User:Amybarch/sandbox

On the page "Hypothalamic–pituitary–thyroid axis"
Everything in the article is relevant to the topic at hand, but some of it isn’t appropriately explained or clarified. For example, the image used is a graphic that includes a lot of information that isn’t discussed in the text of the article itself. Additionally, it sometimes makes allusions to other related topics or issues without detailing what they mean or providing much explanation.

A lot of the text in the article is highlighted red - indicating that it should link to other Wikipedia pages, but those pages do not exist. This is ultimately very distracting in itself.

The article remains neutral, and states only facts, with no viewpoints being represented at all. This is lucky, as hypothyroidism and thyroid regulation can be a contentious topic on medical forums and blogs.

The citations work, and based on the ones I was able to check out, they support the claims in the article. Unfortunately for me, many of the sources were from print copies of journals, and didn’t have links I could refer to. On the bright side, all of the citations used were of neutral, reliable, and authoritative sources - such as medical journals, and PubMed.

However, there wasn’t an appropriate reference for every fact that was stated. For example, there is a claim that axolotls and sloths have a very low set-point re: thyroid homeostasis, but there is no citation after this fact.

The information appears to be relatively up to date, as most of the sources are within the past ten years, including some from 2017. However, many of the subtopics are only briefly touched on and could easily by expanded on. For example, the article links to Low-T3 syndrome (which is a start-class article) and High-T3 syndrome (which doesn’t even exist as an article yet) instead of discussing those the role of the HPT axis in those topics itself.

There is only one comment on the Talk page from 2013, which is similar to the one I made about the figure used - that it is useless without a key or explanation. The article is rated as a Start-Class, but Mid-Importance article, and is part of both WikiProject Physiology and WikiProject Medicine.

This specific topic isn’t one I’ve learned much about in class, except perhaps in my Behavioral Endocrinology - but the article covers the topic similarly, and presents the same information, albeit with a little more detail on dysfunction of the HPT axis.

Annotated Bibliography
1. Fliers, Bianco, Langouche, Boelen. “Endocrine and metabolic considerations in critically ill patients 4: Thyroid function in critically ill patients.” 2015 < https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979220/ >

In this 2015 review published in The Lancet (Diabetes and Endocrinology), a team of doctors and scientists in the Department of Endocrinology and Metabolism in the Academic Medical Centre at the University of Amsterdam review the existing literature and knowledge about non-thyroidal illness syndrome. They discuss the various mechanisms that may play a role in NTIS, and meta-analyze data on whether treating NTIS is beneficial in patients in the ICU.

2. Pappa, Vagenakis, Alevizaki. “The nonthyroidal illness syndrome in the non-critically ill patient.” 2010, European Journal of Clinical Investigation. < https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2362.2010.02395.x >

This review is by Maria Alevizaki (a physician-scientist (MD/PhD) Professor in Endocrinology at the Department of Medical Therapeutics in Athens University School of Medicine), Theodora Pappa (also at Athens University School of Medicine), and Apostolos Vagenakis (a doctor in Endocrinology in the Department of Medicine at University Hospital of Patras in Greece). It was published in the European Journal of Clinical Investigation. They provide an overview of the data about NTIS in non-critically ill patients, and provide insight about its possible role when seen outside of the ICU setting.

3. Warner and Beckett. “Mechanisms behind the non-thyroidal illness syndrome: an update.” 2009. < http://joe.endocrinology-journals.org/content/205/1/1.long >

This 2009 review is by Warner and Beckett in the department of Clinical Biochemistry at University of Edinburgh, and was published in the Journal of Endocrinology. They discuss the mechanisms behind NTIS, and specifically delve into dysregulation of the HPT axis and how this causes central hypothyroidism. They also review the causes of NTIS, such as malnutrition and severe illness.

4. Boelen, Kawakkel, and Fliers. “Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection.” 2011. < https://academic.oup.com/edrv/article/32/5/670/2354759 >

This review, published in 2011 in Endocrine Reviews, is by Boelen, Kawakkel, and Fliers in the Department of Endocrinology and Metabolism at the University of Amsterdam in the Netherlands. Rather than just focusing on low Plasma T3, they discuss the differential effects of inflammation on thyroid metabolism in different organs and tissues. They also discuss the differential effects of acute vs chronic inflammation.

5. Vries, Fliers, and Boelen. “The molecular basis of the non-thyroidal illness syndrome.” 2015 Journal of Endocrinology. < http://joe.endocrinology-journals.org/content/225/3/R67.long >

This review is by nearly the same authors as the previous one, but is published four years later in 2015. In this paper, they focus more on what is happening on a molecular level in NTIS; including central downregulation in the pituitary gland, peripheral thyroid metabolic changes, and the impact of cytokines on thyroid metabolism.

6. Chatzitomaris, Hoermann, Midgley, Hering, Urban, Dietrich B., Abood, Klein, Dietrick J. “Thryoid Allostasos-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming.” 2017. < https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517413/ >

This review is written by a large team of scientists at a number of universities and medical centers around the world but largely centered in Germany, with other authors in the United Kingdom, Australia, the United States, Italy, and Brazil. Rather than focusing specifically on Euthyroid Sick Syndrome, they provide an overview of the adaptive mechanisms of the HPT axis. Uniquely, they discuss the impacts of different types of allostasis (type 1 and type 2) and how this impacts the hypothalamus, and so the HPT axis. They illustrate how the different types of NTIS differ in thyroid metabolism, and the clinical impacts this has.

7. Abelleira, De Cross, Pitoia. “[Thyroid dysfunction in adults infected by human immunodeficiency virus.]” Medicina, 2014. < https://www.ncbi.nlm.nih.gov/pubmed/25188661 >

This review was written in 2014 by scientists in the Division of Endocrinology at the University of Buenos Aires in Argentina, and is originally in Spanish. They integrate the data that shows that patients with HIV have increased rates of thyroid dysfunction; one common presentation of which is euthyroid sick syndrome, in addition to other hypothyroidism and Graves’ disease.

Draft for Editing "Euthyroid Sick Syndrome"
My changes and additions (except for the lead sentence) are in bold. I also intend to change all references to the syndrome to say "NTIS", as this is the term most commonly used in the literature. The added picture is also mine. Euthyroid sick syndrome (ESS), sick euthyroid syndrome (SES), thyroid allostasis in critical illness, tumours, uremia and starvation (TACITUS), non-thyroidal illness syndrome (NTIS) or low T3 low T4 syndrome is a state of adaptation or dysregulation of thyrotropic feedback control[1] wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional.

'''This condition is often seen in starvation, critical illness, or patients in the intensive care unit. Similar endocrine phenotypes are observed in fetal life and in hibernating mammals.[2] The most common hormone pattern in NTIS is low total and free T3, elevated rT3, and normal T4 and TSH levels, although T4 and TSH suppression may occur in more severe or chronic illness. '''

Causes
Causes of euthyroid sick syndrome include a number of acute and chronic conditions, including pneumonia, fasting, starvation, anorexia nervosa, sepsis, trauma, cardiopulmonary bypass, malignancy, stress, heart failure, hypothermia, myocardial infarction, chronic renal failure, cirrhosis, diabetic ketoacidosis,[1] surgery, infection, brain injury, shock, cancer, and Human Immunodeficiency Virus .

In the acute hospital setting, NTIS is common; more than 70% of patients in the ICU have decreased T3, and 3% have suppressed TSH not due to hyperthyroidism '''. T3 can fall as early as 2 hours after the start of surgery. The severity of NTIS in this setting reflects the overall health state, and is associated with clinical outcome. If T4 is decreased, levels less than 40nmol/L are associated with elevated mortality rates. This is exacerbated if cortisol is also elevated. During the recovery phase, TSH may be transiently increased.'''

Outside the hospital setting euthyroid sick syndrome (non-thyroidal illness syndrome) has been assumed closely related with a series of chronic diseases, such as inflammatory bowel disease[3], chronic fatigue syndrome,[4] and autoimmune disease.

Additionally, an NTIS-like phenotype can be present in Major Depressive Disorder , as well as overexercise.

'''An abnormal NTIS phenotype is observed in some circumstances, wherein TSH, T3, and T4 are generally elevated rather than suppressed. This can occur during pregnancy, obesity, cold adaptation, endurance exercise, acute psychosis, and PTSD.'''

Pathophysiology
In critical illness the activity of different deiodinases is altered. Humoral and neuronal inputs at the level of the hypothalamus may adjust the set point of thyroid homeostasis. This may play an important role in the pathogenesis of the central component of NTIS.[5] In addition, both illness and medication (e.g. salicylates and heparin) may impair plasma protein binding of thyroid hormones, resulting in reduced levels of total hormones, while free hormone concentrations may be temporarily elevated.

NTIS probably represents an overlap of an allostatic response with pathologic reactions and drug interferences.[2] Allostatic overload may result in wasting syndrome and myxedema coma. Thyroid storm, on the other hand, represents allostatic failure, where the organism is unable to develop NTIS in the situation of thyrotoxicosis.[2]

Deiodinases
'''There are three primary deiodinases responsible for thyroid hormone conversion and breakdown. Type 1 (D1) deiodinates T4 to the biologically active T3 as well as the hormonally inactive and possibly inhibitory rT3. Type 2 (D2) converts T4 into T3, and breaks down rT3. D3 produces rT3 from T4, and breaks down T3. The balance of D2 and D3 is important for overall T3/rT3 balance. '''

In NTIS, the concentrations of these deiodinases are altered, although it is unclear whether NTIS is the cause or effect of this in peripheral tissues; in some studies, the alterations in thyroid hormone concentrations occured before the changes in deiodinase activity. Typically, peripheral D1 and D2 are downregulated, while peripheral D3 is upregulated; this is associated with lower T4 and increased rT3 .

Hypothalamic-Pituitary-Thyroid axis downregulation
'''Thyrotropin Releasing Hormone (TRH) neurons in the hypothalamus integrate global signals about the body’s energy state. They may be stimulated by signals such as leptin, alpha-MSH, and catecholamines; and inhibited by glucocorticoids, neuropeptide Y, and agouti-related peptide.''' '''In critical illness, inflammation increases tanycyte D2 in the paraventricular nucleus (PVN) of the hypothalamus, leading to local tissue hyperthyroidism. There may also be decreased central D3 . This causes negative feedback on the HPT axis, and therefore reduced TRH gene expression in the PVN. This is exemplified by the common NTIS phenotype of low TSH even in the face of peripheral hypothyroidism. '''

Cytokines
'''Illness can cause inflammation, which often involves an increase in cytokines such as TNFa, IL-1, and IL-6. Cytokines are implicated in NTIS.  IL-1β has been shown to decrease liver D1, as well as thyroid hormone receptor (THR) levels. IL-6 and TNFa downregulate D1 and suppress TSH, are negatively correlated with fT3, and are positively correlated with rT3.  NFkB also inhibits D1, and decreases the expression of Thyroid receptors α and β. IFNy inhibits thyroid and Tg release, and also inhibits the upregulation of TSH receptors.'''

Thyroid Hormone Receptors
'''In chronic liver and renal (kidney) failure, there is increased THR expression. In contrast, in acute illness such as sepsis and trauma, there is decreased THR expression.'''

Transporters
'''During NTIS, there are alterations in the concentrations of thyroid hormone transporters such as MCT8 and MCT10, although whether the levels are increased or decreased depends on the study. It is suggested that the altered concentrations are a result of NTIS, rather than a cause; a study in rabbits showed that administering thyroid hormones normalized transporter expression.'''

Binding Proteins
'''There is decreased Thyroxine-binding globulin (TBG) following bypass surgery, and in chronic illness a less effective form of TBG with lower affinity for thyroxine is synthesized. Reduced quantities of bound thyroid result, leading to decreased total thyroid measurements. Decreases in total thyroid may be more severe than alternations in free hormone levels. '''

Drugs
Dopamine and corticosteroids, commonly given in the hospital setting, can suppress TSH and suppress conversion of T4 to T3 '''. Other drugs such as estrogen, contraceptives, salicylates, and phenytoin can alter the binding of TBG to TH, resulting in different TH concentrations. Additionally, lithium disrupts thyroid function, and thyromimetic endocrine disrupters may downregulate the HPT axis.'''

Fasting
'''Fasting is a common response in inflammation and critical illness. It was originally suggested that selenium deficiency as a result of malnutrition reduces D1 catalytic activity, but this theory has not been supported as a cause of NTIS.'''



NTIS as a result of fasting may be regarded as a healthy and adaptive mechanism that reduces energy expenditure. Fasting in healthy, euthyroid people causes reduced T3 and elevated rT3, although TSH is usually unchanged.  Even moderate weight loss can lower T3.

'''This may be primarily via reduced levels of leptin (the satisfaction hormone). Low leptin levels can downregulate hypothalamic TRH neurons and cause a reduction in TSH. Ιn fasting animals, administering leptin reverses NTIS symptoms and restores thyroid hormone concentrations. In obesity, increased leptin increases TSH and T3, and lowers rT3; possibly as an attempt to increase energy expenditure and return to weight set point.  '''

'''Other signals associated with hunger also affect the HPT axis. Insulin and bile acids, which are elevated after a meal, lead to increased D2 activity, therefore increasing T3 and reducing rT3. Low leptin increases NPY and AGRP (associated with appetite), which inhibit TRH gene expression; this effect is enhanced by ghrelin (the hunger hormone). a-MSH stimulates TRH gene expression in the PVN. This is enhanced by leptin, and inhibited by low leptin. a-MSH is also antagonized by AGRP.'''

Psychiatry
Stress suppresses TSH, '''and there may be alterations in thyroid hormone levels in psychiatric illness. In Major Depressive Disorder, an NTIS-like phenotype may be observed, with reduced T3 and increased rT3. T4 may be elevated, and TSH is usually normal, although TSH's normal circadian rhythm may be disrupted. Bipolar 1 and PTSD can exemplify an anti-NTIS phenotype, with upregulation of the HPT axis and increased T3. This may also occur during acute schizophrenic episodes.'''

Exercise
'''After exercise, there is a transient increase in TSH, T4, and T3. However, this is thought to be due to increased blood concentration as a result of dehydration. The effects normalize after rest. After long-term heavy strain, levels of thyroid hormones decrease. This is exacerbated by other stressors such as undernutrition and lack of sleep, such as in a military training setting. During endurance exercise, before exhaustion, there may be elevated thyroid hormone levels due to increased expected energy demand.'''

Diagnosis
'''Affected patients may have normal, low, or slightly elevated TSH depending on the spectrum and phase of illness. Total T4 and T3 levels may be altered by binding protein abnormalities, and medications. Reverse T3 levels are generally increased, while FT3 is decreased. FT4 levels may have a transient increase, before becoming subnormal during severe illness.''' Correspondingly, in the majority of cases calculated sum activity of peripheral deiodinases (SPINA-GD) is reduced.[3][6][7][8] Several studies described elevated concentrations of 3,5-T2, an active thyroid hormone, in NTIS.[8][9] 3,5-T2 levels were also observed to correlate with concentrations of rT3 (reverse T3)[8] in patients with NTIS.

NTIS is a component of a complex endocrine adaptation process. Therefore, affected patients might also have hyperprolactinemia and elevated levels of corticosteroids (especially cortisol) and growth hormone.

'''NTIS can be difficult to distinguish from other forms of thyroid dysfunction in the hospital setting. Both NTIS and primary hypothyroidism may have reduced fT3, fT4, and elevated TSH (which is common in the hospital, during the recovery phase of NTIS). Prescribing thyroxine to treat this may lead to lifelong thyroid overtreatment.'''

'''Hyperthyroidism may be assumed due to decreased TSH and a transient fT4 increase. This can be distinguished from NTIS via a thyroid ultrasound, which is commonly available in the hospital intensive care unit.'''

NTIS looks similar to central hypopituitarism; both frequently have reduced TSH and thyroid hormone levels.

Treatment
There is an ongoing debate as to whether NTIS is an adaptive or maladaptive mechanism in response to physiological stress.  Some sources indicate that NTIS is beneficial as an acute phase response, but detrimental during the chronic phase of illness.

'''Several trials have investigated a possible therapy for NTIS. However, they yielded inconsistent and partly contradictory results. This may be due to the heterogeneity of investigated populations, and to the lack of a consistent definition of NTIS.[10]'''

Administering exogenous T3 and T4 has variable results but overall seems to confer no improvements to health outcome. Administering TRH to patients with chronic illness, however, seems to normalize thyroid levels and improve catabolic function, '''although whether this is beneficial is unclear. '''

When NTIS is caused by the normal fasting response to illness, early parenteral nutrition has been shown to attenuate alterations in thyroid hormone (TSH, T3, T4, rT3) levels, whereas late parenteral nutrition exacerbates it. However, late parenteral nutrition also reduced complications and accelerated recovery in one study.

History
'''In 1968 a reduced T4 half-life in athletes was discovered. This was the first awareness of thyroid hormone concentration alterations that were not a result of thyroid gland or pituitary dysfunction. In 1971, they also found a transient increase in T4 during bicycle training.'''

'''In 1973, Rothenbuchner et al. discovered that starvation is correlated with reduced T3 concentration. Following this, a similar phenotype was noted in patients with critical illness, tumors, and uremia.'''