Medical

Communication

Biosci. Biotech. Res. Comm. 9(3): 553-557 (2016)

Association of hypo ferritinemia and restless legs

syndrome in patients with iron de ciency anemia

M. Abbasi,

B. Safarzadehkhoushabi

and M S. Rabiei

Department of Hematology, Hamadan University of Medical Sciences, Hamadan, Iran

Department of Community Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

ABSTRACT

Restless legs syndrome (RLS) is one of the sleep disorders which affects sleep stages and causes repetitive awaken-

ings. The patho physiology of RLS is not well de ned, but there are some evidences about the role of iron de ciency

in these patients. Therefore, in the current research we investigated the frequency of iron de ciency anemia in such

cases. 143 patients referred to Hamedan University of Medical Sciences associated Hospital within the year 2015 with

hypoferritinemia underwent a cross sectional study. All collected data were classi ed and analyzed by SPSS 16; t-test

and chi-square tests. Of the 143 hypoferritinemic patients; 39 patients (27.3 %) met RLS criteria. Of that 17 cases

(43.58 %) were male and 22 persons (56.41 %) were female. According to the study restless legs syndrome was signi -

cantly more common in women than men.(P-value = 0.01). Restless legs syndrome was signi cantly associated with

serum ferritin levels in both sexes. And serum ferritin was signi cantly lower in men and women with non-infected

people. (P-value <0.01). RLS was signi cantly more common in females than males. RLS was signi cantly higher in

low ferritin levels. On the other hand its relation with low serum ferritin in both males and females is signi cant.

KEY WORDS: RESTLESS LEGS SYNDROME, HYPOFERRITINEMIA, IRON, ANEMIA

553

ARTICLE INFORMATION:

*Corresponding Author: Babak Safarzadehkhoushabi thesis.

irani@gmail.com

Received 29

Aug, 2016

Accepted after revision 30

Sep, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2015: 3.48 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

INTRODUCTION

Restless legs syndrome is a sleep disorder, including

periodic limb movements in sleep (PLMS). A condition

that occurs voluntary movements of limbs during sleep

cycle and alters the level (stage) of sleep and waking

are consecutive. Restless legs syndrome can be divided

into two types: type of family (primary) with known

genetic component, and acquired (secondary). Primary

type is seen in about  fty percent of  rst-degree rela-

tives of patients and believed to have a hereditary defect

in the metabolism of dopamine.Acquired type includes

changes in the metabolism of iron in a range of patients,

including pregnant women, and people with end stage

554 HYPO FERRITINEMIA AND RESTLESS LEGS SYNDROME WITH IRON DEFICIENCY ANEMIA BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Abbasi, Safarzadehkhoushabi and Rabiei

renal disease patients with iron de ciency and patients

with Vitamin B12 de ciency. Periodic limb movements

in sleep, such as restless legs syndrome may also occur

in a situation such as Parkinson, Narcolepsy and other

diseases with impaired dopamine production. The nega-

tive impact on quality of life is equal to or greater than

chronic obstructive pulmonary disease or myocardial

infarction. Severe restless legs syndrome causes the high-

est levels of sleep deprivation, among all sleep disorders

after mania, (Trenkwalder,1996, Montplaisir 2000,Allen,

2001 Mehmood et al., 2014 and Minár et al 2015).

The prevalence of PLMS is higher in the elderly. Max-

imally thirty percent of people over  fty years’ expe-

rience the disease secondary to an underlying medical

condition or drug side effects Restless legs syndrome is

more common among elderly people and about ten to

twenty percent of people over sixty- ve years’ experi-

ence the symptoms more speci cally. The prevalence of

the disease in women is doubled, (Ohayon,2000, Roth-

dach, 2000 Allen,2003). Studies in North America and

northern Europe also con rm that the prevalence of rest-

less legs syndrome (between  ve to twenty- ve percent

of the population) is common disease, (Zucconi,2004).

The population whom are at risk for restless legs

syndrome include: pregnant women, patients with end-

stage renal disease, patients with a positive family his-

tory, patients with iron de ciency anemia, frequent

blood donors, patients undergoing stomach surgery and

children with hyperactivity syndrome- decreased atten-

tion and vitamin B12 de ciency. It seems characteris-

tic feature of restless legs syndrome, is associated with

circadian functional elements dopamine pathway. The

circadian pattern of blood iron level is such that on the

night,  fty to sixty percent below the level of serum

iron in comparison to day. Patients prone to iron de -

ciency, have a greater chance of developing restless legs

syndrome. These groups included patients undergoing

gastric bypass surgery continuous blood donors as well

as elderly, (Banerji, 1970, Tarquini,1978, O’Keeffer,1994,

Hagan 1999, Silber, 2003, Borreguero, 2004, Earley,

2005 and Gamaldo, 2006 and Çurgunlu et al., 2012).

Restless Legs Syndrome also includes spontaneous or

voluntary movement like walk, shrug, wrong handling

or rubbing the legs on the bed for loss of sensation such

as tingling, itching, burning, heave or electric shock is

felt. Symptoms of this syndrome are the circadian pat-

tern. So in the morning and evening worsen. About

twenty percent of people with restless legs syndrome

have no voluntary movements during sleep (therefore

not required to identify). Although it causes severe sleep

disturbance in most patients, and is known as one of the

causes of sleep de cit in  ve to ten percent of Ameri-

cans. Although restless legs syndrome is a common neu-

rological motor disorder but under diagnosed and under

treated in many cases. On the other hand, due to lack of

awareness of health staff about the syndrome, diagnosis

and treatment of this syndrome is commonly missed,

(Walters, 1995, Hening 2004 Wilson, 2005 and Curgunlu

et al., 2012).

Researches on the prevalence of restless legs syn-

drome is not well established. The proper treat-

ment of this syndrome needs recognizing the extent

of it. Therefore it is concerned, Investigations about

the prevalence of this syndrome, the age and sex

of distribution in the society seems to be effective.

The recognition of this disease by the medical staff will

save the patients from ineffective treatments and some-

times misplaced and can take a step towards improving

the quality of life in these patients.

MATERIAL AND METHODS

This study was cross sectional research which was con-

ducted on patients with Hypoferritinemia, referring to

Hamedan University of medical sciences associated Hos-

pital in 2015. Inclusion criteria included: willingness to

participate in the study, ferritin less than 50 mg per dL

for women and less than 100 milligrams per deciliter for

men.

Exclusion criteria included: impairment of conscious-

ness (inability to respond to questions), physical-mental

disability (inability to work with the researcher), drug

addiction, current pregnancy (prone to anemia), sodium

valproate or carbamazepine or gabapentin or hypnotic

drugs (suppression of the symptoms of restless leg syn-

drome), Parkinson’s disease (mimic symptoms of restless

leg syndrome), history of renal failure (risk of anemia )

and a history of gastric surgery (gastric bypass) (prone

to anemia), diabetes mellitus ( symptoms of neuropa-

thy), history of diseases that can be seen in the process

of neuropathy) malabsorption syndrome, a de ciency of

vitamin B, Lyme disease, AIDS, cancer, malignancies of

the blood system and reticuloendothelial).

Questionnaire Form which was used in this

study, consisted of two parts. The  rst part included

demographic information, including age, sex

and place of residence (urban/rural), respectively.

The second part of the questionnaire included  ve ques-

tions, the patient was asked by the researcher. All of these

questions had yes or no answer and if  rst 4 questions

answered (Yes) the diagnosis of restless legs syndrome

was made for the individual. The last question was about

the family history of the disease in her/his family. Some

of the patients participating in the study refused. The

numbers of patients providing inaccurate information

were prevented from doing the proper research. To solve

this problem, researchers questioned more patients to

achieve the desired volume. The reliability and accuracy

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS HYPO FERRITINEMIA AND RESTLESS LEGS SYNDROME WITH IRON DEFICIENCY ANEMIA 555

Abbasi, Safarzadehkhoushabi and Rabiei

was assessed during questioning meaning that patients

with or without the necessary accuracy in speech, not

included in this study.

Values were presented as Mean ±Standard deviation

(SD). For statistical analysis, SPSS software (Version 16,

Chicago, IL, USA) was used applying chi

and T test. P

< 0.05 was de ned as signi cant.The study population

voluntarily participated in the investigation. Verbal con-

sent was obtained from the participants for publication

of the research results.

RESULTS AND DISCUSSION

In this study, 143 patients referred to the clinic of Hamedan

hospital in 2015 that do not qualify for exclusion criteria

and met the inclusion criteria for the study were involved.

Of these, 102 (71.3%) women and 41 (28.7%) were male.

(Table 1,2,3,4)

The average age of women participating in the study

was 34.35±9.9 years and mean age was 45.8± 9.0 for

men. Based on the  ndings of a CBC among the par-

ticipants, 12 patients (8.4%) had iron de ciency anemia

and 131 (91.6%) did not have iron de ciency anemia.

The mean serum ferritin for women participated in the

project was 35.87±9.4 mg per deciliter and for men was

64.0±21.0 mg per deciliter.

According to the study, 39 cases (27.3%) of

patients with low ferritin diagnosed with restless legs

syndrome And 104 (72.7%) cases did not express

symptoms of this syndrome. The mean serum fer-

ritin level in patients was 29.33±9.9 mg per decili-

ter versus 49.43±18.34 mg per dL in healthy cases.

The average age of men suffering from this syndrome

was 54±6.12 years and in females was 45.045±5.5. Serum

Ferritin level was 40.11±2.2 mg per deciliter in men with

this syndrome and this amount was 21± 2.5 for women.

Moreover, 7 cases (17.9%) of the patients had a positive

family history for this syndrome. And 32 (82.1%) had

no family history. In contrast, 104 (72.72%) of patients

with low ferritin levels were not affected by restless legs

syndrome. Of these, 80 patients (76.92%) were women

and 24 (23.07%) were male, (Table 2,3,4).

According to the study restless legs syndrome was

signi cantly more common in women than men.

(P-value = 0.01).In this study, it was con rmed that

restless legs syndrome is not associated with iron de -

ciency anemia signi cantly. (P-value = 0.24). Accord-

ing to the study restless legs syndrome was signi -

cantly associated with serum ferritin levels in both

sexes. And serum ferritin was signi cantly lower in men

and women with non-infected people. (P-value <0.01)

Ferritin levels in women with this syndrome was asso-

ciated, signi cantly (P-value <0.01), but the men were

not able to determine the signi cance of the data.

In this study, positive family history of the syn-

drome did not approved. (P-value = 0.75)

Restless legs syndrome in both sexes were also signi -

cantly associated with age and was more common in

older age. (P-value <0.01).

Table 1: The distribution of cases in this series

Male percent female percent total

17 43.6 22 56.4 39(100%)

Low ferritin

with iron

de ciency

anemia

Low ferritin

without iron

de ciency

anemia

5 12.8 34 87.2 39(100%)

Table 2: Frequency of restless legs syndrome

in females based on ferritin levels

Serum

ferritin level

Total

females

restless legs

syndrome

cases

0-15 0 0

15-30 22 22

30-50 80 0

Table 3: Frequency of restless legs

syndrome in males based on ferritin levels

Serum

ferritin level

Total

males

restless legs

syndrome

cases

0-15 1 0

15-30 29 7

30-50 11 10

Table 4: Frequency of restless legs

syndrome in females based on age groups

Serum

ferritin level

Total

females

restless legs

syndrome

cases

0-30 42 0

30-50 50 18

More than 50 10 4

Table 5: Frequency of restless legs

syndrome in males based on age groups

Serum ferritin

level

Total

males

restless legs

syndrome

cases

0-30 0 0

30-50 0 0

More than 50 41 17

556 HYPO FERRITINEMIA AND RESTLESS LEGS SYNDROME WITH IRON DEFICIENCY ANEMIA BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Abbasi, Safarzadehkhoushabi and Rabiei

According to the  ndings of our research it was found

that restless legs syndrome was signi cantly seen in

lower levels of ferritin. The syndrome is more common

in women but not signi cantly correlated with anemia.

Çurgunlu and colleagues in Turkey in 2012 reported that

the restless legs syndrome in patients with low ferritin

level was more frequent, (Çurgunlu et al., 2012).

Restless legs Syndrome (RLS) is a kind of sleep disor-

ders; disturbing sleep stages and causes repetitive awak-

ens. High risk populations for RLS including: pregnant

ladies, end stage renal disease patients, patients with

familial history for that, patients with iron de ciency

anemia, chronic blood donors and patients with gastric

bypass surgery and kids with ADHD and people with

vitamin B12 de ciency. The diagnosis of RLS consists of

four essential clinical criteria based solely on symptoms:

A sensation of an urge to move the limbs (commonly

legs); is usually associated with paresthesia. Onset or

worsening of symptoms when at rest; are not associated

with any speci c body position. Relief of symptoms with

movement; complete relief immediately or shortly after

initiating movement was also seen. Marked circadian

variation in degree or occurrence of symptoms; worse in

the evening, got improved in the morning, regardless of

quality or quantity of sleep.

Although Hogl and colleagues in 2005, did not reveal

any relationship between levels of serum ferritin; and

transferrin levels in serum, levels of free iron and restless

legs syndrome, however, stated that the soluble trans-

ferrin receptor (sTR) was signi cantly lower in patients

with this syndrome. In this study, high levels of serum

sTR was independent predictor of the risk of restless legs

syndrome, (Hogl, 2005).

This study, like those of Rothdach et al (2000), Ohayon

et al (2002) and Zucconi et al (2004), presently reports

that the syndrome is more common in older ages, which

is similar to the above  ndings. Bjorvatn and colleagues

in a study in 2005 have also found that the age wise

prevalence of this syndrome existed in two Scandina-

vian countries, being in cases of older than 30 years, on

the other hand, there were no signi cant relationships

with age as reported by Bjorvatn et al., (2005).

In this study, 17.9% of the participants had a positive

family history for this syndrome. Although this percent-

age is about 40-60% which was reported by Zucconi et

al, (2004) but a signi cant relationship was not found

in our study. That’s probably due to lack of recognition

of this syndrome in the past by the public and health

professionals (Zucconi 2004). Çurgunlu et al., have

stated that the prevalence of this syndrome in women

is two times more than men. This  nding has also been

con rmed by Ohayon (2002) and Zucconi, (2004). In

our study, the relationship between restless legs syn-

drome and serum ferritin was observed. Although more

studies are needed to con rm or refuse this theory.

In a study conducted by Blake et al. (1976), it has been

reported that iron is required for the production of tyros-

ine hydroxylase which is the limiting step in the produc-

tion. Some recent workers have reported that patients

who had serious symptoms of restless leg syndrome, got

it declined by supplements of iron, (Connor, et al., 2003,

Mehmood et al., 2014 and Minár et al 2015). Likewise,

we also report in this paper that serum iron level distur-

bances play a signi cant role in the pathophysiology of

restless legs syndrome.

CONCLUSION

Finally, this study concluded that the frequency of restless

legs syndrome in patients with low ferritin is about 27.3%.

This syndrome was signi cantly associated with reduced

levels of serum ferritin. Also this syndrome in elderly and

especially in women is more prevalent. Further studies

with larger sample size and prospective in urban and rural

centers, specialized treatment centers needs to be done. It

is suggested based on the  ndings of this study, subjects

with low serum ferritin, even without laboratory  ndings

of anemia, to improve the quality of sleep, or prevent the

syndrome can be treated with oral iron supplements.

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