The prognostic value of prognostic nutritional index in hepatocellular carcinoma patients: A meta-analysis of observational studies
The prognostic value of prognostic nutritional index in hepatocellular carcinoma patients: A meta-analysis of observational studies
Zhiling Wang 0 1
Jie Wang 0 1
Peijun WangID 1
0 Department of SICU. Affiliated Children 's Hospital of Zhengzhou University, Henan Children's Hospital , Zhengzhou, Henan Province, China, 2 General Surgery , Affiliated Tumor Hospital of Zhengzhou University, Henan Provincial Cancer Hospital , Zhengzhou, Henan Province , China
1 Editor: Ferruccio Bonino, Universita degli Studi di Pisa , ITALY
Background and aims The clinical value of the prognostic nutritional index (PNI) in hepatocellular carcinoma (HCC) has been investigated in previous studies, but the results remain controversial. Here we present a meta-analysis to systematically review the association between PNI and HCC prognosis.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
PubMed, EMBASE, Web of Science databases were systematically searched to identify
relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was
performed to determine the prognostic and clinic-pathological values of PNI in HCC
patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted to estimate
the association of PNI with survival and clinic-pathological characteristics, respectively.
A total of eleven studies involving 3165 patients were analyzed. The pooled results indicated
that low PNI is a significant predictor of poor 1-year, 3-year, 5-year OS (OR, 2.91, 4.05,
3.65; 95%CI, 2.30 to 3.70, 3.27 to 5.03,2.96?4.50; P = 0.14,0.22,0.11 respectively) and
disease-free survival (DFS) (OR,2.35, 2.57, 2.75; 95%CI, 1.71 to 3.23, 1.89 to 3.49,2.01 to
3.75; P = 0.39,0.04,0.11, respectively). Moreover, PNI is significantly associated with serum
AFP, tumor recurrence, tumor size and TNM stages in HCC patients. However, PNI is not
significantly associated with tumor number and the incidence of cirrhosis in HCC patients.
PNI is an independent predictive indicator of survival and associated with serum AFP, tumor
recurrence, tumor size and TNM stages in HCC patients.
Hepatocellular carcinoma (HCC) is one of the most common malignancies [
], the third
leading cause of cancer-related death in the word [
], Unlike other solid malignancies, most
hepatocellular carcinoma evolved from chronic liver disease, especially associated with liver
cirrhosis result from viral hepatitis or ethanol consumption [
]. Despite remarkable
development in early diagnosis, surgery, adjuvant chemotherapy, even liver transplantation, but the
effect remains unsatisfactory because of the high recurrence rate or metastasis within 5 years
after treatment in HCC patients . Therefore, it is important to assess disease progression in
a timely manner and guide clinical treatment to improve the survival of patients.
Immune-nutritional status has been demonstrated to be associated with prognosis in
patients with various malignancies and inflammatory response was known to promote tumor
growth, invasion, angiogenesis and metastasis [
]. Prognostic nutritional index (PNI) based
on albumin concentration and lymphocyte count in the peripheral blood, is a simple and
practical indicator of systemic inflammatory response [
]. Recently, emerging evidence has
reported the prognostic value of PNI in hepatocellular carcinoma [
]. However, those
studies that using the PNI for HCC prognosis reported inconsistent results, largely due to
differences in inclusion criteria and sample sizes [
], as a result, the correlation of PNI with
survival in HCC patients remains controversial. The aim of this study is to perform a
metaanalysis to determine whether PNI is a useful prognostic factor and assess the correlation
between PNI and clinic-pathological parameters in HCC patients.
Materials and methods
PubMed; EMBASE and Web of Science databases were comprehensively searched for relevant
studies published from 1980 to December 2017 with the following keywords: ?hepatocellular
carcinoma?, ?hepatocellular tumor?, ?hepatocellular malignance? and ?Prognostic nutritional
index?, ?PNI? and?prognosis?, ?survival?, ?outcome?. No time and language restrictions
were imposed. Additionally, the relevant literatures including all of the identified studies,
reviews and editorials were also reviewed. All candidate studies were carried out by two
independent reviewers (Zhiling Wang and Peijun Wang) and discrepancies were resolved by
Criteria for inclusion and exclusion. Studies that fulfilled the following criteria were
considered eligible and selected into this article: (1) pathologic examination for diagnosis of
hepatocellular carcinoma; (2) clinic-pathological and prognostic values of PNI in HCC was
reported; (3) case-control studies design; (4) sufficient data to allow for estimation of the OS,
DFS. Nonhuman hepatocellular carcinoma research studies, duplicate articles, abstracts,
recurrent HCC, letters, case reports and meetings reports were excluded from the analysis. Two
reviewers evaluated all candidate literature and resolved any disagreement by discussion.
Data extraction. Two independent investigators reviewed the publications and extracted
the data from relevant identified: author?s first name, year of publication, country, sample size,
TNM stages, follow-up period, cutoff value and outcomes.
Quality assessment. In the included studies, PNI was calculated on the basis of
pretreatment laboratory data and was using the formula: 10?albumin value (g/dl) + 0.005?lymphocyte
count in the peripheral blood. The quality of the included studies was assessed using the
Newcastle-Ottawa quality assessment scale (NOS) and we considered studies awarded with 6 or
higher were classified as high-quality studies [
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Meta-analysis was conducted using Review Manager 5.3 analysis software (Cochrane
Collaboration, Copenhagen, Denmark). The association of PNI with survival and clinic-pathological
characteristics in HCC patients were performed using ORs and 95% CI. The estimates of ORs
were weighted and pooled using the Mantel-Haenszel fixed effects model. Statistical
heterogeneity was assessed using the Cochran?s Q and I2 statistics, if I2 50% or/and P < 0.10 were
used to indicate statistically significant heterogeneity and a random-effects model was applied.
Otherwise, a fixed-effect model was used [
]. Publication bias was assessed by visual
inspection of the funnel plot. All statistical tests were two-sided, and statistical significance was
defined as P<0.05.
A total of 39 potentially relevant studies were retrieved from three databases by the initial
A flow chart showing the study selection was presented in S1 Fig. The initial search
identified 39 studies, of which eleven studies by comprising 3165 patients published from 2012 to
2017 were finally included in this meta-analysis [
]. Eight studies from China, Two
studies from Japan and one from UK. Study characteristics are presented in S1 Table.
PNI and Overall survival (OS) in HCC
There eleven studies reported the prognostic value of PNI for OS. Eleven studies reported the
1-year OS, ten studies and eight studies described the 3-year OS, 5-year OS, respectively. The
results indicated that low PNI is significantly associated with poor prognosis of 1-year, 3-year
and 5-year OS, without heterogeneity (OR, 2.91, 4.05, 3.65; 95%CI, 2.30 to 3.70, 3.27 to 5.03,
2.96?4.50; I2 = 33%, 24%, 0%; P = 0.14, 0.22, 0.11 respectively), these results suggested that low
PNI predict a poor OS in HCC patients. (S2 Fig)
PNI and disease-free survival (DFS) in HCC
DFS was mentioned in four studies. The pooled estimate for DFS indicated low PNI is
significantly associated with poor prognosis of 1-year, 3-year and 5-year DFS in HCC patients (S3
Fig). A random-effects model was applied to calculate the pooled OR and 95%CI because of
significant heterogeneity (OR, 2.35, 2.57, 2.75; 95%CI, 1.71 to 3.23, 1.89 to 3.49, 2.01 to 3.75;
I2 = 0%, 68%, 55%; P = 0.39, 0.04, 0.11 respectively). The results indicating that low PNI is
likely to predict shorter DFS.
Relationship between PNI and clinic-pathological features
PNI and tumor stage. Four studies presented the data that about PNI and tumor stage in
HCC patients. Our results indicated that low PNI have lower incidence of I and II stage
(OR = 1.9, 95% CI = 1.22?1.96, P < 0.01), but there have no statistically significance in the
stage III and IV between high PNI group and low PNI group (OR = 0.74, 95% CI = 0.55?1.01,
P = 0.06) (S4A Fig).
PNI and cirrhosis. Five studies reported the association between PNI and the incidence
of cirrhosis, the pooled results indicated that PNI have no significant association with the
incidence of cirrhosis (OR = 0.86, 95% CI = 0.65?1.12, P = 0.26) (S4B Fig).
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PNI and tumor number. Six studies reported tumor number (single or multiple), the
pooled results suggested that PNI have no correlation with tumor number in HCC patients
(OR = 0.89, 95% CI = 0.45?1.75, P = 0.11) (S4C Fig).
PNI and tumor size. Tumor size( 5cm or <5cm)was reported in 4 studies, the pooled
result indicated that low PNI group have a higher incidence of large tumor (OR = 0.52, 95%
CI = 0.40?0.67, P = 0.004)(S5A Fig).
PNI and AFP. Five studies provided data about the correlation between PNI and serum
AFP, the pooled results suggested that low PNI group have a higher serum AFP than high PNI
group (OR = 0.51, 95% CI = 0.32?0.8, P = 0.003)(S5B Fig).
PNI and tumor recurrence. Tumor recurrence was reported in four studies, the pooled
results suggested that low PNI have a higher recurrence incidences (OR, 0.37; 95% CI 0.23 to
0.59; I2 = 47%; P<0.01) (S5C Fig).
A funnel plot was used to assess the included studies for overt publication bias showed
symmetry for OS and DFS (S6 Fig).
Some studies reported that the prognosis of hepatocellular carcinoma patients have a close
relation with tumor burden, liver function and body immune status [
recurrence and metastasis of hepatocellular carcinoma is still the most important reason for
treatment failure. There are some factors that lead to recurrence include tumor size, vascular
invasion, liver function, cirrhosis, immune status and so on. To our knowledge, the prognostic
and clinic-pathological value of PNI has recently been studied in patients with many
malignancies. However, the prognostic and clinic-pathological role of PNI in HCC patients is still
not reported. This is the first systematic review/meta-analysis to provide a prognostic role of
PNI and the relationship between PNI clinic-pathological characteristics in patients with
Eleven non-randomized trials compared the prognostic effects of PNI in HCC patients.
Our results indicated that low PNI is a poor prognostic factor for OS and DFS in patients with
HCC. These pooled results suggested that high PNI is a beneficial to the survival of HCC
patients and associated with more favorable outcomes such as lower AFP, lower recurrence,
minor tumor size and better TNM. However, PNI does not compromise clinic-pathological
features including tumor number and the incidence of cirrhosis. Given these data, a simple
PNI was shown to be a promising predictor of survival in HCC patients.
Several potential mechanisms may reveal that why low PNI is associated with poor
prognosis in HCC patients. First, more and more evidences confirm that systemic inflammatory
response plays a significant role in the development and progression of HCC. PNI which is a
combination of the albumin and total lymphocyte count, was initially used to evaluate the
immunological and nutritional aspects of patients undergoing surgery of the gastrointestinal
]. Low PNI may be the result of hypoalbuminemia and/or lymphocytopenia. Albumin
as the main component of plasma proteins, hypoalbuminemia reflected the presence of cancer
cachexia is caused by a sustained inflammatory response, either from the tumor itself or as a
host reaction [
]. However, impaired synthetic functions accompanying cirrhosis needs to be
considered as an additional determinant of reduced serum albumin. Lymphocytes are crucial
components of the immune system, play an extremely important role in the biological
behavior of HCC, such as initiation, proliferation, differentiation and metastasis [
], affect the
tumor microenvironment, prevent tumorigenesis and recurrence by generating cytokines and
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causing the cytotoxic effect of cancer cell death , so antitumor effect induced by the cellular
immunity of T lymphocytes decreased because of lymphocytopenia . Therefore, PNI
reflects both the nutritional and immunological status of the host and can be a predictor of
prognosis in HCC patients. Indeed, our findings indicated that PNI was an independent
prognostic factor on OS and DFS in HCC patients and consistent with the above evidences. Second,
our results indicated that low PNI was associated with more advanced tumor features, such as
tumor recurrence, tumor size, serum AFP and TNM. The present meta-analysis showed that
PNI was related to tumor recurrence and TNM, which might be explained by the
immunological status. However, the correlation between PNI and serum AFP worth further study.
The synthesis of albumin is involved in HCC patients accompanied with cirrhosis [
we studied the correlation between PNI and the incidence of cirrhosis, the pooled results
indicated that there is no obvious correlation between PNI and the incidence of cirrhosis.
Mengyun Ke et al found that PNI was associated with tumor number in HCC patients [
analyzed the six studies included in this meta-analysis, pooled results suggested that PNI have
no correlation with tumor number in HCC patients.
There were several limitations in our meta-analysis. First, all the included studies were
retrospective cohort studies. Second, we could not perform other subgroup analyses because of
the limited number of studies included. Third, those studies included in this meta-analysis
mainly from Asian countries, only one from Europe.
In summary, our study suggests that PNI may be a potential marker to predict the prognosis of
S1 Checklist. PRISMA checklist.
S1 Table. Characteristics of the included studies.
S1 Fig. Flow chart of literature search and study selection.
S2 Fig. Forest plots depicting 1-year OS, 3-year OS and 5-year OS reported in the included
studies. ORs are shown with 95% CIs. CI: confidence interval.
S3 Fig. Forest plots depicting 1-year DFS, 3-year DFS and 5-year DFS reported in the
S4 Fig. Forest plots depicting tumor TNM (A), the incidence of cirrhosis (B) and tumor
S5 Fig. Forest plots depicting tumor size (A), serum AFP (B) and the incidence of recurrence
S6 Fig. Begg?s Funnel plot for evaluation of publication bias in OS and DFS.
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Supervision: Jie Wang.
Writing ? original draft: Zhiling Wang.
Writing ? review & editing: Peijun Wang.
6 / 7
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