A message regarding COVID-19 & pediatric endocrinology

Click below to read two statements regarding COVID-19 & pediatric endocrinology.

A reassuring note (click here to read): The healthcare community is still learning about the effects of COVID-19 on specific patients. You may have read that data from China suggest that diabetes is a risk factor for severe COVID-19. Please know however that this data regards adults, mainly older adults. Preliminary indications from China and from Italy suggest that pediatric-aged patients with diabetes are not at increased risk of severe COVID-19 (see this link). It would be reasonable to assume the same is likely true for pediatric aged patients with various endocrine disease, though we have yet to see any data. In any case, it remains important to be careful with your diabetes and endocrine medications. For youth with diabetes, aim to control your blood sugars as best possible, make sure to take your long-acting insulin / keep you insulin pump in good working order. For youth with adrenal insufficiency, make sure to take your prescribed hydrocortisone or other steroids, and give stress dose steroids if ill etc as instructed. Keep your prescriptions up. Be sure to minimize exposures, practice social distancing, frequent hand washing, etc. See our hospital COVID-19 website for additional information.

We remain available 24/7 (click to read): Please know that we are here for our patients. If you have questions or concerns about managing your endocrine condition, please contact us by phone/email/fax. We will work hard with you over the phone to help keep you from needing to come to the hospital. For the sake of our patients, their families, the community, and our staff, we are now conducting routine visits via phone, with in-person clinic visits only for urgent endocrine needs. Soon we expect to also have telehealth video options available as well.

Better congenital hypothyroidism screening

I am excited to report that the Iowa newborn screening program will begin using age-adjusted TSH cut-offs starting March 30, 2020. The purpose is to better screen newborns for congenital hypothyroidism, which is a condition that if untreated leads to profound deficiencies in brain development and body growth. The cutoff changes are expected to improve both the specificity and sensitivity of the screen. Otherwise, in general, there will be no change in workflow as involves endocrinologists and primary care providers. Only the cutoffs are changing. Despite these improvements, the newborn screen remains only a screening test and should not be used as a quantitative test to examine an infant in whom you suspect a thyroid abnormality. –Andrew Norris

Hormone-Secreting Pituitary Tumors

When these tumors occur in children, the manifestations are often different than in adults.

A concise review of hormone-secreting pituitary tumors and their clinical syndromes appears in today’s New England Journal of Medicine. The article starts by noting that hormone secreting pituitary adenomas account for ~15% of all intercranial tumors. Although the article is informative and well written, it largely omits the characteristics of these disorders in childhood. When these tumors occur in children, the manifestations are often different than in adults. Below I have tabulated the anterior pituitary hormones that can be oversecreted by pituitary adenomas, and their common related childhood syndromes / symptoms. The table is listed in order of prevalence, from occasional to exceedingly rare (just a few case reports ever). Some of the symptoms of these conditions are common and non-specific (e.g. headache) and usually do not indicate a pituitary adenoma. Other symptoms almost always warrant an endocrine workup, especially growth failure, galactorrhea, precocious puberty, pubertal failure, gigantism, and acromegaly. On the flip side of hormone-secreting adenomas are pituitary adenomas that do not secrete hormones. Even though such adenomas do not secrete hormones, they eventually can lead to symptoms once their size impinges on local function. These manifestations can include visual field defects, headache, deficiency of pituitary hormones though prolactin can be modestly elevated due to pituitary stalk compression. Importantly, hormone secreting adenomas can also lead to these size-related effects as well.

Hormone oversecretedChildhood manifestations
(prevalence ~1/10,000)

Menstrual disturbance (girls)
Galactorrhea (girls)
Gynecomastia (boys)
Pubertal delay/failure (boys)
(incidence <1/million/yr)
Weight gain
Growth failure
Amenorrhea (girls)
Hirsutism (girls)
Growth hormone (rare)Gigantism
TSH (exceedingly rare)Hyperthyroidism
LH, FSH (exceedingly rare)Precocious puberty

Can insulin degludec reduce ketoacidosis rates? Exciting new data suggests “maybe”.

Diabetic ketoacidosis (DKA) is a diabetes emergency that can result in death when not detected quickly and treated in a timely fashion.  DKA is most commonly caused by taking insufficient insulin, especially forgetting to take long acting insulin, or taking insufficient extra insulin during illness. Children and adolescents with diabetes are at particular risk to develop DKA. For reasons that are not fully understood, rates of DKA are increasing (see this 2018 commentary in Diabetes Care). Insulin degludec is an ultra-long-acting insulin analog. Its duration of action exceeds 30 hours, which is longer than other current long acting insulin types.  For this reason, it has been postulated that use of insulin degludec might reduce DKA risk when compared to other long-acting insulin analogs, especially among those who occasionally forget to take their long acting insulin. However, evidence has mixed. A study in 2015 Pediatric Diabetes found a reduction in ketosis when comparing children on degludec versus insulin detemir (note: the study was funded by Novo Nordisk, the maker of both degludec and detemir).  This is the least meaningful of all possible comparisons since insulin detemir is the shortest acting of current long acting insulins. This 2015 European regulatory document presents an analysis of DKA rates from a company trial comparing insulin degludec versus detemir, finding no differences. A study published in 2018 Diabetes Therapy examined 42 adults who switched to insulin degludec found fewer DKA events after the switch, though the study was not powered for statistical conclusions (again this study was funded by Novo Nordisk). This month, work published in Feb 2020 Hormone Research in Paediatrics reports a retrospective study of 35 adolescents with DKA who switched from insulin glargine (in its most common “U100” formulation) to insulin degludec. The adolescents experienced significantly fewer DKA episodes after the switch. This exciting data suggests that degludec may indeed help reduce risks of DKA in youth at risk.  Although these are encouraging, the retrospective nature of the study and lack of a control group prevents firm conclusions. In general, DKA rates are expected to subside with time in adolescents as they mature and better learn to prevent this unpleasant complication. A control group of adolescents who did not switch to degludec would have helped interpret the results. Degludec has other benefits, especially less hypoglycemia compared to other long acting insulins (see this 2018 meta-analysis).

Watching the brain think: Finding differences between children with and without type 1 diabetes

with the advent of techniques to strengthen brain regions, such as transcranial magnetic stimulation, might this type of research help guide possible interventions?” –Andrew Norris

Dr. Tsalikian

Dr. Tsalikian and collaborators across the country have been studying brain cognitive function in children with and without type 1 diabetes. In a study just published in PLOS Medicine, they report interesting differences. They used functional magnetic imaging resonance (fMRI) to measure activation in various brain locations while the children were given tasks. Compared to children without diabetes, those with type 1 diabetes exhibited two differences. One of the observed changes was impaired control of a region towards the back of the brain and this impairment typically leads to diminished task performance. In contrast, there was enhanced activation of a region towards the front of the brain involved in executive control. It appears that these two changes balanced each other, in that the two groups had similar task performance. Simply put, it appears that the brains of children with type 1 diabetes are able to compensate for impairments presumably induced by long-term exposure to high blood sugars. More study is needed to understand this latter point in particular, for example would the pattern normalize if the blood sugars were held to the normal range during the study? Furthermore, more study is needed to understand the broader implications of this work, for example might these or related changes contribute to the increased risk of depression in persons with diabetes? Finally, with the advent of techniques to strengthen brain regions, such as transcranial magnetic stimulation, might this type of research help delineate important interventions? Also involved in the study from our Division were Dr. Tansey, Julie Coffey, Joanne Cabbage, Sara Salamati, and Rachel Bisbee.

A lower safe threshold for treating hypoglycemia in newborns? An endocrine perspective.

There has long been some controversy regarding what blood glucose threshold should be used in newborns to guide when to initiate therapeutic intervention. This is an important concern, because sufficiently severe hypoglycemia can cause damage to the brain. However, it has been difficult to ascertain what degrees of hypoglycemia induce risk. This week the New England Journal of Medicine has published results from a new study focused on this question. Infants were randomized to receive intervention once blood glucose was under 47 (conventional cutoff) or 36 mg/dL. Psychomotor development was assessed at 18 months of age. The study found that outcomes in the more liberal cutoff group (36 mg/dL) were not any different from the conventional group. This suggests that the more liberal cutoff may be reasonable to use in clinical practice. An important caveat from the perspective of pediatric endocrinology is that this study pertains to healthy infants who do not have any specific endocrinologic or metabolic disorder. In fact the authors “emphasize the need for a higher target glucose concentration in newborns who have persistent hypoglycemia due to endocrine or metabolic disorders“. –Andrew Norris

Impaired glucagon responses in patients with cystic fibrosis and hypoglycemia

“Thus, these data implicate that cystic fibrosis induces defects in glucagon secretion leading to hypoglycemia risk. The association with pancreatic insufficiency suggests a link to pancreatic exocrine disease.” –Andrew Norris

Results from an important recent clinical study of hypoglycemia in patients with cystic fibrosis (CF) are now available. The study was conducted at the University of Washington and headed by preeminent diabetes physiologist Dr. Steven Kahn. Non-diabetic adults with cystic fibrosis were challenged with a 3-hour 75-gram frequently-sampled oral glucose tolerance test.

Half (14/27) of the subjects experienced hypoglycemia during the test. The glycemic pattern during the test was similar between these two groups until 135 minutes and thereafter, when the hypoglycemia group diverged downward. Those who exhibited hypoglycemia were more likely to be pancreatic insufficient. Importantly, those with hypoglycemia had lower plasma insulin & C-peptide levels. Modeling suggest that insulin sensitivity was greater in the subjects with hypoglycemia, accounting for the lower insulin levels. Importantly though, the “oral disposition index” did not differ between the two groups. This indicates that the amount of insulin secreted between the two groups would expected to have the same actions on lowering glucose when accounting for insulin sensitivity. Perhaps one could argue that the “oral disposition index” should have been lower in the hypoglycemia group, but in fact there was a trend towards lower values in this group (P=0.16). Plasma GLP-1 and GIP did not differ between the groups. In the hypoglycemia group, plasma epinephrine rose in the hypoglycemia group, albeit modestly. Cortisol did not rise, though it is not clear how many patients reached the lower blood glucose thresholds needed to trigger cortisol secretion. Growth hormone rose in some but not all patients. Perhaps most importantly, glucagon did not rise with hypoglycemia and did not differ at any point between the two groups.

These results suggest an impairment in counterregulatory response in patients with CF and hypoglycemia. Typically, the threshold for glucagon secretion occurs at less severe degrees of hypoglycemia than for other counterregulatory responses (see this nice review from Elizabeth Seaquist). Furthermore, the hypoglycemia in these subjects was mild. Thus, these data implicate that cystic fibrosis induces defects in glucagon secretion leading to hypoglycemia risk. The association with pancreatic insufficiency suggests a link to pancreatic exocrine disease. However, the mechanisms responsible remain to be determined. The manuscript describing these results is now published in the prestigious journal Diabetologia (link to article).

Senior endocrine fellow publishes research discovering genes that may modify 22q11.2 deletion syndrome.

Dr. Pinnaro

Dr. Pinnaro, pediatric endocrine fellow, has published her recent research that finds several candidate genes which may modify the phenotype of 22q11.2 syndrome. This genetic syndrome can cause congenital structural heart disease, failure of the parathyroid glands to properly form, and immunodeficiency. Although the effects of the syndrome vary from person to person, the reasons for this variability is unknown. Thus, Dr. Pinnaro set out to understand whether other genetic regions might be the reason. Her findings show that various genes might indeed contribute. She is the lead author on the work which is published in the January 2020 issue of Molecular Genetics & Genomic Medicine. Congratulations to Dr. Pinnaro for the results of her hard work in this area.

Might continuous glucose monitoring discern diabetes pathogenesis?

It can be challenging to distinguish type 1 from type 2 diabetes, especially in overweight adolescents and other populations. An upcoming report in the scientific journal Diabetes Care (link here) presents provocative data suggesting that continuous glucose monitoring (CGM) may distinguish forms of diabetes that occur because of loss of insulin secretion capacity (such as type 1) from forms due to insulin resistance (type 2). In particular, when CGM was performed when diabetes was very mild, insulin secretion defects were marked by increased blood glucose variability but normal fasting glucoses, whereas insulin resistance was marked by an overall increase in baseline (i.e. fasting) blood glucose levels.

–Andrew Norris

Endocrine care of children with neuromuscular disorders

Dr. Curtis

Children, adolescents, and young adults with neuromuscular disorders are at risk for various endocrine complications. For example, Duchenne muscular dystrophy is associated with risk of various endocrine conditions including poor bone health, adrenal insufficiency, obesity, pubertal delay, and short stature. To help with these issues, in 2019, Dr. Vanessa Curtis joined the multidisciplinary Neuromuscular team at the University of Iowa to provide endocrine care to patients in this clinic. This week, Dr. Curtis attended the Parent Project MD meeting in San Diego to further her skills in this emerging area of medicine.