Iron Deficiency and Pruritus: A Cross-Sectional Analysis to Assess Its Association and Relationship.

Background: As generalized pruritus can be a symptom of a systemic disease, iron deficiency may be the underlying internal cause of its symptoms. Because data on the relationship between iron deficiency and generalized chronic pruritus are limited, more research is needed to ensure proper diagnosis and management. Aims: To evaluate the prevalence of iron deficiency in patients with generalized chronic pruritus in the southeast region of Rajasthan and to assess the correlation of serum ferritin with iron deficiency variables. Materials and
Methods: An observational, analytical study was conducted among a total of 200 patients complaining of itching all across the body without any skin lesions for more than 6 weeks and enrolled in the outdoor and indoor Dermatology, Venereology, and Leprology departments of the Government Medical College, Kota. The duration of the study experiment was 1 year from June 2018 to May 2019.
Results: Females (108; 54%) were more than males (92; 46%) with a ratio of 1.17:1. The mean age of the patients was 37.35 ± 13.56. S. ferritin was found to be below 15 g/L in 58 (29%) patients. Significant correlation was found between S. ferritin and hemoglobin, MCV, MCH, and MCHC, and the P value was <0.05. Maximum number of patients (70; 35%) achieved visual analog scale (VAS) scores between 4 and 9, followed by 50 (25%) patients obtaining scores >9. Similarly, a correlation was found between the VAS score and hemoglobin, MCV, MCH, and MCHC and a statistically significant P value was obtained. Limitations: The sample size was small in the study. The overall levels of iron and serum transferrin were not checked, keeping patients' compliance in mind.
Conclusion: Although statistically significant results were found, limitations were also present in our study; so, further studies for proper diagnosis and management should be conducted in greater depth. Copyright:

Introduction

Prurigo (from Latin prurigo, synonym: itch) is one of the most perplexing symptoms. A simple definition of pruritus or itch is an unpleasant sensation and emotional experience associated with an actual or perceived skin disturbance, which triggers a desire to scratch.[1] It is an unpleasant sensation, which varies from person to person.[2] Pruritus may be present physiologically or pathologically.[3]

It is a common symptom of several diseases. Depending on the intensity, it may be mild, moderate, severe, or very severe, which may be acute or chronic, localized or generalized.[45] Chronic pruritus and irritation can have a significant impact on the course of illness, the quality of life, and the cost of health care.[6] As a very common complaint, the management of pruritic conditions is still a challenge for physicians and dermatologists due to its multifactorial causes and complex pathophysiology.

Some studies report that 14%–50% of pruritic patients without a clear dermatological cause have an underlying internal cause for their symptoms, including iron deficiency, which may serve an important role.[7] Reliable methods for assessing the status of iron in the population are an important component in the diagnosis of iron deficiency and, ultimately, iron deficiency anemia. If a single marker must be used to describe the prevalence of iron deficiency in a population, the serum ferritin level should be that marker and should be complemented by the hemoglobin (Hb) level of the same patient. Our primary aim was, therefore, to evaluate the prevalence of iron deficiency in patients with generalized chronic pruritus and to assess the correlation of serum ferritin with iron deficiency variables. Our secondary aim was to find a correlation between the visual analog scale (VAS) score and the iron deficiency variables.

Materials and Methods

This was a tertiary care hospital-based cross-sectional study conducted among a total of 200 patients who complained of itching throughout the body without any skin lesions for more than 6 weeks and were taking part in the indoor and outdoor Dermatology, Venereology, and Leprology departments of the Government Medical College, Kota. The duration of the experiment was 1 year from June 2019 to May 2020. The sample size was taken conveniently since there was no previous report on the prevalence of iron deficiency in generalized chronic pruritus.

Inclusion criteria

Patients with chronic generalized itch for more than 6 weeks

The itching was not associated with any skin lesions

The itching was not associated with any systemic symptoms.

Exclusion criteria

History of application of any topical drug formulation to the body in the last 6 weeks or more

History of the intake of any drug that induces or stimulates itch in the last 6 weeks or more

Patients who did not give consent to the study

Patients with a known case of any systemic disease

Smokers, pregnant and lactating mothers

History of drug abuse

History of seasonal variations

Children (up to 15 years)

Elderly patients (>65 years of age).

The informed written consent of each patient was procured after the purpose of the study had been explained. It was duly approved by the institutional ethical committee. All patients recruited were subjected to appropriate history taking, followed by general physical, systemic, and local cutaneous examination.

Laboratory investigations performed included complete blood count (CBC), liver function tests (LFT), renal function tests (RFT), blood sugar, complete urinalysis with microscopy, electrocardiogram (ECG), serum total protein test, serum electrolytes, serum ferritin, and thyroid hormone profile.

Patients were divided into five age groups: 16-25 years, 26-35 years, 36-45 years, 46-55 years, and 56-65 years. Hb values <12 g% for females and <13 g% for males were considered to be indicating anemia.[8] Anemia was rated as mild, moderate, and severe at 11-lower Hb g%, 8-10 g%, 9 g%, and <8 g%, respectively.[9] Patients whose mean corpuscular volume (MCV) were <80 fL, 80-100 fL, and >100 fL were classified as microcytic, normocytic, and macrocytic, respectively.[10] In similar way, three categories were created for mean corpuscular hemoglobin (MCH) values: <27 pg, 27-31 pg, and >31 pg.[10] Patients were also divided into three groups with mean corpuscular hemoglobin concentration (MCHC) values <31, 31-37, and >37, respectively.[10] We used a generally accepted cut-off level (<15 μg/dL) for serum ferritin, below which the iron stores are considered to be depleted.[11121314] Two groups were formed; one having values of S. ferritin <15 μg/L and the other having values of S. ferritin ≥15 μg/L.

The VAS score was used to evaluate the intensity of pruritus. It was graded as no pruritus, mild pruritus, moderate pruritus, severe pruritus, and very severe pruritus.

Mucocutaneous signs associated with anemia were also noted, including pallor conjunctiva (PC), angular cheilitis (AC), bald tongue (BD), koilonychia (K), dry brittle hair (DBH), brittle nail (BN), and cheilitis (C).

All data were recorded in the pre-designed proforma and filled in the MS Excel sheet. Statistical analysis was carried out using SPSS version 21 using appropriate tests, which were computed as mean and standard deviations for quantitative data. Unpaired Student's t-test was used for qualitative data. The coefficient correlation (Pearson's r) was calculated to assess the correlation between the variables. Univariate and multivariate logistic regression tests were also used among variables. P value <0.05 was considered statistically significant.

Results

In the 200 patients, females (108; 54%) outnumbered males (92; 46%), with a female-to-male ratio of 1.17:1. The patients' ages ranged from 16 to 65 years (mean 37.35 ± 13.56 years). The maximum number of cases (52; 26%) was identified in the age groups of 16-25 and 36-45 years. Females (34; 65.4%) outnumbered males (18; 34.6%) in 16-25 years age group, while males (31; 59.6%) outnumbered females (21; 40.3%) in the age range of 36-45 years [Table 1].

Table 1

Demographic data

Gender wise distribution
Gender	Number (%)
Male	92 (46)
Female	108 (54)
Age wise distribution
Age (years)	Number (%)	M (%)	F (%)
16-25	52 (26)	31 (59.6)	21 (40.3)
26-35	38 (19)	10 (26.3)	28 (73.7)
36-45	52 (26)	18 (34.6)	34 (65.4)
46-55	36 (18)	20 (55.6)	16 (44.4)
56-65	22	13 (59.1)	9 (40.9)
Mean±SD	37.35±13.56

F=female, M=male, SD=standard deviation

Hb concentrations ranged from 6 to 16.2 g% (mean 11.65 ± 2.35). A total of 68 out of 108 (63.1%) subjects were found to be anemic, with moderate anemia being found in the highest number of females (40; 37.03%). Similarly, mild anemia was discovered in 22 (23.91%) of 45 (49%) anemic males. MCV values ranged from 48 to 107.5 fL (average 80.50 ± 11.46), with the maximum number of normocytic cells being discovered (115; 57.5%). The majority of patients (84; 42%) fell into the first category, with MCH values ranging from 13.5 to 38.32 pg (mean 27.23 ± 4.60).

According to the VAS score, 70 (35%) patients had moderate pruritus, followed by very severe pruritus found in 50 (25%) patients [Table 2].

Table 2

Distribution of cases according to hemoglobin, MCV, MCH, MCHC, serum ferritin, VAS score

Cases according to hemoglobin values
Grading of anemia	Hemoglobin (g/dL)	Female (108)	Male (92)
Normal	≥12/≥13	40 (37.03%)	47 (51%)
Mild	11-11.9/12.9	19 (17.59%)	22 (23.91%)
Moderate	8-10.9	40 (37.03%)	15 (16.30%)
Severe	<8	9 (8.33%)	8 (8.7%)
Mean±SD		(11.62±2.34)	(11.65±2.35)
Cases according to MCV values
Morphology	MCV (fL)	Number (%)
Microcytic	<80	78 (39)
Normocytic	80-100	115 (57.5)
Macrocytic	>100	7 (3.5)
Mean±SD	80.50±11.46
Cases according to MCH values
MCH (pg)	Number	Percentage
<27	84	42
27-31 (normal)	82	41
>31	34	17
Mean±SD	27.23±4.60
Cases according to MCHC values
MCHC	Number	Percentage
<31	68	34
31-37 (normal)	132	66
>37	Nil	Nil
Mean±SD	31.93±2.56
Cases according to serum ferritin
S. ferritin (g/L)	Number	Percentage
<15	58	29
≥15	142	71
Mean±SD	41.13±42.35
Cases according to VAS score
Grading of pruritus	Range	Number (%)
Mild	1-3	37 (18.5)
Moderate	4-<7	70 (35)
Severe	7-<9	43 (21.5)
Very Severe	>9	50 (25)

Maximum patients with mucocutaneous symptoms had symptoms such as PC (101; 50.5%) along with DBH (46.23%), K (29; 15%), BN (26; 13%), C/AC (18; 9%), and BD (9; 5%). Only one of these signs was found in 23 (11.5%) of the patients, and a maximum of six signs was discovered in only one (0.5%) of the total patients [Figure 1a and b].

Figure 1

Picture showing mucocutaneous signs associated with anemic patients (pallor conjunctiva, bald tongue (a); koilonychia, brittle nail (b))

Using Pearson's coefficient, a positive correlation was found between mean age and S. ferritin. The relationship found, however, was not statistically significant (P ≥ 0.05). But when a positive correlation was calculated between the mean S. ferritin and gender, Hb, MCV, MCH, and MCHC results, the results were found to be statistically significant [Figures 2–4].

Figure 2

Scatter diagram showing positive correlation between S. ferritin and Hb

Figure 4

Scatter diagram showing negative correlation between hemoglobin and VAS

Scatter diagram showing positive correlation between S. ferritin and MCV

Similarly, a negative correlation was found between VAS and age, MCV, MCH, MCHC, and S. ferritin. This was statistically significant [Figure 5].

Figure 5

Scatter diagram showing negative correlation between s. Ferritin and vas

According to univariate logistic regression analysis, only Hb and MCV were significantly associated with S. ferritin; therefore, further analysis was performed using multivariate logistic regression. Both variables were found to have a significant effect on S. ferritin levels. However, the Hb values were more responsive to changes in S. ferritin levels, according to the odds ratio.

Table 3 summarizes all the correlation coefficients and the P values.

Table 3

Summary of study characteristics with statistical analysis values

Variables	r/t	P
Age and S. Ferritin	r=0.061	0.391
Gender and S. Ferritin	T=4.312	<0.0001
Hemoglobin and S. Ferritin	r=0.591	<0.0001
MCV and S. Ferritin	r=0.469	<0.0001
MCH and S. Ferritin	r=0.421	<0.0001
MCHC and S. Ferritin	r=0.391	<0.0001
AGE and VAS	r=−0.106	0.135
Hemoglobin and VAS	r=−0.669	<0.00001
MCV and VAS	r=−0.502	<0.00001
MCH and VAS	r=−0.447	<0.00001
MCHC and VAS	r=−0.493	<0.00001
S. Ferritin and VAS	r=−0.768	<0.00001

Discussion

Pruritus is an unpleasant sensation and emotional experience associated with an actual or perceived skin disturbance, which triggers a desire to scratch.[1] The association between iron deficiency and pruritus is not well established, and so is its pathophysiology, which is why there are no broader data available. Sneddon and Garretts[15] were the first to describe the relationship between iron deficiency and itching. Rook, Wilkinson and Ebling[16] also commented on this condition, and Vickers[17] published a paper in 1974 describing the relationship between iron deficiency and generalized pruritus in 87 patients. Large population prevalence data for chronic pruritus are still lacking, but some small sample studies such as the German pilot study (N = 200) on chronic itch showed a point prevalence of 13.9%, indicating a higher prevalence of chronic itch in the general population than previously reported.[18]

In this study, the ratio of females to males was 1.17:1. Similar gender differences were identified in other chronic pruritus studies in the general population.[192021] The increased number of females can be explained as the prevalence of anemia has been found more in females, so is the complaint of itching.[22]

Depending on age distribution, the maximum number of patients (52; 26%) was found in two age groups: 16-25 and 36-45 years. We did not find enough data to compare this study based on this age group categorization. The crowding of patients in these age groups may be due to the fact that people in these age groups are most active and concerned about their health-related issues.

Discussing Hb, the maximum number of females had normal Hb values (40; 37.03%) and moderate anemia (40; 37.03%). Similarly, there were 47 males with normal Hb (51%). The pattern was similar in a study (N = 753) conducted by Little et al.[23] in which females were more identified in the moderate anemic category and males were more identified with normal Hb values. The mean Hb concentration for females (11.62 ± 2.34) was lower than for males (11.65 ± 2.35) in our study, which was similar to that reported in previous studies.[24]

Hb may vary by gender and race/ethnicity, with women showing 1-2 g/dL lower Hb level than men.[25] According to the 2007 Indian National Family Health Survey (NFHS), approximately 55% of women and 24% of men aged 15-49 years suffered from anemia.[22]

In this study, mean values for MCV, MCH, and MCHC were 80.50 ± 11.46, 27.23 ± 4.60, and 31.93 ± 2.56, respectively. As a result, in females, anemia was present in 68 patients (63.1%), of whom iron deficiency anemia was present in 18 (26.47%) patients. Similarly, 45 (49%) males were anemic, with iron deficiency anemia present in 24 (53.33%) of the patients.

Reliable methods for assessing the iron status of the population are an important component in the diagnosis of iron deficiency and, ultimately, iron deficiency anemia. Key laboratory measures to assess the iron status are transferrin saturation, erythrocyte protoporphyrin, and serum ferritin, and the latter is the most useful and specific biochemical test.[2627] Low serum ferritin levels reflect depleted iron stores, and are therefore a pre-condition for iron deficiency. In this study, only the serum ferritin level was used to assess the status of iron stores and iron deficiency. Considering the high cost, it was not feasible to get all the tests done for patients in the government hospital.

We found 57 (28.5%) patients with S. ferritin levels below 15 μg/dL. In a systematic review, it was concluded that serum ferritin was the most potent test for iron deficiency in both the population and hospital patients.[28] This analysis did not include the transferrin receptor like our study did. The results obtained in our study may vary if the cut-off for S. ferritin is changed, as S. ferritin cut-offs currently recommended by several expert organizations demonstrate considerable inconsistency [Table 4].

Table 4

Examples of recommended serum ferritin cut-off to determine iron deficiency

Organization	Population group	SF cut-off, μg/L
WHO[2915]	Adults	<15
CDC[30]	Persons >6 months of age	<15
Royal College of Pathologists of Australasia[31]	Adults	<30
Group for the Research and Education on Anemia Therapy in Women[32]	Women	<30
American Association of Blood Banks[33]	Female blood donors with hemoglobin 12-12.5 g/dL	<26

Of the females, 34 (31.48%) were found to have an iron deficiency, in which iron deficiency anemia was present in 31 (28.7%) females. Similarly, 24 (26.08%) of the total males were found to have an iron deficiency, in which 22 (24%) males had iron deficiency anemia. Iron deficiency anemia was confirmed using the values of S. ferritin and Hb. Our data indicate that low iron status in the body does not always run parallel to iron deficiency anemia, as not all patients with low iron had iron deficiency anemia in this study. This can be explained by the fact that the status of iron can be considered a continuum from iron deficiency with anemia to iron deficiency without anemia, to normal iron status, and finally to iron overload.[34] Iron deficiency anemia should, therefore, be considered as a subset of iron deficiency.

Statistically significant results were obtained separately on comparing S. ferritin and VAS with Hb, MCV, MCH, and MCHC. Since there was no available severity grading for S. ferritin values <15 μg/L related to Hb, MCV, MCH, and MCHC values, the association between variables was better calculated using the correlation coefficient, P value, univariate and multivariate logistic regression tests.

Based on these results, it can be explained that the VAS is negatively correlated with the variables in our study, as pruritus will be more intense if the values of other variables decrease.

Iron deficiency has been reported to cause symptoms unrelated to anemia, including headache, irritability, exercise intolerance, hair thinning, soreness or burning of the tongue, AC, K, pica, dysphagia, chronic fatigue, and muscle weakness.[35] Among the iron-deficient patients, PC, dry skin, DBH, K, BN, AC, BD, and C were present in 87.9%, 77.5%, 50%, 36.2%, 27.6%, 19%, 15.5%, 10.3% cases, respectively. These skin signs may be explained to amount to iron deficiency anemia as iron is a well-known major constituent of several tissue compounds, usually classified as heme iron compounds (contained in cytochromes, myoglobin, catalase, and peroxidase); iron-sulfur proteins, and metalloproteins, compounds requiring iron as a cofactor.[36]

Limitations

Small sample size

Not determining total iron level and transferrin saturation level.

Conclusion

Iron deficiency can both cause and increase the prevalence of chronic generalized pruritus, according to published research. A statistically significant relationship was found between S. ferritin and the severity of pruritus. This topic should be researched with a larger sample size in order to assist us in our endeavors.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.