ISSN: 0975-766X CODEN: IJPTFI Available through Online ... · level was P value

Hassan Keramati*et al. /International Journal Of Pharmacy & Technology

IJPT| Sep-2016 | Vol. 8 | Issue No.3 | 4616-4628 Page 4616

ISSN: 0975-766X

CODEN: IJPTFI

Available through Online Review Article

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ASSOCIATION BETWEEN SELENIUM LEVEL AND BLADDER CANCER;

SYSTEMATIC REVIEW AND META-ANALYSIS Yadolah Fakhri

1, Vajihe Hassanzadeh

2, Gea Oliveri Conti

3, Nazak Amanidaz

4, Yahya Zandsalimi

5,

Bigard Moradi6, Leila Rasouli Amirhajeloo

7, Hassan Keramati

8,*

1Studends Research Office, Department of Environmental Health Engineering, School of Public Health, Shahid

Beheshti University of Medical Sciences, Tehran, Iran. 2Food and Cosmetic Health Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.

3Environmental and Food Hygiene Laboratories (LIAA), ‘G.F. Ingrassia’ Department, Hygiene and Public Health,

University of Catania, Catania, Italy. 4Environmental Health Research Center, Golstan University of Medical Sciences, Golstan, Iran.

5Environmental Health Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.

6Department of Health Public, Kermanshah University of Medical Sciences, Kermanshah, Iran.

7Department of Environmental Health Engineering, School of Public Health, Qom University of Medical Sciences,

Qom, Iran. 8Department of Environmental Health Engineering, School of Public Health, Semnan University of Medical

Sciences, Semnan, Iran.

Email:[email protected]

Received on 19-07-2016 Accepted on 20-08-2016

Abstract

Bladder cancer is one of the common cancers in men. The different studies have shown different results on the effects

of selenium on the risk of bladder cancer. The aim of this study was to determine the association between the

selenium in serum, Toenail and supplements on the one hand and the risk of bladder cancer on the other. Doing a

systematic review and meta-analysis of 9 studies (4 studies on the selenium level in the toenail, 2 studies in serum

and 3 studies in supplements), therefore, it was tried to achieve some exact results of the association between

selenium and the bladder cancer risk. The results showed there is no publication error in the observational studies

(Begger's test = -0.71; 95% CI (-4, 2.66). In the subgroups of selenium supplement, serum and Toenail, the

heterogeneity was I2 = 0% (P value = 0.81), I

2 = 0% (P value = 0.35) and I

2 = 1.47% (P value = 0.38) and overall I

2 =

63%(P value = 0.005), respectively. The risk ratio in the studies of selenium supplements, serum and Toenail was

FEM = 1.02 (P value = 0.8), FEM = 0.3 (P value<0.001) and FEM = 0.85 (P value = 0.1) and in general FEM = 0.83

(P value = 0.01) respectively. The increase of selenium in supplements does not any effect on the increase or decrease

of the bladder cancer (non-significant). The increase of selenium in serum and toenail reduces (significantly) the risk

of bladder cancer in first case and (non-significantly) in second case. In general, the results of this study supported the

lowering effect of selenium especially in serum on the risk of bladder cancer.



Keywords: selenium, bladder cancer, serum, toenail, supplements, meta-analysis

1. Introduction

The bladder cancer is one of the common types of cancer worldwide, especially among men. The risk factors for

bladder cancer include smoking (65% men and 35% women), occupational exposure, such as absorption of aromatic

amines, excessive absorption of arsenic and schistosomiasis infection [1 ,2] .

The bladder cancer is a complex disease; the polymorphisms of genes of little influence are involved in the

development of this disease [3] . There are strong evidences based on which NAT 2 slow acetylation and GSTM1 null

genotypes increase the risk of bladder cancer [4 ,5] . Although the mentioned factors are more than half of the causes

of bladder cancer [6] , but the still unknown factors have remained about which there is not any explanation. One of

these unknown factors is the environmental pollutants. The environmental pollutants include heavy metals and trace

elements that through influencing the oxidative stress mechanisms can be effective in reducing or increasing the risk

of types of cancer including bladder cancer [7 ,8] . The trace elements such as selenium play an important role in the

different intracellular processes. Lack of sustainability of these elements in the cell causes a cell dysfunction and

ultimately disease [9] . The forms of non-metallic selenium consist of the selenite and the organic selenium comprises

the methylselenic acid and selenomethionine [11] . Selenium has combined with amino acids; hence the name of

selenoproteins [11 ,12] . EPA has proclaimed the reference dose of selenium for preventing the adverse effects of

selenium on the health as 0.005 mg/kg-day [13] . Selenium can be both beneficial and harmful to human health. The

absorption of selenium to a certain extent has the anti-cancer effects, but the excessive absorption of it causes a

chronic toxicity in humans and diseases such as loss of hair and Toenail, gastrointestinal problems, skin rash, garlic

breath odor, nervous system abnormalities [14] and Keshan disease and Kashin-Beck disease [15] . Several

mechanisms have been proposed to explain the anti-cancer effects of selenium, including: rehabilitation of damaged

DNA, induction of phase II enzymes, increase of immunity, inhibition of cell cycle, angiogenesis and the induction of

apoptosis [16 ,17] . However it should be noted that the mechanism of rare elements in inhibition and development of

cancers is very complex. Although the anti-cancer effects of selenium have not still been fully known, but the

different studies have shown an inverse association of selenium level with gastrointestinal, lung and prostate cancers

[18-21] . Therefore, in this study we tried to carefully evaluate the association between selenium level in the toenail,

serum and supplements on the one hand and the risk of bladder cancer on the other by doing a systematic review and

meta-analysis.

2. Materials and Methods



This study was a systematic review and meta-analysis on the association between the selenium level in supplement,

serum and Toenail on the one hand and the risk of bladder cancer on the other. For finding the studies conducted in

Iran and the world, the databases SID, Irandoc, Scopus, Pubmed and ISI Web of Science was used.

1.2. The criteria of selection and evaluating quality of studies

At first a list of titles and abstracts of all studies available on the databases mentioned by three researchers (Mi. A,

Ya.F, Ha.K,) was procured in order to avoid the bias of researchers. Titles and abstracts of articles, published

between 1985 and 2016, were examined independently. The search for 2 weeks from 04/15/2016 to 30/04/2016 was

done and then the related studies were entered into the research process independently and by method of blinding the

initial evaluation. The similar studies were excluded. The main criterion of inclusion of different articles to this study

was a reference to the selenium level and the bladder cancer risk. In the second stage, the abstracts of the selected

different studies were investigated by researchers using the check-list STROBE that is a standard check-list. This

check-list contains 43 sections and evaluates the different and varied aspects of methodology, including the sampling

methods, measurement of variables, statistical analysis and the objectives of study [21] .

In this check-list the score of 40 was considered as the least achievable point and the score of 45 as the maximum

one. Finally the top articles that had gained the least point (40) given to questions of check-list, were entered to the

research and their data for meta-analysis were extracted. For determining the Bias Publication, the funnel plot and

Egger's test were used.

2.2. Data extraction

In this study, 9 articles (8 case-control studies and one cohort study) in all of which the almost same methodology had

been used and had been completed in the period 1989 to 2012, were meta-analyzed. The important information

needed to analyze the data, including information on the subject, title, method of study, type of study, study time,

score of each one in the system of (NOS) [Newcastle-Ottawa scale], the risk ratio of bladder cancer, the number of

cases, control and confidence level was collected.

3.2. Data synthesis and analysis

According to qualitative evaluation criterion NOS which includes Selection, Comparability and Exposure, the case-

control and cohort studies were scored. In the system NOS the score range is determined from 0 to 9. In this study,

the studies were classified into two groups of low score (<7) and high score (> = 7).

4.2. Statistical synthesis and analysis of data


IJPT| Sep-2016 | Vol. 8 | Issue No.3 | 4616-4628 619

The meta-analysis of data was done by software of Comprehensive Meta-Analysis V. 2.2.064. For calculating the

heterogeneity of the studies, I2 Higgins was used. For meta-analysis, in the studies in which I

2 was greater than 50%

the random effect model was used and one in which I2

was less than 50% the fixed effect one was applied. The

subgroups in this study included the qualitative score of study (high and low) and type of study. The significance

level was P value <0.05.

3. Results

1.3. Identification of the relevant studies

As shown in Figure 1, in general 498 articles were obtained by searching the databases SID, Irandoc, Ovid, Scopus,

Embase, ISI web of science and PubMed. Based on titles and abstracts and some other reasons, 352 articles were

excluded in the stage Eligibility. From among remaining 146 articles, 137 articles including the reported correlation,

hazard risk, mean missing key data for were set aside. Finally, 9 articles remained for meta-analysis. In general, from

between these 9 articles 8 case-control studies and one cohort study was obtained (figure 1). 4 studies measured the

selenium level in toenails, 2 studies the selenium level in serum and 3 studies that in complement.

2.3. Characteristics of the studies

General characteristics of studies such as year of publication, country, type of study, confrontation cases, cases, the

age of the participants, measurement of selenium level and the results have been shown in Table 1. The range of

publication years of articles was 1989 to 2012. In 9 articles 94248 participants in general (2410 patients and 91,838

controls) were detected. The average age of study participants was 62.5 year.

Figure-1. Studies selection process for meta-analysis.

Table1. Characteristics of studies included in the systemic review and meta-analysis.

Record identified through database in SID,

Irandoc, Ovid, Scopus, Embase, ISI web of

science and PubMed studies; (n=498)

Excluded on basis of title and

abstract (n=311)

Excluded for other reason (n=41)

Full text article on se and pc extracted

(n=146)

Studies excluded because they only reported

correlation, hazard risk, mean (n=79),

Studies excluded because they were missing

key data for meta-analysis (n=25),

Studies reported on se biomarkers (n=33)

Selenium supplement and

bladder cancer (n=3)

Serum selenium and bladder

cancer (n=2)

Toenail selenium and

bladder cancer (n=4)



First

Author

Yea

r

Country Type

study

Subje

ct

Cas

e

Age Measureme

nts of

selenium

Odd

s

rati

o

Lo

w

Hig

h

outcome

Hotaling

et al

201

1

USA cohor

t

77050 330 50–

76

Selenium

supplement

0.97 0.7

2

1.31 not support

the use of

commonly

taken vitamin

or mineral

supplements

or 6 common

anti-

inflammatory

supplements

for the

chemopreventi

on of

urothelial cell

carcinoma

[22

]

Clark et

al

199

6

USA case-

contr

ol

653 6 mea

n 63

Selenium

supplement

1.27 0.4

4

3.67 support the

hypothesis

that

supplemental

selenium may

reduce the

incidence of,

and mortality

from,

carcinomas of

several sites.

[23

]

Wallace

et al

200

9

Germany case-

contr

ol

2048 857 25–

74

Toenail

selenium

0.9 0.6

8

1.19 selenium is

not inversely

related to risk

of bladder

cancer overall;

however, they

raise the

possibility that

selenium may

be preventive

in certain

molecular

phenotypes of

tumors

[24

]

Kellen et

al

200

6

Belgium case-

contr

ol

540 362 ≥ 50 Serum

selenium

0.27 0.1

5

0.47 an inverse

association

between

serum

selenium

concentration

and bladder

cancer risk

[25

]

Zeegers

et al

200

2

Netherlan

ds

case-

cohor

t

2890 431 55–

69

Toenail

selenium

0.67 0.4

7

0.97 evidence is in

favor of an

inverse

association

[26

]



between

selenium and

bladder cancer

risk

Michaud

et al

200

5

USA case-

contr

ol

446 222 mea

n 62

Toenail

selenium

1.17 0.6

6

2.07 Prediagnostic

selenium

concentrations

measured in

archived

toenails were

inversely

associated

with bladder

cancer risk in

women

[27

]

Michaud

et al

200

2

Finland case-

contr

ol

264 132 50–

69

Toenail

selenium

0.9 0.4

5

1.78 association

between

toenail

selenium

concentrations

and bladder

cancer risk

in a cohort of

male smokers

with 132

bladder cancer

cases

[28

]

Helzlsou

er et al

198

9

USA case-

contr

ol

95 35 mea

n 59

Serum

selenium

0.49 0.1

6

1.49 support a role

for selenium

in the

prevention of

bladder cancer

[29

]

Lotan et

al

201

2

USA case-

contr

ol

7852 35 ≥ 50 Selenium

supplement

1.13 0.7 1.84 no preventive

effect of

selenium or

vitamin E

alone or

combined on

bladder cancer

in this

population of

men. Further

studies are

needed to

assess the

effect in

women, and at

different doses

and

formulations

[30]

Based on the criterion for qualitative evaluation (NOS) Newcastle-Ottawa Case scale, in the case-control and cohort

studies all of them were of score higher than 7; therefore they have high quality (Tables 2 and 3).



Table-2. Methodological Quality of Studies Included in the Final Analysis Based on the Newcastle-Ottawa

Scale for Assessing the Quality of Case-Control Studies.

Table-3. Methodological quality of studies included in the final analysis based on the Newcastle-Ottawa scale

for assessing the quality of cohort.

Ye

ar

Selection (Score) Compara

bility

(Score)

Exposure (Score)

Study Adequ

ate

definit

ion of

patient

cases

Representati

veness

of patient

cases

Select

ion

of

contro

ls

Definit

ion

of

control

s

Control

for

important

factor or

additional

factor

Ascertain

ment

of

Exposure

(blinding)

Same

Method

of

Ascertain

ment

for

Participan

ts

Nonresp

onse

Rate1

Tota

l

Scor

e2

Clark

et al

19

96

1 1 1 0 2 1 1 1 8

Wallac

e et al

20

09

1 1 1 0 2 1 1 1 8

Kellen

et al

20

06

1 1 1 1 2 1 1 1 9

Zeeger

s et al

20

02

1 1 1 1 2 1 1 1 9

Michau

d et al

20

05

1 1 1 0 2 1 1 1 8

Michau

d et al

20

02

1 1 1 1 2 1 1 1 9

Helzlso

uer et

al

19

89

1 1 1 1 2 1 1 0 8

Lotan

et al

20

12

Year Selection (Score) Compar

ability

(Score)

Exposure (Score)

Study Repr

esent

ative

ness

of

the

expo

sed

coho

rt

Selec

tion

of

the

non-

expo

sed

coho

rt

Ascertai

nment

of

exposur

e

Demonst

ration

that

outcome

of

interest

was not

present

at start

of study

Compar

ability

of

cohorts

on the

basis of

the

design

or

analysis

Assess

ment

of

outco

me

Was

follo

w-up

long

enou

gh

for

outco

mes

to

occur

Adeq

uacy

of

follo

w up

of

cohor

ts

Total

Score

Hotaling

et al

2011 1 1 1 1 1 1 1 1 8



The heterogeneity in subgroups of selenium supplement, serum and toenail was respectively (P value = 0.81) I2= 0%,

(P value = 0.35) I2= 0% and (P value = 0.38) I

2= 1.47% and in general ( P value = 0.005) I

2= 63%. Since the

heterogeneity in all subgroups was less than 50%, therefore for calculating the mean of risk the fixed effect model

was used. The risk ratio in studies of selenium supplement, serum and toenail was respectively FEM = 1.02 (P value

= 0.8), FEM = 0.3 (P value<0.001) and FEM = 0.85 (P value = 0.1). in general it was REM = 0.83 (P value = 0.01).

Results showed that an increase of selenium in supplements does not any effect in increase and decrease of the

bladder cancer. The risk of bladder cancer has decreased significantly in serum. It has decreased in toenail but non-

significantly (Figure 2).

Figure2. Forest plot of meta-analysis on selenium and bladder cancer in the selenium supplements , serum

selenium and toenail selenium subgroups.

The heterogeneity in studies of other countries and the United States was respectively 79%, 0% and in general 63%.

Therefore, for studies conducted in other countries the model of random effect was used and for studies of the United

States the fixed effect model. The risk ratio in other countries and the United States was respectively REM = 0.71 (P

value = 0.001) and FEM = 1 (P = 0.89) and in general FEM = 0.83 P value = 0.01) (Figure 3). Results of other

countries showed that risk of bladder cancer reduces significantly. However, the studies done in the United States

showed that selenium has not a significant effect on reducing the risk of bladder cancer. In general, the risk of bladder

cancer decreased 18% , significantly.

Figure 3. Forest plot of meta-analysis on selenium and bladder cancer in the Usa and other countries.



4. Discussion

The meta-analysis results of this study showed that an increase of selenium reduces 18% of the risk of bladder cancer.

Of course, the lowering effect in the studies of serum, toenail and supplement was different. Although our knowledge

of the effect of selenium on bladder cancer is little, many studies have reported its protective effect on the some kinds

of cancer [18 ,21 ,31-33] .

The various studies of clinical trials on the use of selenium supplement had contradictory results. For example, in

studies of Nutritional Prevention of Cancer (NPC) and Supplementation Vitamins et Minéraux Antioxidants there

was observed a non-significant inverse association between selenium and prostate cancer as well as between selenium

and vitamin E on the one hand and the prostate cancer on the other [21 ,32 ,34] .

NPC also reported that due to insufficient number of incident cases the association between selenium and cancer is

unknown [35] . The study of Longnecker et al and Satia et al showed that in high concentration of selenium in toenail

(~0.9 μg / g) and serum (~100 μg / L), the selenium in toenail and serum had a significant correlation [36 ,37] .

In addition, the great amount of the glutathione peroxidases and Selenoproteins P activities was observed in the

concentration range of 80- 95 μg / L of selenium in serum [38] .

Selenium may have an anti-cancer nature mainly through selenoproteins, although its special mechanisms are not

fully known. In development of colorectal cancer, the glutathione peroxidases and selenoproteins P have an anti-

oxidant nature, especially through scavenging reactive oxy-gen species and diminishing further oxidative damage

[39] .

The protective nature of selenium is related also to the activities of hydrogen selenide and selenomethionine inside

the cell; they can modify the proteins of thiols and mimicking methionine [41] .

Due to the effectivity of selenium on apoptosis, DNA repair and carcinogen metabolism, some studies have suggested

that adding it to the diet is essential. On the other hand, the oxidative stresses that are caused by exposing to arsenic,

cadmium and lead can be prevented or reduced by increasing the level of selenium [41] ; because these metals act as

selenium antagonist [41] .

The overall heterogeneity (I2 =63%) of the studies was due to difference in the type of sampling (serum or toenail),

smoking, type of study and the selenium level.

In this study the various studies showed different results. The cohort study of Hotaling et al showed that the long-

term use of selenium supplement (6 years) does not reduce the risk of bladder cancer [22]. In a case-control study,



Lotan et al obtained similar results [30]. The study of Michaud et al showed the increase of level of selenium in

toenail reduces the risk of bladder cancer, especially in women [28].

The inversion of funnel plot and the results of Eggers’ test showed that there is not a considerable publication error in

the results of this study (Figure 4).

Figure-4. Funnel plot of standard error by log adds ratio.

Limitations of this study included being incomplete the subgroups, time range of studies, the disease level (primary,

high grade and advanced), language of studies (except Persian and English), a difference of some confounding factors

such as age, income, race, smoking status, body mass index, physical activity, the lack of studies on selenium

supplements. For obtaining the association between age and the risk of bladder cancer, in some studies the exact age

was not specified. Finally, the measurement errors, including difference in equipment, measurement method, the staff

constitute the other limitations of this study.

5. Conclusions

The results of a systematic review and meta-analysis of nine studies showed that an increase of the selenium

concentration in serum reduces significantly the risk of bladder cancer (P-value <0.05). The effect of consuming the

selenium supplements as well as the selenium in toenail on the bladder cancer was not significantly lowering. In

general, the results of this study supported the lowering effect of selenium on bladder cancer.

6. Acknowledgment

Students research office of Semnan university of medical sciences was supports the financial of this research

(Code:7541, Date:2016/04/17).

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*Corresponding author;

Hassan Keramati*,

Email: [email protected]

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