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Expert Review of Hematology

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Pica as a manifestation of iron deficiency

Caterina Borgna-Pignatti & Sara Zanella

To cite this article: Caterina Borgna-Pignatti & Sara Zanella (2016) Pica as a manifestation of iron deficiency, Expert Review of Hematology, 9:11, 1075-1080, DOI: 10.1080/17474086.2016.1245136

To link to this article: https://doi.org/10.1080/17474086.2016.1245136

Accepted author version posted online: 04 Oct 2016. Published online: 19 Oct 2016.

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REVIEW

Pica as a manifestation of iron deficiency Caterina Borgna-Pignatti and Sara Zanella

Department of Medical Sciences, Section of Pediatrics, University of Ferrara, Ferrara, Italy

ABSTRACT Introduction: Pica is the compulsive eating of non-nutritive substances. It is often associated with iron deficiency but its pathophysiology is unknown. Areas covered: We searched the literature using the keywords listed below. Our aim was to describe the phenomenon in its various aspects, to touch briefly on the historical and cultural background, and to examine in more detail the studies that tried to analyze the relative roles of iron deficiency and pica. Expert commentary: Pica is an intriguing symptom known for centuries. Pregnant women and preadolescents are at the highest risk of pica. Iron absorption is reduced in the presence of non- nutritive substances. Iron therapy usually cures the pica behavior. There are different forms of pica, one caused directly by iron deficiency probably due to the lack of iron in some areas of the brain and one more culturally driven and including mostly geophagy.

ARTICLE HISTORY Received 28 July 2016 Accepted 3 October 2016 Published online 19 October 2016

KEYWORDS Geophagy; iron deficiency; pagophagia; pica

1. Introduction

The Latin word pica indicates a bird, the magpie, that is supposed to eat indiscriminately whatever it finds. In the medical language, the term refers to the compulsive eating of nonedible substances for more than 1 month [1]. The practice has been known since antiquity and Hippocrates documented it more than 2000-years ago, considering it a ‘corruption of the blood’ [2]. It is of great historical interest that Cornelius Celsus [3] wrote in 40 AD that those who have a bad color labor under a malacia (the craving for nonfood substances). Livingstone [4] mistranslated the Swahili term for anemia with ‘disease of earth eating,’ and in American plantations the pallor of slaves was attributed to earth eating (all the historical citations are taken from Young et al. [5])

The name of the habit differs according to the substance eaten. There are many nonfoods that can be introduced: geophagy is the intentional consumption of earth, pagopha- gia the eating of at least a tray of ice daily for 2 months or of ice chips [6], rhizophagy the eating of uncooked rice, amy- lophagy describes eating starch and uncooked pasta. Many other unusual types of pica have been reported, including heads of burnt matches (cautopyreiophagia), cigarettes and cigarette ashes, paper, cardboard, mothballs, egg shells, coins, vinyl gloves, baking powder, and others. Smooth clay is the kind of earth eaten more often, while gritty pieces of earth are usually avoided. Sponge and rubber foam, and even stones (lithophagy) have been reported as nonfood substances craved by iron-deficient celiac children [7,8]. The introduction of more than one substance is called polypica. A subtype of pica is food pica that consists of compulsively eating one particular food, especially if crunchy, such as carrots, cabbage, turnips, etc. [9]. While pagophagia appears

to be common in the USA, affecting 25% of iron-deficient patients [10], geophagy is probably more common in the rest of the world. Pica has been reported from many coun- tries; it is an accepted habit in some cultures, especially in Africa, and is present also in nonhuman primates and other animals. A literature review indicated that pregnant women and preadolescents are those who consume clay most fre- quently. Surprisingly enough, an entire industry has origi- nated from geophagy, involving excavators, traders, and vendors. Young et al. [5] published a detailed and fascinating review of reports on geophagy written by anthropologists, geographers, nutritionists, and medical doctors creating a ‘pica literature database.’ In the attempt to understand the physiological basis for the craving, the authors formulated two adaptive and one nonadaptive hypothesis. The adaptive ones include (1) nutrient deficiency according to which cal- cium, sodium, zinc, and iron are ingested to compensate for their lack and (2) protection from enterotoxin or parasites by reducing the permeability of the gut wall or binding directly to toxins. According to the third, nonadaptive hypothesis, there would be no benefit from geophagy which, instead, could be an epiphenomenon of neurological problems, pos- sibly caused by nutrient deficiencies. Collateral effects of pica, in addition to various kinds of poisoning, include abdominal problems ranging from discomfort and pain to intestinal occlusion requiring surgery [11], tooth damage, and electrolyte disturbances. The eating of hair can lead to the formation of trichobezoars [12]. Infestation with hel- minths was found to be more common in geophagous than in nongeophagous Zambian children [13]. Geophagic pregnant women from South Africa were reported to have high levels of blood lead, which can represent a risk for the developing fetus [14]. Lead poisoning has been common in

CONTACT Caterina Borgna-Pignatti c.borgna@unife.it Department of Medical Sciences, Section of Pediatrics, University of Ferrara, Via A.Moro 8 44124, Ferrara, Italy

EXPERT REVIEW OF HEMATOLOGY, 2016 VOL. 9, NO. 11, 1075–1080 http://dx.doi.org/10.1080/17474086.2016.1245136

© 2016 Informa UK Limited, trading as Taylor & Francis Group

nutritionally iron-deficient toddlers living in older houses who ingested the flaking paint. As much as 40% lead by weight is present in dried paint used before World War II and is still present in millions of dwellings inhabited by under- privileged people in the USA [15].

2. Pica and iron deficiency

There are many reports in the literature, both clinical cases and case series, on the association between the two condi- tions. The reported frequency in iron-deficient patients is highly variable, reaching in a study 55% [10]. A recent research identified pica in 11% of iron deficient, compared with 4% of iron replete, American blood donors [16]. A metanalysis of 83 studies including 6,407 individuals with pica and 10,277 con- trols was recently reported [17]. Pica was associated with 2.35 times greater odds of anemia, and lower Zn concentration. More iron-deficient women than men are affected by pica. More recently, pica has been observed also among patients who had undergone Roux-en-Y gastric bypass who are fre- quently affected by iron deficiency because of reduced iron absorption and decreased iron intake. In fact, acid secretion is nearly absent in the remaining small gastric pouch and both heme and nonheme iron depend on the acidic environment of the stomach for efficient absorption [18–20]. Patients do not usually volunteer the information, either because they under- rate its importance, or out of shame for what might be con- sidered a weakness or a vice. On the other hand, physicians do not often inquire about pica, despite the potential harm that it may cause. Iron treatment stops the craving for nonnutrients in the majority of reports, but not all. In the above-mentioned study of blood donors [16], those given iron reported a marked reduction in the desire to eat the nonnutritive sub- stance (mostly ice) by days 5–8 of therapy, with disappearance of the symptoms by days 10–14. Auerbach and Adamson [21] have reported the near instantaneous elimination of pagopha- gia during intravenous infusion of iron. In 16 of 17 iron- deficient French teenagers from the island of La Réunion who ingested large amounts of raw rice and ice cubes, treat- ment with iron cured pica within a few weeks [22]. In a study, 47 children with iron-deficiency anemia and pica were com- pared with iron-deficient children without pica, and with non- anemic children. The results demonstrated significantly lower levels of selenium and zinc and significantly higher oxidative stress index in the iron-deficient pica group as compared with both control groups [23].

3. Pica and pregnancy

Pica is frequent in pregnancy, and in many countries it is considered a sign of beginning gestation. Horner et al. [24] reviewing the pica practices of pregnant women found that pica had declined between the 1950s and 1970s, and that affected mainly women of lower socioeconomic status. The authors recorded a fourfold increase in pica prevalence in pregnant African-Americans. The risk of pica was twice as high for women residing in rural areas. The observation is in accordance with the data of Edwards et al. [25–27] who noticed a decrease in the prevalence of the phenomenon

with time. A recent metanalysis including 70 studies revealed an aggregate prevalence estimate of 28%.

Pica prevalence was higher in Africa compared with the rest of the world, increased as the prevalence of anemia increased, and decreased with the level of education. These variables partially explained the heterogeneity in prevalence reported in the literature [28].

In the past, pregnant women in the rural South of the USA were known to travel to specific river banks to gather clay that was then baked in the oven to the desired texture. Edwards and coworkers [25], wanting to compare the habits of the rural women with those of women living in a urban environment, studied the frequency of pica, the biochemical parameters during the course of pregnancy, and pregnancy outcomes in 553 African-American women accessing prenatal clinics in Washington D.C. They noticed that urban pregnant women did not report geophagy. Instead, pagophagia was present in 8% and craving for starch in 1.4% of the women. It can be hypothesized that the widespread availability of ice could change the habit from geophagia to pagophagia in the major- ity of women. Gestational age, body length, and body weight were not different, but head circumferences of infants deliv- ered to pica women were smaller than those of non-pica women. In conclusion, they found that in women living in an urban environment there was a decrease in the prevalence of pica and a shift in taste from clay and dirt to ice and freezer frost. In the island of Pemba, Zanzibar, Tanzania, 40% of the pregnant women interviewed suffered from some kind of pica. By multivariate logistic regression, any pica was associated with anemia, nausea, and abdominal pain [29]. A study of 158 American pregnant adolescents (aged ≤18 years), two- thirds of whom were African-American and 25% were Hispanic, revealed that 46% engaged in pica behavior. The substances ingested included ice (37%), starch (8%), powders (4%), and soap (3%). Serum ferritin and hepcidin concentration were significantly lower in pica women [30]. It appears that pica is very infrequent in privileged populations. In a cohort of well-nourished Danish women, only 0.02% had pica [31].

4. Is pica responsible for iron deficiency?

Some authors have suggested that pica may induce iron deficiency by replacing dietary iron sources or inhibiting the absorption of iron [9,32,33]. Although pica is probably attribu- table to lack of iron in the central nervous system, substances interfering with iron absorption may exacerbate the iron defi- ciency. Interesting reports came in the early 1970s from Turkey, where geophagy was a common finding among chil- dren and women. The children, in addition to severe iron- deficiency anemia and to zinc depletion, presented with a syndrome characterized by growth retardation, hypogonad- ism, and hepatosplenomegaly. Some patients with this syn- drome also had a thalassemia-like appearance with the typical skull-bone changes. The syndrome had been known in Turkey for several decades. Oral absorption of inorganic and radio- active iron and zinc was reduced in the presence of clay in some cases with prolonged geophagy. Treatment with oral zinc for 6 months corrected impaired growth and delayed puberty [34]. In the above-mentioned randomized controlled

1076 C. BORGNA-PIGNATTI AND S. ZANELLA

trial performed in Zambian schoolchildren, 74% of whom were geophageous, iron supplementation did not reduce the pre- valence of geophagy or the amount of earth introduced. The authors concluded that iron deficiency, that was slightly more prevalent in children eating earth, could be due to impaired iron absorption [13]. An earlier study had demonstrated that absorption of 55Fe ascorbate was greatly decreased when 250 g of earth was eaten by five habitual geophagists [35]. A few years later another study was carried out to determine the effect of laundry starch on the intestinal absorption of inor- ganic and hemoglobin iron. In vitro, laundry starch bound 19– 80% of the available 59FeSO4 and 34–68% of the available 59Fe-hemoglobin. In vivo, laundry starch significantly inhibited mucosal uptake of 59FeSO4 from isolated duodenal loops. The researchers observed inhibition of iron absorption both in anemic and non-anemic rats to whom laundry starch was administered 1 hour before a dose of 59FeSO4. The data obtained indicated that laundry starch in addition to decrease the mucosal uptake or inorganic iron blunts the compensatory increased iron absorption induced by anemia [32]. It can be concluded that eating earth, clay, and starch interferes with the absorption of iron and zinc. However, this hypothesis cannot be invoked for other substances and especially for ice. Also, this hypothesis is in contrast with the rapid disap- pearance of pagophagia when iron deficiency is corrected [21,36,37].

In contrast with previous in vivo and in vitro studies, recent results reported by Seim et al. [38] suggest that geophagic substances do not bind to bioavailable iron and are not responsible for reduced iron absorption. These authors have proposed a novel in vivo model for assessing the impact of geophagic earth on iron status. They gavaged chickens with clay commonly eaten by pregnant women in Tororo, Uganda, at doses proportional to the quantities typically consumed by humans. The authors checked weekly for hemoglobin, and, at the end of the study, for liver iron, liver ferritin, and gene expression of the iron transporters divalent metal transporter 1 (DMT1), duodenal cytochrome B, and ferroportin. Only mini- mal impact was detected on iron status indicators and in the transcript levels of duodenal transporters in the gavaged ani- mals, suggesting that all birds were iron deficient. However several methodological problems, among which the dose of clay administered, weaken the significance of the study.

5. Is iron deficiency responsible for pica?

It is commonly felt by pediatricians and hematologists that iron deficiency itself can induce pica. In the attempt to clarify the matter, Young et al. [5] examined the nutrient-deficiency hypothesis, according to which geophagy would be an attempt to compensate for the lack of iron, zinc, or calcium. If that were the case, people with the greatest needs would practice geophagy more often. After careful review of the literature and calculation of the nutritional requirements for each substance, the authors excluded the hypothesis. In fact in their study there was no correlation between the age when calcium and zinc were most needed and the prevalence of geophagy. Things are a little different for iron. Young et al. [5] found a statistically significant correlation between geophagy

and anemia, but geophagy did not seem to be aimed at correcting it. In fact, they observed that clay eaters tended to prefer white clay instead of the iron-richer red clay, and the Ewe people of Ghana actually are known to remove iron from red clay before consumption [39]. In addition, the fact that pica occurs twice as often at the beginning of pregnancy than in late pregnancy, when the need for iron is greatest, made the authors to reject the hypothesis. Nausea of the first trime- ster or pregnancy could well explain the craving for earth. However, iron deficiency could be an indirect cause of pica, mediated through complex neurological mechanisms, fitting with the authors’ nonadaptive hypothesis.

Several reports testify to the efficacy of iron therapy in reducing or abolishing pica. Iron therapy cured pica even before increasing the hemoglobin level of 13 iron-deficient pagophagic patients (16% of 81 iron-deficient patients) who ate at least one tray of ice daily [40]. The correlation between serum iron levels and symptoms of pagophagia was best demonstrated by disappearance of symptoms in 22 of 23 patients with the symptom of pagophagia and iron- deficiency anemia, when serum iron levels rose to or above 70 μg/100 ml [36]. Even the striking symptom of an individual eating from 4 to 9 Kg of ice a day was relieved within a few days by iron therapy [6]. Resolution of ice craving was obtained also in a small group of iron-deficient women who had undergone a gastric bypass [18]. Association of pica, iron deficiency, and celiac disease has been reported, suggesting the primary role of iron malabsorption in the genesis of pica. A gluten-free diet was often sufficient to completely resolve the habit [7,41]. In a study of 230 women and 32 men with iron deficiency, 118 patients (45%) reported pica; of these, 87% craved ice. In logistic regression analyses, young age and severity of iron deficiency were found to predict pica [42]. The same group of researchers could not find a correlation between common alleles of the TMPRSS6 gene that encodes matriptase-2, a serine protease that represses hepcidin, and pica [43].

A study aimed to determine the relationship between pagophagia and H. pylori infection in patients with iron- deficiency anemia found that intestinal iron absorption was neither influenced by pagophagia nor by H. pylori infection. In fact, ice does not affect the environment of the duodenum. Together these results suggest that pagophagia is not a cause, but a consequence of iron deficiency [44].

6. Psychiatric cases

Severe cases of pica have been included among the obsessive compulsive spectrum of symptoms and disorders. In a large French study [45], 23 adults out of 943 hospitalized patients, but none of the 108 hospitalized children, were found to have pica, with a prevalence estimated at 2.4%. Among psychiatric patients, pica is often a secondary diagnosis associated with profound mental deterioration. The ingestion of nonnutrient substances in those cases is probably due to an incapacity of discerning among different mouth-introduced substances. Only two patients presented with iron-deficiency anemia but iron therapy did not improve pica. In these cases, pica could

EXPERT REVIEW OF HEMATOLOGY 1077

therefore benefit from specific therapy [46], either behavioral or with selective serotonin reuptake inhibitors. These cases, however, are completely different from the form of pica asso- ciated with iron deficiency normally seen by hematologists.

7. Neurological basis of pica

The predominant cause of pica associated with iron deficiency could be the scarce amount of iron in the tongue, olfactory apparatus, or other locations in the brain [47]. In the 1970s, Mackler and coworkers demonstrated in animal models that iron deficiency results in altered energy production, reduced levels of iron containing enzymes, and impaired intermediary metabolism [48]. More recently, experiments in rats have shown that iron deficiency can modify olfactory behavior and that DMT1 levels are significantly higher in the olfactory bulbs of iron-deficient rats. Thus, the molecular mechanism of olfactory iron absorption and possibly of olfactory or gustatory function involves DMT1 and is influenced by body iron reple- tion [49]. The gustatory function might also involve DMT1 and might be influenced by body iron repletion. It has been sug- gested that the iron content of the hippocampus influences the expression of pica in humans. To investigate the role of micronutrients in gustatory function, thresholds were esti- mated for four basic tastes in 38 young Japanese women: iron deficiency was found to be responsible for hypogeusia for all tastes except salty [50]. Hunt et al. [51] demonstrated that individuals with iron-deficient anemia, but not controls, had a significantly improved response time on a neuropsycho- logical test when chewing ice. These authors hypothesized that chewing ice triggers vascular changes that lead to pre- ferential or increased perfusion of the brain. Potential explana- tions include activation of the dive reflex, which would lead to peripheral vasoconstriction and preferential perfusion of the brain or, alternatively, sympathetic nervous system activation, which would also increase blood flow to the brain. This would result in increased alertness and processing speed in anemic patients and would explain why anemic individuals crave ice.

The hypothesis that ice is eaten to reduce the burning of glossitis and stomatitis due to iron deficiency seems too sim- plistic [52], also in view of the rapid resolution of pica follow- ing iron infusion [21].

8. Conclusion

Pica is an overlooked phenomenon that is often associated with iron deficiency. Pagophagia, the compulsive eating of ice is the most common form associated with iron deficiency in adults in the USA, while in children and in other parts of the world geophagy (earth eating) and eating of paint or other unusual substances is more common. Pregnant women are at a higher risk of pica than the rest of the population. Whether the greater availability of ice to rural women will in the future modify the habit from geophagy to pagophagia is not known. The causative role of iron deficiency is suggested by the appearance of the behavior in conditions of iron malabsorp- tion, and by the rapid response to iron therapy. In addition, patients do not necessarily crave for iron-containing sub- stances (e.g. for ice). The pathophysiological basis of pica is

probably to be researched in the decreased iron levels in the central nervous system. The dangerous side effects of eating nonnutritive substances should be kept in mind.

9. Expert commentary

Pica is a fascinating phenomenon and its association with iron-deficiency anemia has been well known for centuries. There appear to be at least three different kinds of pica, one culturally driven, more frequent among certain ethnic groups (African, Asian), one related to iron deficiency (crav- ing for ice, or pagophagia in half of the cases), and one present in psychiatric patients, as an expression of an obses- sive compulsive disorder. The patients do not spontaneously offer the information on their habit which should be actively elicited because of its potential adverse effects. The inges- tion of clay, stones, or fibers can cause complications requir- ing surgery. Particular attention should be given to pregnant women, especially African and Asian, of low socioeconomical level. The ingestion of toxic substances such as lead is dangerous for the fetus. Lead poisoning can cause severe neurological problems in children eating flaking paint. Iron- deficient individuals may be cured of pica when treated with iron. Until recently, not many studies have been performed in order to clarify the pathophysiology of the symptom. On the basis of the studies reported so far, it can be said that eating earth and starch seems to decrease iron absorption, and therapy with iron resolves the craving only in a propor- tion of those patients. On the contrary, pica for other sub- stances, and in particular for ice, responds well to iron treatment suggesting the causative role of iron depletion. The explanation of the different behaviors could be that ice does not interfere with iron absorption while earth does, creating a loop between reduced absorption and lack of response to iron. These data would fit with Young et al’s [5] nonadaptive hypothesis.

Recently, research on iron absorption in animals has received a new impulse, and a role for the olfactory bulb and for the hippocampus is being discovered. Also, the finding of pica in patients with iron malabsorption, as in celiac disease, points to the primary role of iron deficiency. The precise pathophysiology of pica, however, remains an enigma and is still the source of speculation. It is clear that iron deficiency in the presence of pica must be treated and the eating of non- foods strongly discouraged, although pica developed on cul- tural basis will likely continue.

10. Five-year view

The relationship between pica and micronutrient deficiencies merit further study. The striking developments that are being obtained in the field of iron metabolism [53] might help to clarify this physiological enigma. Promising fields involve the study of the molecular mechanisms of olfactory iron absorp- tion and possibly of gustatory function. Both the olfactory and gustatory function might involve DMT1 and other molecules at the basis of the iron metabolism. Also, the role of the iron content of the hippocampus could provide interesting information.

1078 C. BORGNA-PIGNATTI AND S. ZANELLA

Key issues

● Pica is defined as the compulsive eating of non-nutritive substances. It frequently accompanies iron deficiency. Careful inquiry is necessary to take it to light, because the patients are sometimes ashamed of their behavior

● Its frequency is highest in pregnant women and in preadolescents.

● Side effects span from tooth wearing to helminth infesta- tion and lead poisoning.

● Several hypotheses have been proposed to explain pica (and in particular geophagy) including hunger, nutrient deficiency, protection from toxins and other pathogens, neurological or sensory defects caused by iron and zinc deficiency [5].

● The craving for non-food substances usually responds to iron therapy, even earlier than does hemoglobin.

● Most studies in animals and in humans have shown a reduction in iron absorption when earth, clay or starch, but not ice, are administered with iron.

● Iron deficient individuals obtain better results on neuropsy- chological tests when allowed to chew ice.

● The precise cause of the phenomenon is still unknown but it is probably attributable to iron deficiency in the central nervous system.

Funding

This paper was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

ORCID

Caterina Borgna-Pignatti http://orcid.org/0000-0002-2577-6871

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• Research on the effects of chewing ice on the results of a neuropsychological test. An interesting hypothesis is presented.

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