Cytomegalovirus: neglected problem endangers pregnant women, children

Medscape Cytomegalovirus

Cytomegalovirus (CMV) hasn’t gotten the press accorded to Zika, yet it infects 2%-4% of pregnant women and is transmitted to the fetus. The resulting congenital infection in 40% of these cases can result in a host of serious problems that include brain maldevelopment and microcephaly. An article recently published in Medscape Family Medicine draws needed attention to his common but poorly recognized hazard.

“Congenital CMV is well recognized as a common, endemic congenital infection, infecting over 30,000 newborns each year in the United States. Although many newborns congenitally infected with CMV may have no symptoms or sequelae, up to 8000 each year will have in utero growth restriction; petechiae; liver and spleen disease; thrombocytopenia; congenital and progressive hearing loss; vision loss; brain maldevelopment syndromes; microcephaly; and permanent neurodevelopmental and motor disabilities such as cerebral palsy. In addition, fetal and neonatal death from in utero CMV occurs in approximately 400 babies each year.”

Cytomegalovirus awareness is low

Most people have heard of Zika but very few are aware of cytomegalovirus though it is a far more widespread problem.

“…despite this well-recognized and well-accepted public health impact, only 9%-15% of women of childbearing age, including those with graduate degrees and those entering medical school, have even heard of CMV.”

“CMV Knowledge Vaccine”

Just knowing that cytomegalovirus is a common infection and serious hazard in pregnancy is the start. Then there are three simple precautions based on the fact that young children commonly excrete CMV in their saliva and/or urine for a year and transmit it to their parents 45-53% of the time, often without either manifesting any symptoms. The paper cites three recommendations to reduce exposure:

  1. Not sharing food, drink, straws or eating utensils with young children;

  2. Not kissing young children on or around the mouth or lips; and

  3. Washing hands well after changing all diapers (wet with urine or dirty with stool) and wiping runny noses or mouth drool.

Unfortunately, the American College of Obstetrics and Gynecology (ACOG) has not supported active education of women about CMV risk. The author concludes:

The greatest risk reduction strategy available now to prevent CMV transmission to pregnant women is education about CMV. Patients; healthcare professionals, especially obstetricians and midwives; and public health agencies should be partners in providing women with factual information and allowing them to make informed choices regarding their pregnancy health and prevention of CMV. In other words, spread the word, not the virus.”

Thyroid disorders in children and adolescents: clinical review

JAMA Pediatrics: Thyroid disordersThyroid disorders are widespread and can occur at any age. An excellent clinical review just published in JAMA Pediatrics offers a comprehensive and detailed yet succinct review of the various types that occur in children and adolescents. The authors state:

“Normal thyroid gland function is critical for early neurocognitive development, as well as for growth and development throughout childhood and adolescence. Thyroid disorders are common, and attention to physical examination findings, combined with selected laboratory and radiologic tools, aids in the early diagnosis and treatment.”

They provide a “provide a practical review of the presentation, evaluation, and treatment of thyroid disorders commonly encountered in a primary care practice” based on 479 articles relevant to…

“…the incidence, pathophysiology, laboratory evaluation, radiological assessment, and treatment of hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer in children and adolescents. Eighty-three publications were selected for inclusion in this article based on their relevance to these topics.”

They cover these topics:

  • Congenital hypothyroidism
  • Acquired hypothyroidism
  • Hyperthyroidism
  • Thyroid nodules

Autoimmune thyroiditis is by far the most common

Pediatric thyroid examReaders here surely know that autoimmunity prevails as the leading cause of hypothyroidism in developed countries. As part of the ‘epidemic’ of loss of immune tolerance it can occur amidst a constellation of other autoimmune phenomena, some noted here:

Autoimmune hypothyroidism (Hashimoto thyroiditis) is the most common cause of acquired hypothyroidism in children, adolescents, and adults. The prevalence of autoimmune hypothyroidism in childhood is an estimated 1% to 2% with a 4:1 female predominance. Approximately 50% of cases have a family history of autoimmune thyroid disease… An additional autoimmune disorder in the same patient is also associated with an increased risk, most commonly diabetes, alopecia, vitiligo, and celiac disease.”

Interestingly, hypothyroidism is not typically associated with weight gain in this population:

“The most common symptoms of hypothyroidism are fatigue, cold intolerance, constipation, and menstrual irregularities. Children may present with pubertal delay or, in cases of severe longstanding hypothyroidism, precocious puberty. A goiter is the most common physical examination finding. Other examination findings include bradycardia, delayed reflexes, and myxedema of the face and extremities. Hypothyroidism causes poor linear growth and/or growth failure and, if undiagnosed, may compromise adult height. However, contrary to common belief, hypothyroidism is rarely the etiology of weight gain. In fact, excess weight gain is associated with mild elevations in thyrotropin (between 5 and 10 mIU/L), with normalization of the thyrotropin level after achieving weight loss.”

Thyroid examination and diagnosis

I recommend that practitioners desiring a review of thyroid examination and diagnosis in the pediatric patient peruse the entire paper for details on the examination and diagnosis of each condition.

Pediatric endocrinologist Andrew J. Bauer, MD, on of the authors, demonstrates an exam on a healthy child and others illustrating the main diagnoses in this helpful video…

Evidence lacking for most common ADHD drug

Cochrane LibraryADHD in kids is most often medicated with methylphenidate (Ritalin®, Concerta®), but a comprehensive Cochrane Review finds there is little evidence showing that it really benefits. Because of the potential for harm experts urge caution. The authors note:

“Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive…Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms.”

They set out to assess the beneficial and harmful effects of methylphenidate for children and adolescents by reviewing all randomised controlled trials (RCTs) comparing methylphenidate versus placebo (or no intervention) in children and adolescents aged 18 years and younger. They mined comprehensive data from six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers and contacted the pharmaceutical companies that manufacture methylphenidate for their published and unpublished data.

“We found 185 randomised controlled trials (RCTs; studies in which participants are randomly assigned to one of two or more treatment groups), involving 12,245 children or adolescents with a diagnosis of ADHD. Most of the trials compared methylphenidate to a placebo – something designed to look and taste the same as methylphenidate but with no active ingredient. Most trials were small and of low quality. Treatment generally lasted an average of 75 days (range 1 to 425 days), making it impossible to assess the long-term effects of methylphenidate. Seventy-two of the 185 included trials (40%) were funded by industry.”

Some ADHD symptoms might improve but the evidence is poor

Methylphenidate can have side effects including sleep problems and loss of appetite, and there is no scientific data on its long term effects—a grave consideration for a brain-modifying drug.

The quality of the evidence was very low for all outcomes. It was possible for people in the trials to know which treatment the children were taking, the reporting of the results was not complete in many trials and for some outcomes the results varied across trials. These considerations limit our confidence in the overall results of the review.

The lead authors lOle Jakob Storebø, PhD, clinical psychologist, Region Zealand, Roskilde, Denmark, and Morris Zwi, MBBCh, consultant child and adolescent psychiatrist, Whittington Health, London, UK, are quoted in Medscape Medical News:

“The evidence is not as convincing as many clinicians have believed regarding the benefits of methylphenidate…In general, our findings raise concerns about how much we should expect of this medicine, and there needs to be more caution when prescribing methylphenidate.”

Furthermore…

Clinicians need to weigh what we now believe to be an uncertain degree of benefit against the many adverse events that are known to be associated with methylphenidate, such as appetite suppression and sleep difficulties. The general perception of methylphenidate as an effective drug for all children with ADHD seems out of step with the new evidence. This new information from our review should challenge the mindset of clinicians because there is more uncertainty to factor in to balancing the benefits and risks of this medication.”

Clinical Note

Practitioners participating in case management of ADHD should overcome any bias and consider the authors’ conclusions:

“At the moment, the quality of the available evidence means that we cannot say for sure whether taking methylphenidate will improve the lives of children and adolescents with ADHD. Methylphenidiate is associated with a number of non-serious adverse events such as problems with sleeping and decreased appetite. Although we did not find evidence that there is an increased risk of serious adverse events, we need trials with longer follow-up to better assess the risk of serious adverse events in people who take methylphenidate over a long period of time.”

Improving brain health by treatment plans that target dysfunction and deficiencies with appropriate objective tests is preferable to medicating a stimulant that has side effects, uncertain benefit and unknown long term effects. For a list of fundamental methods of assessing brain physiology that can form the basis of a rational treatment plan download the free Parents’ Guide To Brain Health from Useful Links on the right.

Inhaled steroids may worsen asthma with air pollution

Journal of Allergy and Clinical ImmunologyAsthma is condition characterized by episodes of acute symptomatic flare-ups within the context of of chronic lung inflammation. Steroid medications are problematic as a long-term solution for any chronic inflammatory disorder and can contribute to the degradation of immune tolerance. Research recently published in the Journal of Allergy and Clinical Immunology demonstrates that inhaled corticosteroids may in fact worsen asthma in the presence of CO (carbon monoxide). The authors state:

“Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthmatic patients are lacking…We sought to investigate pollution effects in a longitudinal asthma study and effect modification by controller medications.”

Lung function not protected by inhaled steroid medication

They examined lung function for 1003 children with asthma in response to ozone, carbon monoxide (CO), nitrogen dioxide, and sulfur dioxide concentrations over four years, quantifying the effects of budesonide (Pulmicort) and nedocromil. Indices of lung function included FEV1 and forced vital capacity (FVC) percent predicted, FEV1/FVC ratio, and PC20. Their data show that lung function was not protected by the medications during pollutant exposure, and the treatment worsened the effect of CO (carbon monoxide):

“Same-day and 1-week average CO concentrations were negatively associated with postbronchodilator percent predicted FEV1 (change per interquartile range, −0.33 and −0.41, respectively) and FVC (−0.19 and −0.25, respectively). Longer-term 4-month CO averages were negatively associated with prebronchodilator percent predicted FEV1 and FVC (−0.36, respectively). Four-month averaged CO and ozone concentrations were negatively associated with FEV1/FVC ratio. Increased 4-month average nitrogen dioxide concentrations were associated with reduced postbronchodilator FEV1 and FVC percent predicted. Long-term exposures to sulfur dioxide were associated with reduced PC20 (percent change per interquartile range, −6%). Treatment augmented the negative short-term CO effect on PC20.”

Quoted from a news release in Medscape Medical News, coauthor Diane R. Gold, MD, MPH, from the Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts stated:

This means use of controller medication may not protect asthmatic children from pollutant effects and may actually worsen the negative effects of some pollutants.”

Underlying causes of chronic airway inflammation

Investigating and targeting the underlying causes that promote loss of immune tolerance and chronic inflammation including loss of barrier integrity, a dysbiotic microbiome, imbalanced cytokine signaling, food intolerance, deficiencies in key co-factors, and others are fundamental to the functional approach to asthma case management. This deeper analysis by the clinician but produces more gratifying outcomes than immunosuppression by corticosteroids. The authors conclude:

“Air pollution adversely influences lung function and PC20 in asthmatic children. Treatment with controller medications might not protect but rather worsens the effects of CO on PC20.”

Perinatal brain injury and inflammation

Nature Reviews NeurologyPerinatal brain injury involves neuroinflammation with consequences for neuropsychiatric disease extending into adult life as reported in a paper recently published in Nature Reviews Neurology. The authors state:

Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development.”

Preterm birth gets a head start with neuroinflammation

Inflammation plays a role in the incidence of preterm birth occurring in the first place:

“Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity.”

A risk factor for adult neuropsychiatric disorders

The authors’ conclusion reminds practitioners to consider perinatal brain injury as an etiologic factor in adult disorders:

Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.”

Blood from children with autism induces autistic features in rats

PLOS ONEAutism and autism spectrum disorders (ASD), which present evidences suggests to result from multiple causes, has been shown to be consistently associated with accelerated brain growth during early development followed by impaired brain growth and development. In a fascinating study just published in PLOS One the investigators report the ability to induce anatomical and behavioral features of autism in their laboratory subjects by injecting serum from children with autism. They were also able to ameliorate these effects by treating with Peptide 6 (P6), an agent that mimics a natural neuroprotective peptide. The authors note:

Neurotrophic factors play essential roles in all stages of central nervous system development and maintenance; they critically influence the formation and elimination of neuronal connections. Several studies suggest that aberrant cerebral connectivity and synaptic plasticity constitute essential features of the pathogenesis of autism. Thus, neurotrophic factors which are essential mediators of neuronal and synaptic plasticity have been hypothesized to play a major role in the pathophysiology of autism.”

Abnormal neurotrophic factors in patients with autism

Neurotrophic factors such as BDNF (brain derived neurotrophic factor) and CNTF (ciliary neurotrophic factor) are altered in autism patients:

“Altered brain, CSF, and serum levels of neurotrophic factors have been reported in patients with autism. For example, serum level of BDNF, which plays an essential role in brain development, neurogenesis and synaptogenesis, and synaptic plasticity, was shown to be decreased in children, adolescents, and adults with autism…The serum levels of CNTF were found to be lower and the levels of FGF-2 and LIF were found to be higher in children with autism compared to age-matched healthy controls. Previously, increased oxidative stress which is widely implicated in the pathophysiology of autism was shown to block CNTF activity in neurons which is essential for neuronal survival and maintenance…Our data suggest that the levels of various neurotrophic factors are altered in sera from children with autism and this imbalance along with the increased oxidative stress could be among the primary factors responsible for the altered development and neurodegeneration observed in both in vivo and in vitro models.”

Levels of various neurotrophic factors in sera from autistic and control children

Levels of various neurotrophic factors in sera from autistic and control children.

 Neuronal oxidative stress increased by sera from children with autism

Oxidative stress which can damage DNA and promote immune dysfunction has been associated with the altered brain development seen in autism.

“We found that culturing the mouse primary cortical neurons in the presence of sera from autistic children result in increase in levels of ROS and lipid peroxidation. Similarly, in- creased oxidative stress-induced DNA damage was observed in brain tissue from rats exposed to sera from autistic children during the early period of development. These findings support the notion that altered brain environment contributes to increased oxidative stress in early developmental stages in autism. Increased oxidative stress has been suggested to lead to membrane lipid abnormalities, mitochondrial dysfunction, excitotoxicity, and immune dysfunction in autism, and may ultimately contribute to the behavioral phenotype of autism.”

Inflammation increased

Neuroinflammation is emerging as a common denominator in a wide range of neuro-developmental and neuropsychiatric disorders. Here the authors showed that sera from children with autism increased the inflammatory activity of brain immune cells (astrocytes and glia).

Inflammatory changes especially astroglial activation have been described in the brains of patients with autism and may contribute to the pathogenic mechanisms involved in cortical and neuronal dysfunction. Astrocytes and microglia play critical roles in the neurobiological processes of cortical organization, neuroaxonal guidance, and synaptic plasticity. Increased GFAP [glial fibrillary acidic protein, a marker for neuroinflammatory astrocyte activity] level observed in the present study in autism sera treated rats could signify gliosis, reactive injury and impaired neuronal migration processes.”

Moreover…

“The rescue of astorgliosis by P6 treatment in the present study signifies the potential therapeutic usage of neurotrophic factor based strategy for ameliorating neuroinflammation in ASD.”

Amelioration of autistic features by P6 treatment

Remarkably, the authors were able to significantly reduce the damage done with the peptide P6 which appears to mediate its beneficial effects through BDNF:

“The beneficial effect we observed with P6 treatment further strengthens the idea that autism could be caused by an early imbalance of neurotrophic factors and increased oxidative stress…In the current study, we found that P6 was able to rescue autism serum-induced neurodegeneration and oxidative stress in cultured neurons and rat brains. The neuroprotective effect of P6 could have been because of increased BDNF expression we observed in P6 treated rat brains. We previously showed that P6 and its fragment peptide, Peptide 021 (P021) enhance BDNF mRNA and protein levels; BDNF is known to exert protective effect against oxidative stress. Recently, a relationship has been suggested between BDNF, sonic hedgehog (SHH), and oxidative stress in autism. Wu et al showed that BDNF induces up-regulation of SHH at both mRNA and protein levels, and the protective effect of BDNF in cortical neurons could be abolished by using SHH signaling inhibitor. Based on this, we can speculate that the protective effect of P6 against autism serum-induced neurodegenration and oxidative stress could have been mediated via BDNF.”

Summary

This extraordinary study expands our understanding of the causative factors in autism and suggests advances in treatment by modulating pathways of oxidative stress, inflammation and neurodegeneration. The authors conclude:

One of the most remarkable findings of the current study is the development of several features of autism in young rats whose brains were exposed to sera from autistic children via i.c.v. injections. This single finding strongly suggests the important role brain environment plays during early development in the pathophysiology of autism. Early postnatal exposure of brain tissue to sera from autistic children which had abnormalities in neurotrophic factor levels led to developmental delay and social communication, interaction, and memory deficits in young rats. Several of these deficits such as developmental delay and social memory deficits were rescued by P6 treatment. Interestingly, the early postnatal exposure to autistic sera resulted in increased oxidative stress induced DNA damage and neurodegeneration in cortical tissue of young rats providing the structural correlate for behavioral abnormalities observed in these rats. Remarkably, P6 treatment was able to rescue these structural abnormalities probably via increased BDNF expression.”

Therapeutic potential

“…this study provides evidence regarding the neurotrophic abnormalities in autism and the potential role they play in the pathophysiology of the disease. We speculate that the brain milieu of autistic children is altered and favors increased oxidative stress and neurodegeneration. Ameliorating the neurotrophic imbalance during early stages of brain development can serve as a potential therapeutic approach for autism. P6 represents a new class of neurotrophic peptide mimetics that has potential therapeutic value for ASD and related conditions.”

This, of course, further validates testing for and targeting factors contributing to neuroinflammation and oxidative stress on an individual case basis. Moreover, it heightens awareness of practitioners to the need to assess the inflammatory and oxidative status of pregnant patients, and even better prior to pregnancy.

Autism and maternal antibodies that attack the fetal brain

Translational PsychiatryAutism spectrum disorders and maternal autoantibodies  have been linked in early research. A study just published in Translational Psychiatry now pins down some of the specific antibodies made by the mother’s immune system that attack the fetal brain, leading to autism. The authors state:

“Findings of dysregulated immune function, neuroinflammation, as well as the presence of maternal autoantibodies directed against rodent, human and non-human primate fetal brain tissue, strongly support an etiological role for the immune system in some forms of ASD…We previously described ASD-specific maternal autoantibodies that recognize fetal brain antigens.”

Moreover…

“An etiological role for maternal antibodies in ASD is plausible because of the gestational transfer of maternal IgG during pregnancy where maternal IgG is detected in fetal circulation as early as 13 weeks of gestation in humans. By 30 weeks of gestation, levels in the fetal compartment reach approximately 50% of circulating levels in the mother, with levels at birth exceeding maternal IgG levels…The developing blood–brain barrier is actively changing during fetal neurodevelopment and is permissive to IgG molecules during this period…Recognizing that identification of the target antigens for MAR autism is the next critical step toward advancing this area of research, we employed a proteomic approach to attain this goal.”

To do so they enrolled consenting mothers through the Center for Children’s Environmental Health as part of the continuing CHARGE (CHildhood Autism Risks from Genetics and Environment) Study at the University of California at Davis which included included 246 children diagnosed with autism or ASD and 149 children from the general population. Using multiple procedures to identify and verify antibodies and antigen-binding specificity and link them with behavioral correlates, they found clear evidence of specific IgG antibodies reacting to proteins that are highly expressed in the developing human brain:

“Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies.”

The authors elaborate on their evidence:

“Several studies have implicated maternal immune dysregulation during pregnancy in association with ASD. Prominent among them are reports of maternal antibodies that react against fetal brain proteins. The hypothesis is that gestational exposure to maternal antibodies directed against proteins abundantly expressed in the fetal brain could lead to alterations in the neurodevelopment characteristic of ASD is further supported by the identification of specific IgG reactivity to LDH, YBX1, cypin, STIP1, CRMP1 and CRMP2, six proteins highly expressed in developing brain. Thus, MAR autoantibodies could represent one mechanism underlying the development of one or more of the ASD core features in a subgroup of cases. Moreover, with their exceptionally high specificity, several of the MAR autoantibody profiles could serve as the first true biomarkers of ASD risk…Consistent with our early studies on fetal brain homogenates, each of the identified antigens is expressed at significant levels in the human fetal brain and has an established role in neurodevelopment.”

The authors conclude:

“Addressing the basis for the association between maternal autoantibodies and autism risk in the child is also of urgent concern…We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism…The clinical significance of these findings may be twofold: (1) early diagnosis of a MAR-ASD child would allow for early behavioral intervention and (2) if pathologically significant, medical interventions that would limit fetal exposure to these antibodies might prove helpful in reducing risk of ASD symptom development in the children of affected mothers.”

Clinical note: While further research needs to be done to grade the predictive capability of these antibodies, these findings offer a compelling reason for the clinician to be thorough in evaluating the integrity of immune regulation, presence of established predictive antibodies and quality of immune tolerance in female patients anticipating pregnancy.

Iodine deficiency, pregnancy, and autoimmunity

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Iodine deficiency is still a serious concern, especially for pregnant women in North America, as reported in a review just published in the journal Thyroid. Despite global improvements since 1990, iodine sufficiency has actually been declining in US adults. As the authors state, the consequences can be severe:

Thyroid“Dietary iodine intake is required for the production of thyroid hormone. Consequences of iodine deficiency include goiter, intellectual impairments, growth retardation, neonatal hypothyroidism, and increased pregnancy loss and infant mortality. Thyroid hormone is particularly crucial for fetal and infant neurodevelopment in utero and in early life, and insufficient iodine during pregnancy and infancy results in neurological and psychological deficits in children…Iodine deficiency remains the leading cause of preventable mental retardation worldwide. In adults, mild-to-moderate iodine deficiency increases the incidence of hyperthyroidism due to toxic goiter.”

The authors defined population iodine sufficiency as a median urinary iodine concentrations of 100–299 μg/L in school-aged children and equal to or more than 150 μg/L in pregnant women, with these serious implications for pregnant women and their children in the US:

“Based on National Health and Nutrition Examination Surveys (NHANES), the median UIC in U.S. adults decreased by >50% between the early 1970s and the late 1990s. Of particular concern, the prevalence of UICs <50 μg/L among women of childbearing age increased by almost fourfold, from 4% to 15%, over this period. The most recent NHANES survey (2009–2010) demonstrated that the overall U.S. population remains iodine-sufficient, with a median UIC of 144 μg/L among individuals aged six years and older. However, aggregate NHANES data from 2001 to 2006 showed that U.S. pregnant women sampled were only marginally iodine-sufficient (median UIC, 153 μg/L) and the most recent NHANES data from 2007 to 2010 demonstrated that the median UIC among pregnant U.S. women had dropped to <150 μg/L, indicating mild iodine deficiency.”

Considering possible causes for this growing insufficiency they note…

“Reductions in U.S. dietary iodine over the last several decades have been variously ascribed to a possible reduction in the iodine content of dairy products, the removal of iodate dough conditioners in commercially produced bread, new recommendations for reduced salt intake for blood-pressure control, and the increasing use of noniodized salt by the food industry.”

Processed food producers in the US typically do not use iodized salt. Iodate dough conditioners have been largely replaced by bromate which competes with iodine (as does fluoride). Iodizing salt is the tried and true method for preventing iodine deficiency in the general population, but considering the shortfall lead author Dr. Elizabeth Pearce commented for Medscape:

“That leaves public-health recommendations for groups at risk and the recommendation for women who are pregnant, planning a pregnancy, or breast-feeding is to take an iodine-containing supplement of 150 µg of iodine daily in the form of potassium iodide.”

But the authors note caution must be taken when supplementing iodine:

“Following exposure to high iodine levels, the synthesis of thyroid hormone is normally inhibited via the acute Wolff–Chaikoff effect. If excessive iodine exposure persists, the thyroid is able to “escape” from the acute Wolff–Chaikoff effect within a few days…Conversely, individuals with subtle defects in thyroid hormone synthesis, such as those with Hashimoto’s thyroiditis, may be unable to escape from the acute Wolff–Chaikoff effect, and can develop iodine-induced hypothyroidism. In addition, even small increases in population iodine intake are associated with an increased prevalence of thyroid autoimmunity.”

Bear in mind that by far the most common form of hypothyroid in developed countries is Hashimoto’s thyroiditis (autoimmune thyroiditis). The authors conclude:

“Although substantial progress has been made over the last several decades, iodine deficiency remains a significant public health problem worldwide, including in developed nations. The ongoing monitoring of the population iodine status remains crucially important, and particular attention may need to be paid to monitoring the status of vulnerable populations. There is also a need for ongoing monitoring of iodized salt and other dietary iodine sources in order to prevent excess as well as insufficient iodine nutrition. Finally, it will be essential to coordinate interventions designed to reduce population sodium intake with salt iodization programs in order to maintain adequate levels of iodine nutrition as salt intake declines.”

The LancetA paper just published in the prestigious medical journal The Lancet documented the serious effects of even mild iodine deficiency during pregnancy. The authors state:

“As a component of thyroid hormones, iodine is essential for fetal brain development. Although the UK has long been considered iodine replete, increasing evidence suggests that it might now be mildly iodine deficient. We assessed whether mild iodine deficiency during early pregnancy was associated with an adverse effect on child cognitive development.”

They examined data for measured urinary iodine concentration for 1040 first-trimester pregnant women andlater the intelligence quotient (IQ) in their children at age 8 years and reading ability at 9 years of age. To define iodine deficiency they used the WHO criteria of 150 μg/g in pregnancy. Their data revealed a growing public health problem:

The group was classified as having mild-to-moderate iodine deficiency on the basis of a median urinary iodine concentration of 91·1 μg/L. After adjustment for confounders, children of women with an iodine-to-creatinine ratio of less than 150 μg/g were more likely to have scores in the lowest quartile for verbal IQ, reading accuracy, and reading comprehension than were those of mothers with ratios of 150 μg/g or more. When the less than 150 μg/g group was subdivided, scores worsened ongoing from 150 μg/g or more, to 50—150 μg/g, to less than 50 μg/g.”

For the authors, this is an issue that demands attention:

“Our results show the importance of adequate iodine status during early gestation and emphasise the risk that iodine deficiency can pose to the developing infant, even in a country classified as only mildly iodine deficient. Iodine deficiency in pregnant women in the UK should be treated as an important public health issue that needs attention.”

NIH Office of Dietary SupplementsHow do we go about testing for iodine deficiency when a single spot collection is only accurate for large populations studies and doesn’t reliably apply to the individual and ten spot collections are cumbersome? According to the National Institute of Health Office of Dietary Supplements:

“Iodine status is typically assessed using urinary iodine measurements. Urinary iodine reflects dietary iodine intake directly because people excrete more than 90% of dietary iodine in the urine. Spot urine iodine measurements are a useful indicator of iodine status within populations. However, 24-hour urinary iodine or multiple spot urine measurements are more accurate for individuals.”

Journal of Nutrition 141 (9)Both 10 spot collections and one 24-hour collection are acceptable even though a study published in The Journal of Nutrition found a bit less intra-individual variation (CV) with the 24-hour collection:

“In a prospective, longitudinal, 15-mo study, healthy Swiss women (n = 22) aged 52–77 y collected repeated 24-h urine samples (total n = 341) and corresponding fasting, second-void, morning spot urine samples (n = 177). From the UIC in spot samples, 24-h urinary iodine excretion (UIE) was extrapolated based on the age- and sex-adjusted iodine:creatinine ratio. Measured UIE in 24-h samples, estimated 24-h UIE, and UIC in spot samples were (geometric mean ± SD) 103 ± 28 μg/24 h, 86 ± 33 μg/24 h, and 68 ± 28 μg/L, respectively, with no seasonal differences. Intra-individual variation (mean CV) was comparable for measured UIE (32%) and estimated UIE (33%). The CV tended to be higher for the spot UIC (38%) than for the estimated 24-h UIE (33%).”

American Journal of Clinical NutritionThe issue of how to test for iodine deficiency was examined in a study published in the American Journal of Clinical Nutrition in which the authors showed that the spot check ofurinary iodine concentration (UIC) could be confounded by hydration status, but that a 24-hour collection was not. They investigated how well each tracked the effect of iodine supplementation:

“Urine osmolality (Uosm) and 24-h urinary excretion rates of iodine (24-h UI), sodium, creatinine, and total urine volume (24-h Uvol) were measured in 1046 specimens that were collected at repeated intervals from 1996 to 2003 in a sample of 358 German children aged 6–12 y. Energy intake and food consumption were calculated from 3-d weighed dietary records that were collected in parallel to the urine samples.”

It was only the 24-hour collection which matched the ‘real world’ changes:

“During the 4-y period from 1996 to 1999, the median 24-h UI increased from 87 to 93 μg I/d, whereas urinary iodine concentration (UIC), Uosm, and 24-h Uvol did not change significantly. Thereafter (from 2000 to 2003), UIC stagnated and Uosm decreased, whereas 24-h Uvol and 24-h UI increased. The final median 24-h UI reached 120 μg I/d. Milk, fish, egg, and meat intakes and 24-h sodium excretion were all significant predictors of IS, with an almost doubled contribution from milk intake during the second 4-y period.”

Their conclusion highlights the 24-hour collection as a more dependable metric for iodine sufficiency (IS):

“Our study shows a continuous improvement of IS in a longitudinal sample of German schoolchildren. This improvement was masked when UIC was used as an IS index, especially from 2000 to 2003 because of changes in hydration status. Thus, in research-oriented studies that focus on UIC measurements, hydration status can be a relevant confounder. Longitudinal analyses of 24-h UI in cohort studies may represent an alternative hydration status–independent tool to examine trends in IS and the contribution of relevant foods to IS.”

Clinical EndocrinologyClinical caution: There are a number of studies linking iodine supplementation to increases in autoimmune thyroiditis (Hashimoto’s thyroiditis). This is understandable considering that up-regulating thyroid peroxidase, thyroglobulin and other iodine driven activity could ‘wave a red flag in front of the bull’ in individuals who have lost tolerance and are in the stage of silent autoimmunity. Even iodine introduced cautiously can trigger this problem as described in a paper published in Clinical Endocrinology. The authors state:

“Autoantibodies against the thyroid gland with thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) as the most common can often be demonstrated in serum.”

They used these to measure the incidence of thyroid autoimmunity in the Danish population before and after their mandatory iodization of salt:

“Two identical cross-sectional population studies were performed before (Cohort 1 (C1), year 1997–1998, n = 4649, median urinary iodine 61 μg/l) and 4–5 years after (Cohort 2 (C2), year 2004–2005, n = 3570, median urinary iodine 101 μg/l) mandatory iodine fortification of salt was implemented in Denmark. Blood tests were analysed for TPO-Ab and Tg-Ab using sensitive assays.”

There was a definite increase in thyroid autoimmunity:

Antibodies were more frequent in C2 than in C1: TPO-Ab > 30 U/ml, C1 vs C2: 14·3 vs 23·8% (P < 0·001) and Tg-Ab > 20 U/ml, C1 vs C2: 13·7 vs 19·9% (P < 0·001). The C2 vs C1 effect was confirmed in multivariate regression models (C1 reference): TPO-Ab: OR (95% CI): 1·80 (1·59–2·04) and Tg-Ab: 1·49 (1·31–1·69). The increase in the frequency of thyroid antibodies was most pronounced in young women and especially observed at low concentrations of antibodies.”

Clinicians considering iodine supplementation must take care to assess patients for the potential for loss of immune tolerance to thyroid, even when supplementation is undertaken with cautious amounts. The authors conclude:

The prevalence of both TPO-Ab and Tg-Ab was higher 4–5 years after a cautious iodine fortification of salt was introduced in Denmark. The increase was most pronounced in young women and in the low concentrations of antibody. Further studies are needed to evaluate the long-term effects of increased iodine intake on thyroid autoimmunity in the population.”

JAMA Vol 308 No. 23How much iodine should be supplemented during pregnancy and breast feeding? The authors of a paper published in JAMA last December first state:

Dietary iodine requirements are increased during pregnancy due to increased thyroid hormone production, increased renal iodine losses, and fetal iodine requirements. Dietary requirements remain increased in lactation due to the concentration of iodine in breast milk…Adverse effects of iodine deficiency in pregnancy, when the deficiency leads to severe decreases in maternal thyroxine (T4), include include…increased pregnancy loss and infant mortality. Decreases in maternal T4 associated with even mild iodine deficiency may have adverse effects on the cognitive function of offspring, and iodine deficiency remains the leading cause of preventable intellectual disability worldwide.”

This begs the question how much postpartum depression might be contributed to by suboptimal iodine. Regarding supplementation…

“…all US women who are pregnant, lactating, or planning a pregnancy should ingest dietary supplements containing 150 µg of potassium iodide per day. The Endocrine Society has recently advocated that all daily prenatal multivitamins should contain 150 to 200 µg. The addition of 150 µg does not pose a risk, even for women who are iodine replete, because a total iodine intake of as much as 500 too 1100 µg per day is considered safe in pregnancy.”

For selected food sources of iodine and other information see the National Institute of Health Office of Dietary Supplements.

Autism spectrum disorders and altered immune function

Research in Autsim Spectrum DisordersAutism and autoimmunity have been linked in a number of earlier studies. A paper just published in Research in Autism Spectrum Disorders sheds more light on the role of immune dysregulation in ASDs. The authors state:

“Previous studies have shown that children with autism spectrum disorders (ASDs) have impaired executive function, disordered neural connectivity, and abnormal immunologic function. The present study examined whether these abnormalities were associated.”

They compared two groups of seventeen high-functioning (HFA) and 17 low-functioning (LFA) children with ASD, aged 8–17 years, for general intelligence in terms of IQ; executive and non-exective task functions as measured by seven standardized tests; neural connectivity by theta coherence in the anterior and posterior regions; and immunologic function as measured by the level of circulating CD3+ CD8+ suppressor/cytotoxic T lymphocytes in a blood sample. The low-functioning children were notable for immune dysregulation along with disordered EEG connectivity:

“Results on executive function showed that LFA children performed significantly poorer than HFA children as shown on their lower Executive Composite as well as individual executive function scores. However, there was no group difference on the Picture Completion Task. Results on neural connectivity showed that LFA children demonstrated a different pattern of electroencephalography (EEG) coherence from HFA children as shown in the significantly elevated theta coherence in the anterior network, as well as at the left intra-hemispheric (LA-LP) and right-to-left inter-hemisphere (RA-LP) connections of LFA children. In immunologic function, results showed that LFA children had significantly elevated level of suppressor/cytotoxic T lymphocytes (CD3+ CD8+). In addition, the executive dysfunction, disordered neural connectivity, and abnormal immunologic function were found to be associated.”

Interested readers can return here for forthcoming posts that illustrate the importance of immune function in a wide range of brain and CNS disorders. Implementation in case management must be individualized on a case by case basis, but no assessment of autism spectrum disorders is complete without carefully investigating a possible autoimmune component. The authors conclude:

“These results provided some initial evidence to support the notion that immunologic factors are associated with neuronal damage, measureable by EEG coherence and manifested as executive dysfunctions.”

The human microbiome, breast milk and autoimmunity

A fascinating study published in The American Journal of Clinical Nutrition illuminates how the microbiome of human breast milk changes depending on the mode of delivery (vaginal, elective and nonelective cesarean) and weight of the mother. This has great significance for the development of autoimmune and allergic diseases.

Current Opinion in RheumatologyTo put the matter in context, consider also a paper recently published in Current Opinion in Rheumatology and describes how changes in the human microbiome can drive autoimmunity. The authors observe:

“Humans are superorganisms. The human body harbors an extensive microbiome, which has been shown to differ in patients with autoimmune diagnoses. Intracellular microbes slow innate immune defenses by dysregulating the vitamin D nuclear receptor, allowing pathogens to accumulate in tissue and blood. Molecular mimicry between pathogen and host causes further dysfunction by interfering with human protein interactions. Autoantibodies may well be created in response to pathogens.”

Changes in the human microbiome can either promote or hinder immune system dysregulation and the process of molecular mimicry (cross-reaction between microbes and human tissues) that elicits autoimmune inflammation. The authors further state:

“The catastrophic failure of human metabolism observed in autoimmune disease results from a common underlying pathogenesis – the successive accumulation of pathogens into the microbiome over time, and the ability of such pathogens to dysregulate gene transcription, translation, and human metabolic processes. Autoimmune diseases are more likely passed in families because of the inheritance of a familial microbiome, rather than Mendelian inheritance of genetic abnormalities.”

Am Journal Clin NutritionBearing this in mind helps us appreciate the significance of the study on human breast milk. The authors were inspired by noting that…

Breast milk is recognized as the most important postpartum element in metabolic and immunologic programming of health of neonates. The factors influencing the milk microbiome and the potential impact of microbes on infant health have not yet been uncovered…Our objective was to identify pre- and postnatal factors that can potentially influence the bacterial communities inhabiting human milk.”

They examined the communities of microbes in breast milk at birth (colostrum within 2 days of birth, 1 month and 6 months after delivery) among women who varied in BMI, weight gain, and the mode of delivery. Also…

“…to shed light on the potential origin of the milk microbiome, its microbiota was compared with the available data for female skin, vaginal, oral cavity, fecal, and gut mucosal microbiota, including a total of 500,000 16S rRNA sequences.”

Relatedness between milk bacteria and the rest of the human microbiomeThis showed that the breast milk microbiome is different from the microbes in other parts of the body and is not simply a contaminant from the skin. The dynamism of the breast milk microbiome and its implications for autoimmunity shone through in their results for the several hundred species that are present:

“We found that the human milk microbiome changes over lactation. Weisella, Leuconostoc, Staphylococcus, Streptococcus, and Lactococcus were predominant in colostrum samples, whereas in 1- and 6-mo milk samples the typical inhabitants of the oral cavity (eg, Veillonella, Leptotrichia, and Prevotella) increased significantly. Milk from obese mothers tended to contain a different and less diverse bacterial community compared with milk from normal-weight mothers. Milk samples from elective but not from nonelective mothers who underwent cesarean delivery contained a different bacterial community than did milk samples from individuals giving birth by vaginal delivery, suggesting that it is not the operation per se but rather the absence of physiological stress or hormonal signals that could influence the microbial transmission process to milk.”

Interestingly, the contents of the mother’s intestines can contribute:

“Dendritic cells have been described to penetrate the intestinal epithelium to take up commensal bacteria from the gut lumen, to reach the systemic circulation, and to retain even live bacteria for several days; recently, the transfer of intestinal bacteria to the mammary glands within dendritic cells has been proposed.”

Bacterial taxonomic composition of human breast milkThe authors note the vital significance of the breast milk microbiome for the development of an infant’s immune system:

Prenatal and postnatal microbial exposures have profound effects on the microbial colonization of the intestine and maturation of the naive immune system. Given that the bacteria present in breast milk are among the very first microbes that enter the human body and given the vital role of bacteria in the infant’s physiology and development of the immune system, our data emphasize the necessity to understand the biological role that the breast milk microbiome could potentially play for human health. If the bacterial composition of human breast milk has coevolved to maximize the infant’s metabolic efficiency and to optimally stimulate the immune system, a skewed microbial milk composition might have important consequences for the infant’s health, and those potential consequences would need to be evaluated for future recommendations in child nutrition.”

Clearly we are ‘super organisms’ consisting of a vast ocean of diverse DNA, and this is significantly influenced by the breast milk microbiome that is subject to change depending on time, metabolic status of the mother, and the mode of delivery.

“Our results indicate that milk bacteria are not contaminants and suggest that the milk microbiome is influenced by several factors that significantly skew its composition. Because bacteria present in breast milk are among the very first microbes entering the human body, our data emphasize the necessity to understand the biological role that the milk microbiome could potentially play for human health.”

This is one of multiple factors that must be borne in mind by the clinician responsible for case management of autoimmune conditions.