Brain Findings Associated with Iodine Deficiency Identified by Magnetic Resonance Methods: A Systematic Review

Objectives: Iodine deficiency (ID) is a common cause of preventable brain damage and mental retardation worldwide, according to the World Health Organisation. It may adversely affect brain maturation processes that potentially result in structural and metabolic brain abnormalities, visible on Magnetic Resonance (MR) techniques. Currently, however, there has been no review of the appearance of these brain changes on MR methods. Methods: A systematic review was conducted using 3 online search databases (Medline, Embase and Web of Knowledge) using multiple combinations of the following search terms: iodine, iodine deficiency, magnetic resonance, MRI, MRS, brain, imaging and iodine deficiency disorders (i.e. hypothyroxinaemia, congenital hypothyroidism, hypothyroidism and cretinism). Results: Up to May 2013, 1673 related papers were found. Of these, 29 studies confirmed their findings directly using MR Imaging and/or MR Spectroscopy. Of them, 28 were in humans and involved 157 subjects, 46 of whom had primary hypothyroidism, 97 had congenital hypothyroidism, 3 had endemic cretinism and 11 had subclinical hypothyroidism. The studies were small, with a mean relevant sample size of 6, median 2, range 1 - 35, while 14 studies were individual case reports. T1-weighted was the most commonly used MRI sequence (20/29 studies) and 1.5 Tesla was the most commonly used magnet strength (6/10 studies that provided this information). Pituitary abnormalities (18/29 studies) and cerebellar atrophy (3/29 studies) were the most prevalent brain abnormalities found. Only fMRI studies (3/29) reported cognition-related abnormalities but the brain changes found were limited to a visual description in all studies. Conclusions: More studies that use MR methods to identify changes on brain volume or other global structural abnormalities and explain the mechanism of ID causing thyroid dysfunction and hence cognitive damage are required. Given the role of MR techniques in cognitive studies, this review provides a starting point for researching the macroscopic structural brain changes caused by ID.

• Iodine Deficiency; MRI; Brain; Hypothyroidism

1. Introduction

Iodine is an important micronutrient and a fundamental substrate for the synthesis of thyroid hormones [1,2]. Triiodothyronine (T3) and thyroxine (T4) are examples of iodinated thyroid hormones essential for several cellular metabolic processes and the development of the central nervous system [3]. Thyroid hormone functions are impaired by iodine deficiency [4], reflected as increased plasma thyroid stimulating hormone (TSH) and plasma T3 concentrations with reduced tissue and plasma T4 levels [5].

Iodine deficiency (ID) is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation: in 1990, 1.6 billion people, or 28.9% of the global population, were at risk and it was thus considered a serious public health issue throughout the world [6-8]. In 2011 this figure had risen to 2 billion and, after starvation, ID is currently the single greatest cause of preventable mental retardation and brain damage [9]. European countries are usually assumed to be iodine sufficient, however, several pockets of insufficiency have been described (including UK, Italy, Belgium), with no official data available for several countries.

The degree of neurological impairment and the likelihood of its permanence are not only related to the severity of ID but also to the stage of life at which the individual is exposed to it [10]. Iodine deficiency disorders, such as hypothyroidism, may reflect a maternal, fetal or neonatal childhood thyroid hormone insufficiency [11]. At differing time-points, thyroid hormones have particular effects on brain maturation, regulation of neuronal development and microglial proliferation [12], dendritic arborisation, synaptogenesis, cell migration and myelination [11]. Fetal’s thyroid hormones rely on iodine supplemented from the maternal circulation so as to ensure adequate mental development [13]. Iodine insufficiency in fetal life and early childhood is associated with decreased IQ even in the absence of manifest hypothyroidism [14]. Many studies in areas of mild iodine deficiency have shown a range of developmental impairments including poor visual-motor performance and motor skills, decreased neuromotor and perceptual ability and lower developmental and intelligence quotients [7]. There is clearly an association between sub-optimal intellectual performance and iodine deficiency including maternal iodine deficiency during pregnancy [7,14-18].

Despite recommendations to increase daily iodine intake from 150 µg/day to 250 µg/day during pregnancy, up to 40% of pregnant women in Scotland have been shown to be at risk of iodine deficiency [19]. Although few people have frank iodine deficiency and diet-driven hypothyroidism, a low or marginal intake will present a potential hazard in pregnancy, when demand is increased [20]. Iodine is obtained mainly through the diet. The iodine content of food and water is dependent on a variety of factors: including geographical location, mineral content of the soil, bacteria, rainfall, altitude and fertilisers used [21] as well as longstanding fortification programmes with iodine-supplemented salt introduced to counteract dietary deficiency [22,23]. There is no ongoing iodine-fortification programme in the UK [24]. Main sources of iodine in the British diet are milk and dairy products, and fish and seafood [25]. It is likely that a substantial proportion of the young female population excludes at least one of these food groups from their diets, leading to either low or marginal iodine intake [16]. Meanwhile, fast-food meals and pre-cooked dishes do not ensure that the minimum iodine requirement is fulfilled: 150 - 300 µg I per day [26]. The most recent survey conducted in the UK revealed a median urinary iodine excretion (i.e. marker of ID at population level) of 80 μg/L, indicative of mild deficiency (50 - 99 μg/L) [9].

The brain is particularly sensitive to the adverse effects of ID since neural development occurs at a critical period, prior to the rest of the body [27]. This is reflected in the disproportionate weight of the brain in a neonate, representing 10% of total body mass, compared to 2% in a fully grown adult [27]. Animal models of ID have provided evidence of changes to the morphology and cytoarchitecture of the brain. In sheep models of ID, reduced brain DNA and brain weight with delayed cerebellar maturation were identified [28-30]. In rat brains studies have reported altered metabolic activity and laminar volumes in the hippocampus and dentate gyrus [31] and altered tissue distribution of other trace elements [32-34]. It is also suggested that certain brain proteins may be down-regulated in particular brain regions [35], anterior commissure axons and mRNA expression may be reduced [36,37], dendrite size may be altered [38] and premature cell apoptosis may result [39]. Additionally, ID may cause a reduction in cerebellar cell size and decreased myelination throughout the Central Nervous System [40].

Magnetic Resonance (MR) is a powerful, non-invasive tool for detecting and quantifying structural and metabolic brain changes in life over time. Although access is limited in some regions, it is increasingly available throughout the world. Despite the strong link between iodine insufficiency and neurodevelopment and impaired cognition, brain structural changes have rarely been investigated in the context of iodine insufficiency. We hypothesise that insufficient dietary iodine intake or aberrant iodine metabolism results in structural and metabolic neurological changes in the brain that can be assessed by MR methods. Currently, few reports exist regarding the appearance of these changes on MR. Studies in ID disorders report histological, psychological, physical and behavioural changes but use no brain MR confirmation and brain changes are often inconsistently described. This systematic review was necessary to clarify reported changes on brain MR.

2. Aims and Hypothesis

2.1. Aims

This review aims to identify what brain structural and metabolic abnormalities related to ID are documented using Magnetic Resonance Imaging (MRI) and other MR techniques such as Magnetic Resonance Spectroscopy (MRS).

2.2. Hypothesis

The hypothesis of this review is that insufficient dietary iodine content or aberrant iodine metabolism results in structural and metabolic neurological changes in the brain, detectable on MR methods.

3. Methods

3.1. Search Criteria

Primary research studies, published in full and using MR techniques to determine brain region modifications, were identified in a literature search. A combination of case reports, prospective and retrospective studies were reviewed. The electronic search was conducted up to May 2013 using the following databases: Medline^©, Web of Knowledge^© and Embase^©. It was supplemented by hand-searching reference lists of the review papers and by request to the corresponding authors of identified papers not openly accessible. Multiple combinations of the following search terms were used: iodine, iodine deficiency, iodine deposits, magnetic resonance imaging/ MRI, brain, imaging, hypothyroxinaemia, congenital hypothyroidism, hypothyroidism and cretinism. The latter four search terms were proposed as they may be considered as iodine deficiency disorders. Maternal hypothyroxinaemia may result from inadequate iodine intake [41-44] and may cause neurodevelopmental defects. Neonatal hypothyroxinaemia, from postnatal reductions in T4 concentration, but with normal TSH, may occur due to in utero iodine insufficiencies [45,46]. Congenital hypothyroidism, caused by maternal and thence fetal hypothyroidism, may, therefore, also result from iodine deficiency, with an incidence of 1:3000 to 1:4000 live births [47,48]. One of the worst consequences of ID and a more severe form of hypothyroidism is endemic cretinism, a condition characterised by neurological deficits, deaf-mutism and spasticity [49-51] that occurs where ID is common in the community.

One reviewer independently carried out the primary literature search, paper selection, duplicate removal and data extraction up to March 2012 and other reviewer extended the search up to May 2013. Three different reviewers assessed a sample of papers for inclusion and helped extract the relevant data on each occasion. Although papers may have passed eligibility checks according to the inclusion/exclusion criteria listed below, full texts were read prior to final rejection of studies.

3.2. Inclusion Criteria

Studies were included which used MR methods to identify brain structural and/or metabolic changes in the brain associated with ID or ID disorders. Inclusion criteria also comprised studies available in English only. Both human and animal studies were included as well as studies from healthy or diseased brains.

3.3. Exclusion Criteria

Studies were excluded if they did not meet the inclusion criteria or were published only as abstracts without full publication available. Studies in which iodine was used therapeutically or as a drug treatment were rejected and studies which involved the injection of radioactive iodine used as a contrast agent for visualising a specific pathology (e.g. thyroid carcinoma) were also excluded. Studies in which hypothyroidism was induced by thyroidectomy or was due to other non-iodine related causes (such as autosomal, goitrogen, steroid consumption, following head trauma, caused by Hashimoto’s thyroiditis, stress or autoimmune aetiology) were rejected. Studies on cancer patients or those in which the MR method did not involve studying or imaging the brain (e.g. thyroid scintigraphy) were also rejected. The literature search produced many papers which involved non relevant subject areas and/or diseases; diabetes mellitus, multiple sclerosis, epilepsy, Parkinson’s, Alzheimer’s, bipolar disorder and Turner’s syndrome are examples which were excluded as the non-iodine related consequences of these diseases may affect the appearance of brain changes. Reviews which discuss MR changes associated with iodine deficiency were excluded from the data analysis unless they included new data that was not published elsewhere. If the cause of the disorder (e.g. hypothyroidism) was not ID or not stated the study was rejected.

3.4. Data Extraction

For each study that was included: the type of MR confirmation, the appearance on MR method, the location of the abnormality, the pathology/disease studied and the sample size (i.e. number of subjects) was independently extracted. Often the particular type of MR technique used was not discussed in the body of the text and so the relevant information was extracted from MR image descriptions. Additionally, information related to subject pathology was sometimes acquired from tables.

3.5. Data Analysis

The techniques used to identify structural and/or metabolic brain changes were quantified, including:

Number of subjects included in the studies

• How many studies successfully used MR techniques to determine brain changes

• How many studies that  used MR methods reported discrepancies on the brain changes

• Whether the studies included blinding, randomisation or an inclusion/exclusion criteria Moreover, two further questions were posed:

• Where are the most common locations of the brain changes?

• What diseases/pathologies discussed in the studies were associated with which brain changes/ MR abnormality appearances?

However, these last two questions are not the main focus of this review since results only encompass studies which used MR confirmation, rather than all of the literature that discusses the relationship between iodine deficiency and the brain.

4. Results

The literature search identified 1673 publications; 553 from Medline, 625 from Web of Knowledge, 490 from Embase and 5 from review paper reference lists. 29 of these studies were included in the review (Table 1 and

Figure 1). 1155 papers were rejected because the paper involved non-relevant diseases [Exclusion Criteria], was not related to the effects of ID on the brain and/or used iodine as a contrast medium or therapy, the full paper was not written in English (i.e. no translation was available for 330 papers) or was not attainable through the search databases. Further 60 duplicate papers were rejected. Of the remaining 128, 46 review articles and 47 that did not confirm findings using MR techniques (i.e. used CT, Nuclear Medicine methods and/or ultrasound) or those in which the MR technique was not applied to the brain, such as thyroid or whole body scintigraphy, were excluded from the data analysis. Finally, six studies on hypothyroidism that did not specify the cause [Exclu-

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