’Original article

Platelets-to-lymphocyte ratio is a good predictor of

liver fibrosis and insulin resistance in hepatitis C
virus-related liver disease
Ayman Alsebaey, Mostafa Elhelbawy and Imam Waked

Background Hepatitis C virus (HCV) is a global health problem that is complicated by liver fibrosis and insulin resistance (IR).
Aim The aim of this study was to validate neutrophils-to-lymphocytes ratio (NLR) and platelets-to-lymphocytes ratio (PLR) as
indirect biomarkers of liver fibrosis and IR in HCV patients.
Patients and methods One hundred and fifty patients were enrolled. Physical examination, BMI, liver function tests, serum
creatinine, complete blood count, serum HCV RNA count by PCR, and abdominal ultrasonography were performed. Transient
elastography measurement using FibroScan was performed. Patients were classified into those with mild fibrosis (F1–F3) and
significant fibrosis (F4). IR was defined as homeostasis model assessment of IR more than 2. NLR and PLR were calculated.
Results The average age of the patients was 47.21 ± 10.51 years, mainly men (n = 119; 79.3%), and 87.3% (n = 131) had IR and
44.7% (n = 67) had significant fibrosis. PLR was lower in patients with IR (74.95 ± 37.90 vs. 94.71 ± 31.45; P = 0.032) unlike the
NLR, which was comparable (P > 0.05). Patients with significant fibrosis had lower PLR (66.43 ± 39.38 vs. 86.35 ± 33.85;
P = 0.001) unlike NLR (P > 0.05). PLR (cutoff ≥ 77.47) had 78.9% sensitivity, 60.3% specificity, 22.4% positive predictive value,
and 95.2% negative predictive value for non-IR (P = 0.008). At a cutoff of at least 63.71, PLR had 73.5% sensitivity, 61.2%
specificity, 70.1% positive predictive value, and 65.1% negative predictive value for nonsignificant fibrosis (P = 0.001). Age and
PLR (odds ratio = 0.99; 95% confidence interval = 0.976–0.999) were predictors of IR, whereas age, total bilirubin, serum
albumin, liver stiffness, and PLR (odds ratio = 0.98; 95% confidence interval = 0.974–0.994) were predictors of significant fibrosis.
Conclusion PLR is useful in distinguishing the patients with significant fibrosis or IR unlike NLR. Eur J Gastroenterol Hepatol
00:000–000
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Introduction Liver biopsy remains the gold standard for fibrosis

Hepatitis C virus (HCV) is a RNA virus that harbors mainly
the liver. Millions of individuals worldwide are infected,
and 350 000 die annually. Contaminated blood products,
invasive procedures, and illicit intravenous drug abuse are
the main sources of infection. Most patients progress from
acute hepatitis even if they are asymptomatic for chronic
hepatitis C. Some of the patients may progress to cirrhosis
and fatal hepatocellular carcinoma (HCC) [1,2].
Liver fibrosis is one of the complications of chronic
hepatitis C. It is a reversible wound-healing response in
which there is derangement in the liver repair and extra-
cellular matrix, with subsequent scar formation. One of
the main features is activation of the hepatic stellate cells
that undergo morphological–genetic changes into myofi-
brocytes with collagen deposition. This occurs through
multiple signaling pathways [3].
European Journal of Gastroenterology & Hepatology 2017, 00:000–000
Keywords: fibrosis, hepatitis C virus, insulin resistance,
neutrophils-to-lymphocytes, platelets-to-lymphocytes
Department of Hepatology and Gastroenterology, National Liver Institute,
Menoufia University, Shebeen El-Koom, Egypt
Correspondence to Ayman Alsebaey, MD, Department of Hepatology and
Gastroenterology, National Liver Institute, Menoufia University, Shebeen El-Koom
32511, Egypt
Tel: + 20 100 375 1248; fax: + 20 482 234 586;
e-mail: ayman@liver.menofia.edu.eg
Received 22 June 2017 Accepted 8 August 2017
diagnosis, staging, and follow-up despite being invasive.
Recently, noninvasive laboratory and physical approaches
were used. Transient elastography using FibroScan is one
of the noninvasive physical approaches with high yield and
reproducibility [4].
HCV is not a single-facet disease with only liver insult
but in fact a systemic multifaceted disease [5]. There is a
close interplay between HCV and diabetes mellitus [6].
The prevalence of HCV is high in patients with diabetes
mellitus [7]. HCV-related liver disease patients have a high
prevalence of diabetes mellitus [8]. HCV-related insulin
resistance (IR) is associated with steatosis, liver fibrosis,
cirrhosis-related complications, especially varices, and
HCC [9,10]. Neutrophils-to-lymphocytes ratio (NLR) and
platelets-to-lymphocytes ratio (PLR) are used to express
the inflammatory milieu [11,12].
This study aimed to validate NLR and PLR in liver
fibrosis and IR in HCV patients.
Patients and methods
This study was carried out in National Liver Institute
Hospitals, Menoufia University. An informed consent was
obtained from all enrolled patients after previous institu-
tional review board approval.
This study was carried out on 150 patients with HCV-
related liver disease who were eligible for treatment with HCV
direct-acting antivirals. They were either chronic hepatitis C

0954-691X Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001013 1

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2 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00

patients with persistent positive serum HCV RNA for more Meanwhile, there was no statistically significant differ-
than 6 months [13] or compensated cirrhotic patients stages ence (P > 0.05) between patients with and without IR in
I and II [14]. Liver cirrhosis was diagnosed on the basis of sex, presence of diabetes mellitus, BMI, total bilirubin,
clinical, laboratory, abdominal ultrasonographic, and transient serum albumin, AST, serum creatinine, hemoglobin, white
elastography (FibroScan; Echosens, Paris, France) findings [15]. blood cells, INR, HCV RNA, and the liver stiffness score.
Patients who fulfilled the following criteria were Both groups did not differ statistically (P > 0.05) in neu-
excluded: non-HCV-related liver disease, dual HCV and trophils, lymphocytes, and NLR (Fig. 1).
HBV, HIV coinfection, decompensated liver disease (stage Patients with significant fibrosis compared with
III and IV) [14], HCC, or extrahepatic malignancy. those without significant fibrosis (Table 2) were older
All patients underwent a thorough assessment of his- (51.04 ± 9.16 vs. 44.12 ± 10.56 years; P = 0.001), with
tory, complete clinical examination, BMI, liver function higher serum bilirubin [0.9 (0.55) vs. 0.68 (0.35) mg/dl;
tests [bilirubin, albumin, aspartate aminotransferase P = 0.001], AST [67 (42) vs. 39 (31) U/l; P = 0.001], ALT
(AST), alanine aminotransferase (ALT)], serum creatinine, (77.51 ± 46.47 vs. 58.10 ± 47.96 U/l; P = 0.014), INR [1.13
complete blood count, international normalized ratio (0.16) vs. 1.04 (0.1); P = 0.001], but lower albumin
(INR), and serum HCV RNA count by PCR. (3.87 ± 0.52 vs. 4.31 ± 0.52 g/dl; P = 0.001) and hemoglobin
Transient elastography measurement was performed (14.25 ± 1.94 vs. 14.95 ± 1.71 g/dl; P = 0.02).
after 6–8 h of fasting in the supine position using There was no statistically significant difference (P > 0.05)
FibroScan (Echosens) [4,16]. Patients were classified between patients with and without F4 fibrosis (Table 2) in
according to the transient elastography values into those
with mild fibrosis (F1–F3) and significant fibrosis (F4).
Diabetes mellitus type 2 was diagnosed on the basis of the Table 1. Comparison of patients with and without insulin resistance
following criteria: a fasting plasma glucose level of
None Insulin resistance
126 mg/dl (7.0 mmol/l) or higher or a 2-h plasma glucose [N = 19 (12.7%)] [N = 131 (87.3%)] P
level of 200 mg/dl (11.1 mmol/l) or higher during a 75-g
Age (years) 40.68 ± 7.56 48.16 ± 10.57 0.003
oral glucose tolerance test, or a random plasma glucose of Male sex 15 (78.9) 104 (79.4) 1
200 mg/dl (11.1 mmol/l) or higher in a patient with classic Diabetes mellitus 3 (15.8) 34 (26) 0.408
symptoms of hyperglycemia or hyperglycemic crisis [17]. BMI (kg/m2) 29.49 ± 3.96 29.60 ± 4.89 0.928
Total bilirubin (mg/dl) 0.78 ± 0.29 0.86 ± 0.52 0.479
The homeostasis model assessment of insulin resistance
Serum albumin (g/dl) 4.22 ± 0.50 4.10 ± 0.57 0.383
(HOMA-IR) was used to assess IR [18,19]. HOMA-IR AST (U/l) 65.16 ± 46.98 58.26 ± 38.08 0.475
more than 2 was used to identify patients with IR [20]. ALT (U/l) 68 (55) 50 (53) 0.028
Calculations: BMI calculation = body weight (kg)/height2 Serum creatinine (mg/dl) 0.81 ± 0.18 0.82 ± 0.19 0.84
HOMA-IR 1.35 (0.54) 3.46 (2.83) 0.001
(m); HOMA-IR = fasting insulin (mIU/l) × fasting glucose Hemoglobin (g/dl) 14.97 ± 1.96 14.59 ± 1.83 0.339
(mg/dl)/405; NLR = neutrophils (109/l)/lymphocytes (109/l), WBCs (103/µl) 7.46 ± 2.85 6.43 ± 2.26 0.075
PLR = platelets (109/l)/lymphocytes (109/l). Platelets (103/µl) 204.47 ± 63.49 159.94 ± 68.03 0.008
INR 1.08 ± 0.11 1.10 ± 0.14 0.536
HCV RNA (105 IU/ml) 12.23 ± 24.66 18.14 ± 29.73 0.41
Statistical analysis Liver stiffness (kPa) 9.2 (11.2) 12.9 (21.3) 0.125#
Neutrophils (µl) 4.26 ± 1.88 3.81 ± 2.31 0.425
Data were analyzed statistically using IBM SPSS Statistics, Lymphocytes (µl) 2.24 ± 0.54 2.28 ± 0.68 0.798
version 21 for Windows (IBM Corporation, North Castle Neutrophils/lymphocyte ratio 2.00 ± 0.98 1.83 ± 1.41 0.606
Platelets/lymphocyte ratio 94.71 ± 31.45 74.95 ± 37.90 0.032
Drive, Armonk, New York, USA). Data are expressed as
mean ± SD for parametric data, number with column per- Values are represented as mean ± SD or n (%).
centage for nominal data, and the median ± interquartile ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCV, hepatitis C
range for nonparametric data. All P values are two tailed, virus; HOMA-IR, homeostasis model assessment of insulin resistance; INR,
international normalized ratio; WBC, white blood cell.
with values less than 0.05 considered statistically significant; #
Mann-Whittney test.
a P value of 0.01 is highly significant and a P value of 0.001
is very highly significant. Comparisons between two groups
were performed using the Student t-test for parametric data
and the Mann–Whitney test for nonparametric data. χ2 and
Fisher’s exact tests were used for categorical data analysis.
Univariate and multivariate binary logistic regression was
performed for detecting the predictors of IR and significant
fibrosis. The receiver operating characteristic curve analysis
was carried out for detection of the cutoff value of the
non-IR and nonsignificant fibrosis.

Results
As shown in Table 1, there was a statistically significant
difference between patients with and without IR, where
patients with IR were older (48.16 ± 10.57 vs.
40.68 ± 7.56 years; P = 0.003), and had lower ALT levels
[50 (53) vs. 68 (55) U/l; P = 0.028] and platelet counts Fig. 1. Neutrophils/lymphocytes ratio in patients with insulin resistance or
(159.94 ± 68.03 vs. 204.47 ± 63.49 103/µl; P = 0.008). liver fibrosis.

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 PLR and IR is a good predictor of liver fibrosis Alsebaey et al. www.eurojgh.com 3

sex, diabetes mellitus, IR, BMI, serum creatinine, white blood
cells, and HCV RNA. Although there was a statistically
significant difference between both groups in neutro-
phils (4254.22 ± 2564.17 vs. 3394.18 ± 1711.97 µl; P = 0.02)
and lymphocytes (2382.77 ± 600.6 vs. 2151.64 ± 709.39 µl;
P = 0.032), in contrast, NLR was statistically nonsignificant
(1.96 ± 1.61 vs. 1.71 ± 0.97; P = 0.265) as shown in Fig. 1.
For the PLR, patients with IR had lower values
(74.95 ± 37.90 vs. 94.71 ± 31.45; P = 0.032; Table 1). The
same result was obtained with significant fibrosis
(66.43 ± 39.38 vs. 86.35 ± 33.85; P = 0.001; Table 2 and
Fig. 2).
As shown in Table 3, the predictors of IR were age [odds
ratio (OR) = 1.07; 95% confidence interval (CI) = 1.020–
1.119] and PLR (OR = 0.99; 95% CI = 0.976–0.999).
The predictors of significant liver fibrosis were age
(OR = 1.07; 95% CI = 1.035–1.112), total bilirubin
(OR = 6.65; 95% CI = 2.389–18.521), serum albumin
(odds ratio = 0.17; 95% CI = 0.079–0.375), liver stiffness
(OR = 1.36; 95% CI = 1.226–1.508), and PLR (OR = 0.98;
95% CI = 0.974–0.994). On multivariate analysis, PLR was
not statistically significant for IR and significant fibrosis.
At a cutoff of at least 77.47 (Table 4), PLR had 78.9%
sensitivity, 60.3% specificity, 22.4% positive predictive
value, and 95.2% negative predictive value for non-IR
status (P = 0.008). Furthermore, at a cutoff of at least
63.71, PLR had 73.5% sensitivity, 61.2% specificity,
70.1% positive predictive value, and 65.1% negative
predictive value for nonsignificant fibrosis (P = 0.001). Of
course, values below the cutoff will mean indirectly IR or
significant fibrosis (Fig. 3).

Table 2. Comparison of patients with and without F4 fibrosis Discussion

Non-F4 fibrosis F4 fibrosis Chronic hepatitis C in most cases is complicated by liver
[N = 83 (55.3%)] [N = 67 (44.7%)] P
fibrosis that may be progress to cirrhosis with fatal com-
Age (years) 44.12 ± 10.56 51.04 ± 9.16 0.001 plications, especially HCC [1]. The clinical manifestations
Male sex 61 (73.5) 58 (86.6) 0.067
Diabetes mellitus 15 (18.1) 22 (32.8) 0.056 of HCV are not just localized to the liver, but affect most
Insulin resistance 69 (83.1) 62 (92.5) 0.137
BMI (kg/m2) 29.54 ± 4.31 29.65 ± 5.31 0.884
Total bilirubin (mg/dl) 0.68 (0.35) 0.9 (0.55) 0.001
Serum albumin (g/dl) 4.31 ± 0.52 3.87 ± 0.52 0.001
AST (U/l) 39 (31) 67 (42) 0.001
ALT (U/l) 58.10 ± 47.96 77.51 ± 46.47 0.014
Serum creatinine (mg/dl) 0.81 ± 0.18 0.82 ± 0.20 0.76
HOMA-IR 3.63 ± 2.17 4.01 ± 2.58 0.330
Hemoglobin (g/dl) 14.95 ± 1.71 14.25 ± 1.94 0.02
WBCs (103/µl) 6.77 ± 2.18 6.30 ± 2.56 0.228
Platelets (103/µl) 194.89 ± 57.12 129.27 ± 65.13 0.001
INR 1.04 (0.1) 1.13 (0.16) 0.001
HCV RNA (105 IU/ml) 19.07 ± 32.69 15.32 ± 24.09 0.436
Liver stiffness (kPa) 8.7 (3.3) 29.7 (16.5) 0.001
Neutrophils (µl) 4.25 ± 2.56 3.39 ± 1.71 0.02
Lymphocytes (µl) 2.38 ± 0.60 2.15 ± 0.71 0.032
Neutrophils/lymphocyte ratio 1.96 ± 1.61 1.71 ± 0.97 0.265
Platelets/lymphocyte ratio 86.35 ± 33.85 66.43 ± 39.38 0.001

Values are represented as mean ± SD or n (%).

ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCV, hepatitis C
virus; HOMA-IR, homeostasis model assessment of insulin resistance; INR, Fig. 2. Platelets/lymphocytes ratio in patients with insulin resistance or liver
international normalized ratio; WBC, white blood cell. fibrosis.

Table 3. Univariate analysis of predictors of insulin resistance and significant liver fibrosis
Univariate Multivariate

P Odds ratio 95% CI P Odds ratio 95% CI

Insulin resistance
Age 0.005 1.07 1.020–1.119 0.014 1.06 1.012–1.112
BMI 0.928 1 0.907–1.113
Total bilirubin 0.477 1.54 0.469–5.051
Serum albumin 0.38 0.66 0.261–1.669
Liver stiffness 0.097 1.04 0.993–1.087
HCV RNA 0.416 1.01 0.986–1.035
Neutrophils/lymphocyte ratio 0.606 0.92 0.680–1.252
Platelets/lymphocyte ratio 0.038 0.99 0.976–0.999 0.116 0.99 0.978–1.002
Significant liver fibrosis
Age 0.001 1.07 1.035–1.112 0.132 1.06 0.984–1.136
BMI 0.883 1.01 0.939–1.075
Total bilirubin 0.001 6.65 2.389–18.521 0.915 1.11 0.164–7.503
Serum albumin 0.001 0.17 0.079–0.375 0.607 1.37 0.411–4.579
Liver stiffness 0.001 1.36 1.226–1.508 0.001 1.35 1.209–1.509
HCV RNA 0.438 1 0.984–1.007
Neutrophils/lymphocyte ratio 0.277 0.86 0.654–1.129
Platelets/lymphocyte ratio 0.002 0.98 0.974–0.994 0.158 0.99 0.970–1.005

CI, confidence interval; HCV, hepatitis C virus.

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4 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00

systems such as the endocrinal system. HCV is associated
with IR and increased prevalence of diabetes mellitus [5].
Although liver biopsy is the gold standard for fibrosis
diagnosis and staging, noninvasive methods have replaced
this such as laboratory formulae and physical methods
such as FibroScan [4]. Actually, we needed a simple
equation from routine labs for the diagnosis of IR and liver
fibrosis; hence, we evaluated NLR and PLR.
In fact, multiple studies were carried out on utilization
of NLR in the different aspects of liver diseases. The results
of most studies were conflicting [11,12,21–24].
In patients with nonalcoholic fatty liver disease, NLR
was not a predictor of liver histology as it did not differ
with fibrosis stage and was not different in patients with
simple steatosis versus nonalcoholic steatohepatitis [21]. In
contrast, other studies found that NLR correlated with
activity index and fibrosis stage in patients with nonalco-
holic steatohepatitis [22,23].
In patients with chronic hepatitis B, NLR values were
lower in those with advanced fibrosis [25,26]. On the one
hand, in patients with HCV-related liver disease, NLR did
not differ in patients with mild (F1–F2), high fibrosis
(F3–F6), and cirrhosis [12]. Another confirmatory study
found that NLR was higher than that in controls, but did
not differ in stages of disease e.g. hepatitis, cirrhosis, and
Table 4. Receiver operating characteristic curve analysis of platelets/
lymphocyte ratio for noninsulin resistance and nonsignificant fibrosis
Noninsulin resistance Nonsignificant fibrosis
Area under curve 0.69
P 0.008
95% confidence interval 0.577–0.803
Platelets/lymphocyte ratio cutoff 77.47
Sensitivity 78.9
Specificity 60.3
Positive predictive value 22.4
Negative predictive value 95.2
HCC [11]. However, another contradictory study found
NLR to be higher in advanced fibrosis (F3–F4) [24].
NLR correlated with IR, where patients with HOMA-IR
more than 3 had higher NLR values [24]. NLR was also
applied in patients with HCC. It was studied as a useful
marker for recurrence after radiofrequency ablation [27,28],
trans-arterial chemoembolization [29,30], and resection
[31]. In addition, NLR was also used for the assessment of
mortality in patients with end-stage liver disease [32–34].
Even in liver transplantation field, NLR was useful [35,36].
For PLR, patients with cirrhosis or HCC had lower
values than chronic hepatitis patients [11]. PLR predicted
HCC recurrence [37,38].
In the current study, NLR did not differentiate patients
with significant fibrosis from those without significant
fibrosis. These findings are in agreement with Meng et al.
[11] and Coskun et al. [12] and not in agreement with
Abdel-Razik et al. [24]. NLR did not differ between
patients with and without IR. This result is not in agree-
ment with Abdel-Razik et al. [24], although they used
higher values for IR definition (HOMA-IR > 3).
For PLR, lower values were detected in patients with
significant fibrosis than in those without significant fibro-
sis. This is in agreement with Meng et al. [11].
Furthermore, patients with IR had lower values than those
without IR. To our knowledge, this the first study to dis-
cuss the relationship between PLR and INR in chronic
hepatitis C patients.
PLR by univariate logistic regression analysis was a
predictor of IR and significant fibrosis in contrast with
0.694 NLR. As PLR values were lower in patients with IR or
0.001 significant fibrosis, a receiver operating characteristic curve
0.606–0.783
63.71 analysis cannot be carried out to determine the cutoff for
73.5 these items. Thus, we carried out the analysis, but for non-
61.2 IR and nonsignificant fibrosis; thus, values below the cut-
70.1
65.1 off will mean indirectly IR and significant fibrosis. It had
78.9% sensitivity and 60.3% specificity for non-IR status;

Fig. 3. Receiver operating characteristic curve analysis of platelets/lymphocyte ratio for noninsulin resistance (a) and nonsignificant fibrosis (b).

Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 PLR and IR is a good predictor of liver fibrosis Alsebaey et al.
in addition, it had 73.5% sensitivity and 61.2% specificity
for nonsignificant fibrosis.
The limitation of this study is the small number of the
patients; the sample size in future research. Longitudinal
follow-up of the patients, especially after HCV treatment,
may be needed.
In conclusion, PLR is beneficial in distinguishing
patients with advanced fibrosis or IR unlike NLR.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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