
The sensitivity and specificity of FCI, FIB4, King's score, APRI and API to differentiate between F0-F1 and F2-F4 and also between F0-F2 and F3-F4 fibrosis grades were examined at different cutoff points using ROC curve analysis to determine the best cutoff point as well as the diagnostic power of each test.A P -value < 0.05 was considered statistically significant in all analyses.
There is a statistically significant difference between cases and control groups (p 0.05) as regards platelets, ALT, AST, ALP, APRI, FCI, FIB4, king's score, and API.Cases group had significantly lower platelets count, higher ALT, AST, ALP levels and higher APRI, FCI, FIB4, king's score and API values (Table 1).
As shown in table (5) and figure (20)     In the current study the platelet count showed a statistically highly significant decline with advancement of hepatic fibrosis as shown in table (2).This comes in agreement with other studies that reported a highly significant decline in platelet count with the progression of fibrosis [22].On the other hand another study reported that differences in platelet count were not significantly affected with the progression of liver fibrosis.This disagreement may be explained by the character of patients included in their study as they had genotype 1 and the small number of their cases with advanced hepatic fibrosis stages compared to the present study [23].
The present study showed that APRI had a statistically significant higher values with advancement of hepatic fibrosis, as shown in table (2).Similar results obtained by study [8].
In the present study, the age-platelet index (API) showed a statistically significant higher values with advancement of hepatic fibrosis, as shown in table (5).These results came in agreement with study which created this index.Reported that there was a significant positive correlation between API and necro-inflammatory activity and stage of fibrosis [24].
In the study, FIB4 showed a statistically higher significant values with advancement of hepatic fibrosis, as shown in table (2).Similar results were obtained by study which reported that FIB4 was significantly increased with progression of fibrosis stages [8].
In the present study, King's sore showed a statistically significant higher values with advancement of hepatic fibrosis as shown in table (5).
In the present study FCI showed a statistically significant higher values with advancement of hepatic fibrosis (P<0.001), as shown in table (2).
In the present study, the independent variables for prediction of liver fibrosis were FCI, FIB4, King's score, API and APRI.Using ROC curves to assess and compare the diagnostic accuracy of blood markers as FCI, FIB4, King's score, API and APRI in patients with different stages of

Figure ( 1 ):
Figure (1): Gender of the studied groups within the study

Table ( 1
): Laboratory findings of the studied cases and control groups.

Table ( 3
): Age, Laboratory data and fibrosis biomarkers in patients with (F≤1) METAVIR stages compared to those with (F ≥2) stages.