Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
------------
The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
Sunday, June 23, 2013
Thyroid hormone metabolism in the developing brain
Charged with the task of covering both pediatric endocrine as well as the H/P/T axis, I found these talks most interesting.
Dr. Hernandez of Maine Medical Center taught me a great deal about T3 metabolism in the brain. As we all know, the thyroid hormones include T4 and T3, with T3 being the active form. T4 and T3, as well as other forms of thyroid hormone, are metabolized by enzymes called deiodinases. In the brain, two types of deiodinases are important. Type 2 (D2) converts T4 to T3, thereby increasing the more potent form for use in the brain. D2 is increased in the setting of hypothyroidism in order to continue to provide active thyroid hormone to the brain even in this compromised state. On the other hand, Type 3(D3) converts T3 to the inactive T2 and can protect the brain from states of thyroid hormone excess, such as hyperthyroidism.
We already know that thyroid hormone is important for the developing brain because the birth defect of being born without one (Congenital Hypothyroidism) is associated with poorer learning, and if left untreated, marked mental under-development. This is painted with a wide brush: thyroid hormone important for brain, but a recent paper by Ng in Nature Reviews of Endocrinology and Diabetes 2013 p. 246 details the importance of both the location (spatial) and time (temporal) of the activity of the deiodinases to lead to the development of the cochlea in the inner ear.
The speaker's group from Maine examined mice to see the detailed ways in which thyroid hormone helps our brain develop. They did this by examining mice without D2 expression in the brain (also called D2 knockout, or D2KO, without D3 expression in the brain (D3KO), or both. Mice from the Ng study above, both D2KO and D3KO, were found to have hearing loss.
As D3 protects against hyperthyroidism, a knockout creates hyperthyroidism in the brain. These mice were noted to have mild hydrocephalus (water on the brain), a brain of smaller dimensions, in particular, "shorter" from front to back, and a smaller cerebellum, which helps to control our motor functions. I addition, these animals had malformed skulls (craniofacial abnormalities) which left less room for the cerebellum to grow, and were also noted to have a thicker cortex.
T3 is crucial in the part of the brain called the hypothalamus, in particular the pre-optic nucleus and the amygdala. The timing is important too: late gestation and just after being born, a time when the brain is enriched with sex-steroid receptors (meaning when the brain is "listening intently" for either the testosterone present in baby boys or estrogen in baby girls). This led the investigators to wonder if D3KO boys were different than D3KO girls, and indeed they were.
Not only that, but the offspring (kiddoes) of male D3KO and normal females still had problems with less gene expression (activity) in the thalamus and hypothalamus than offspring of female D3KO and normal males, which is called imprinting. Now, (here is where I got a little lost), even the grandchildren of D3KO have some residual effects via a phenomenon called epigenetics.
So, in addition to exploring the role of deiodinases in the brain, they reinforced to me that there is quite a bit more to genetics than just sequencing the genome.
--------
The next speaker Heike ????? Of Germany spoke about the transport of the various thyroid hormones from one cell type to another in the developing brain. Both T4 and T3 pass the blood-brain barrier. T4 is taken up by the astrocytes, converted to T3, and released for use by other brain cells oligodendricytes and neurons. So, just like we're flying home today, those hormones have got to get there from here.
A protein called MCT8 is a thyroid hormone transporter (think "tunnel") in humans. When there are problems with MCT8, patients have psychomotor retardation, developmentaldelays, speech delays, marked muscle weakness, and seizures. In addition, they have abnormal thyroid labs, with low Free T4 and elevated Total T3.
Mice are a great way to learn more about humans. These scientists created a MCT8KO mouse which had similar thyroid labs, but otherwise acted like a normal mouse. On closer look, transport of T4 into the brain was mildly impaired, and markedly impaired transport of T3. However, the mice compensated by increasing D2 (remember this enzyme? It converts T4 to T3). So even though T3 wasn't being effectively transported into the brain, the brain just made it locally.
Mice have other transport proteins, so to create a mouse with differrent problems with transport, they knocked out another gene, Oatp1C1. These knockouts (I don't mean "gorgeous" here) acted similarly to the MCT8KO, so they just added them up together and created, yes, a double-Knockout. Finally, they got what they were looking for. Thyroid hormone uptake into the brain, normal in healthy mice, was about 50% in each of the MCT8KO and Oatp1C1KO, but down by 95% in the double KO (2KO).
Careful examination of the 2KO mice showed the cells of the cerebellum, called Purkinje fibers, were less branched and developed than the normal mice. As those branches are what forms connections throughout the cerebellum, once could suspect these mice would be more clumsy than normal.Do I have under-developed Purkinje fibers?
The hypothalamus is transiently less developed in 2KO, but recovery was noted by adulthood. (Begs the question, how? Upregulation of other transporters?) The cerebral cortex was permanently underdeveloped. Interestingly (well, it's ALL interesting), the specific neurons that keep us calm, the GABA-Ergic tone was less in the 2KO, which increased their likelihood to have seizures.
Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
------------
The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
------------
The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
Sent from my iPad
Charged with the task of covering both pediatric endocrine as well as the H/P/T axis, I found these talks most interesting.
Dr. Hernandez of Maine Medical Center taught me a great deal about T3 metabolism in the brain. As we all know, the thyroid hormones include T4 and T3, with T3 being the active form. T4 and T3, as well as other forms of thyroid hormone, are metabolized by enzymes called deiodinases. In the brain, two types of deiodinases are important. Type 2 (D2) converts T4 to T3, thereby increasing the more potent form for use in the brain. D2 is increased in the setting of hypothyroidism in order to continue to provide active thyroid hormone to the brain even in this compromised state. On the other hand, Type 3(D3) converts T3 to the inactive T2 and can protect the brain from states of thyroid hormone excess, such as hyperthyroidism.
We already know that thyroid hormone is important for the developing brain because the birth defect of being born without one (Congenital Hypothyroidism) is associated with poorer learning, and if left untreated, marked mental under-development. This is painted with a wide brush: thyroid hormone important for brain, but a recent paper by Ng in Nature Reviews of Endocrinology and Diabetes 2013 p. 246 details the importance of both the location (spatial) and time (temporal) of the activity of the deiodinases to lead to the development of the cochlea in the inner ear.
The speaker's group from Maine examined mice to see the detailed ways in which thyroid hormone helps our brain develop. They did this by examining mice without D2 expression in the brain (also called D2 knockout, or D2KO, without D3 expression in the brain (D3KO), or both. Mice from the Ng study above, both D2KO and D3KO, were found to have hearing loss.
As D3 protects against hyperthyroidism, a knockout creates hyperthyroidism in the brain. These mice were noted to have mild hydrocephalus (water on the brain), a brain of smaller dimensions, in particular, "shorter" from front to back, and a smaller cerebellum, which helps to control our motor functions. I addition, these animals had malformed skulls (craniofacial abnormalities) which left less room for the cerebellum to grow, and were also noted to have a thicker cortex.
T3 is crucial in the part of the brain called the hypothalamus, in particular the pre-optic nucleus and the amygdala. The timing is important too: late gestation and just after being born, a time when the brain is enriched with sex-steroid receptors (meaning when the brain is "listening intently" for either the testosterone present in baby boys or estrogen in baby girls). This led the investigators to wonder if D3KO boys were different than D3KO girls, and indeed they were.
Not only that, but the offspring (kiddoes) of male D3KO and normal females still had problems with less gene expression (activity) in the thalamus and hypothalamus than offspring of female D3KO and normal males, which is called imprinting. Now, (here is where I got a little lost), even the grandchildren of D3KO have some residual effects via a phenomenon called epigenetics.
So, in addition to exploring the role of deiodinases in the brain, they reinforced to me that there is quite a bit more to genetics than just sequencing the genome.
--------
The next speaker Heike ????? Of Germany spoke about the transport of the various thyroid hormones from one cell type to another in the developing brain. Both T4 and T3 pass the blood-brain barrier. T4 is taken up by the astrocytes, converted to T3, and released for use by other brain cells oligodendricytes and neurons. So, just like we're flying home today, those hormones have got to get there from here.
A protein called MCT8 is a thyroid hormone transporter (think "tunnel") in humans. When there are problems with MCT8, patients have psychomotor retardation, developmentaldelays, speech delays, marked muscle weakness, and seizures. In addition, they have abnormal thyroid labs, with low Free T4 and elevated Total T3.
Mice are a great way to learn more about humans. These scientists created a MCT8KO mouse which had similar thyroid labs, but otherwise acted like a normal mouse. On closer look, transport of T4 into the brain was mildly impaired, and markedly impaired transport of T3. However, the mice compensated by increasing D2 (remember this enzyme? It converts T4 to T3). So even though T3 wasn't being effectively transported into the brain, the brain just made it locally.
Mice have other transport proteins, so to create a mouse with differrent problems with transport, they knocked out another gene, Oatp1C1. These knockouts (I don't mean "gorgeous" here) acted similarly to the MCT8KO, so they just added them up together and created, yes, a double-Knockout. Finally, they got what they were looking for. Thyroid hormone uptake into the brain, normal in healthy mice, was about 50% in each of the MCT8KO and Oatp1C1KO, but down by 95% in the double KO (2KO).
Careful examination of the 2KO mice showed the cells of the cerebellum, called Purkinje fibers, were less branched and developed than the normal mice. As those branches are what forms connections throughout the cerebellum, once could suspect these mice would be more clumsy than normal.
The hypothalamus is transiently less developed in 2KO, but recovery was noted by adulthood. (Begs the question, how? Upregulation of other transporters?) The cerebral cortex was permanently underdeveloped. Interestingly (well, it's ALL interesting), the specific neurons that keep us calm, the GABA-Ergic tone was less in the 2KO, which increased their likelihood to have seizures.
Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
------------
The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
------------
The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
Sent from my iPad
Monday, June 17, 2013
“Abstract” thinking about Pediatric Endocrinology
A rapid-fire presentation of several papers on Saturday educated me about some very-new aspects of research into pediatric endocrine issues.
Molecular Changes in the aromatase gene in girls with Early Puberty
Dr. Stueve of Keck School of Medicine at the University of Southern California, LA presented work done in conjunction with Mount Sinai School of Medicine. They reminded the audience that both obesity and early thelarche (onset of breast development) are risk factors for estrogen-sensitive breast cancer, presumably due to a longer time spent in an estrogen-exposed status. The enzyme that catalyzes the final step in estrogen formation is called aromatase, or CYP19A1. The hypothesis was that patients with overweight and early thelarche would have less methylation (and therefore increased expression) of the CYP19A1 gene. This investigative team analyzed salivary tissue DNA of 6-8 yo girls with both pubic hair and breast development, and indeed found such an association. In essence, heavier girls with early breast development had DNA with more availability of the aromatase gene to be expressed.
àWould be interesting to see what would happen if these girls lost weight. Would the methylation status of this gene change? Is it static or dynamic?
Optimizing outcomes in preterm, Very-Low Birthweight (VLBW) babies
Work from the German Neonatal Network sought to establish causes for different outcomes in VLBW babies treated with steroids. Steroids called glucocorticoids are dosed in this population to optimize lung development, which is important, though not without its attendant risks. This medication suppresses the immune system in an already vulnerable population, and increase the likelihood for sepsis. The gene for the receptor for this medication (glucocorticoid receptor) was analyzed from 2200 infants, and noted to be different in those with varying alleles.
è Allows for future pharmacogenomics, which is tailoring therapy to a specific patient’s genes. While treatment for the lung maturation would still need to occur, knowledge of the individual patient’s susceptibility to infection may be crucial to minimizing complications and length of NICU stay.
Establishing a new test for Cushing Syndrome in Children
Cushing Syndrome is a rare disorder of cortisol excess. This hormone level varies in a diurnal fashion, high in the morning, and low in evening and overnight. Endocrinologists take advantage of this, and note that one of the first sign of Cushing Syndrome is loss of this diurnal variation, and in adults, measurement of salivary cortisol is an established means to test for this condition. However, to use this convenient test in children (as opposed to the current 24hr urine collection or midnight serum level), one must first establish normal levels. Dr. Rajiv Kumar of Stanford University Medical Center (link) analyzed salivary cortisol of children of normal height referred for short stature to their endocrine clinic who were otherwise healthy, and separated them into those 8yrs and older, and those less than 8. Data were gathered at both bedtime and midnight, and levels were quite close, obviating a need for a later bedtime, kids!
è More normal data makes a diagnostic test robust. One of the presenting signs of Cushing is weight gain, and with the epidemic of obesity in children, it would be nice to have an easier test than 24hr urine to use in special situations when clinical suspicion is higher.
Increasing diagnostic accuracy of newborn screening for CAH
Congenital Adrenal Hyperplasia (CAH) is a rare disease, but in those who go undetected, can be life-threatening at 1-2 weeks of life due to adrenal crisis. For this reason, screening for it is part of the Newborn screen. The cause is a deficiency in 21hydroxylase, which is important in cortisol synthesis, and leads to a buildup of the precursor 17 hydroxyprogesterone (17OHP). Testing should be straightforward, just an elevated level of 17OHP would be indicative. However, 17OHP varies with gestational age, and the test (immunometric assay) is fraught with error, so false positives and false negatives occur, even with “second tier” testing. The investigators considered that perhaps a ratio 17OHP (upstream of 21hydroxylase) to Cortisol (downstream of 21hydroxylase) would provide another parameter help to clarify the presence or absence of disease. Data from the California Department of Public Health was used, and 197 samples were analyzed. Using the ratio of 17OHP/Cortisol, as well as 17OHP/Androstenedione, assignments could be made to “normal”, simple virilizing, CAH carrier, as well as CAH.
è Newborn screening is a powerful tool, but increasing accuracy of the testing, particularly in rare conditions, will aid in prevention of undue worry with false positives, and missed diagnoses in false negatives.
Blog posts from this meeting have been quite Peds-heavy. My plan is to cover thyroid as well, which will be tomorrow’s (well, Wednesday’s, since we’re travelling tomorrow) post. However, I missed some great talks Sunday afternoon due to a gas leak at the Moscone Center.
Instead, our party took the MUNI to Embarcadero to see the Ferry Building, so here are some pictures, enjoy!
A gorgeous heirloom tomato from a market inside the Ferry Building
The Ferry Building on a clear day
The Bay BridgeNews-worthy Adolescent Health Issues
Being an Official Blogger has its privileges. Yesterday, I saw a live Press Conference where 3 experts spoke about their cutting-edge research in adolescent health. Read on.
Gender Dysphoria in Children and Adolescents
Dr. Henriette Delemarre-van de Waal of the Leiden University Medical Center in Leiden, The Netherlands discussed the treatment of gender dysphoria. This condition, also known as transgender, often presents early, and can be present in pre-pubertal children. Once puberty sets in, and the secondary sexual characteristics such as breast development and testicular enlargement are noted by the patient, the stress of this dysphoria worsens. An Endocrine Society Guideline paper from 2009 recommends the use of leuprolide to halt puberty in those who have started puberty (Tanner stage II). Puberty is also a time of decreased insulin sensitivity, worsening lipid profile, and increasing bone mass, and Dr. Delemarre-van de Waal’s group looked at the safety profile of GnRH agonists in 12-16 year-olds with regards to these issues. Over a 24-month treatment period, no changes were noted with regard to the ratio of total cholesterol to HDL or in LDL, and this consistency was noted even when cross-sex hormones were added.
Gender dysphoric females transferring to males can be treated with oxandrolone to augment height velocity to achieve a mean height in the male normal range. Similarly, gender dysphoric males transferring to females will note a decrease in height velocity on GnRH therapy. Initial addition of estrogen will increase height velocity, but as levels increase to that of normal adult women, the growth velocity slows to zero, achieving a height closer to that of an average female. In these patients, it was noted that adequate peak bone mass was achieved, even with use of cross-sex hormones.
I have to admit this is an area with which I have very little comfort. A recent request was made of my services to help an adolescent with this condition, and I have been reluctant. However, I think a review of the guideline paper (see link above), as well as knowledge that I can help a patient, will help nudge me along in this still-controversial area.
Anxiety in Anorexia Nervosa
Dr. Madhumsmita Misra of Harvard Medical School has studied the endocrine manifestations of anorexia nervosa (AN) at length. Her newest work was to investigate the effect of estrogen replacement on anxiety in adolescents with AN. Using ovariectomized rats as a model, these animals were noted to have increase in anxious behaviors that abated with use of estrogen treatment. For this reason, it was thought patients, in the hypoestrogenic state due to AN, may also benefit from estrogen replacement to treat the anxiety component of this difficult-to-treat disease. Her group studied teen girls meeting DSM-IV criteria for diagnosis of AN and with bone age >15. In addition to other tests, they were given questionnaires to assess their levels of anxiety, as well as propensity toward anxiety, and randomized them either to treatment with estrogen patches and oral progesterone for 10 days each month or placebo patches and pills. They followed 72 girls for 18 months, then questionnaires were repeated for the 37 that completed the study. Although no change was noted in weight, BMI, % body fat, or eating attitudes, the TRAIT anxiety score of tendency to anxiety, was improved in those who had received estrogen treatment. In addition, the use of estrogen and progesterone prevented the increase of current anxiety that frequently occurs in these patients when weight increases. While the use of birth control pills (OCPs) has not been studied in this population for this purpose, prior work revealed OCPs did not have benefit on bone health, whereas physiologic replacement with estrogen patches and progesterone was effective. More studies are being planned with this preliminary data in mind.
Vitamin D Deficiency: Nothing at Which to Sneeze
Dr. Candace Percival, an endocrine fellow training at the Walter Reed National Military Medical Center, reviewed the increase of rates of obesity across the US, and that the military population is not spared. Higher rates of allergy and asthma are seen in the obese population, and their team sought to investigate this further.
Vitamin D is activated by immune cells, and deficiency is associated with increase in allergy, asthma, and increased levels of IgE. Adipose tissue, far from being just a storage organ, secretes leptin and adiponectin. Leptin, increased in obesity, suppresses appetite, and increases inflammatory markers. Adiponectin, decreased in obesity, appears protective for coronary artery disease, and when present in low levels, is associated with asthma. Additionally, adipose tissue serves as a “sponge” for vitamin D, collecting it and keeping it from circulating.
The study compared 19 obese 10-18 year-olds with 20 normal-weight controls. Leptin was increased in those with BMI z-scores>1.5, and adiponectin was lower in this population. The obese children also had higher levels of allergy-associated cytokines IL-6 and IL-13, IgE, and lower levels of Vitamin D. While this study associates the two conditions, studies planned to see the effect on these cytokines and antibody levels with Vitamin D treatment will help determine if the relationship is causal.
I frequently test vitamin D levels in both my adult and pediatric patients sent for evaluation of endocrine disease, and treat it aggressively as benefits far outweigh the risks. Although this relationship between vitamin D and allergies is only an association, the low risks of treatment offer another possibility to decrease the severity of allergies and asthma in the obese population.
On lunch break on Saturday, was treated to hula dancing and lovely weather while eating soup in the Yerba Buena Gardens. It was a lovely break amidst all the high-level science.
Sunday, June 16, 2013
1st Story of Day 1 at ENDO2013
Day 1 of ENDO 2013
Well, despite difficult travel, including the dreaded lost bags, I was set up in fine fashion by my sister-in-law, and made it to a full 1st day at the Moscone Center. And what a day it was. So many topics, so little time. Let me try to break it down just a bit.
Of Mice and Men
The first talk did not actually have to do with either of my topic areas, Hypothalamic/Pituitary/Thyroid (HPT) axis or Pediatric Endocrinology, but was such a great talk, I feel I have to say just a bit about it. Dr. Randy Seeley of the University of Cincinnati, spoke about the mechanism of weight loss after two different kinds of bariatric surgery. The Vertical Gastric Sleeve (VSG) creates a smaller stomach, but maintains the other anatomy. The Roux-en-Y Gastric Bypass (RY) creates not just a smaller pouch, but limits the absorption of the nutrients that are ingested by disconnecting the stomach from the duodenum, then reconnecting it at a later point down the small intestine. Although it seems obvious the main mechanism by which these procedures work is just by limiting intake, this group has done elegant experiments to prove indeed there is more to this than meets the eye.
After proving the stomach will indeed stretch (a female mouse, after having had the VSG, can double her intake to have adequate calories to sustain a pregnancy and to lactate for her pups), the team observed that the most robust finding after surgery is a change in the composition of the diet. Post-surgical mice (either VSG or RY) consistently chose a diet of lower fat intake and higher carbohydrate intake, why?
Whether the gastroenterologists want to admit it or not, the gut is actually an endocrine organ. Signals such as insulin, Glucagon-like peptide (GLP-1), the GLP-1 Receptor, and Ghrelin were each systematically tested with knock-out mice (all very remarkable studies), and found not to be the cause of the decreased intake. Ultimately, bile acids seem to play an important role. These compounds indeed help digest fats, but also bind to cell surface and nuclear receptors. One receptor, FXR, on the cell surface, showed particular promise. If bile acids play such an important role in decreasing caloric intake, other, less-altering surgeries may be possible, an idea tantalizing for these surgeons.
Another important aspect of health changed about post-surgical mice: the bacteria in the gut (called the microbiome), changed after surgery. In particular, Roseburia, a genus decreased in Type 2 Diabetes, increased in those after VSG or RY. This raises even more questions for investigation.
So, despite sounding quite “gee, whiz!” from the get go, I was impressed by this talk, delivered so well, representing the work of so many, and it makes me excited about what else is to come.
Friday, June 14, 2013
Off to See Many Wizards . . .
Today I'm headed to ENDO 2013, the annual meeting of the Endocrine Society, in San Francisco, California.
As some of you may know, I've been chosen to blog while I'm there about the Pediatric Endocrine aspects, as well as the Hypothalamic/Pituitary/Thyroid Axis, very exciting!
This meeting will have thousands of attendees in a great city where we'll have the opportunity to rub elbows with the experts in endocrinology from all over the world. Needless to say, it is quite an intense meeting, with high-level science, presented in darkened rooms for best PowerPoint visualization, from 8AM to 6:30PM. Despite my best attempts to caffeinate adequately, I may miss some points. Even if I am able to maintain the stamina, there is just so much material, some of it presented simultaneously, that I have elected to have access to the whole library of presentations even after the fact, so the blogs about that material may continue well after the meetings.
I hope you'll find it useful. I am a clinician, and most of what I present will try to have the practical utility of the information at hand. I welcome comments.
Wish me luck!
As some of you may know, I've been chosen to blog while I'm there about the Pediatric Endocrine aspects, as well as the Hypothalamic/Pituitary/Thyroid Axis, very exciting!
This meeting will have thousands of attendees in a great city where we'll have the opportunity to rub elbows with the experts in endocrinology from all over the world. Needless to say, it is quite an intense meeting, with high-level science, presented in darkened rooms for best PowerPoint visualization, from 8AM to 6:30PM. Despite my best attempts to caffeinate adequately, I may miss some points. Even if I am able to maintain the stamina, there is just so much material, some of it presented simultaneously, that I have elected to have access to the whole library of presentations even after the fact, so the blogs about that material may continue well after the meetings.
I hope you'll find it useful. I am a clinician, and most of what I present will try to have the practical utility of the information at hand. I welcome comments.
Wish me luck!
Saturday, May 11, 2013
Thyroid Hormone Replacement
Not many organs in the body are easily replaced with a pill,
but we are lucky the thyroid is one of them.
Hypothyroidism, regardless of cause, is treated with thyroid hormone
replacement. As straightforward as this
sounds, once treatment is recommended, the questions begin: Synthetic or biologic? Levothyroxine (LT4)
only, or in combination with liothyronine(LT3)?
Synthetic thyroid hormones (Synthroid, Levothroid, Tirosint,
to name a few) have the same molecular structure as the levothyroxine (LT4) our
native thyroids produce. They have been
available since the 1950s, but in 1997, documentation of stability, consistency,
safety and efficacy, was required as part of a New Drug Application by the year
2000. However, all formulations were allowed to
remain on the market during that interval due to necessity of the
medicine. Synthetic forms are now
approved (most recently Tirosint in 2006) and regulated by the FDA. This is important, as cooperation with the
FDA can lead to appropriate (perhaps over-cautious) precautions for
patients. Recently Levoxyl was recalled
for an uncharacteristic odor. The
factories are off-line, and Levoxyl is not expected to be available until 2014. Generic forms are typically lower in cost,
but ensuring the source is always the same factory is difficult. Even within the same factory, there can be
about a 6% variability from lot to lot, which is additive when more than one
factory is involved. For some patients,
minimizing error is crucial to maintaining euthyroidism, and it is difficult to
achieve when mixing multiple sources in this very-low-dose medication.
Animal (pig) extracts of thyroid (e.g. Armour, Nature-Throid),
have been available since 1862. They
received the same invitation to submit a New Drug Application to the FDA the
synthetic forms did, but have not done so.
They remain available on the market as they have been “grandfathered” in,
having come into production before 1938.
There was a shortage of extracts in 2009 for unclear reasons, but their
production was specifically not disrupted by the FDA, as had been rumored. These medications do contain both LT4 and
LT3, and remain a favorite amongst certain patients and providers for this
reason. The ratio of LT4 and LT3 is
different in pigs than in humans (pigs have more T3). This is important to keep in mind when
reviewing labs of patients on this form of thyroid hormone replacement, as the Total
or Free T4 will frequently be low in the setting of a normal (or suppressed)
TSH and normal (or elevated) Total or Free T3.
Compounded forms of LT4 and LT3 allow customization of dose,
format, and flavor. They are not
regulated by the FDA, though there is some regulation of compounding pharmacies
on the state level. The same concerns
remain regarding safety and efficacy.
Also, the stability of the medications is not verified, and no
assurances are made the products are free of impurities. A slow-release T3 is marketed, though there
are no FDA-approved forms available at this time.
Should LT4 be dosed alone, or in combination with LT3
(Cytomel or liothyronine)? When
patients’ symptoms persist despite a normal TSH or T4, consideration may be
given to adding the more potent form of thyroid hormone, LT3. Most patients have the enzyme deiodinase D2,
which converts LT4 to LT3, in organs other than the thyroid. In fact, 75-80% of circulating LT3 has been peripherally
converted from LT4, rather than produced in the thyroid. Of 16 randomized, controlled studies
investigating the advantages of adding LT3, only one demonstrated objective
benefit. Four demonstrated subjective
benefit, and 4 studies indicated a patient preference for the combination. This option should be tailored individually,
with a goal of keeping the Total T3 and TSH in the normal range.
When there are this many treatment options available, it is
clearly because no one treatment fits all patients. However, knowledge of the risks and benefits
of the different options is the key to optimizing each patient’s condition.
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