Vitamin D, Iodine, and Lead Levels in Haitian Infants and Children.
Condition: Vitamin D Deficiency; Iodine Deficiency; Hypothyroidism; Rickets; Lead Intoxication
MeSH terms: Rickets; Vitamin D Deficiency; Hypothyroidism
Study type: Observational

Summary: 
      Vitamin D deficiency is common worldwide, including in infants and children, and rickets
      remains a public health concern in many developing countries. The vitamin D status and
      prevalence of vitamin D deficiency in the Haitian population has not been studied. There is
      currently no approved point-of-care testing device for vitamin D deficiency. Iodine
      deficiency and resulting hypothyroidism is the leading cause of preventable
      neuro-developmental delay and cognitive impairment worldwide. Young infants and children are
      especially susceptible to sequelae of disruption in thyroid function given the dependence of
      the developing brain on sufficient levels of thyroid hormone. Perchlorate and thiocyanate
      have been described as potential environmental disrupters of thyroid function. Lead
      intoxication is a significant cause of disease throughout the world. Millions of people have
      suffered the effects of lead poisoning. Although most developed countries have taken drastic
      measures to limit the environmental lead levels, many countries in the developing world have
      not been able to address, or even assess, the problem.

      Our objectives are to study the following three components in 300 Haitian children between 9
      months and 6 years of age in three different geographical areas of Haiti: 1) Vitamin D status
      and prevalence of rickets, environmental factors associated with low vitamin D levels, and
      the accuracy and efficacy of a vitamin D point-of-care testing (POCT) device for the
      screening of vitamin D insufficiency. 2) Iodine status and thyroid function, and
      environmental disruptors such as perchlorate and thiocyanate as potential risk factors for
      abnormal thyroid function. 3) Lead levels and the extent of childhood lead poisoning.
    

Detailed description: 
      BACKGROUND:

        1. Vitamin D Deficiency

           Vitamin D deficiency is common in the United States and worldwide, including in infants
           and children 1,2. Moderate to severe deficiency in children can manifest as rickets, a
           skeletal disease which results from a failure of mineralization of developing bones and
           cartilage. In most industrialized countries, infantile vitamin D supplementation
           represents the standard of care and has lead to a dramatic reduction in the incidence of
           rickets. However, in many developing countries, rickets remains a public health problem
           3.In addition, recent literature indicates that there may be a resurgence of rickets
           even in industrialized countries 4, especially among immigrant populations 5. Potential
           extraskeletal effects of vitamin D deficiency are also being increasingly recognized,
           including an increased susceptibility to type 1 diabetes, insulin resistance and the
           metabolic syndrome, pulmonary disease such as asthma, pneumonia and tuberculosis, and
           possible modulation of the innate immune system 6.

           Growing children with severe vitamin D deficiency, most commonly defined as serum
           25-hydroxy-vitamin D (25OHD) levels less than 8 ng/ml, are at greatest risk for rickets
           and should undergo a diagnostic evaluation. When physical exam findings such as bowing
           of weight-bearing extremities, rachitic rosary, or frontal bossing are not evident, the
           level of serum alkaline phosphatase as an indicator for increased bone turnover and
           calcium mobilization from bone can be used as a screening test 4,7. X-rays of knees and
           wrists are typically obtained to confirm the diagnosis and establish a baseline for
           follow up.

           The vitamin D status and prevalence of vitamin D deficiency in the Haitian population
           has not been studied. The prevalence of rickets is also unknown. Two studies conducted
           in Puerto Rican children 8 and in newly immigrated adults of Caribbean background 9
           found prevalence rates of 47% and 59%, respectively, suggesting the possibility of
           moderate to high prevalence rates in Haiti.

           The best indicator to assess vitamin D status is the 25OHD metabolite, the major
           circulating form of vitamin D 10. There is no international consensus on the definition
           of vitamin D deficiency. The Institute of Medicine defines deficiency as a 25OHD <
           20ng/mL and suggests levels be maintained above this threshold for healthy children and
           adolescents 11. The Endocrine Society recommendations were aimed at children and adults
           with chronic conditions placing them at risk for a low bone mass and/or vitamin D
           deficiency, and recommend using a level below 30 ng/mL (80 nmol/L) to define
           insufficiency and below 20 ng/mL (50 nmol/L) to define deficiency 6. The Endocrine
           Society treatment guideline for vitamin D deficiency for children 0-18 years suggests
           administering oral vitamin D3 2000 IU daily or 50,000 IU weekly for 6 weeks, followed by
           an age-appropriate maintenance dose.

           In resource limited settings, laboratory facilities for vitamin D testing are frequently
           unavailable. A point-of-care testing method would greatly facilitate screening for
           vitamin D deficiency and insufficiency. The test 4D is a novel point-of-care test device
           that is not yet FDA licensed. Only manufacturer based information on test accuracy are
           currently available. The device has not been tested in children (package insert is
           attached to this protocol).

        2. Iodine Deficiency

           Iodine deficiency and resulting hypothyroidism is the leading cause of preventable
           neuro-developmental delay and cognitive impairment worldwide. Young infants and children
           are especially susceptible to sequelae of disruption in thyroid function given the
           dependence of the developing brain on sufficient levels of thyroid hormone.

           Urinary iodine has been established as the gold standard for the assessment of iodine
           status12. Values of 100-199 mcg/L are considered optimal, whereas levels <100 mcg/L, <50
           mcg/dL and <20 mcg/dL define mild, moderate and severe iodine deficiency, respectively.
           On the other hand, the risk of iodine induced hyperthyroidism increases when levels rise
           to 200 mcg/dl and above, and risk of adverse health consequences increases with levels
           exceeding 300 mcg/L12. Perchlorate and thiocyanate are environmental chemicals known to
           inhibit the sodium-iodine symporter when administered at pharmacologic doses. This leads
           to interference with normal thyroidal iodine uptake and results in decreased thyroid
           hormone production13,14. Both chemicals do not undergo significant metabolism and can be
           readily detected in the urine. The effect of environmental exposure to either is thought
           to be dependent on adequate iodine, and should thus be assessed concurrent with urinary
           iodine status14.

           Studies assessing the iodine status in Haiti are few in number and have mainly included
           school-age children and adults. Three studies in school-aged children conducted between
           1996 and 2002 have found moderate to severe iodine deficiency, with urinary iodine
           levels ranging between 38.8 and 43.4 mcg/dL15-17, regardless of whether children from
           coastal15,16 or mountainous regions17 were surveyed. One study found elevated TSH values
           >5 mU/L in 78.5% of participants15. A more recent study conducted in 2008 examined 88
           subjects between ages 2 and 72 years, and found a similar median urinary iodine
           concentration18. Overall, between 60 and over 90% of the Haitian population may be
           iodine deficient17-19, with up to 20% falling into the range of severe deficiency18.
           Based on WHO data from 2005 to 2006, only 3% of households are consuming adequately
           iodized salt19. No studies have been conducted in infants and children under the age of
           5 years..

           The proposed study will be the first to assess the iodine status of Haitian infants and
           young children. The study will be conducted in 3 different geographical areas of the
           country, including an urban setting (Port-au-Prince), a mountainous region (Central
           Plateau), and a coastal area (Saint Marc) in an attempt to differentiate between areas
           where iodine deficiency is more likely (Central Plateau) from those were it is less
           likely (Saint Marc). For the first time, urinary iodine concentration in young children
           will be obtained along with a clinical goiter assessment, concentrations of urinary
           perchlorate and thiocyanate, as well as thyroid function studies (thyroid stimulating
           hormone and free thyroxine).

           Confirmation of iodine deficiency may have significant public health implications for
           one of the most vulnerable populations: infants and young children. Improving their
           access to iodized salt and/or iodine supplementation could have a major impact on
           reducing the number of children (and future adults) with hypothyroidism-related mental
           retardation. The study results may raise awareness of medical providers with regards to
           the problem of iodine deficiency and related hypothyroidism, and may provide an
           incentive to test children for hypothyroidism. There may be other major clinical
           implications, including the ability to detect and treat affected children, and improve
           their prognosis with regards to cognitive impairment. On a larger scale, depending on
           the magnitude of the problem, the study findings may underline the need to assess iodine
           deficiency and hypothyroidism in even younger infants, including newborns. Results may
           further obviate the need for a newborn screening program for hypothyroidism in Haiti.

        3. Lead Intoxication

      Lead intoxication is a significant cause of disease throughout the world. Millions of people
      have suffered the effects of lead poisoning. Although most developed countries have taken
      drastic measures to limit the environmental lead levels, many countries in the developing
      world have not been able to address, or even assess, the problem.

      Lead poisoning is a medical condition caused by increased levels of lead in the body. Lead is
      a highly toxic heavy metal environmental toxicant and nerve poison that can contribute to the
      destruction of many developmental functions by interfering with a variety of body processes.
      Due to its insidious nature, lead causes subtle and sometimes unnoticeable effects in
      children. Even low levels of lead exposure among children can be associated with
      developmental problems including impaired cognitive function, reduced intelligence, impaired
      hearing, reduced stature or damage to the bone marrow 20,21. Lead poisoning can cause severe
      toxicities including convulsions, coma, and death 22. In the United States, the Centers for
      Disease Control and Prevention (CDC) define an elevated child BLL as ≥ 10 µg/dL. At this BLL,
      the CDC has given permission to initiate public health actions. Additionally, the CDC has
      also recommended that children with BLLs ≥ 45 µg/dL receive intensive medical management and
      chelation therapy 23 to prevent irreversible damage to the child.

      Among developing countries, major sources of childhood lead poisoning include lead mining and
      smelting, paint, leaded gasoline, battery recycling, and traditional medicines 24,25 Despite
      the abundance of lead containing materials available in these developing countries, there are
      still a limited number of studies that have actually documented environmental lead
      contamination. Even with documented cases, information is further limited to adults living in
      small-scale gold ore-processing communities 26-29. Despite the many advances of treatment of
      lead poisoning in the US, there is still a paucity of information for childhood lead
      poisoning in the developing world.

      The proposed study will document lead levels in the pediatric population in three different
      regions of Haiti. Data obtained from this study may lead to clinically relevant prognostic,
      diagnostic or therapeutic modalities. This information may further be used to implement or
      even eradicate lead as a public health hazard.

      STUDY OBJECTIVES

      Our objectives are to study the following three components in 300 Haitian children between 9
      months and 6 years of age in three different geographical areas of Haiti: 1) Vitamin D status
      and prevalence of rickets, environmental factors associated with low vitamin D levels, and
      the accuracy and efficacy of a vitamin D point-of-care testing (POCT) device for the
      screening of vitamin D insufficiency. 2) Iodine status and thyroid function, and
      environmental disruptors such as perchlorate and thiocyanate as potential risk factors for
      abnormal thyroid function. 3) Lead levels and the extent of childhood lead poisoning.

      Aim 1: To determine the proportion of children with vitamin D insufficiency, deficiency and
      severe deficiency, as defined by serum 25-hydroxyvitamin D (25OHD) levels <30ng/ml, <20
      ng/ml, and <10 ng/ml, respectively.

      Aim 2: To determine the proportion of children at high risk for rickets as defined by vitamin
      D deficiency and elevations in alkaline phosphatase.

      Aim 3: To determine the extent to which dietary vitamin D intake and sun exposure are related
      to serum 25OHD levels.

      Aim 4: To correlate the results from a vitamin D POCT device with serum 25OHD levels.

      Aim 5: To determine the prevalence of iodine deficiency. Aim 6: To assess the subjects'
      thyroid function (TSH and free T4). Aim 7: To screen for urinary presence of two potential
      environmental disruptors of thyroid hormone production.

      Aim 8: To determine the correlation of abnormal thyroid function, geographical area, and
      presence of urinary perchlorate and thiocyanate with iodine status.

      Aim 9: To determine the mean and range of blood lead levels (BLL). Aim 10: To determine the
      proportion of children with a blood lead level (BLL) ≥ 10 µg/dL.
    

Observational model: Ecologic or Community
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Healthy infants and young children, recruited from participating local churches in three
        different geographical areas of Haiti, including in the capital Port-au-Prince, a
        mountainous region, and a coastal region.
      
Keywords: Vitamin D; Iodine; Lead; Thyroid function; point-of-care test