Arab Journal of Gastroenterology 10 (2009) 87–91

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Arab Journal of Gastroenterology

journal homepage: www.elsevier .com/ locate/a jg

Original Article

Evaluation of routine biochemical indices and a-fetoprotein versus histologyin chronic hepatitis C patients

Mohamed Said *

Endemic Medicine and Hepatology Department, Faculty of Medicine-Cairo University, 69 Rabaei El-Gizi St. Borg Soteir Giza, Egypt

a r t i c l e i n f o a b s t r a c t

Article history:Received 14 April 2009Accepted 14 August 2009

Keywords:Non-invasive biochemical indicesa-FetoproteinLiver fibrosisHCV

1687-1979/$ - see front matter � 2009 Arab Journal odoi:10.1016/j.ajg.2009.08.002

* Tel.: +20 0235734045; fax: +2 0223682774.E-mail address: msabdelaziz76@yahoo.com

Background and study aims: This study was conducted to investigate the value of routine biochemicalindices and a-fetoprotein in the evaluation of liver fibrosis in chronic hepatitis C patients.Patients and methods: One hundred and sixty two chronic hepatitis C patients were recruited for antiviraltherapy in a national centre in Egypt. Patients were 127 males and 35 females with a mean age of38.4 years. Patients were evaluated with laboratory tests needed to decide eligibility for antiviral therapy.Indices were calculated from aspartate to alanine aminotransferase ratio index (AARI), AST/platelet countfor APRI, age/platelets index (API) and a-fetoprotein. Metavir score was used to stage fibrosis. ReceiverOperator Characteristic curves was used.Results: Prevalence of significant fibrosis (F2–4) was 86 patients (53%); 10 patients (6.1%) were cirrhotics.In patients with significant fibrosis AARI had sensitivity rate (80%), specificity (30%) and AUC value(0.594). APRI, API and AFP had a better specificity than AARI (54%, 76% and 55%, respectively), with alower sensitivity (68%, 61% and 62%) and AUC (0.644, 0.699 and 0.613, respectively). Combining non-invasive indices with a-fetoprotein, the specificity did not improve, though sensitivity increased. age/platelets count index (API) had highest sensitivity (100%) with specificity (59%) and AUC = 0.832 for pre-diction of liver cirrhosis, whereas APRI showed higher specificity (65%) but lower sensitivity rates (70%)and AUC = 0.644.Conclusion: API is useful in discriminating patients with significant fibrosis, showing the best results inthis study in predicting cirrhosis. Adding AFP to AARI, APRI or API showed no value in increasing predic-tion of significant fibrosis.

� 2009 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction

Chronic hepatitis C virus (HCV) infection is responsible for liverfibrosis and can lead to potential long-term complications such asliver cirrhosis and hepatocellular carcinoma. Worldwide, Egypt hasthe highest HCV prevalence: around 10% of adults in urban areasare affected, with this figure growing to around 20% in rural areas[1]. Diagnosis of the stage of liver fibrosis is essential for making aprognosis and deciding on antiviral therapy. Liver biopsy is thegold standard for fibrosis staging, yet this procedure is somewhatlimited by its invasive nature, poor acceptance, availability, cost,intra- and inter-observer variability, and sampling errors [2,3].

To avoid biopsy, a number of alternative tests for liver fibrosisevaluation have been developed. Some of the tested biochemicalmarkers have been shown capable of estimating the severity ofliver disease by discriminating patients with low-stage fibrosis fromthose with septal fibrosis/cirrhosis [11]. Tests include aspartate to

f Gastroenterology. Published by El

alanine aminotransferase ratio (AAR), AST and platelet count forAPRI [4], age and platelet count [5,13].

The clinical and morphological significance of raised a-fetopro-tein (AFP) levels in patients with chronic hepatitis C is undefined.Some studies have shown a significant correlation of AFP withthe diagnosis of cirrhosis or advanced hepatic fibrosis, and correla-tion with raised AST and prolonged INR [6–8]. However, none ofthese studies investigated these routine biochemical indices andraised AFP in the HCV genotype 4 infected population. Accordingly,this study was designed to investigate the value of routine bio-chemical indices compared with liver histology in order to ascer-tain if adding AFP to such indices could improve the sensitivityand specificity in a cohort of HCV genotype 4 infected patients.

Patients and methods

A total of 162 chronic hepatitis C patients were recruited forcombined interferon and ribavirin therapy in one of the nationalcentres for HCV treatment in Egypt. They were 127 males and 35females, with mean age 38.4 years old (range 20–58 years). These

sevier B.V. All rights reserved.

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88 M. Said / Arab Journal of Gastroenterology 10 (2009) 87–91

patients were retrospectively evaluated and assessed with com-plete laboratory tests needed to decide eligibility for antiviral ther-apy. Tests included blood glucose, serum creatinine, serumalbumin, liver profile, complete blood count, prothrombin timeand INR, urine analysis, pregnancy test for females, HBs Ag, antinu-clear antibody, TSH, a-fetoprotein, HCV RNA with PCR to assessquantitatively viral load, and anti-Schistosomal antibody to assessfor exposure to Schistosomiasis. Rectal snip or stools analysis usingthe Kato technique was conducted for positive cases. In addition,ECG was conducted for men older than 40 years and for femalesolder than 50 years. Fundus examination, a prerequisite beforestarting Interferon therapy (particularly for diabetic patients),was also conducted. Body mass index (BMI) was measured pre-treatment for all patients (see Figs. 1–8).

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Fig. 1. The ROC curve of AARI in predicting significant fibrosis (F2–4).

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Fig. 2. The ROC curve of APRI in predicting significant fibrosis (F2–4).

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Fig. 3. The ROC curve of APRI in predicting cirrhosis (F4).

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Fig. 4. The ROC curve of API in predicting significant fibrosis (F2–4).

Non-invasive biochemical indices were calculated from routinelaboratory tests; aspartate to alanine aminotransferase ratio index(AARI), AST and platelet count for APRI (calculated as follows: ASTfolds � 100 � age/platelets count) [4], platelet count to calculateage/platelets index (API) and a-fetoprotein (AFP).

All liver specimens were reviewed by an experienced patholo-gist. A minimum of five portal tracts in the specimen was requiredfor the appropriate assessment of histological data. The degree offibrosis and histological activity index were staged according toMetavir score [9], where F0 stands for no fibrosis, F1 for portalfibrosis without septa, F2 for portal fibrosis with rare septa, F3for numerous septa without cirrhosis, and F4 for cirrhosis.

Statistical analysis

All patients’ data were tabulated and processed using SPSS 10.0for Windows XP. Quantitative variables were presented by

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Fig. 5. The ROC curve of API in predicting cirrhosis (F4).

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Fig. 6. The ROC curve of platelets count and AFP for prediction of significant fibrosis(F2–4).

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Fig. 7. The ROC curve of combining non-invasive indices with AFP for prediction ofsignificant fibrosis (F2–4).

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Fig. 8. The ROC curve of combining non-invasive indices with AFP for prediction ofcirrhosis (F4).

M. Said / Arab Journal of Gastroenterology 10 (2009) 87–91 89

mean ± standard deviation (SD) and compared by ANOVA (analysisof variance). Pearson and Searson correlations were conducted tocorrelate continuous parameters. ROC curves (Receiver OperatorCharacteristic) were drawn to assess performance of the new bio-markers in diagnosis of fibrosis.

Quantitative variables were expressed by number and percent.Variables were compared by v2 test or Fischer’s exact test whenappropriate.

In all tests, P value was considered significant if <0.05.

Results

The study group consisted of 162 patients whose baseline char-acteristics are reported in Table 1. Markers of liver synthetic capac-ity, such as albumin and prothrombin, were all within normalvalues, and serum ALT levels were up to 1.5 times the normal va-

lue. At histology, the overall prevalence of significant fibrosis (F2and F4) was 86 patients (53%) while 10 patients (6.1%) werecirrhotics.

Mean value for platelet count and P value are shown in Table 2.Platelet count was significantly reduced in patients with significantfibrosis (F2–4). Sensitivity, specificity and P value of all non-inva-sive indices for the detection of significant fibrosis (F2–F4) are re-ported in Table 3. Sensitivity, specificity, AUC values and P value ofall non-invasive indices for the detection of significant fibrosis (F2–4) are reported in Table 4. In patients with significant fibrosis athistology (53%), AST/ALT ratio index (AARI) had excellent sensitiv-ity rate (80%), but suboptimal specificity (30%). The other threeindices (APRI, API and AFP) had a better specificity rate than that

Table 1Demographic, biochemical and histological features of 162 patients with chronichepatitis C.

Mean/range

Age (years) 38.4/(20–59)Male/female 127 (78%)/35 (22%)AST (n. value = 37) 43/(7–270)ALT (n. value = 41) 68.6/(8–353)Platelets count 209/(97–400)a-Fetoprotein (mg/dl) 5.86/(0.2–9.46)Inflammation in biopsy (1–3) 1.6Fibrosis in biopsy (0–4) 1.77

Stage of fibrosis, n (%)F0 7 (4.3%)F1 69 (42.6%)F2 50 (30.8%)F3 26 (16%)F4 10 (6.1%)

Table 2Platelets count in HCV patients with or without significant fibrosis.

N Mean Standard deviation

F0–1 76 221.05 57.577F2–4 86 198.84 67.219

P < 0.01 (HS) for platelets.P = 0.02 (S) by Mann–Whitney U test.

Table 3Sensitivity, specificity, AUC value and P value for non-invasive indices for significantfibrosis (F2–4) versus (F0–1).

Cut-offvalue

AUC Sensitivity(%)

Specificity(%)

Pvalue

AARI 0.6895 0.594 80 30 .039APRI 0.3882 0.644 68 54 0.002API 0.20 0.699 61 79 0.000AFP 2.91 0.613 62 55 0.014AARI + AFP 3.8 0.627 66 55 0.006APRI + AFP 3.1 0.629 69 50 0.005API + AFP 2.78 0.625 68 47 0.007

P value < 0.05 (significant).P value < 0.01 (highly significant).P value > 0.05 (non-significant).

Table 4Sensitivity, specificity and P value for non-invasive indices for cirrhosis (F4).

Cut-offvalue

AUC Sensitivity(%)

Specificity(%)

P value

AARI 0.550 0.597APRI 0.551 0.689 70 65 0.046 (S)API 0.197 0.832 100 59 0.000 (HS)AFP 0.156AARI + AFP 0.640 0.139APRI + AFP 0.636 0.149API + AFP 0.641 0.137

P value < 0.05 (S = significant).P value < 0.01 (HS = highly significant).P value > 0.05 (NS = non-significant).

90 M. Said / Arab Journal of Gastroenterology 10 (2009) 87–91

of AARI (54%, 76%, and 55%, respectively) with a lower sensitivity(68%, 61% and 62%). By combining the non-invasive indices withAFP, the specificity did not consistently improve over that providedby each index alone, whereas the sensitivity, albeit increased, wasstill inferior to that of AARI. The performance of the consideredindices in identifying the 10 patients with liver cirrhosis is given

in Table 4. Age/platelets count index (API) had highest sensitivity(100%) with lower specificity (59%) for the prediction of liver cir-rhosis, APRI showed higher specificity (65%) but lower sensitivityrates (70%).

Discussion and conclusion

The limitations of liver biopsy for the diagnosis of liver fibrosishave lead to a search for an alternative diagnostic tool, includingthe investigation of the use of routine biochemical markers to cal-culate scores and indices for fibrosis. The current study evaluatedthe performance of several scores and indices in a series of patientsinfected with HCV, showing the diagnostic value of AARI inpatients with significant fibrosis (F2–4) (P value = 0.039 andAUC = 0.594) with excellent sensitivity (80%); however it showedsuboptimal specificity (30%). Unlike several recent reports docu-menting the value of AARI in discriminating cirrhotic patients,AARI in this study showed no significant predicative value for cir-rhosis. As regards the value of APRI score to diagnose significantfibrosis (F2–4), this study showed AUC of 0.664 and 0.689 for diag-nosis of cirrhosis, although these AUC values were lower than hasbeen reported by recent meta-analysis conducted by Shaheen [12],which showed AUC values of 0.76 and 0.82 for significant fibrosisand cirrhosis, respectively, however it is still of value for the pre-diction of cirrhosis with sensitivity 70% and specificity of 65% atcut-off value 0.551.

Serum platelet concentration and age were the two main factorssignificantly and independently correlated with the presence offibrosis and/or histological activity in a study conducted by Poy-nard in 2003 [12]. A simple score referred to as AP, combiningage and platelet count, had a specificity of 0.93 and a sensitivityof 0.52%. In the validation population, the area under the curvewas 0.690 ± 0.085, API in the current study showed a highly signif-icant value at cut-off value 0.2 (P = 0.000) with AUC value of 0.699;a finding similar to Poynard’s study. API showed AUC value of0.832 and 100% sensitivity and 59% specificity in prediction of cir-rhosis at cut-off value of 0.197, being the best result obtained com-pared with other indices used. Platelet count as a single parameter,as shown in Table 2, showed significant correlation with increasingfibrosis, although age alone was not studied. However, it does seemthat platelet count is the significant variable which provides suchhigh sensitivity in API score.

Serum a-fetoprotein (AFP) is a debated marker for hepatocellu-lar carcinoma in patients with chronic liver disease [10], but it issignificantly elevated in non-malignant hepatic conditions, as inchronic hepatitis C [8]. Its high level has been correlated with ad-vanced fibrosis and cirrhosis [6,7]. In the current study, AFP wasfound to be associated with significant fibrosis (F2–4) with AUC va-lue of 0.613 (sensitivity = 62% and specificity = 55%), but it was notable to predict cirrhosis (P = 0.16). By combining the non-invasiveindices with AFP, AUC value was not much improved, and even de-creased when AFP added to the APRI and API. Further, the specific-ity of indices did not consistently improve over that provided byeach index alone, whereas the sensitivity increased.

It seems API is significantly useful in discriminating patientswith significant fibrosis. In the present study it showed the best re-sults among other indices in predicting cirrhosis with AUC value0.832 with 100% sensitivity and 59% specificity. Adding AFP toany of the studied indices (AARI, APRI and API) showed no valuein increasing its usefulness in prediction of significant fibrosis inthe current study.

Conflict of interest statement

None declared.

M. Said / Arab Journal of Gastroenterology 10 (2009) 87–91 91

Acknowledgements

I would like to thank Professor Gamal Esmat and Dr. Wafaa Ela-kel (Endemic Medicine and Hepatology Department, Cairo Univer-sity) for kind support and advice.

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