Thyroid Disease Diagnosis, Treatment and Health Prevention: an Overview
THYROID DISEASE DIAGNOSIS, TREATMENT AND HEALTH PREVENTION: AN OVERVIEW
Jassin M. Jouria, MD
Dr. Jassin M. Jouria is a medical doctor, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serves as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.
Abstract
Management of the common forms of thyroid disease has undergone significant study and development, as evidenced by the latest guidelines to diagnose and treat the thyroid. Because the thyroid gland’s role is so pervasive in the body, it is important for clinicians to understand the common symptoms of various thyroid diseases, including those not so commonly known. The diagnosis, treatment and prevention of thyroid conditions are discussed.
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This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.
Continuing Education Credit Designation
This educational activity is credited for 4 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.
Statement of Learning Need
The thyroid gland is active in virtually every cell of the body, regulating cellular respiration, energy expenditure, overall metabolism, growth and development of cells and tissues. It is important to understand the symptoms of thyroid diseases, and to know the management and treatment of these conditions.
Course Purpose
To provide advanced learning for clinicians interested in the diagnosis, treatment and prevention of thyroid disease.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 2 Target Audience
Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,
Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 3 1. The thyroid gland has been called the “Master Gland” because it
a. produces parathormone. b. is a member of the hormone-responsive nuclear transcription factors superfamily. c. is active in virtually every cell of the body. d. plays a vital role in controlling calcium and phosphate levels.
2. True or False: Embryologically, the developing thyroid forms the floor of the pharynx, around the base of the tongue, descending the neck to its adult location.
a. True b. False
3. The thyroid is supplied by the superior and inferior thyroid arteries, and on rare occasions, there is an additional artery known as the
a. innominate artery. b. subclavian artery. c. deep artery. d. thyroidea ima.
4. Thyroid hormone is
a. required for normal human growth and development. b. required for the regulation of metabolism in infants and adolescents. c. mostly active during the neonatal and pre-adolescent periods. d. primarily used for the production of iodine.
5. Thyroid hormone ______begins with the organification of iodide to iodine and then condensed onto tyrosine residues found on thyroglobulin protein.
a. absorption b. secretion c. synthesis d. conversion
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 4 Introduction
The thyroid gland has been called the Master Gland because it is active in virtually every cell of the body, regulating cellular respiration, energy expenditure, overall metabolism, growth and development of cells and tissues. Because the thyroid gland’s role is so pervasive in the body, it is important to understand the symptoms of the types of thyroid disease such as hypothyroidism and hyperthyroidism, and to know the management and treatment of these conditions.
Anatomy Of The Thyroid
The anatomy of the thyroid gland is reviewed in this first section of this course to provide a basic understanding of thyroid structures, hormones, and the blood and nerve supply. There are various ways to evaluate the thyroid gland to rule out pathology, which is covered in later course sections and as well as in subsequent course series on thyroid disease, diagnostic testing, pathology and treatment.1-6
The thyroid gland consisting of two lobes and connected by an isthmus, is located at the anterior neck, just below the cricoid cartilage, roughly at the level of C5 to T1 and overlaying the second to the fourth tracheal rings. The parathyroid glands are four small glands usually located at the posterior portions of the thyroid and which produce parathyroid hormone (PTH) and play a vital role in controlling calcium and phosphate levels. The parathyroid glands share blood supply, lymphatic drainage and venous supply with the thyroid.
Embryologically, the developing thyroid forms the floor of the pharynx, around the base of the tongue, descending the neck in the adult. As it descends during the 4th to 8th week of gestation, the thyroglossal duct,
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 5 a duct that has regressed in the adult, guides the thyroid gland. In about half of individuals, however, the distal portion of the thyroglossal duct remains, essentially as an extra lobe of thyroid tissue with no apparent clinical significance. Thyroglossal cysts, resulting from persistent sections of the thyroglossal duct, occur relatively commonly. These can be diagnosed with ultrasonography. The most common complications of a thyroglossal cyst are infection and malignancy, occurring in 1 to 4% of individuals.
The mass and dimensions of the thyroid can vary, but tends to be slightly heavier in females, enlarging during monthly cycles and in pregnancy. In both males and females, the mass is 25 – 30 gm with each lobe 50 – 60 mm. The thyroid gland is principally enervated by the autonomic nervous system with parasympathetic fibers from the vagus, and sympathetic enervation is derived from the superior, middle and inferior ganglia of the sympathetic trunk. The fibers enter the gland alongside the vasculature and appear to primarily regulate perfusion rates.
The basic structural unit of the thyroid are the follicles, formed by multiple septae, dividing the gland into lobes and lobules, with the follicles consisting of a layer of epithelial cells surrounding a colloid-
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 6 filled center surrounded by fenestrated capillaries, lymphatic vessels and sympathetic nerves. Within the colloid, iodothyroglobulin (the precursor of the thyroid hormones) can be found. The principle or follicular cells secrete the colloid. The parafollicular cells, embedded within the basal laminae and adjacent to the follicles secrete calcitonin (a hormone that regulates calcium in the blood).
Vascular and Lymphatic Anatomy of the Thyroid
The superior and inferior thyroid arteries supply the thyroid. Relatively rarely, there is an additional artery, the thyroidea ima that originates from the aortic arch or the innominate artery, entering the gland at the inferior border of the isthmus. The arterial supply has numerous anastomoses that are present both ipsilaterally and contralaterally.
The superior thyroid artery is the first branch (anterior) off the external carotid. After branching, it descends laterally to the larynx, posterior to the omohyoid and sternohyoid muscles. It then runs superficially along the anterior border, delivering a deep branch before curving towards the isthmus. The superior thyroid artery then anastomoses with the contralateral artery. The inferior thyroid artery branches off from the thyrocervical trunk (a branch of the subclavian artery). After branching off, the inferior thyroid artery ascends superiorly and then laterally, entering the tracheoesophageal groove posterior to the carotid sheath. Sub-branches then enter along the posterior portion of the lobes.
The recurrent pharyngeal nerve is closely associated with the inferior thyroid artery, but the exact relationship is variable — it can be found deep, superficial or between branches of the artery and can be
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 7 asymmetric, comparing the right to the left side. Extralaryngeal branches may be present, and these must be preserved in thryoidectomies. The recurrent pharyngeal nerve emerges from the superior thoracic outlet in an anatomic triangle bounded by the common carotid artery (laterally), the trachea (medially) and the thyroid (superiorly). It enters the larynx between the cricoid cartilage and the inferior cornu of the thyroid cartilage.
Venous drainage of the thyroid is through three pairs of veins — the superior, middle and inferior thyroid veins. The inferior veins may form a common trunk, the thyroid ima vein. The superior thyroid vein ascends alongside the internal jugular vein while the middle thyroid vein follows a more direct course passing lateral to the internal jugular vein; both superior and middle thyroid veins drain into the internal jugular vein. The inferior thyroid vein can be asymmetric in form and drains into the brachiocephalic vein.
Lymphatic drainage follows many directions and is extensive but can be variable. The periglandular, prelaryngeal, pretracheal and paratracheal nodes are found along the path of the recurrent pharyngeal nerve, passing to the mediastinal lymph nodes.
Nerve Supply of the Thyroid
The thyroid is enervated by the sympathetic nervous system through the superior, middle and inferior sympathetic ganglia. Parasympathetic enervation is through the vagus nerve. The nerves follow the course of the superior and inferior thyroid arteries.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 8 Functions Of The Thyroid Gland
The main function of the thyroid gland is to produce the thyroid hormones, thyroxine (T4) and triiodothyrodine (T3). Thyroid hormone is required for both normal growth and development as well as for the regulation of metabolism in the adult. Parafollicular cells (C cells) secrete calcitonin in response to hypercalcemia, causing a decrease in serum calcium levels. Triiodothyrodine (T3) is the active form of hormone while T4 has a longer half-life than T3. Thyroxine (T4) is converted to T3 in most tissues, thus serving as a prohormone. Thyroid functions and hormonal regulation are highlighted below.6-18
Sites of Thyroid Hormone Action
Thyroid hormone is essential for growth, development and metabolism acting in nearly all cells. Thyroid hormone status is also related to body weight and total energy expenditures. Thyroid hormones exert effects on lipogenesis, lipolysis, energy storage/expenditure (Basal Metabolic Rate or BMR), carbohydrate metabolism, circadian rhythms, appetite, insulin sensitivity and production, among other effects.
Thyroid Hormone Receptors
Thyroid hormone receptors should be briefly discussed here to provide a whole overview of how T3 functions. Firstly, thyroid-stimulating hormone (TSH) is part of the feedback system in the body that helps regulate T4 and T3, and is produced by the pituitary gland. The TSH test is frequently ordered along with or preceding a free T4 test. Other thyroid tests that may be ordered include a free T3 test and thyroid antibodies (if autoimmune-related thyroid disease is suspected).
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 9 Sometimes TSH, free T4 and free T3 are ordered together as a thyroid panel. Triiodothyrodine (T3) action is primarily exerted through its nuclear thyroid receptor (nTR) isoform. There are two primary isoforms of the nTR — the α and the β isoforms. Both isoforms undergo posttranslational modification. This posttranslational modification is essential for both positive and negative gene regulation by thyroid hormone, including that of genes important for overall metabolic regulation.
Tissue specificity and relative levels of isoforms is important within different tissues; nTR- α2, a splice product, does not bind to T3 and is an inhibitor of T3. And, nTR β2 is primarily expressed in the brain, pituitary, liver, and cardiac ventricles while nTR-α is primarily expressed in white adipose tissue (WAT), brain and cardiac atria. Brown adipose tissue (BAT) contains both the isoforms.
Isoform-specific actions forming the basis for clinical thyroid hormone resistance is highlighted in the table below. For patients having short stature, showing developmental delays, bony deformities, and chronic constipation, elevated cholesterol and increased BMI, there is a corresponding defect and effect upon the hypothalamic-pituitary- thyroid (HPT) axis.
Importantly, nuclear thyroid receptors are involved in crosstalk with other nuclear hormone receptors. While there is much work to be done in this area, it appears that the crosstalk allows for finer control and coordination of carbohydrate and lipid metabolism. Thyroid hormone also has non-genomic actions including interactions with membrane
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 10 integrin receptors and cytoplasmic effects on signal transduction pathways.
Defect Hypothalamic- Clinical Expression/Metabolic Pituitary-Thyroid Effect Axis Effects Reduced T3 Resistance or non- Clinical: Goiter, enhanced binding and responsiveness to metabolic rates, hyperphagia. irreversible feedback. Generally euthyroid, with interactions with possible tachycardia. Possible, corepressors. short stature, impaired hearing, bone defects, ADHD More commonly ↑ T4, T3 seen. ~ Normal TSH
Reduced T3 Pituitary is Short stature, developmental binding and normally sensitive delay, chronic constipation, bone irreversible to feedback. deformities. interactions with Elevated cholesterol, BMI corepressors. ↑ T3/T4
Rarely seen. ~ Normal TSH, absolute values T3, T4
Thyroid Hormone Synthesis
Thyroid hormone synthesis begins with the conversion (organification) of iodide to iodine and condensed onto tyrosine residues found on thyroglobulin. Iodide, derived from nutritional sources, is pumped across the cell membrane with a Na+-I- symport.
The mono- or di-iodinated thyroglobulin is the primary component of the follicular colloid. The second step is the coupling of the mono- or di-iodinated molecules. If a mono-iodinated tyrosine is coupled with a
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 11 di-iodinated tyrosine, the result is T3. If two di-iodinated tyrosines are coupled, T4 is the result. This second reaction is the major reaction. De-iodination by three different deiodinases, D1, D2 and D3, found in different levels in various tissues, including the liver, is an important control point for thyroid hormone biosynthesis.
The deiodinases are peroxidases. D1 is not significant in the pituitary, so is not believed to be critical for the control by feedback inhibition of thyroid hormone synthesis. D1 is found at high levels in the liver, kidney and in the thyroid gland itself and is expressed on the cellular membrane in these tissues. D1 is suppressed in response to various stressors, decreasing the conversion of T4 to T3. These stressors include weight gain, depression, leptin resistance, insulin resistance, diabetes, inflammation, hypoxia and chronic pain. Selenium deficiency is also associated with D1 suppression.
Highly expressed in the brain, pituitary, thyroid and BAT, D2 is the primary deiodinase providing active T3 derived from the de-iodination of T4. Polymorphisms of D2 are associated with type 2 diabetes, insulin resistance, and obesity in some studies, but this association has not been universal. D3 inactivates T4 and is found in the skin, vascular tissue and the placenta.
De-iodination of T4 can result in reverse T3 (RT3). RT3, a metabolite of T4, develops to conserve body energy by converting T4 into RT3, an inactive form of T3 that is incapable of delivering oxygen and energy to the cells as does T3. Elevated rT3 levels (>10-24 ng/dL) may also be associated with sick euthyroid syndrome, but may also be elevated in patients on propylthiouracil, ipodate, propranolol, amiodarone,
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 12 dexamethasone and halothane. Dilantin displaces rT3 from thyroglobulin and increases rT3 clearance. Currently, measurement of rT3 levels appears to be most useful in critically ill or elderly patients with little justification for routine testing. Some patients, particularly those with a specific D2 gene polymorphism, may benefit from a combination of T3/T4 (synthetic or desiccated extract) over T4 alone, particularly those who are still symptomatic with normal TSH values and an elevated free T4/free T3 ratio.
In some tissues, T4 may enter cells via passive transport. However, in other tissues, particularly the brain, the monocarboxylate transporter 8 (MCT8) is required though not necessarily obligatory; a genetic disorder, the Allan-Herndon-Dudley Syndrome, presenting with low serum T4, and elevated serum T3, and severe neurologic deficits, was shown to be due to a mutation in the MCT8 gene. Treatment with diiodothyropropionic acid (DITPA) in humans resulted in improvement in patients with the MCT8 mutation, and may indicate that there are other transporters, which while not as efficient as the MCT8 transporter, allowed tissues to remain sensitive to the effects of thyroid hormone.
The Role of the Deiodinases
Thyroid hormone enters the target cells via the thyroid hormone receptors, but must be converted to the active form, T3 with a deiodinase. Differentially expressed deiodinase allows specific cell types to play an active role in thyroid hormone signaling, essentially “customizing” the signaling to become tissue specific and, importantly for clinical purposes, not necessarily reflecting the measured levels of TSH, free T4 and free T3 commonly used for diagnostic purposes.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 13 As mentioned above, the deiodinases are expressed in various tissues and appear to have varied functions. D1 appears to perform primarily a scavenger function, clearing sulfated thyroid hormone for excretion in the bile and the urine. D1 is considered to be important for adaptation to iodine deficiency and to abrogate the effects of high levels of T4 in hyperthyroidism. D3, located at the cellular membrane, is expressed at high levels in the placenta where it may function to protect a developing fetus from high levels of maternal T4. D3 may also perform similar functions in the skin and the vasculature. Its expression is stimulated by hypoxia, mediated by hypoxia-inducible factor (HIF-1). D2 is expressed in the endoplasmic reticulum in the cells of the brain, pituitary, thyroid and BAT. D2 appears to be the primary controller responsible for the conversion of T4 to T3, both intracellularly and in producing measured T3 levels in the serum.
As with the other deiodinases, D2 is selenium dependent — deficiencies of nutritional selenium and thereby defects in selenoproteins are associated with abnormal thyroid hormone production, metabolism and feedback control. D2 has a short half-life because it is prone to ubiquitination and degradation by proteosomes. De-ubinquitination can increase D2 activity and is stimulated by low levels of T4 and by adrenergic activation, preserving T3 levels in those tissues where it is located. D2 has been linked to metabolic phenotypes in at least two ways. As mentioned, D2 polymorphisms have been associated with type 2 diabetes, insulin resistance, and obesity. In addition, D2 activity may be associated with the stimulation of bile acid secretion via the G-protein coupled receptor for bile acids (TGR5).
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 14 Interestingly, bile salt synthesis has recently been shown as controlled by pituitary TSH. It is believed that various stimuli such as bile acid secretion, adrenergic stimuli, endoplasmic reticulum stress (a disruption in endoplasmic reticulum homeostasis associated with obesity, insulin resistance and Type 2 Diabetes), cold exposure and generalized stress can affect D2 expression by both transcriptional and post-transcriptional control mechanisms, reducing D2 activity and thus reducing intracellular T3 levels in a tissue-specific manner. D2- mediated T3 production plays a critical role in the pituitary- hypothalamic-thyroid T4/T3 mediated feedback loop.
During periods of iodine deficiency, T4 levels decrease while T3 levels can remain stable. This results by the expected feedback mechanisms, an increase in serum TSH. In patients acutely given large amounts of propylthiouracil, the serum levels of T3 drop while the T4 levels remain stable. Somewhat surprisingly, under these conditions, TSH levels also increase. The decrease in T3 levels is sensed by neurons in the paraventricular nucleus of the hypothalamus with the pituitary thyrotrophs responding by de-repressing the expression of both the TRH and TSH-β genes. This is in contrast to the mechanisms based on T4 levels — D2 is required to convert the existing T4 to T3, which can then de-repress the TRH and TSH genes.
Regulation of Thyroid Hormone Production
The hypothalamus detects T3 levels produced by the action of the D2 deiodinase. The monocarboxylate transporter 8 (MCT8) is required for the transport of T4 into both hypothalamic and pituitary cells. Thyrotropin releasing hormone (TRH) is released when T3 levels reach
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 15 a threshold, but can also be released via the action of leptin in the hypothalamus.
Leptin stimulates Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. This phosphorylation directly stimulates the production of TRH. TRH acts on the cells of the pituitary gland, binding to TRH receptors and resulting in an increase in TSH release. TSH secretion, in turn, can be modulated by a number of different molecules and states — these include dopamine, somatostatin, leptin, renal failure, starvation, moods such as depression and anxiety, cortisol, growth hormone, reproductive hormones and sleep deprivation. In addition, adrenergic regulation is an important factor in the secretion of both TRH and TSH as well as in the overall regulation of energy balance as an effect of T4/T3 action.
The various hypothalamic nuclei receive multiple inputs from diverse sources including sensory (i.e., taste, odor of foods), motor (i.e., the process of digestion) and metabolic (i.e., absorption, glucose levels) and respond to signals such as the levels of fatty acids, lipids, the aforementioned glucose as well as hormones associated with appetite, i.e., insulin, estrogens and T4/T3. The hypothalamus functions to integrate these diverse signals to modulate hepatic insulin sensitivity and resistance, control WAT fat depots and fatty acid oxidation in skeletal muscle and overall energy expenditure in the BAT.
Once released, TSH stimulates the production and the release of T4 into the bloodstream by the thyroid gland. Local and both hypothalamic and pituitary deiodinases serve to provide T3 for
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 16 feedback inhibition, resulting in decreases in both TRH and TSH production until the set point for lowered T3 is reached.
Central Control of Thyroid Hormone and Feeding Behavior
Follicular cells are enervated by sympathetic fibers utilizing norepinephrine (NE). Norepinephrine release increases T4 to T3 conversion. The sympathetic nervous system (SNS) plays a critical role. While the physiological relevance is not completely clear, SNS stimulation of BAT is correlated with increased de novo lipogenesis specifically in the hypothalamus. This occurs via AMP-activated protein kinase (AMPK). During fasting, hypothalamic D2 is increased and there is a concomitant increase in hypothalamic T3 levels. During this same timeframe, pituitary and liver D2 is decreased.
Leptin
Leptin is an adipocyte hormone that acts as a signal from adipose tissue to the brain, regulating appetite by inhibiting both food intake and increasing energy expenditure by interacting with leptin receptors in the hypothalamus. Leptin inhibits transmitters in the ventromedial hypothalamus, and activates melanin-concentrating hormone and corticotropin-releasing hormone. In obesity, there is significant leptin resistance and leptin does not stimulate TRH. In addition, in animal studies, leptin resistance allows for a euthyroid state in the face of obesity. Notably, thyroid hormone can influence feeding behaviors such as appetite and hunger through several related pathways. During fasting periods, there is increased T3 production, which stimulates mitochondrial proliferation and rebound feeding.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 17 Thermogenesis, Body Weight And Thyroid Hormone
Adrenergic-mediated thermogenesis is, in part, due to direct actions on the brown adipose tissue (BAT). However, both central and peripheral actions of thyroid hormone can play an important role in energy balances. Thyroid hormone plays a role in maintaining the basal metabolic rate, adaptive thermogenesis, appetite, food intake, and body weight.1-3,22-31
Basal Metabolic Rate
The basal metabolic rate or BMR is the main source of energy outlay — significant reductions in BMR can result in weight gain and obesity while increases in BMR can result in weight loss and undernutrition. Resting energy expenditure is highly sensitive to changes in thyroid hormone levels and the BMR correlates with both lean body mass and the levels of thyroid hormone. In general, thyroid hormone increases the BMR by increasing the production of ATP, the main source of cellular energy, though the specific targets of thyroid hormone action are not entirely clear. It is known that thyroid hormone stimulates ion gradients, the primary ones being the Na+/K+ gradient across the cell membrane and the Ca2+ gradient found between the cytoplasm and sarcoplasmic reticulum. For example, one action of thyroid hormone is to alter the levels of sodium and potassium, thus requiring ATP consumption (via Na+/K+-ATPase).
Thyroid hormone also directly stimulates the Na+/K+-ATPase pump as well, but this effect appears to be most significant under conditions of hyperthyroidism rather than strictly physiologic. The expression of the sarcoplasmic/endoplasmic reticulum Ca2+-dependent ATPase (SERCA) in skeletal muscle is also regulated by thyroid hormone, producing
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 18 heat during ATP hydrolysis. Thyroid hormone affects the ryanodine receptors in both cardiac and skeletal muscle, stimulating efflux of Ca2+ ions and requiring ATP to pump calcium back into the sarcoplasmic reticulum.
Facultative Thermogenesis
Facultative or adaptive thermogenesis can be defined as the regulated production of heat in response to environmental changes in temperature and diet. It is adaptive in that it “resets” the CNS-defined set point. Shivering is another mechanism to produce heat but is essentially inefficient because it also induces convective heat loss. Clinically and practically, the reset is reflected in the difficulty many patients have in losing weight and keeping it off. Much of the resistance to sustained weight maintenance may be due to the actions of leptin and the “interactions of genes favoring energy conservation and storage with an environment which enables access to food calories and a more sedentary lifestyle.” Evolution tended to favor individuals able to store calories efficiently and to sustain fetal and maternal energy stores. This, however, does not favor many individuals eating calorie dense foods without the extra physical activity that might reduce energy storage.
Both the sympathetic nervous system and thyroid hormone are needed to maintain core body temperature. The expression of proteins (UCPs or uncoupling proteins) is regulated both by norepinephrine and by thyroid hormone in BAT stores, functioning synergistically. D2 knockout mice raised in temperatures at or slightly above mouse body temperature (30OC), develop insulin resistance, obesity and hepatic steatosis because of impaired BAT thermogenesis. These same mice,
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 19 when raised at levels below normal body temperature (22o C), activate alternative heat production pathways.
In humans, there is both visceral and subcutaneous BAT, and until recently was considered important only in neonates and hibernating animals. However, it is becoming clear that in the adult, BAT thermogenesis has important functions as well, mainly to generate classical non-shiver related heat. The mitochondria in BAT have very high numbers of mitochondria containing UCP-1 that when activated stimulates the respiratory chain.
Thyroid Hormones and Regulation of Body Weight
Changes in TSH levels have been associated with changes in weight in normal individuals and those with either hypo- or hyper-thyroid states. Treatment with T4 replacement, with the establishment of a euthyroid state, have been associated with reduction in body weight as well as an increase in resting energy expenditure (REE) in hypothyroid patients, but the loss in body weight is primarily through the excretion of excess water with no changes in total body fat, though this effect may be due to an increased caloric intake or altered leptin levels. Treatment with T3 (as a monotherapy) resulted in significant weight loss accompanied by other changes such as decreases in total cholesterol and apolipoprotein B levels without any increased cardiovascular risk.
Carbohydrate Metabolism and Thyroid Hormone
Thyroid hormones affect nearly all aspects of carbohydrate metabolism, including enhancement of insulin-dependent glucose
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 20 transport, gluconeogenesis and glycogenolysis. Hyperthyroid states are associated with increased gluconeogenesis and glycogenolysis in the liver and peripheral tissues. In the liver, the rate-limiting step in gluconeogenesis is phosphoenolpyruvate carboxykinase (PEPCK) and the gene for this enzyme is upregulated by T3. Rats with a mutation affecting the thyroid receptor beta chain have impaired gluconeogenesis and are more insulin sensitive. Inactivation of D2 or hypothyroid states is associated with insulin resistance, pre-diabetic states and obesity.
There exists a relationship between thyroid hormone status and diabetes, but it is complex, particularly Type 2 diabetes. Patients with Type 1 diabetes have an increased risk of autoimmune thyroid disease. In Type 2 diabetes, a significant number of diabetic patients have abnormal serum TSH levels. In a recent prospective study, there was an association between higher levels of TSH and diabetes while higher free T4 levels were associated with a lower risk. In the same study, the risk of progression from prediabetes to diabetes was higher in clinical and subclinical hypothyroid states. T3 bound to its receptor directly upregulate target genes and the gluconeogenic enzymes in the liver. T3 also increases gluconeogenesis. Also, the inhibition of insulin signaling pathways may stimulate hepatic glucose production.
Cholesterol and Lipid Metabolism
The primary sites of action regarding cholesterol and lipid metabolism are the liver and BAT. Thyroid-hormone dependent regulation of lipid metabolism is regulated via T3, TRβ and crosstalk between nuclear hormone receptors.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 21 In the liver, regulation of lipid homeostasis is directly by T3 and indirectly via crosstalk between nutrient-dependent nuclear receptors. Both HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis and sterol response element binding protein (SREBP2) are directly stimulated by T3. Indirect actions are via other nuclear receptors. In addition, T3 increases fatty acid (FA) uptake in the liver using fatty acid transporter proteins and to increase hepatic lipogenesis via the upregulation of a number of proteins and carbohydrate-responsive element-binding protein.
Clinically, these effects can be seen in patients with hypothyroidism:
• Decreased basal metabolic rate • Cholesterolemia (due to decreased hepatic low-density lipoprotein receptor (LDL-R) expression) • Hyperlipdemia • Increased risk of non-alcoholic fatty liver disease (NAFLD) • Weight gain with an increased risk of obesity • Increased risk of Type 2 diabetes
In patients with hyperthyroid disease:
• Increased basal metabolic rate • Weight loss • Decreased total cholesterol • Decreased triglyceride levels • Increased hepatic lipid oxidation • Hyperglycemia and worsening glycemic control in Type 2 diabetes patients
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 22 Common Thyroid and Hyperthyroid Conditions
The more common conditions of the thyroid gland may be due to hormone production, excess or deficiency. Additionally, illness related to the thyroid gland may be due to a growth or mass in the neck, and may involve nodule or lump formation within the thyroid. The following sections highlight the more common thyroid conditions, including etiology, genetic influences and diagnostic testing to identify a thyroid condition in order to treat.3,33-41,45-59
Simple Nontoxic Goiter
Simple nontoxic goiter is a non-inflammatory or non-neoplastic hypertrophy of the thyroid that may appear diffusely or as nodules. It is noncancerous and may be asymptomatic with the exception of an enlarged, palpable, non-tender goiter. Thyroid function often remains normal except in cases of severe iodine deficiency. Endemic goiter can occur if greater than 10% of a population exhibits it, as can be seen in iodine-deficient areas of the world.
Simple nontoxic goiter may be somewhat dependent on reproductive hormone interactions — it is frequently found during puberty, pregnancy and at menopause or perimenopause. Known causes of goiter include:
• Iodine deficiency • Congenital errors of thyroid hormone synthesis • Ingestion of large amounts of goitrogens such as cassava, broccoli, cauliflower and cabbage, predominantly in areas with a high risk of iodine deficiency
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 23 • Medications that inhibit the synthesis of thyroid hormone, particularly iodine contain drugs such as amiodarone, iodine supplements, interferon-α, interleukin-2 • TSH receptor agonists including TSH receptor antibodies, • Pituitary resistance to thyroid hormone • Hypothalamic or pituitary adenomas • Human chorionic gonadotropin-producing tumors
Thyroid function tests are usually within the range of normal values, as are thyroidal radioactive iodine uptake tests. Thyroid antibodies are also usually normal.
Goiter is about 4 times more common in women than in men, increasing risk is associated with age. Nodules are also less frequent in men, but have a greater tendency to be malignant, when found. Nodular goiter occurs where areas of involution and fibrosis become interspersed with areas of hyperplasia. Some nodules may be “hot” appearing on scintigraphy with high levels of isotope (99mTc) uptake while others are less active. In a minority of patients, high thyroid function may result in thyrotoxicosis. The rate of malignancy is low in both multinodular and uninodular goiter.
Table salt has been iodized since the 1920s to prevent cretinism and endemic goiter. The NHANES II study indicated that iodine status is generally adequate for the U.S. population, but there were some groups, notably non-Hispanic African-Americans, that were at higher risk for iodine deficiency. Median urinary iodine of 100-199µg/L is considered as reflecting adequate iodine intake.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 24 The use of table salt has been discouraged in the U.S. and around the world to control hypertension. It is believed that other foods contain sufficient iodine. However, in some populations such as in children with food restrictions or adults avoiding dairy products intake of iodine may not be adequate. A recent review of iodine nutrition indicated that in both developed and developing countries, iodine deficiency is a cause for concern, particularly in pregnant mothers and in those for whom a reduced salt intake has been recommended. In 2014, the Office of Dietary Supplements (ODS: a division of the NIH) convened workshops around the concern that pregnant women may be at risk of iodine deficiency and hypothyroidism and that their infants may be at risk for hypothyroxinemia, congenital hypothyroidism or abnormal cognitive development.
Clinically, a non-toxic goiter is palpable and non-tender. It generally grows outward but can compress the trachea and the esophagus. The patient may complain of difficulty in swallowing or other obstructive symptoms such as a dry cough, dyspnea, and stridor, especially with exertion. Recent or an accelerated rate of growth or a lobe or nodule(s) should arouse a suspicion of malignancy. The history should include an examination of dietary iodine deficiency or dietary or medication-based excess of iodine. Evaluation of the family history should include any history of familial papillary thyroid carcinomas or medullary thyroid cancer including multiple endocrine neoplasia (MENs).
Nodules may be evaluated using a thin-needle aspiration biopsy. The differential diagnosis of an enlarged thyroid can include:
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 25 • Carcinoma − Follicular Thyroid Carcinoma − Medullary Thyroid Carcinoma − Papillary Thyroid Carcinoma • Thyroiditis − Hashimoto Thyroiditis − Riedel Thyroiditis − Subacute Thyroiditis − Lymphoma
• Thyroid Lymphoma • Thyroid Nodule
Malignancies occur in approximately 7–15% of nodules, but the incidence of both thyroid nodules and malignancy has been increasing.
While many patients with non-toxic goiter will present with essentially normal levels of TSH, some may present with either high levels (hypothyroidism) or low levels (hyperthyroidism) of TSH. Free T3 and free T4 levels may be particularly useful if the TSH is within normal range or at the limits of normal ranges. Thyroid antibodies should be tested (i.e., serum antithyroid peroxidase (anti-TPO) antibody and antithyroglobulin (anti-Tg) antibody levels particularly if there is a family history of thyroid diseases or autoimmune disease.
Scintigraphy is not necessarily a routine test, though if scintigraphy is performed, it should be noted that 5-8% of warm or cold nodules are malignant.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 26 Ultrasonography is a highly sensitive tool in determining the number and sizes of thyroid nodules. Combining ultrasonography with Doppler and spectral analysis to determine vascularization is proving useful in discerning malignant from benign nodules.
Fine needle aspiration biopsy (FNAB) is highly accurate and specific for the diagnostic evaluation of thyroid nodules. Ultrasonography-guided FNAB is becoming more and more common. Patients with any follicular cytopathology seen on FNAB or if there is any abnormalities on U.S. should be referred to a surgeon. For atypical cytopathology, FNAB should be repeated within 3-6 months.
Graves’ Disease
In Graves’ disease, also known as Toxic Nodular Goiter (TNG), there are independently functioning thyroid nodules with a resultant hyperthyroidism. Iodine deficiency (overt or subclinical) leads to compensation via hyperplasia. The hyperplasia may increase the risk of somatic mutation of the TSH receptor or activation of the TSH receptor. In areas with endemic goiter or in the elderly, toxic nodular goiter is the most common cause of hyperthyroidism.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 27 In the U.S., Graves’ disease is the more common cause of hyperthyroid disease. TNG is a spectrum of disorders that can range from a single nodule (toxic adenoma) producing thyroid hormone to multiple nodules hypersecreting the hormone. Most patients with TNG will present with signs and symptoms of hyperthyroidism.
Elderly patients may have somewhat atypical symptoms including weight loss as the most common complaint. Constipation is more common than frequent bowel movements in this population along with tremors that may be easily confused with essential senile tremor. Cardiovascular complications are much more common in the elderly population as well. Finally, some elderly patients may present with apathetic hyperthyroidism, characterized by a lack of hyperkinetic motor activity, slowed cognitive processes and a blunted affect, resembling severe hypothyroidism. In TNG, the most common lab finding is a decreased TSH with a normal free T4.
Physical examination may reveal findings less severe than those found in Graves’ disease. There may be a single dominant nodule or multiple nodules along with hoarseness, tracheal deviation, proximal muscle weakness, rapid deep tendon reflexes, tremor, moistened and cool skin, tachycardia and hyperkinesis.
The stigmata of Graves’ disease are not generally seen (orbitopathy, pretibial mixedema and dermopathy). Differential diagnosis primarily is to exclude Graves’ disease (Diffuse Toxic Goiter), though it can also include the following conditions:
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 28 • Carcinoma − Papillary Thyroid Carcinoma • Thyroiditis − Hashimoto Thyroiditis − Riedel Thyroiditis − Subacute Thyroiditis • Lymphoma − Thyroid Lymphoma • Thyroid Nodule • Non-toxic goiter • Struma ovarii
In Graves’ disease, treatment options usually are the use of antithyroid drugs, ablation with radioactive iodine and surgery. In toxic nodular goiter, the options are generally reduced to ablation and surgery as these patients rarely go into remission.
Other signs and symptoms of Graves’ disease include ophthalmopathy, thyroid dermopathy, and thyroid acropachy. Thyroid dermopathy is rare, occurring in 1-4% of patients. Nearly all patients with dermopathy have the orbitopathy as well. Lesions are primarily at the pretibial area and are typically areas of slightly pigmented and thickened skin.
Acropachy is the most rare extrathyroidal manifestation of Graves’ disease and is the clubbing of the fingers and toes. Complications include cardiovascular events such as atrial fibrillation, congestive heart failure and embolic stroke. A very serious complication that is more common in Asian-background patients is thyrotoxic periodic
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 29 paralysis, occurring in 2% of patients in Japan. In the U.S., the incidence is approximately 0.2%.
A triad of muscle paralysis, acute hypokalemia, and thyrotoxicosis characterizes thyrotoxic periodic paralysis. The condition is caused by a shift of potassium into the muscle cells: thyroid hormones control the transcription of potassium channels and it is believed that aberrant transcription may be the underlying cause of the disorder. Treatment consists of replacement with low doses of potassium and a non- selective β-blocker to prevent arrhythmias and restore muscle function. Finally, long-standing and poorly controlled Graves’ disease increases the risk of osteoporosis, gynecomastia, infertility and menstrual irregularities.
Pathophysiology of Graves’ Disease
Graves’ disease is an autoimmune disorder. As with many if not most autoimmune disorders, it is more common in women and more common with increasing age. Graves’ disease involves both B- and T- lymphocyte mediated immunity directed at least at four different antigens: • Thyroid Stimulating Hormone (TSH/ thyrotropin) receptors • Thyroglobulin • Thyroid peroxidase • The Na+/ I- symporter
Graves’ disease has a strong genetic component. The pathogenesis of Graves’ disease and Hashimoto’s Thyroiditis share a number of similarities, one being shared susceptibility genes. These shared genes can carry a strong risk.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 30 The TSH-receptor antibodies so prevalent in Graves’ disease have been recognized in the etiology of Graves’ disease for decades, but until recently, the specific variant has been relatively elusive. It is postulated that increased expression on thyrocytes could lead to a localized inflammatory reaction and to an eventual autoimmune response.
In Graves’ disease and Hashimoto’s thyroiditis, the mechanism appears to be a suppression of T-cell activation and disruption of the regulatory network. T-cell receptor signal transduction utilizes several enzymes. Inhibitors of T-cell receptor signaling is associated with Graves’ disease and Hashimoto’s, though it is not clear how the suppression of cell signaling leads to an autoimmune response.
Epigenetic Influences In Graves’ Disease
Epigenentics can be defined as the heritable changes in the expression and activity of genes occurring without alterations in the gene sequence. The two major alterations are the methylation- demethylation of cytosine residues in DNA and histone modification.
Histone modification can take the form of acetylation-deacetylation or methylation-demethylation. The epigenome integrates all the information in the genome with information derived from the intracellular, extracellular and environmental influences, such as food, xenobiotics, stress, radiation and chemical exposures. The epigenetic changes manifested in the genome represent an adaptation to environmental stimuli.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 31 While currently it is not very clear how to integrate many epigenetic findings into clinical practice, it is becoming clearer that while genetic influences on disease are important, environmental and lifestyle factors also play a critical role in the risk of the development of disease, including thyroid disease. The Genome Wide Association Studies (GWAS) indicated that most of the genetic loci associated with thyroid disease had very low odds ratios associated with them — other studies indicate that these loci are indeed correlated with the disease process, demonstrating that there are other factors at play. One of the most important factors that can impact a disease process is epigenetics.
Recently, it was discovered that a transcription factor, IRF-1, binds to the thyroglobulin gene promoter only in association with a disease- linked variant of the promoter — and that the binding of IRF-1 was dependent on epigenetic changes in the histone methylation pattern — this methylation pattern was further associated with viral infection. The authors postulated that during a viral infection, with increasing levels of alpha-interferon and IRF-1, the permissive variant of the thyroglobulin promoter binds IRF-1. This binding may disrupt the regulatory processes with autoimmunity as the result.
Non-genetic Factors Involved in Graves’ Disease
Other non-genetic (but potentially epigenetic) factors appear to be involved in the pathogenesis of Graves’ disease. These include Vitamin D levels, selenium levels and infection with Yersinia enterocolitica, which exhibits molecular mimicry with the TSH receptor.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 32 Vitamin D Level:
Low vitamin D levels (below 12.5 ng/ml) are considered an important risk factor for Graves’ disease. Low vitamin D levels are also associated with chronic autoimmune thyroiditis. There is also an association with disease and polymorphisms in the gene encoding the vitamin D binding receptor as well as the receptor for the active form of vitamin D - 1,25-(OH)(2)D(3). These polymorphisms may also be important in the development of thyroid cancer. Whether supplementation has preventive or therapeutic value is currently being investigated.
Selenium:
Selenium is an essential trace mineral, which binds to cysteine, forming selenocysteine, the core of a group of enzymes known as the selenoproteins. The selenoproteins are intimately involved in antioxidant and anti-inflammatory reactions. Selenium has been shown to help protect the thyroid follicular cells from apoptosis.
Selenium deficiency can result in several conditions, including impaired immunity and an increased risk of autoimmune disease and is strongly associated with Graves’ disease. Selenium, however, also has a relatively narrow therapeutic window and deficiency in not uniform — in areas with sufficient selenium, there may be little need to supplement as selenium is found in adequate amounts. In other areas, however, the soil is selenium deficient and supplementation may be therapeutically useful.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 33 Iodine:
The role of iodine deficiency in the etiology of Graves’ disease has been accepted for decades. Iodine excess can also have deleterious effects, however. High levels of iodine are associated with the infiltration into the thyroid of T-helper17 cells and inhibit the development of regulatory T cells. In addition, high levels of iodine increase the expression of tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) in thyrocytes. TRAIL induces apoptosis and parenchymal destruction. In a mouse model of Graves’ disease, high levels of iodine can alter thyroglobulin, altering its antigenic potential.
Thyroid Eye Disease
Thyroid orbitopathy is an autoimmune inflammatory disorder that occurs in 90% of patients with Graves’ disease. Approximately 5% of patients with thyroid orbitopathy are hypothyroid while the remainder are euthyroid. Approximately 25% of patients with Graves’ disease will experience some ophthalmopathy. Orbital inflammation is characterized by cytokines and by the overexpression of macrophage- derived inflammatory cytokines. Oxidative stress is also a significant factor in thyroid orbitopathy.
Treatment of thyroid orbitopathy consists of systemic corticosteroids, orbital radiation (though this is controversial as treatment with radioactive iodine has been shown in some studies to exacerbate Graves’ orbitopathy. A number of potential therapeutic agents are in pre-clinical or clinical trials. These include Rotuximab, Tocilzumab, Adalimumab, Infliximab, Etanercept, Org 274179-0113, NCGC00229600114 and NCGC0024259560 (which block the signal transduction of TSH), Teprotumumab, and Sodium selenite.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 34 Graves’ Disease Treatment
The commonly used antithyroid drugs are thionamide and include propylthiouracil, thiamazole, and carbimazole. All these drugs are actively transported into the thyroid. The thionamides are inhibitors of thyroid peroxidase and the coupling of the iodotyrosines to synthesize T4 to T3. Propylthiouracil also inhibits the conversion of T4 to T3 in peripheral tissues.
Thiamazole is the preferred antithyroid drug except in the first trimester of pregnancy and in patients who cannot tolerate it. Thiamazole, as compared to propylthiouracil, has a longer half-life and duration of action allowing a once-daily dosing protocol. Thiamazole also has better efficacy.
Antithyroid drugs may be used in one of two ways: 1) Titration to find the dosage to maintain a euthyroid state, and 2) High dose antithyroid drug plus levothyroxine to replace thyroid hormone.
The block and replace method has the disadvantage of a higher incidence of side effects. Antithyroid drugs, once discontinued, show a high rate of relapse. Relapse is more frequent in the first year and uncommon after 5 years.
Major side effects of the antithyroid drugs include agranulocytosis and hepatotoxicity both of which can occur in up to 0.3% of patients. Antithyroid drug treatment should be withdrawn as soon as the thyroid function becomes normalized.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 35
Factors To Consider Block and Replace Titrate
Stability Euthyroid state easier to May cycle: Hypo↔Hyper maintain
Lab monitoring Fewer More
Adverse Effects High risk Low risk
Remission 6-12 months, cannot be 12-18 months. Early predicted remission can be predicted by dose reduction success
Cost High Low
Compliance More complex Easier to follow Considerations
Radioactive Iodine
Radioactive ablation of the thyroid is a safe, effective and often first- line treatment of Graves’ disease, toxic adenomas and toxic multinodular goiter. Contraindications include pregnancy, lactation, intention to get pregnant and the inability to comply with safety recommendations. Radioactive ablation is also contraindicated in patients who are suspected of having thyroid cancer.
The treatment may worsen or cause orbitopathy, but this is controversial. In those patients with existing orbitopathy, radiation treatment should be followed by daily prednisone (0·3–0·5 mg/kg of prednisone daily, beginning 1–3 days after radioactive iodine. The prednisone is tapered over a 3-month period). Pretreatment with antithyroid drugs may be required for some patients with comorbidities, particularly cardiovascular comorbidities or severe
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 36 thyrotoxicosis. This again is controversial, but if done, antithyroid drug therapy should be stopped at least 3-5 days prior to ablation and restarted within 3-7 days after radioactive iodine treatment.
Surgery
Surgery is overall the most successful treatment for Graves’ disease, but patients must take replacement hormone for the rest of their lives. Total thyroidectomy is most commonly recommended as it has significantly better surgical outcomes than partial thyroidectomy. Thyroidectomy is recommended especially for those with “large goitres or low uptake of radioactive iodine (or both); suspected or documented thyroid cancer; moderate-to-severe ophthalmopathy, for which radioactive iodine therapy is contraindicated; and, finally, a preference for surgery.” Pregnancy is considered a relative contraindication.
Hyperthyroidism
As mentioned above, in those areas with endemic goiter or in the elderly, toxic nodular goiter is the most common cause of hyperthyroidism or thyrotoxicosis. In the U.S., and areas without endemic goiter (i.e., areas of low iodine intake), Graves’ disease is the most common cause of hyperthyroid disease. Other causes of hyperthyroidism include those outlined in the section below.
Thyroiditis
Thyroiditis is a generalized term referring to an inflammation of the thyroid gland. The term can include Hashimoto’s thyroiditis and others.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 37 Subacute Thyroiditis
Subacute thyroiditis is self-limiting and has three phases of 1) hyper-, 2) hypo- and 3) euthyroid. Subacute thyroiditis is important to recognize because it generally needs no treatment. While the etiology is different in each of the three types of subacute thyroiditis, the clinical course is similar. The first phase is hyperthyroid, with thyroid follicles undergoing destruction with concomitant release of T4. The initial hyperthyroid phase can last for up to 10-12 weeks. This hyperthyroid phase is then followed by a hypothyroid phase.
Thyroid Hormone Depletion
Most commonly, hypothyroidism is mild, with no need for treatment with replacement hormone unless there are overt signs and symptoms of hypothyroidism. This phase can last 8 weeks, although in some patients it will extend to 6 months. Most patients (~ 95%) will revert to a euthyroid state with only supportive treatment.
• Acute complications can include: − Severe and permanent hypothyroidism − Multiple system organ failure − Pancreatitis − Vocal cord paralysis
Subacute (nonsuppurative) granulomatous thyroiditis is also known as de Quervain’s thyroiditis, which is described here.
• A painful condition, usually with a diffusely tender thyroid. Patients often present with chills, fever and neck pain. The accepted cause is a viral illness and the condition most that often occurs is upper
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 38 respiratory infections. The causative virus has been variably identified as influenza, adenovirus, mumps, and coxsackievirus. There may be a transient increase in autoantibodies, but subacute granulomatous thyroiditis is not considered an autoimmune disease. The condition is linked (75%) to HLA-Bw35.
• May also be caused by medical treatments that manipulate or affect the immune system in various ways. Examples of treatments that appear to induce subacute granulomatous thyroiditis include IL-2, TNF-α, γ-IFN, influenza vaccinations, peginterferon α-2a and others.
• More common in women.
• Subacute (Silent) lymphocytic thyroiditis appears to be autoimmune in nature, but is also self-limiting — it occurs most commonly during the postpartum period. − Histologic examination reveals lymphocyte infiltration. Fine needle aspiration biopsy provides a definitive diagnosis − Physical exam reveals a non-tender thyroid − Antibodies to thyroid peroxidase are often found. Less common are antibodies to thyroglobulin. − Treatment may include β-blocker during hyperthyroid phase and thyroid hormone replacement during hypothyroid phase − Antithyroid drugs, radiation or surgery are contraindication
• Subacute (Postpartum) thyroiditis (Commonly identical to subacute lymphocytic thyroiditis)
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 39 − Most postpartum thyroiditis involves an inflammatory lymphocytic infiltration − Hypothyroidism may become permanent − Commonly recurs in subsequent pregnancy
• Drug induced thyroiditis
Drug Induced Thyroiditis
As discussed, several drugs are known to induce a higher risk of thyroiditis. Most commonly, drug induced thyroiditis is lymphocytic in nature. The drugs known to induce thyroiditis include those listed below.
Amiodarone (Cordarone, Nexterone, Pacerone):
• This form of subacute (lymphocytic) thyroiditis is more common in men and generally occurs after prolonged therapy and occurs in 15-20% of patients treated with the drug. Amiodarone is an antiarrhythmic agent.
• Amiodarone-induced thyroiditis can be characterized either as type 1 (hyperthyroidism) which is less common than type 2 (destructive thyroiditis often leading to eventual hypothyroidism). Mixed and indeterminate forms exist as well.
• Treatment of type 1 includes thionamides, potassium perchlorate and if needed, oral glucocorticoids. For type 2, glucocorticoids are first-line treatment. Amiodarone should be discontinued in either type or indeterminate types. • α- Interferon (Intron® A (interferon alfa-2b), Roferon®-A (interferon alfa-2a))
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 40 • This can occur in up to 40% of patients receiving α-interferon therapy for Hepatitis C and commonly occurs within 3 months after therapy has begun. It is associated with autoantibodies. Hashimoto’s thyroiditis and Graves’ disease occurs in up to 20% of patients. Recent analysis has indicated genetic associations • Lithium can induce the release of preformed thyroid hormone • Antiretroviral therapy May be autoimmune or involve the release of preformed thyroid hormone • Tyrosine kinase inhibitors May be autoimmune or involve the release of preformed thyroid hormone
Other Causes or Associations of Thyroiditis
• Radiation induced thyroiditis: Radiation induced thyroiditis is commonly associated with radioiodine treatment of Graves’ disease. Inflammation is transient].
• TSH secreting pituitary adenoma − Excess TSH secreted by the adenoma induces excess thyroid hormone production
• Molar pregnancy, choriocarcinomas and hyperemesis gravidarum − β- human chorionic gonadotropin can stimulate thymocytes
• Nonautoimmune autosomal dominant hyperthyroidism − Germline mutation causes a constitutive activation of TSH receptor
• Toxic solitary or multinodular goiter, also known as Plummer disease
• Thyrotoxicosis factitia due to conscious or unconscious excess intake of thyroid hormone
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 41 • Excess ingestion of iodine
• Metastatic thyroid cancer
• Struma ovarii − Ovarian teratoma with functioning thyroid tissue
Subacute Subacute Subacute thyroiditis: thyroiditis: includes thyroiditis: includes includes granulomatous, granulomatous, granulomatous, lymphocytic lymphocytic lymphocytic postpartum postpartum postpartum Initial Lab Findings Lab Findings Lab Findings (Phase 1: (Phase 2: (Phase 3: Hyperthyroid) Hypothyroid) Euthyroid)
TSH WNL or â - WNL
fT4 - â WNL
fT3 - â WNL
ESR -- WNL or slight- WNL or slight -
123I Low uptake
TSH= Thyroid Stimulating Hormone; fT4= free T4; fT3= free T3 ESR= Erythrocyte Sedimentation Rate
Thyroid Storm
Thyroid storm is a severe and often sudden form of hyperthyroidism – it may result from untreated or inadequately treated Graves’ disease, multinodular goiter, solitary nodules or ingestion of excess thyroid hormone, either as levothyroxine or as a glandular preparation. Thyroid storm may be life threatening, commonly because of cardiovascular effects such as tachycardia, arrhythmias or
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 42 cardiovascular collapse. Symptoms are often florid with muscle weakness, extreme restlessness, emotional swings, confusion, psychosis, nausea, vomiting, and diarrhea. Labs indicated significantly lower than normal TSH with high fT3 and fT4.
ATA Guidelines: Hyperthyroidism
In 2016, the American Thyroid Association produced guidelines of the diagnosis and management of hyperthyroidism and thyrotoxicosis. This is outlined in the following table.60
American Thyroid Association produced guidelines of the diagnosis and management of hyperthyroidism and thyrotoxicosis
Causes of In general, thyrotoxicosis can occur if (i) the thyroid is Thyrotoxicosis excessively stimulated by trophic factors; (ii) constitutive activation of thyroid hormone synthesis and secretion occurs, leading to autonomous release of excess thyroid hormone; (iii) thyroid stores of preformed hormone are passively released in excessive amounts owing to autoimmune, infectious, chemical, or mechanical insult; or (iv) there is exposure to extrathyroidal sources of thyroid hormone, which may be either endogenous (struma ovarii, metastatic differentiated thyroid cancer) or exogenous (factitious thyrotoxicosis).
Hyperthyroidism is generally considered overt or subclinical, depending on the biochemical severity of the hyperthyroidism, although in reality the disease represents a continuum of overactive thyroid function. Overt hyperthyroidism is defined as a subnormal (usually undetectable) serum thyrotropin (TSH) with elevated serum levels of triiodothyronine (T3) and/or free thyroxine estimates (free T4).
Subclinical hyperthyroidism is defined as a low or undetectable serum TSH with values within the normal reference range for both T3 and free T4. Both overt and subclinical disease may lead to characteristic signs and symptoms, although subclinical hyperthyroidism is usually considered milder.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 43 Overzealous or suppressive thyroid hormone administration may cause either type of thyrotoxicosis, particularly subclinical thyrotoxicosis.
Endogenous overt or subclinical thyrotoxicosis is caused by excess thyroid hormone production and release or by inflammation and release of hormone by the gland.
Endogenous hyperthyroidism is most commonly due to GD or nodular thyroid disease. GD is an autoimmune disorder in which thyrotropin receptor antibodies (TRAb) stimulate the TSH receptor, increasing thyroid hormone production and release.
The development of nodular thyroid disease includes growth of established nodules, new nodule formation, and development of autonomy over time. In TAs, autonomous hormone production can be caused by somatic activating mutations of genes regulating thyroid growth and hormone synthesis.
Germline mutations in the gene encoding the TSH receptor can cause sporadic or familial nonautoimmune hyperthyroidism associated with a diffuse enlargement of the thyroid gland.
Autonomous hormone production may progress from subclinical to overt hyperthyroidism, and the administration of pharmacologic amounts of iodine to such patients may result in iodine-induced hyperthyroidism.
GD is the most common cause of hyperthyroidism in the United States. Although toxic nodular goiter is less common than GD, its prevalence increases with age and in the presence of dietary iodine deficiency. Therefore, toxic nodular goiter may actually be more common than GD in older patients, especially in regions of iodine deficiency.
Unlike toxic nodular goiter, which is progressive (unless triggered by excessive iodine intake), remission of mild GD has been reported in up to 30% of patients without treatment.
Less common causes of thyrotoxicosis include the entities of painless and subacute thyroiditis, which occur due to inflammation of thyroid tissue with release of preformed hormone into the circulation.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 44 Painless thyroiditis caused by lymphocytic inflammation appears to occur with a different frequency depending on the population studied: in Denmark it accounted for only 0.5% of thyrotoxic patients, but it was 6% of patients in Toronto and 22% of patients in Wisconsin.
Painless thyroiditis may occur during lithium, cytokine (i.e., interferon-α), or tyrosine kinase inhibitor therapy, and in the postpartum period it is referred to as postpartum thyroiditis. A painless destructive thyroiditis (not usually lymphocytic) occurs in 5%– 10% of amiodarone-treated patients.
Subacute thyroiditis is thought to be caused by viral infection and is characterized by fever and thyroid pain.
Clinical The cellular actions of thyroid hormone are mediated consequences of by T3, the active form of thyroid hormone. T3 binds to thyrotoxicosis two specific nuclear receptors (thyroid hormone receptor α and β) that regulate the expression of many genes. Nongenomic actions of thyroid hormone include regulation of numerous important physiologic functions.
Thyroid hormone influences almost every tissue and organ system. It increases tissue thermogenesis and basal metabolic rate and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels occur within the cardiovascular system. Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death.
Only moderate correlation exists between the degree of thyroid hormone elevation and clinical signs and symptoms. Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters.
The signs and symptoms of mild, or subclinical, thyrotoxicosis are similar to those of overt thyrotoxicosis but differ in magnitude. Measurable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function can be present in mild thyrotoxicosis.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 45
HOW SHOULD CLINICALLY OR INCIDENTALLY DISCOVERED THYROTOXICOSIS BE EVALUATED AND INITIALLY MANAGED?
Assessment of Assessment of thyrotoxic manifestations, and disease severity especially potential cardiovascular and neuromuscular complications, is essential in formulating an appropriate treatment plan. Although it might be anticipated that the severity of thyrotoxic symptoms is proportional to the elevation in the serum levels of free T4 and T3, in one small study of 25 patients with GD, the Hyperthyroid Symptom Scale did not strongly correlate with free T4 or T3 and was inversely correlated with age. The importance of age as a determinant of the prevalence and severity of hyperthyroid symptoms has recently been confirmed.
Cardiac evaluation may be necessary, especially in the older patient, and may require an echocardiogram, electrocardiogram, Holter monitor, or myocardial perfusion studies.
The need for evaluation should not postpone therapy of the thyrotoxicosis. In addition to the administration of β-blockers, treatment may be needed for concomitant myocardial ischemia, congestive heart failure, or atrial arrhythmias. Anticoagulation may be necessary in patients in atrial fibrillation.
Goiter size, obstructive symptoms, and the severity of Graves' orbitopathy (GO), the inflammatory disease that develops in the orbit in association with autoimmune thyroid disorders, can be discordant with the degree of hyperthyroidism or hyperthyroid symptoms.
All patients with known or suspected hyperthyroidism should undergo a comprehensive history and physical examination, including measurement of pulse rate, blood pressure, respiratory rate, and body weight. Thyroid size, tenderness, symmetry, and nodularity should also be assessed along with pulmonary, cardiac, and neuromuscular function and the presence or absence of peripheral edema, eye signs, or pretibial myxedema.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 46 Biochemical Serum TSH measurement has the highest sensitivity Evaluation and specificity of any single blood test used in the evaluation of suspected thyrotoxicosis and should be used as an initial screening test. However, when thyrotoxicosis is strongly suspected, diagnostic accuracy improves when a serum TSH, free T4, and total T3 are assessed at the initial evaluation. The relationship between free T4 and TSH when the pituitary–thyroid axis is intact is an inverse log-linear relationship; therefore, small changes in free T4 result in large changes in serum TSH concentrations. Serum TSH levels are considerably more sensitive than direct thyroid hormone measurements for assessing thyroid hormone excess.
In overt hyperthyroidism, serum free T4, T3, or both are elevated, and serum TSH is subnormal (usually <0.01 mU/L in a third-generation assay). In mild hyperthyroidism, serum T4 and free T4 can be normal, only serum T3 may be elevated, and serum TSH will be low or undetectable. These laboratory findings have been called “T3-toxicosis” and may represent the earliest stages of hyperthyroidism caused by GD or an autonomously functioning thyroid nodule. As with T4, total T3 measurements are affected by protein binding. Assays for estimating free T3 are less widely validated and less robust than those for free T4. Therefore, measurement of total T3 is frequently preferred over free T3 in clinical practice.
Subclinical hyperthyroidism is defined as a normal serum free T4 and normal total T3 or free T3, with subnormal serum TSH concentration. Laboratory protocols that store sera and automatically retrieve the sample and add on free T4 and total T3 measurements when the initial screening serum TSH concentrations are low avoid the need for subsequent blood draws.
In the absence of a TSH-producing pituitary adenoma or thyroid hormone resistance, or in the presence of spurious assay results due to interfering antibodies, a normal serum TSH level precludes the diagnosis of thyrotoxicosis.
The term “euthyroid hyperthyroxinemia” has been used to describe a number of entities, primarily thyroid hormone–binding protein disorders, which cause elevated total serum T4 concentrations (and frequently elevated total serum T3 concentrations) in the absence of hyperthyroidism.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 47 These conditions include elevations in T4 binding globulin (TBG) or transthyretin; the presence of an abnormal albumin, which binds T4 with high capacity (familial dysalbuminemic hyperthyroxinemia); a similarly abnormal transthyretin; and, rarely, immunoglobulins that directly bind T4 or T3.
TBG excess may occur as a hereditary X-linked trait, or it may be acquired as a result of pregnancy or estrogen administration, hepatitis, acute intermittent porphyuria or during treatment with 5-fluorouracil, perphenazine, or some narcotics.
Other causes of euthyroid hyperthyroxinemia include drugs that inhibit T4 to T3 conversion, such as amiodarone or high-dose propranolol, acute psychosis, extreme high altitude, and amphetamine abuse. Estimates of free thyroid hormone concentrations frequently also give erroneous results in these disorders. Spurious free T4 elevations may occur from heterophilic antibodies or in the setting of heparin therapy, due to in vitro activation of lipoprotein lipase and release of free fatty acids that displace T4 from its binding proteins.
Heterophilic antibodies can also cause spurious high TSH values, and this should be ruled out by repeating the TSH in another assay, measurement of TSH in serial dilution, or direct measurement of human anti-mouse antibodies. Ingestion of high doses of biotin may cause spurious results in assays that utilize a streptavidin– biotin separation technique.
In immunometric assays, frequently used to measure TSH, excess biotin displaces biotinylated antibodies and causes spuriously low results, while in competitive binding assays, frequently used to measure free T4, excess biotin competes with biotinylated analogue and results in falsely high results.
Patients taking high doses of biotin or supplements containing biotin, who have elevated T4 and suppressed TSH, should stop taking biotin and have repeat measurements at least 2 days later.
After excluding euthyroid hyperthyroxinemia, TSH- mediated hyperthyroidism should be considered when thyroid hormone concentrations are elevated and TSH is normal or elevated. A pituitary lesion on magnetic resonance imaging (MRI) and a disproportionately high ratio of the serum level of the α-subunit of the pituitary glycoprotein hormones to TSH supports the diagnosis of a TSH-producing pituitary adenoma.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 48 A family history and genetic testing for mutations in the thyroid hormone receptor β (THRB) gene supports the diagnosis of resistance to thyroid hormone.
Determination of The etiology of thyrotoxicosis should be determined. Etiology If the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation, diagnostic testing is indicated and can include, depending on available expertise and resources, (1) measurement of TRAb, (2) determination of the radioactive iodine uptake (RAIU), or (3) measurement of thyroidal blood flow on ultrasonography.
A 123I or 99mTc pertechnetate scan should be obtained when the clinical presentation suggests a TA or TMNG.
Symptomatic Beta-adrenergic blockade is recommended in all Management patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease.
HOW SHOULD OVERT HYPERTHYROIDIS M DUE TO GD BE MANAGED?
Patients with overt Graves' hyperthyroidism should be treated with any of the following modalities: RAI therapy, ATDs, or thyroidectomy.
Clinical situations that favor a particular modality as treatment for Graves' hyperthyroidism RAI therapy:
Women planning a pregnancy in the future (in more than 6 months following RAI administration, provided thyroid hormone levels are normal), individuals with comorbidities increasing surgical risk, and patients with previously operated or externally irradiated necks, or lack of access to a high-volume thyroid surgeon, and patients with contraindications to ATD use or failure to achieve euthyroidism during treatment with ATDs.
Patients with periodic thyrotoxic hypokalemic paralysis, right heart failure pulmonary hypertension, or congestive heart failure should also be considered good candidates for RAI therapy.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 49 ATDs: Patients with high likelihood of remission (patients, especially women, with mild disease, small goiters, and negative or low-titer TRAb); pregnancy; the elderly or others with comorbidities increasing surgical risk or with limited life expectancy; individuals in nursing homes or other care facilities who may have limited longevity and are unable to follow radiation safety regulations; patients with previously operated or irradiated necks; patients with lack of access to a high- volume thyroid surgeon; patients with moderate to severe active GO; and patients who need more rapid biochemical disease control.
Surgery: Women planning a pregnancy in <6 months provided thyroid hormone levels are normal (i.e., possibly before thyroid hormone levels would be normal if RAI were chosen as therapy); symptomatic compression or large goiters (≥80 g); relatively low uptake of RAI; when thyroid malignancy is documented or suspected (i.e., suspicious or indeterminate cytology); large thyroid nodules especially if greater than 4 cm or if nonfunctioning, or hypofunctioning on 123I or 99mTc pertechnetate scanning; coexisting hyperparathyroidism requiring surgery; especially if TRAb levels are particularly high.
For patients with moderate to severe active GO.
RAI therapy: Definite contraindications include pregnancy, lactation, coexisting thyroid cancer, or suspicion of thyroid cancer, individuals unable to comply with radiation safety guidelines and used with informed caution in women planning a pregnancy within 4–6 months.
ATDs: Definite contraindications to ATD therapy include previous known major adverse reactions to ATDs.
Surgery: Factors that may mitigate against the choice of surgery include substantial comorbidity such as cardiopulmonary disease, end-stage cancer, or other debilitating disorders, or lack of access to a high- volume thyroid surgeon.
Pregnancy is a relative contraindication, and surgery should only be used in the circumstance when rapid control of hyperthyroidism is required and antithyroid medications cannot be used.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 50 Thyroidectomy is best avoided in the first and third trimesters of pregnancy because of teratogenic effects associated with anesthetic agents and increased risk of fetal loss in the first trimester and increased risk of preterm labor in the third. Optimally, thyroidectomy is performed in the second trimester; however, although it is the safest time, it is not without risk (4.5%–5.5% risk of preterm labor). Thyroid surgery in pregnancy is also associated with a higher rate of complications, including hypoparathyroidism and recurrent laryngeal nerve (RLN) injury.
Patient values that may impact choice of therapy:
RAI therapy: Patients choosing RAI therapy as treatment for GD would likely place relatively higher value on definitive control of hyperthyroidism, the avoidance of surgery, and the potential side effects of ATDs, as well as a relatively lower value on the need for lifelong thyroid hormone replacement, rapid resolution of hyperthyroidism, and potential worsening or development of GO.
ATDs: Patients choosing ATD as treatment for GD would place relatively higher value on the possibility of remission and avoidance of lifelong thyroid hormone treatment, the avoidance of surgery, and exposure to radioactivity and a relatively lower value on the avoidance of ATD side effects, and the possibility of disease recurrence.
Surgery: Patients choosing surgery as treatment for GD would likely place a relatively higher value on prompt and definitive control of hyperthyroidism, avoidance of exposure to radioactivity, and the potential side effects of ATDs and a relatively lower value on potential surgical risks, and need for lifelong thyroid hormone replacement.
IF RAI THERAPY IS CHOSEN, HOW SHOULD IT BE ACCOMPLISHED?
Preparation of Because RAI treatment of GD can cause a transient patients with GD exacerbation of hyperthyroidism, β-adrenergic for RAI therapy blockade should be considered even in asymptomatic patients who are at increased risk for complications due to worsening of hyperthyroidism (i.e., elderly patients and patients with comorbidities). nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 51 In addition to β-adrenergic blockade, pretreatment with MMI prior to RAI therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism. MMI should be discontinued 2–3 days prior to RAI.
In patients who are at increased risk for complications due to worsening of hyperthyroidism, resuming MMI 3– 7 days after RAI administration should be considered.
Medical therapy of any comorbid conditions should be optimized prior to RAI therapy.
Administration of Sufficient activity of RAI should be administered in a RAI in the single application, typically a mean dose of 10–15 mCi treatment of GD (370–555 MBq), to render the patient with GD hypothyroid.
A pregnancy test should be obtained within 48 hours prior to treatment in any woman with childbearing potential who is to be treated with RAI. The treating physician should obtain this test and verify a negative result prior to administering RAI.
The physician administering RAI should provide written advice concerning radiation safety precautions following treatment.
If the precautions cannot be followed, alternative therapy should be selected.
Follow-up within the first 1–2 months after RAI therapy for GD should include an assessment of free T4, total T3, and TSH. Biochemical monitoring should be continued at 4- to 6-week intervals for 6 months, or until the patient becomes hypothyroid and is stable on thyroid hormone replacement.
When hyperthyroidism due to GD persists after 6 months following RAI therapy, retreatment with RAI is suggested. In selected patients with minimal response 3 months after therapy additional RAI may be considered.
IF ATDs ARE CHOSEN AS INITIAL MANAGEMENT OF GD, HOW SHOULD THE THERAPY BE MANAGED?
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 52 Initiation of ATD MMI should be used in virtually every patient who therapy for the chooses ATD therapy for GD, except during the first treatment of GD trimester of pregnancy when PTU is preferred, in the treatment of thyroid storm, and in patients with minor reactions to MMI who refuse RAI therapy or surgery.
Patients should be informed of side effects of ATDs and the necessity of informing the physician promptly if they should develop pruritic rash, jaundice, acolic stools or dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis. Preferably, this information should be in writing.
Before starting ATDs and at each subsequent visit, the patient should be alerted to stop the medication immediately and call their physician if there are symptoms suggestive of agranulocytosis or hepatic injury.
Prior to initiating ATD therapy for GD, we suggest that patients have a baseline complete blood count, including white blood cell (WBC) count with differential, and a liver profile including bilirubin and transaminases.
Monitoring of A differential WBC count should be obtained during Patients Taking febrile illness and at the onset of pharyngitis in all ATD’s patients taking antithyroid medication. There is insufficient evidence to recommend for or against routine monitoring of WBC counts in patients taking ATDs.
Liver function and hepatocellular integrity should be assessed in patients taking MMI or PTU who experience pruritic rash, jaundice, light-colored stool or dark urine, joint pain, abdominal pain/bloating, anorexia, nausea/fatigue.
There is insufficient information to recommend for or against routine monitoring of liver function tests in patients taking ATDs.
Minor cutaneous reactions may be managed with concurrent antihistamine therapy without stopping the ATD. Persistent symptomatic minor side effects of antithyroid medication should be managed by cessation of the medication and changing to RAI or surgery, or switching to the other ATD when RAI or surgery are not options.
In the case of a serious allergic reaction, prescribing the alternative drug is not recommended.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 53 Measurement of TRAb levels prior to stopping ATD therapy is suggested because it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission.
If MMI is chosen as the primary therapy for GD, the medication should be continued for approximately 12– 18 months, then discontinued if the TSH and TRAb levels are normal at that time.
If a patient with GD becomes hyperthyroid after completing a course of MMI, consideration should be given to treatment with RAI or thyroidectomy. Continued low-dose MMI treatment for longer than 12– 18 months may be considered in patients not in remission who prefer this approach.
Persistently Patients with persistently high TRAb could continue Elevated TRAb ATD therapy (and repeat TRAb after an additional 12– 18 months) or opt for alternate definitive therapy with RAI or surgery.
In selected patients (i.e., younger patients with mild stable disease on a low dose of MMI), long-term MMI is a reasonable alternative approach. Another study reported that MMI doses of 2.5–10 mg/d for a mean of 14 years were safe and effective for the control of GD in 59 patients.
A recent retrospective analysis compared long-term outcomes (mean follow-up period of 6–7 years) of patients who had relapsed after a course of ATDs, who were treated with either RAI and levothyroxine or long-term ATD therapy. Those patients treated with RAI (n = 114) more often had persistent thyroid eye disease, continuing thyroid dysfunction, and experienced more weight gain compared with patients receiving long-term ATD treatment (n = 124).
If continued MMI therapy is chosen, TRAb levels might be monitored every 1–2 years, with consideration of MMI discontinuation if TRAb levels become negative over long-term follow-up. For patients choosing long-term MMI therapy, monitoring of thyroid function every 4–6 months is reasonable, and patients can be seen for follow-up visits every 6–12 months.
Negative TRAb If TRAb is negative and thyroid function is normal at the end of 12–18 months of MMI therapy, it is reasonable to discontinue the drug.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 54 If a patient experiences a relapse in follow-up, RAI therapy or surgery can be considered.
Technical remarks: In patients with negative TRAb, relapses tend to occur relatively later than those that develop in patients whose MMI is stopped when TRAb is still positive, although 5% occurred within the first 2 months in one study. Therefore, in this population, thyroid function testing should be monitored at 2- to 3- month intervals for the first 6 months, then at 4- to 6- month intervals for the next 6 months, and then every 6–12 months in order to detect relapses as early as possible.
The patient should be counseled to contact the treating physician if symptoms of hyperthyroidism are recognized. Should a relapse occur, patients should be counseled about alternatives for therapy, which would include another course of MMI, RAI, or surgery.
If ATD therapy is chosen, patients should be aware that agranulocytosis can occur with a second exposure to a drug, even many years later, despite an earlier uneventful course of therapy.
If the patient remains euthyroid for more than 1 year (i.e., they are in remission), thyroid function should be monitored at least annually because relapses can occur years later, and some patients eventually become hypothyroid.
HOW SHOULD THYROIDECTOMY BE ACCOMPLISHED IF CHOSEN FOR TREATMENT OF GD?
Preparation of If surgery is chosen as treatment for GD, patients patients with GD should be rendered euthyroid prior to the procedure for thyroidectomy with ATD pretreatment, with or without β-adrenergic blockade.
A KI-containing preparation should be given in the immediate preoperative period.
Calcium and 25-hydroxy vitamin D should be assessed preoperatively and repleted if necessary, or given prophylactically.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 55 Calcitriol supplementation should be considered preoperatively in patients at increased risk for transient or permanent hypoparathyroidism.
In exceptional circumstances, when it is not possible to render a patient with GD euthyroid prior to thyroidectomy, the need for thyroidectomy is urgent, or when the patient is allergic to ATDs, the patient should be adequately treated with β-adrenergic blockade, KI, glucocorticoids, and potentially cholestyramine in the immediate preoperative period.
The surgeon and anesthesiologist should have experience in this situation.
THE SURGICAL PROCEDURE AND CHOICE OF SURGEON
If surgery is chosen as the primary therapy for GD, near-total or total thyroidectomy is the procedure of choice.
If surgery is chosen as the primary therapy for GD, the patient should be referred to a high-volume thyroid surgeon.
POSTOPERATIVE CARE
Following thyroidectomy for GD, alternative strategies may be undertaken for management of calcium levels: serum calcium with or without intact parathyroid hormone (iPTH) levels can be measured, and oral calcium and calcitriol supplementation administered based on these results, or prophylactic calcium with or without calcitriol prescribed empirically.
ATD should be stopped at the time of thyroidectomy for GD, and β-adrenergic blockers should be weaned following surgery.
Communication among different members of the multidisciplinary team is essential, particularly during transitions of care in the pre- and postoperative settings.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 56
HOW SHOULD THYROID NODULES BE MANAGED IN PATIENTS WITH GD?
If a thyroid nodule is discovered in a patient with GD, the nodule should be evaluated and managed according to recently published guidelines regarding thyroid nodules in euthyroid individuals.
HOW SHOULD THYROID STORM BE MANAGED?
The diagnosis of thyroid storm should be made clinically in a severely thyrotoxic patient with evidence of systemic decompensation. Adjunctive use of a sensitive diagnostic system should be considered. Patients with a Burch–Wartofsky Point Scale (BWPS) of ≥45 or Japanese Thyroid Association (JTA) categories of thyroid storm 1 (TS1) or thyroid storm 2 (TS2) with evidence of systemic decompensation require aggressive therapy. The decision to use aggressive therapy in patients with a BWPS of 25–44 should be based on clinical judgment.
A multimodality treatment approach to patients with thyroid storm should be used. Multimodality treatment includes β-adrenergic blockade, ATD therapy, inorganic iodide, corticosteroid therapy, cooling with acetaminophen and cooling blankets, volume resuscitation, nutritional support, and respiratory care and monitoring in an intensive care unit, as appropriate for an individual patient.
IS THERE A ROLE FOR IODINE AS PRIMARY THERAPY IN THE TREATMENT OF GD?
Potassium iodide may be of benefit in select patients with hyperthyroidism due to GD, those who have adverse reactions to ATDs, and those who have a contraindication or aversion to RAI therapy (or aversion to repeat RAI therapy) or surgery.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 57 Treatment may be more suitable for patients with mild hyperthyroidism or a prior history of RAI therapy.
HOW SHOULD OVERT HYPERTHYROIDIS M DUE TO TMNG OR TA BE MANAGED?
It is suggested that patients with overtly TMNG or TA be treated with RAI therapy or thyroidectomy. On occasion, long-term, low-dose treatment with MMI may be appropriate.
IF RAI THERAPY IS CHOSEN AS TREATMENT FOR TMNG OR TA, HOW SHOULD IT BE ACCOMPLISHED?
Preparation of Because RAI treatment of TMNG or TA can cause a patients with transient exacerbation of hyperthyroidism, β- TMNG or TA for adrenergic blockade should be considered even in RAI therapy asymptomatic patients who are at increased risk for complications due to worsening of hyperthyroidism (i.e., elderly patients and patients with comorbidities).
In addition to β-adrenergic blockade (see Recommendations 2 and 38) pretreatment with MMI prior to RAI therapy for TMNG or TA should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism, including the elderly and those with cardiovascular disease or severe hyperthyroidism.
In patients who are at increased risk for complications due to worsening of hyperthyroidism, resuming ATDs 3–7 days after RAI administration should be considered.
Evaluation of Nonfunctioning nodules on radionuclide scintigraphy or thyroid nodules nodules with suspicious ultrasound characteristics before RAI should be managed according to published guidelines therapy regarding thyroid nodules in euthyroid individuals.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 58 Administration of Sufficient activity of RAI should be administered in a RAI in the single application to alleviate hyperthyroidism in treatment of TMNG patients with TMNG. or TA Sufficient activity of RAI should be administered in a single application to alleviate hyperthyroidism in patients with TA.
Patient follow-up Follow-up within the first 1–2 months after RAI after RAI therapy therapy for TMNG or TA should include an assessment for TMNG or TA of free T4, total T3, and TSH.
Biochemical monitoring should be continued at 4- to 6- week intervals for 6 months, or until the patient becomes hypothyroid and is stable on thyroid hormone replacement.
Treatment of If hyperthyroidism persists beyond 6 months following persistent or RAI therapy for TMNG or TA, retreatment with RAI is recurrent suggested. In selected patients with minimal response hyperthyroidism 3 months after therapy additional RAI may be following RAI considered. therapy for TMNG or TA
IF SURGERY IS CHOSEN, HOW SHOULD IT BE ACCOMPLISHED?
Preparation of If surgery is chosen as treatment for TMNG or TA, patients with patients with overt hyperthyroidism should be TMNG or TA for rendered euthyroid prior to the procedure with MMI surgery pretreatment, with or without β-adrenergic blockade. Preoperative iodine should not be used in this setting.
The surgical If surgery is chosen as treatment for TMNG, near-total procedure and or total thyroidectomy should be performed. A high- choice of surgeon volume thyroid surgeon should perform surgery for TMNG.
If surgery is chosen as the treatment for TA, a thyroid ultrasound should be done to evaluate the entire thyroid gland. An ipsilateral thyroid lobectomy, or isthmusectomy if the adenoma is in the thyroid isthmus, should be performed for isolated TAs.
It is suggested that a high-volume surgeon perform surgery for TA.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 59 If ATDs are chosen Long-term MMI treatment of TMNG or TA might be as treatment of indicated in some elderly or otherwise ill patients with TMNG or TA, how limited life expectancy, in patients who are not good should the therapy candidates for surgery or ablative therapy, and in be managed? patients who prefer this option.
How should GD be Children with GD should be treated with MMI, RAI managed in therapy, or thyroidectomy. RAI therapy should be children and avoided in very young children (<5 years). adolescents? RAI therapy in children is acceptable if the activity is >150 µCi/g (5.55 MBq/g) of thyroid tissue, and for children between 5 and 10 years of age if the calculated RAI administered activity is <10 mCi (<473 MBq).
Thyroidectomy should be chosen when definitive therapy is required, the child is too young for RAI, and a high-volume thyroid surgeon can perform surgery.
IF ATD’s ARE CHOSEN AS INITIAL MANAGEMENT OF GD IN CHILDREN, HOW SHOULD THE THERAPY BE MANAGED?
Initiation of ATD MMI should be used in children who are treated with therapy for the ATD therapy. treatment of GD in children Pediatric patients and their caretakers should be informed of side effects of ATD preferably in writing, and the necessity of stopping the medication immediately and informing their physician if they develop pruritic rash, jaundice, acolic stools or dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis.
Prior to initiating ATD therapy, we suggest that pediatric patients have, as a baseline, complete blood cell count, including WBC count with differential, and a liver profile including bilirubin, transaminases, and alkaline phosphatase.
Symptomatic Beta-adrenergic blockade is recommended for children management of experiencing symptoms of hyperthyroidism, especially Graves' those with heart rates in excess of 100 beats/minute. hyperthyroidism in children
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 60 Monitoring of ATDs should be stopped immediately and WBC counts children taking measured in children who develop fever, arthralgias, MMI mouth sores, pharyngitis, or malaise.
Monitoring of In general, PTU should not be used in children. But if it children taking is used, the medication should be stopped immediately PTU and liver function and hepatocellular integrity assessed in children who experience anorexia, pruritus, rash, jaundice, light-colored stool or dark urine, joint pain, right upper quadrant pain or abdominal bloating, nausea, or malaise.
Management of Persistent minor cutaneous reactions to MMI therapy in allergic reactions children should be managed by concurrent in children taking antihistamine treatment or cessation of the medication MMI and changing to therapy with RAI or surgery. With a serious adverse reaction to an ATD, prescribing the other ATD is not recommended.
Duration of MMI If MMI is chosen as the first-line treatment for GD in therapy in children children, it may be tapered in those children requiring with GD low doses after 1–2 years to determine if a spontaneous remission has occurred, or it may be continued until the child and caretakers are ready to consider definitive therapy, if needed.
Pediatric patients with GD who are not in remission following at least 1–2 years of MMI therapy should be considered for treatment with RAI or thyroidectomy. Alternatively, if children are tolerating ATD therapy, ATDs may be used for extended periods. This approach may be especially useful for the child not considered to be a candidate for either surgery or RAI.
Individuals on prolonged ATD therapy (>2 years) should be reevaluated every 6–12 months and when transitioning to adulthood.
IF RAI IS CHOSEN AS TREATMENT FOR GD IN CHILDREN, HOW SHOULD IT BE ACCOMPLISHED?
Preparation of It is suggested that children with GD having total T4 pediatric patients levels of >20 µg/dL (260 nmol/L) or free T4 >5 ng/dL with GD for RAI (60 pmol/L) who are to receive RAI therapy be therapy pretreated with MMI and β-adrenergic blockade until total T4 and/or free T4 normalize before proceeding with RAI treatment.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 61 Administration of If RAI therapy is chosen as treatment for GD in RAI in the children, sufficient RAI should be administered in a treatment of GD in single dose to render the patient hypothyroid. children
THYROIDECTOMY CHOSEN AS TREATMENT FOR GD IN CHILDREN SHOULD BE ACCOMPLISHED AS FOLLOWS
Preparation of Children with GD undergoing thyroidectomy should be children with GD rendered euthyroid with the use of MMI. A KI- for thyroidectomy containing preparation should be given in the immediate preoperative period.
If surgery is chosen as therapy for GD in children, total or near-total thyroidectomy should be performed.
High-volume thyroid surgeons should perform thyroidectomy in children.
HOW SHOULD SUBCLINICAL HYPERTHYROIDIS M BE MANAGED?
Prevalence and The prevalence of subclinical hyperthyroidism (SH) in causes of SH an adult population depends on age, sex, and iodine intake. In a representative sample of U.S. subjects without known thyroid disease, 0.7% had suppressed TSH levels (<0.1 mU/L), and 1.8% had low TSH levels (<0.4 mU/L).
Similar rates have been reported in studies from Europe, with higher levels in women and older subjects. The differential diagnosis of an isolated low or suppressed TSH level includes exogenous thyroid hormone use, nonthyroidal illness, drug effects, and pituitary/hypothalamic disease, all of which need to be ruled out before the diagnosis of SH can be established in a patient with an isolated low or suppressed TSH level.
In addition, mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 62 Finally, some otherwise healthy older persons may have low serum TSH levels, low-normal serum levels of free T4 and total T3, and no evidence of thyroid or pituitary disease, suggesting an altered set point of the pituitary–thyroid axis.
The natural history of SH is variable; annually, 0.5%– 7% progression to overt hyperthyroidism and 5%– 12% reversion to normal TSH levels. In one study, 51.2% of patients had spontaneously developed a normal TSH when first checked at some time within 5 years (mean time to repeat TSH, 13 months).
Progression from SH to overt hyperthyroidism appears more likely if the TSH is suppressed (<0.01 mU/L), rather than low but detectable (0.01–0.4 mU/L).
Patients with GD rather than a TMNG as the cause of SH may be more likely to spontaneously remit. In patients at high risk of complications from SH, TSH and free T4 should be repeated within 2–6 weeks. For all other patients, it is important to document that SH is a persistent problem by repeating the serum TSH at 3–6 months, prior to initiating therapy.
In clinical series, TMNG is the most common cause of SH, especially in older persons. The second most common cause of SH is GD, which is more prevalent in younger persons and is also common in patients who previously received ATD therapy.
Other unusual causes include solitary autonomously functioning nodules and various forms of thyroiditis, the latter of which would be more strictly termed “subclinical thyrotoxicosis.
Clinical Since SH is a mild form of hyperthyroidism, it is not significance of SH surprising that deleterious effects seen in overt hyperthyroidism might also occur in SH. A large number of recent studies have elucidated these effects.
When to treat SH When TSH is persistently <0.1 mU/L, treatment of SH is recommended in all individuals ≥65 years of age; in patients with cardiac risk factors, heart disease or osteoporosis; in postmenopausal women who are not on estrogens or bisphosphonates; and in individuals with hyperthyroid symptoms.
When TSH is persistently <0.1 mU/L, treatment of SH should be considered in asymptomatic individuals <65 years of age without the risk factors listed in Recommendation 73.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 63 When TSH is persistently below the lower limit of normal but ≥0.1 mU/L, treatment of SH should be considered in individuals ≥65 years of age and in patients with cardiac disease, osteoporosis, or symptoms of hyperthyroidism.
When TSH is persistently below the lower limit of normal but ≥0.1 mU/L, asymptomatic patients under age 65 without cardiac disease or osteoporosis can be observed without further investigation of the etiology of the subnormal TSH or treatment.
How to treat SH If SH is to be treated, the treatment should be based on the etiology of the thyroid dysfunction and follow the same principles as outlined for the treatment of overt hyperthyroidism.
End points to be The goal of therapy for SH is to render the patient assessed to euthyroid with a normal TSH. Since the rationale for determine therapy of SH is to a large degree preventive, few end effective therapy points can be used to document that therapy has been of SH successful.
Based on the original indication for treatment, it is reasonable to follow hyperthyroid symptoms or bone density; otherwise, the major end point is a TSH level within the age-adjusted reference range.
Prevention of GO Current therapeutic approaches to GO, including local measures, corticosteroids, orbital radiation, and surgery, often fail to significantly improve the QoL of patients with this debilitating condition. Therefore, efforts should be made to prevent the development or progression of GO in patients with Graves' hyperthyroidism.
Pertinent risk factors for GO are RAI therapy for hyperthyroidism, untreated hyperthyroidism, smoking, high serum pretreatment TRAb levels (normal <1.75 IU/L, high risk for progression if >8.8 IU/L), and any delay in treating hypothyroidism after therapy for hyperthyroidism.
High pretreatment levels of T3 and T4 were each reported to have a predictive role in GO, but these conclusions were not validated by subsequent studies, suggesting the possibility of higher TRAb values measured on less sensitive assays early-on being partly responsible for this variation.
Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with GO or risk factors for the development of orbitopathy. nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 64 We recommend clinicians advise patients with GD to stop smoking and refer them to a structured smoking cessation program. As both firsthand and secondhand smoking increase GO risk, patients exposed to secondhand smoke should be identified and advised of its negative impact.
Treatment of In nonsmoking patients with GD without apparent GO, hyperthyroidism in RAI therapy (without concurrent steroids), ATDs, or patients with no thyroidectomy should be considered equally acceptable apparent GO therapeutic options in regard to risk of GO.
In smoking patients with GD without apparent GO, RAI therapy, ATDs, or thyroidectomy should be considered equally acceptable therapeutic options in regard to risk of GO.
Treatment of In patients with Graves' hyperthyroidism who have hyperthyroidism in mild active ophthalmopathy and no risk factors for patients with deterioration of their eye disease, RAI therapy, ATDs, active GO of mild and thyroidectomy should be considered equally severity acceptable therapeutic options.
In the absence of any strong contraindication to GC use we suggest considering them for coverage of GD patients with mild active GO who are treated with RAI; in absence of risk factors for GO deterioration.
In GD patients with mild GO who are treated with RAI we recommend steroid coverage if there are concomitant risk factors for GO deterioration.
Treatment of In patients with active and moderate-to-severe or hyperthyroidism in sight-threatening GO we recommend against RAI patients with therapy. Surgery or ATDs are preferred treatment active and options for GD in these patients. moderate-to- severe or sight- threatening GO Treatment of GD in In patients with inactive GO we suggest RAI therapy patients with can be administered without steroid coverage. inactive GO However, in cases of elevated risk for reactivation (high TRAb, CAS ≥1 and smokers) that approach might have to be reconsidered.
HOW SHOULD IODINE-INDUCED AND AMIODARONE- INDUCED THYROTOXICOSIS BE MANAGED?
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 65 Iodine-induced Routine administration of ATDs before iodinated hyperthyroidism contrast media exposure is not recommended for all patients.
Beta-adrenergic blocking agents alone or in combination with MMI should be used to treat overt iodine-induced hyperthyroidism.
Amiodarone- We suggest monitoring thyroid function tests before induced and within the first 3 months following the initiation of thyrotoxicosis amiodarone therapy, and at 3- to 6-month intervals thereafter.
The decision to stop amiodarone in the setting of thyrotoxicosis should be determined on an individual basis in consultation with the treating cardiologist, depending on the clinical manifestations and presence or absence of effective alternative antiarrhythmic therapy.
In clinically stable patients with AIT, we suggest measuring thyroid function tests to identify disorders associated with iodine-induced hyperthyroidism (type 1 AIT), specifically including toxic nodular disease and previously occult GD.
MMI should be used to treat overt thyrotoxicosis in patients with proven underlying autonomous thyroid nodules or GD as the cause of AIT (type 1 disease). Corticosteroids should be used to treat patients with overt amiodarone-induced thyroiditis (type 2 disease).
Combined ATD and corticosteroid therapy should be used to treat patients with overt AIT who are too unstable clinically to allow a trial of monotherapy or who fail to respond to single modality therapy, or patients in whom the etiology of thyrotoxicosis cannot be unequivocally determined.
Patients with AIT who are unresponsive to aggressive medical therapy with MMI and corticosteroids should undergo thyroidectomy.
HOW SHOULD THYROTOXICOSIS DUE TO DESTRUCTIVE THYROIDITIS BE MANAGED?
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 66 Subacute Patients with mild symptomatic subacute thyroiditis thyroiditis should be treated initially with β-adrenergic-blocking drugs and nonsteroidal anti-inflammatory agents (NSAIDs). Corticosteroids should be used instead of NSAIDs when patients fail to respond or present initially with moderate to severe pain and/or thyrotoxic symptoms.
Painless Patients with symptomatic thyrotoxicosis due to thyroiditis painless thyroiditis should be treated with β- adrenergic-blocking drugs to control symptoms.
Acute thyroiditis Acute thyroiditis should be treated with antibiotics and surgical drainage as determined by clinical judgement. Beta-blockers may be used to treat symptoms of thyrotoxicosis.
How should other Patients taking medications known to cause causes of thyrotoxicosis, including interferon (IFN)-α, thyrotoxicosis be interleukin-2, tyrosine kinase inhibitors, and lithium, managed? should be monitored clinically and biochemically at 6- month intervals for the development of thyroid dysfunction.
Patients who develop thyrotoxicosis should be evaluated to determine etiology and treated accordingly.
TSH-secreting The diagnosis of a TSH-secreting pituitary adenoma pituitary tumors should be based on an inappropriately normal or elevated serum TSH level associated with elevated free T4 and total T3 concentrations, generally associated with a pituitary tumor on MRI or CT and the absence of a family history or genetic testing consistent with resistance to thyroid hormone.
Struma ovarii Patients with struma ovarii should be treated initially with surgical resection following preoperative normalization of thyroid hormones.
Choriocarcinoma Treatment of hyperthyroidism due to choriocarcinoma should include both MMI and treatment directed against the primary tumor.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 67 Euthyroid Sick Syndrome
Euthyroid sick syndrome is also known as non-thyroidal illness syndrome. Euthyroid sick syndrome occurs in patients with a number of different non-thyroidal illnesses such as metabolic syndrome, acute coronary syndrome, other acutely ill cardiac patients, trauma, starvation, chronic kidney disease, diabetic ketoacidosis, eating disorders and other conditions. It is primarily a lab diagnosis as there are often few if any symptoms of thyroid disease. Decreased fT3 and tissue T3 levels, presumably because of decreased deiodinase activity, characterize this. fT4 and TSH usually are within the reference ranges.
In more severe cases, the total T4 also decreases and T3 resin uptake increases as does reverse T3 (rT3). D1 activity is reduced while D3 activity is increased. TSH are usually low-normal or somewhat below normal. fT4 may in normal, increased or decreased. In euthyroid sick syndrome the T3 is decreased proportionately more than T4 (the reverse is true in hypothyroidism).3,61-66
Euthyroid sick syndrome is believed to be cause by inflammatory cytokines resulting from the primary condition. It may be an adaptive process that reduces peripheral energy use. Treatment is controversial; many clinicians believe that the best approach is to treat the overlying disorder while others believe that supporting thyroid function can speed recovery overall. Low T3 levels have been shown to have prognostic significance, particularly in patients with ischemic heart disease, valvular disease, congestive heart failure, meningococcal sepsis, cancer (such a lung adenocarcinoma, breast cancer, squamous cell carcinoma) and other conditions in the setting of an ICU.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 68 A recent report indicated that there may be two phases of euthyroid sick syndrome/non-thyroidal illness, at least in the setting of the ICU. The first phase, coinciding with admission to the ICU is a “fasting “and an adaptive response and it may be beneficial to the patient to allow the adaptation to proceed without interference. This first phase accounts for the majority of ICU patients. The second phase, however, occurs in patients with prolonged, chronic illness who are adequately nourished and who may benefit from treatment.
Hypothyoidism And Associated Conditions
Hypothyroidism may be primary, secondary, tertiary or subclinical. Hypothyroidism is a hormone deficiency disease diagnosed by physical signs and symptoms as well as lab results.3,64-70
Primary Hypothyroidism Consultation with an endocrinologist is Primary hypothyroidism is caused by recommended in the following disease in the thyroid. Across the situations: world, most hypothyroidism is caused • In children and infants • In those patients where a by iodine deficiency. In the U.S., the euthyroid state has been difficult to achieve or most common cause of primary maintain. • In pregnancy or if hypothyroidism is autoimmune and planning a pregnancy results in Hashimoto’s thyroiditis. The • In patients with cardiac disease second most common cause in the • In those patients with goiter, nodule, or other U.S. is post-therapeutic structural changes in the thyroid gland hypothyroidism, particularly after the • If other endocrinopathies exist treatment of goiter or Graves’ • If lab results present with disease with surgery or radiation. unusual results • Unusual causes of This form of hypothyroidism may not hypothyroidism
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 69 be permanent. Primary hypothyroidism may result in goiter, though goiter is more commonly associated with hyperfunctioning of the thyroid.
Iodine deficiency can also cause congenital hypothyroidism — in the past, this was known as cretinism (now referred to as congenital hypothyroidism) because of its effects on cognitive development and learning.
Primary hypothyroidism can also be drug induced. Drugs that can induce hypothyroidism include those that can induce hyperthyroidism — lithium, amiodarone and other iodine-containing drugs, α-interferon, tyrosine kinase inhibitors and checkpoint inhibitors. Radiation treatment can also induce hypothyroidism.
The differential diagnosis of hypothyroidism can be difficult because presenting signs and symptoms are often non-specific. The patient may complain of fatigue, or the chief complaint can be weight gain. Diagnostic considerations include anemia and familial or personal tendency to autoimmune diseases.
Differential diagnoses include:
• Addison’s disease • Syndrome of Inappropriate ADH secretion • Other thyroid disorders such as thyroiditis (de Quervains, Reidel’s, Euthyroid Sick Syndrome, drug/radiation induced thyroiditis, subacute, postpartum), goiter, thyroid lymphoma, thyroxine-binding globulin deficiency, iodine deficiency • Types I, II, III Polyglandular Autoimmune Syndrome
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 70 • Hypopituitarism • Pituitary macroadenoma • Prolactin deficiency • Chronic fatigue syndrome • Depression • Gynecologic disorders or states such as anovulation, dysmenorrhea, menopause, ovarian insufficiency • Eosinophilia, eosinophilia-myalgia syndrome • Familial hypercholesterolemia, polygenic hypercholesterolemia • Hypoalbuminemia • Infectious mononucleosis • Obesity • Sleep apnea. Sleep disorders • Cardiac tamponade, pericardial effusion • Chronic megacolon, ileus, constipation • Obesity
Postpartum Thyroiditis
Postpartum thyroiditis occurs within 2-12 months of delivery. In women with a personal or family history of autoimmune disease, the frequency of postpartum thyroiditis is increase. In 2012, guidelines for the management of thyroid dysfunction during pregnancy and postpartum were produced:65
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 71 ATA Recommendations for Management of Hypothyroidism in Pregnancy
Management of It is recommended that caution be exercised in the hypothyroidism: interpretation of serum free T4 levels during maternal and fetal pregnancy and that each laboratory establish aspects trimester-specific reference ranges for pregnant women if using a free T4 assay.
The nonpregnant total T4 range (5–12 µg/dl or 50– 150 nmol/liter) can be adapted in the second and third trimesters by multiplying this range by 1.5-fold. Alternatively, the free T4 index (“adjusted T4”) appears to be a reliable assay during pregnancy. Overt maternal hypothyroidism is known to have serious adverse effects on the fetus. Therefore, maternal hypothyroidism should be avoided.
Subclinical hypothyroidism (SCH; serum TSH concentration above the upper limit of the trimester- specific reference range with a normal free T4) may be associated with an adverse outcome for both the mother and offspring, as documented in antibody- positive women.
In retrospective studies, T4 treatment improved obstetrical outcome, but it has not been proved to modify long-term neurological development in the offspring. However, given that the potential benefits outweigh the potential risks, the panel recommends T4 replacement in women with SCH who are thyroid peroxidase antibody positive (TPO-Ab+).
If hypothyroidism has been diagnosed before pregnancy, we recommend adjustment of the preconception T4 dose to reach before pregnancy a TSH level not higher than 2.5 mIU/liter. The T4 dose usually needs to be incremented by 4 to 6 wk gestation and may require a 30% or more increase in dosage.
If overt hypothyroidism is diagnosed during pregnancy, thyroid function tests should be normalized as rapidly as possible. T4 dosage should be titrated to rapidly reach and thereafter maintain serum TSH concentrations of less than 2.5 mIU/liter (in an assay using the International Standard) in the first trimester (or 3 mIU/liter in second and third trimesters) or to trimester-specific TSH ranges. Thyroid function tests should be remeasured within 30–40 d and then every 4–6 wk.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 72 Women with thyroid autoimmunity who are euthyroid in the early stages of pregnancy are at risk of developing hypothyroidism and should be monitored every 4–6 wk for elevation of TSH above the normal range for pregnancy. After delivery, most hypothyroid women need to decrease the T4 dosage they received during pregnancy to the prepregnancy dose.
Management of hyperthyroidism: maternal and fetal aspects
Management of If a subnormal serum TSH concentration is detected maternal during gestation, hyperthyroidism must be hyperthyroidism: distinguished from both normal physiology of maternal aspects pregnancy and gestational thyrotoxicosis because of the adverse effects of overt hyperthyroidism on the mother and fetus. Differentiation of Graves' disease from gestational thyrotoxicosis is supported by the presence of clinical evidence of autoimmunity, a typical goiter, and presence of TSH receptor antibodies (TRAb). TPO-Ab may be present in either case.
For overt hyperthyroidism due to Graves' disease or thyroid nodules, antithyroid drug (ATD) therapy should be either initiated (before pregnancy if possible, and for those with new diagnoses) or adjusted (for those with a prior history) to maintain the maternal thyroid hormone levels for free T4 at or just above the upper limit of the nonpregnant reference range, or to maintain total T4 at 1.5 times the upper limit of the normal reference range or the free T4 index in the upper limit of the normal reference range.
Propylthiouracil (PTU), if available, is recommended as the first-line drug for treatment of hyperthyroidism during the first trimester of pregnancy because of the possible association of methimazole (MMI) with specific congenital abnormalities that occur during first trimester organogenesis.
MMI may also be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU. MMI 10 mg is considered to be approximately equal to 100–150 mg of PTU.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 73 Recent analyses reported by the U.S. Food and Drug Administration (FDA) indicate that PTU may rarely be associated with severe liver toxicity. For this reason we recommend that clinicians change treatment of patients from PTU to MMI after the completion of the first trimester. Available data indicate that MMI and PTU are equally efficacious in the treatment of pregnant women.
Practitioners should use their clinical judgment in choosing the ATD therapy, including the potential difficulties involved in switching patients from one drug to another. If switching from PTU to MMI, thyroid function should be assessed after 2 wk and then at 2- to 4-wk intervals. Although liver toxicity may appear abruptly, it is reasonable to monitor liver function in pregnant women on PTU every 3–4 wk and to encourage patients to promptly report any new symptoms.
Subtotal thyroidectomy may be indicated during pregnancy as therapy for maternal Graves' disease if: 1) a patient has a severe adverse reaction to ATD therapy; 2) persistently high doses of ATD are required (over 30 mg/d of MMI or 450 mg/d of PTU); or 3) a patient is nonadherent to ATD therapy and has uncontrolled hyperthyroidism. The optimal timing of surgery is in the second trimester. There is no evidence that treatment of subclinical hyperthyroidism improves pregnancy outcome, and treatment could potentially adversely affect fetal outcome.
Management of Because thyroid receptor antibodies (thyroid maternal receptor stimulating, binding, or inhibiting hyperthyroidism: antibodies) freely cross the placenta and can fetal aspects stimulate the fetal thyroid, these antibodies should be measured by 22 wk gestational age in mothers with: 1) current Graves' disease; or 2) a history of Graves' disease and treatment with 131I or thyroidectomy before pregnancy; or 3) a previous neonate with Graves' disease; or 4) previously elevated TRAb.
Women who have a negative TRAb and do not require ATD have a very low risk of fetal or neonatal thyroid dysfunction. 131I should not be given to a woman who is or may be pregnant. If inadvertently treated, the patient should be promptly informed of the radiation danger to the fetus, including thyroid destruction if treated after the 12th week of gestation. USPSTF recommendation level: A; evidence, good.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 74 There are no data for or against recommending termination of pregnancy after 131I exposure.
In women with TRAb or thyroid-stimulating Ig elevated at least 2- to 3-fold the normal level and in women treated with ATD, maternal free T4 and fetal thyroid dysfunction should be screened for during the fetal anatomy ultrasound done in the 18th-22nd week and repeated every 4–6 wk or as clinically indicated.
Evidence of fetal thyroid dysfunction could include thyroid enlargement, growth restriction, hydrops, presence of goiter, advanced bone age, tachycardia, or cardiac failure. If fetal hyperthyroidism is diagnosed and thought to endanger the pregnancy, treatment using MMI or PTU should be given with frequent clinical, laboratory, and ultrasound monitoring.
Umbilical blood sampling should be considered only if the diagnosis of fetal thyroid disease is not reasonably certain from the clinical and sonographic data and the information gained would change the treatment.
All newborns of mothers with Graves' disease (except those with negative TRAb and not requiring ATD) should be evaluated by a medical care provider for thyroid dysfunction and treated if necessary.
Gestational Thyroid function tests (TSH, total T4, or free T4 hyperemesis and index, or free T4) and TRAb should be measured in hyperthyroidism patients with hyperemesis gravidarum (5% weight loss, dehydration, and ketonuria) and clinical features of hyperthyroidism.
Most women with hyperemesis gravidarum, clinical hyperthyroidism, suppressed TSH, and elevated freeT4 do not require ATD treatment.
Clinical judgment should be followed in women who appear significantly thyrotoxic or who have in addition serum total T3 values above the reference range for pregnancy.
Beta-blockers such as metoprolol may be helpful and may be used with obstetrical agreement. Women with hyperemesis gravidarum and diagnosed to have Graves' hyperthyroidism (free T4 above the reference range or total T4 > 150% of top normal pregnancy value, TSH < 0.01 µIU/liter, and presence of TRAb) will require ATD treatment, as clinically necessary.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 75 Autoimmune thyroid A positive association exists between the presence of disease and thyroid antibodies and pregnancy loss. Universal miscarriage screening for antithyroid antibodies, and possible treatment, cannot be recommended at this time.
As of January 2011, only one randomized interventional trial has suggested a decrease in the first trimester miscarriage rate in euthyroid antibody-positive women, but treatment duration was very brief before the outcome of interest. However, because women with elevated anti-TPO antibodies are at increased risk for progression of hypothyroidism, if identified such women should be screened for serum TSH abnormalities before pregnancy, as well as during the first and second trimesters of pregnancy.
Thyroid nodules and Fine-needle aspiration (FNA) cytology should be cancer performed for predominantly solid thyroid nodules larger than 1 cm discovered in pregnancy. Women with nodules 5 mm to 1 cm in size should be considered for FNA if they have a high-risk history or suspicious findings on ultrasound, and women with complex nodules 1.5 to 2 cm or larger should also receive an FNA.
During the last weeks of pregnancy, FNA can reasonably be delayed until after delivery. Ultrasound-guided FNA is likely to have an advantage for maximizing adequate sampling.
When nodules discovered in the first or early second trimester are found to be malignant or highly suspicious on cytopathological analysis, to exhibit rapid growth, or to be accompanied by pathological neck adenopathy, pregnancy need not be interrupted, but surgery should be offered in the second trimester.
Women found to have cytology indicative of papillary cancer or follicular neoplasm without evidence of advanced disease and who prefer to wait until the postpartum period for definitive surgery may be reassured that most well-differentiated thyroid cancers are slow growing and that delaying surgical treatment until soon after delivery is unlikely to change disease-specific survival. It is appropriate to administer thyroid hormone to achieve a suppressed but detectable TSH in pregnant women with a previously treated thyroid cancer, in those with an FNA positive for or suspicious for cancer, or in those who elect to delay surgical treatment until postpartum.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 76 High-risk patients may benefit more than low-risk patients from a greater degree of TSH suppression. The free T4 or total T4 levels should ideally not be increased above the normal range for pregnancy. Radioactive iodine (RAI) with 131I should not be given to women who are breastfeeding or for at least 4 wk after nursing has ceased.
Furthermore, pregnancy should be avoided for 6 months to 1 yr in women with thyroid cancer who receive therapeutic RAI doses to ensure stability of thyroid function and confirm remission of thyroid cancer.
Iodine nutrition Women in the childbearing age should have an during pregnancy average iodine intake of 150 µg/d. As long as possible before pregnancy and during pregnancy and breastfeeding, women should increase their daily iodine intake to 250 µg on average.
Iodine intake during pregnancy and breastfeeding should not exceed twice the daily recommended nutrient intake (RNI) for iodine, i.e., 500 µg iodine per day.
Although not advised as a part of normal clinical practice, the adequacy of the iodine intake during pregnancy can be assessed by measuring urinary iodine concentration (UIC) in a representative cohort of the population. UIC should ideally range between 150 and 250 µg/liter.
If there is significant concern, the caregiver should assay TSH and thyroid hormone levels.
To reach the daily recommended nutrient intake for iodine, multiple means must be considered, tailored to the iodine intake level in a given population.
Different situations must therefore be distinguished: 1) countries with iodine sufficiency and/or with a well-established universal salt iodization (USI) program; 2) countries without a USI program or with an established USI program where the coverage is known to be only partial; and 3) remote areas with no accessible USI program and difficult socioeconomic conditions. It is recommended that once-daily prenatal vitamins contain 150–200 µg iodine and that this be in the form of potassium iodide or iodate, the content of which is verified to ensure that all pregnant women taking prenatal vitamins are protected from iodine deficiency.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 77 Ideally, supplementation should be started before conception. Preparations containing iron supplements should be separated from thyroid hormone administration by at least 4 h. It is recommended that breastfeeding women maintain a daily intake of 250 µg of iodine to ensure that breast milk provides 100 µg iodine per day to the infant.
Postpartum There are insufficient data to recommend screening thyroiditis of all women for postpartum thyroiditis (PPT). Women known to be TPO-Ab+ should have TSH measured at 6–12 wk gestation and at 6 months postpartum, or as clinically indicated.
Because the prevalence of PPT in women with type 1 diabetes, Graves' disease in remission, and chronic viral hepatitis is greater than in the general population, screening by TSH is recommended at 3 and 6 months postpartum. Women with a history of PPT have a markedly increased risk of developing permanent primary hypothyroidism in the 5- to 10-yr period after the episode of PPT. An annual TSH level should be performed in these women.
Asymptomatic women with PPT who have a TSH above the reference range but less than 10 mIU/liter and who are not planning a subsequent pregnancy do not necessarily require intervention but should, if untreated, be remonitored in 4–8 wk. When a TSH above the reference range continues, women should be treated with levothyroxine. Symptomatic women and women with a TSH above normal and who are attempting pregnancy should be treated with levothyroxine.
There is insufficient evidence to conclude whether an association exists between postpartum depression (PPD) and either PPT or thyroid antibody positivity (in women who did not develop PPT). USPSTF recommendation level: I; evidence, poor. However, because hypothyroidism is a potentially reversible cause of depression, women with PPD should be screened for hypothyroidism and appropriately treated.
Screening for Universal screening of healthy women for thyroid thyroid dysfunction dysfunction before pregnancy is not recommended. during pregnancy However, caregivers should identify individuals at “high risk” for thyroid illness on the basis of their medical history, physical exam, or prior biochemical data. When such individuals are identified, prenatal measurement of serum TSH is recommended.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 78 If it is above 2.5 mIU/liter, the test should be confirmed by repeat assay. Although no randomized controlled trials are available to guide a response, the committee believes it is appropriate to give low- dose T4 treatment to bring TSH below 2.5 mIU/liter. This treatment can be discontinued if the woman does not become pregnant or postpartum. All women considering pregnancy with known thyroid dysfunction and receiving levothyroxine should be tested for abnormal TSH concentrations before pregnancy. If hypothyroidism has been diagnosed before pregnancy, the recommendation is for adjustment of the preconception T4 dose to reach before pregnancy a TSH level not higher than 2.5 mIU/liter.
All women receiving levothyroxine should be verbally screened prenatally to assess their understanding of changing levothyroxine requirements after conception. These women should be counseled to contact a physician or medical professional immediately upon a missed menstrual cycle or suspicion of pregnancy to check their serum TSH level. An additional recommendation may be to increase their levothyroxine dose by 30%, which is often two additional tablets per week (nine tablets per week), until their serum TSH can be checked.
Universal screening for the presence of anti-TPO antibodies either before or during pregnancy is not recommended. However, women with elevated anti- TPO antibodies are at increased risk for miscarriage, preterm delivery, progression of hypothyroidism, and PPT. Therefore, if identified, such women should be screened for serum TSH abnormalities before pregnancy, as well as during the first and second trimesters of pregnancy. The committee could not reach agreement with regard to screening recommendations for all newly pregnant women. Two versions are therefore presented. Some members recommended screening of all pregnant women for serum TSH abnormalities by the ninth week or at the time of their first visit.
Some members recommended neither for nor against universal screening of all pregnant women for TSH abnormalities at the time of their first visit. These members strongly support aggressive case finding to identify and test high-risk women for elevated TSH concentrations by the ninth week or at the time of their first visit before and during pregnancy, and they recognize that in some situations ascertainment of the individual's risk status may not be feasible.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 79 In such cases, and where the local practice environment is appropriate, testing of all women by wk 9 of pregnancy or at the first prenatal visit is reasonable
If serum TSH is greater than 2.5 mIU/liter at the time of testing (or > 3.0 mIU/liter in the second trimester), levothyroxine therapy should be instituted.
If TSH concentration is 2.5–10 mIU/liter, a starting levothyroxine dose of 50 µg/d or more is recommended. Other thyroid preparations (such as T3) are not recommended.
Women at high risk for PPT in the postpartum months should be screened via assessment of serum TSH. These high-risk groups include: 1) women known to be TPO-Ab+; 2) women with type 1 diabetes; and 3) women with a prior history of PPT.
Screening should occur at 6–12 wk postpartum. Women with Graves' disease who enter remission during pregnancy should be screened for recurrence by TSH assay at 3–6 months.
Subclinical Hypothyroidism
Subclinical hypothyroidism can be defined as a condition with minimal or absent signs and symptoms but with mildly elevated TSH in the face of essentially normal fT4 and other values with no recent or ongoing severe illness. Estimations of frequency of subclinical hypothyroidism vary and have not been extensively studied, but generally fall within 10-15% of the elderly. Four major studies did look at prevalence rates of subclinical hypothyroidism. The NHANESIII study indicated the subclinical hypothyroidism (defined as TSH over 4.5 mIU/mL) could be found in 4.3% of an unselected U.S. population.66-68
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 80 The Colorado Thyroid Disease Prevalence Study, with a slightly higher cutoff for TSH of over 5.0 mIU/mL, found 8.5% of self-selected individuals were determined to have subclinical hypothyroidism.
In the Framingham study, 5.8% of women over 60 years and 2.3% of men had TSH levels of over 10 mIU/mL. In this population, 39% also had subnormal T4. Finally, the British Whickham study indicated that 9.3% of women and 1.2% of men had TSH levels of over 10mIU/mL.
Treatment is controversial, with many clinicians recommending watchful waiting, while others suggest watchful waiting with intervention in specific groups of patients — those with elevated TSH (4-10 mIU/mL) along with symptoms that cannot be otherwise explained and whose symptom significantly affect their quality of life.
The American Thyroid Association recently produced clinical guidelines for the treatment and management of hypothyroidism in adults. The general clinical issue and recommendations are highlighted in the table below.67
ATA Recommendations for the Treatment of Hypothyroidism in Adults
When should anti- thyroid antibodies be measured? Anti–thyroid peroxidase antibody (TPOAb) measurements should be considered when evaluating patients with subclinical hypothyroidism
TPOAb measurement should be considered in order to identify autoimmune thyroiditis when nodular thyroid disease is suspected to be due to autoimmune thyroid disease
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 81 TPOAb measurement should be considered when evaluating patients with recurrent miscarriage, with or without infertility.
Measurement of TSHRAbs using a sensitive assay should be considered in hypothyroid pregnant patients with a history of Graves’ disease who were treated with radioactive iodine or thyroidectomy prior to pregnancy.
This should be initially done either at 20–26 weeks of gestation or during the first trimester and if they are elevated again at 20–26 weeks of gestation.
What is the role of clinical scoring systems in the diagnosis of patients with hypothyroidism? Clinical scoring systems should not be used to diagnose hypothyroidism.
What is the role of diagnostic tests apart from serum thyroid hormone levels and TSH in the evaluation of patients with hypothyroidism? Tests such as clinical assessment of reflex relaxation time, cholesterol, and muscle enzymes should not be used to diagnose hypothyroidism
What are the preferred thyroid hormone measurements in addition to TSH in the assessment of patients with hypothyroidism? Apart from pregnancy, assessment of serum free T4 should be done instead of total T4 in the evaluation of hypothyroidism.
An assessment of serum free T4 includes a free T4 index or free T4 estimate and direct immunoassay of free T4 without physical separation using anti- T4 antibody.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 82 Assessment of serum free T4, in addition to TSH, should be considered when monitoring L- thyroxine therapy.
In pregnancy, the measurement of total T4 or a free T4 index, in addition to TSH, should be done to assess thyroid status. Because of the wide variation in the results of different free T4 assays, direct immunoassay measurement of free T4 should only be employed when method-specific and trimester-specific reference ranges for serum free T4 are available.
Serum total T3 or assessment of serum free T3 should not be done to diagnose hypothyroidism.
TSH measurements in hospitalized patients should be done only if there is an index of suspicion for thyroid dysfunction.
In patients with central hypothyroidism, assessment of free T4 or free T4 index, not TSH, should be done to diagnose and guide treatment of hypothyroidism.
When should TSH levels be measured in patients being treated for hypothyroidism? Patients being treated for established hypothyroidism should have serum TSH measurements done at 4–8 weeks after initiating treatment or after a change in dose.
Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise.
What should be considered the upper limit of the normal range of TSH values? The reference range of a given laboratory should determine the upper limit of normal for a third generation TSH assay. The normal TSH reference range changes with age. If an age-based upper limit of normal for a third generation TSH assay is not available in an iodine sufficient area, an upper limit of normal of 4.12 should be considered.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 83 In pregnancy, the upper limit of the normal range should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges for TSH are not available in the laboratory, the following upper normal reference ranges are recommended: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; third trimester, 3.5 mIU/L.
Which patients with TSH levels above a given laboratory’s reference range should be considered for treatment with L- thyroxine? Patients whose serum TSH levels exceed 10 mIU/L are at increased risk for heart failure and cardiovascular mortality, and should be considered for treatment with L-thyroxine.
Treatment based on individual factors for patients with TSH levels between the upper limit of a given laboratory’s reference range and 10 mIU/L should be considered particularly if patients have symptoms suggestive of hypothyroidism, positive TPOAb or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases.
In patients with hypothyroidism being treated with L- thyroxine, what should the target TSH ranges be? In patients with hypothyroidism who are not pregnant, the target range should be the normal range of a third generation TSH assay. If an upper limit of normal for a third generation TSH assay is not available, in iodine-sufficient areas an upper limit of normal of 4.12 mIU/L should be considered and if a lower limit of normal is not available, 0.45 mIU/L should be considered.
In patients with hypothyroidism being treated with L- thyroxine who are pregnant, what should the target TSH ranges be?
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 84 In patients with hypothyroidism who are pregnant, the target range for TSH should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges are not available in the laboratory, the following upper-normal reference ranges are recommended: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; and third trimester, 3.5 mIU/L.
Which patients with normal serum TSH levels should be considered for treatment with L- thyroxine? Treatment with L-thyroxine should be considered in women of childbearing age with serum TSH levels between 2.5 mIU/L and the upper limit of normal for a given laboratory’s reference range if they are in the first trimester of pregnancy or planning a pregnancy including assisted reproduction in the immediate future.
Treatment with L-thyroxine should be considered in women in the second trimester of pregnancy with serum TSH levels between 3.0 mIU/L and the upper limit of normal for a given laboratory’s reference range, and in women in the third trimester of pregnancy with serum TSH levels between 3.5 mIU/L and the upper limit of normal for a given laboratory’s reference range.
Treatment with L-thyroxine should be considered in women of childbearing age with normal serum TSH levels when they are pregnant or planning a pregnancy, including assisted reproduction in the immediate future, if they have or have had positive levels of serum TPOAb, particularly when there is a history of miscarriage or past history of hypothyroidism.
Women with positive levels of serum TPOAb or with a TSH greater than 2.5 mIU/L who are not being treated with L-thyroxine should be monitored every 4 weeks in the first 20 weeks of pregnancy for the development of hypothyroidism.
For patients who are pregnant, or planning pregnancy, or with other characteristics, should be screened for hypothyroidism? nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 85 Universal screening is not recommended for patients who are pregnant or are planning pregnancy, including assisted reproduction.
‘‘Aggressive case finding,’’ rather than universal screening, should be considered for patients who are planning pregnancy.
Screening for hypothyroidism should be considered in patients over age 60.
“Aggressive case finding’’ should be considered in those at increased risk for hypothyroidism.
How should patients with hypothyroidism be treated and monitored? Patients with hypothyroidism should be treated with L-thyroxine monotherapy.
The evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism.
L-thyroxine and L-triiodothyronine combinations should not be administered to pregnant women or those planning pregnancy.
There is no evidence to support using desiccated thyroid hormone in preference to L-thyroxine monotherapy in the treatment of hypothyroidism and therefore desiccated thyroid hormone should not be used for the treatment of hypothyroidism.
3,5,3’-triiodothyroacetic acid (TRIAC; tiratricol) should not be used to treat primary and central hypothyroidism due to suggestions of harm in the literature.
Patients resuming L-thyroxine therapy after interruption (less than 6 weeks) and without an intercurrent cardiac event or marked weight loss may resume their previously employed full replacement doses.
When initiating therapy in young healthy adults with overt hypothyroidism, beginning treatment with full replacement doses should be considered.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 86 When initiating therapy in patients older than 50– 60 years with overt hypothyroidism, without evidence of coronary heart disease, an L-thyroxine dose of 50 lg daily should be considered.
In patients with subclinical hypothyroidism, initial L-thyroxine dosing is generally lower than what is required in the treatment of overt hypothyroidism.
A daily dose of 25–75 lg should be considered, depending on the degree of TSH elevation. Further adjustments should be guided by clinical response and follow-up laboratory determinations including TSH values.
Treatment with glucocorticoids in patients with combined adrenal insufficiency and hypothyroidism should precede treatment with L- thyroxine.
L-thyroxine should be taken with water consistently 30–60 minutes before breakfast or at bedtime 4 hours after the last meal. It should be stored properly per product insert and not taken with substances or medications that interfere with its absorption.
In patients with central hypothyroidism, assessments of serum free T4 should guide therapy and targeted to exceed the mid-normal range value for the assay being used.
In patients with hypothyroidism being treated with L-thyroxine who are pregnant, serum TSH should be promptly measured after conception and L-thyroxine dosage adjusted, with a goal TSH of less than 2.5 mIU/L during the first trimester.
In patients with hypothyroidism being treated with L-thyroxine who are pregnant, the goal TSH during the second trimester should be less than 3 mIU/L and during the third trimester should be less than 3.5 mIU/L.
Maternal serum TSH (and total T4) should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation and L-thyroxine dosages adjusted as indicated.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 87 In patients receiving L-thyroxine treatment for hypothyroidism, serum TSH should be remeasured within 4–8 weeks of initiation of treatment with drugs that decrease the bioavailability or alter the metabolic disposition of the L-thyroxine dose.
Apart from pregnant patients being treated with L-thyroxine for hypothyroidism, the evidence does not support targeting specific TSH values within the normal reference range.
When should endocrinologists be involved in the care of patients with hypothyroidism? Physicians who are not endocrinologists, but who are familiar with the diagnosis and treatment of hypothyroidism should be able to care for most patients with primary hypothyroidism.
However, patients with hypothyroidism who fall into the following categories should be seen in consultation with an endocrinologist.
These categories are (i) children and infants, (ii) patients in whom it is difficult to render and maintain a euthyroid state, (iii) pregnancy, (iv) women planning conception, (v) cardiac disease, (vi) presence of goiter, nodule, or other structural changes in the thyroid gland, (vii) presence of other endocrine disease such as adrenal and pituitary disorders, (viii) unusual constellation of thyroid function test results, and (ix) unusual causes of hypothyroidism such as those induced by agents that interfere with absorption of L- thyroxine, impact thyroid gland hormone production or secretion, affect the hypothalamic– pituitary–thyroid axis (directly or indirectly), increase clearance, or peripherally impact metabolism.
Which patients should not be treated with thyroid hormone? Thyroid hormones should not be used to treat symptoms suggestive of hypothyroidism without biochemical confirmation of the diagnosis.
Thyroid hormones should not be used to treat obesity in euthyroid patients.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 88 There is insufficient evidence to support using thyroid hormones to treat depression in euthyroid patients.
What is the role of Iodine supplementation, including kelp or other iodine iodine containing functional foods, should not be supplementation, used in the management of hypothyroidism in dietary supplements, iodine-sufficient areas. and nutraceuticals in the treatment of hypothyroidism? Iodine supplementation in the form of kelp or other seaweed-based products should not be used to treat iodine deficiency in pregnant women.
Selenium should not be used to prevent or treat hypothyroidism.
Patients taking dietary supplements and nutraceuticals for hypothyroidism should be advised that commercially available thyroid- enhancing products are not a remedy for hypothyroidism and should be counseled about the potential side effects of various preparations particularly those containing iodine or sympathomimetic amines as well as those marked as ‘‘thyroid support’’ since they could be adulterated with L-thyroxine or L- triiodothyronine.
Congenital Hypothyroidism
Congenital hypothyroidism (formerly termed cretinism) is the inadequate production of thyroid hormone in newborns. It can occur because of iodine deficiency, anatomic defects, rarely by maternal anti-thyroid antibodies or an inborn error in thyroid metabolism. Signs and symptoms are not always evident at birth but can include: decreased activity, poor feeding and weight gain, small stature or poor growth, jaundice, decreased stooling or constipation, hypotonia, large anterior fontanelle, hoarse cry, coarse facial features, macroglossia,
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 89 large fontanelles, umbilical hernia, mottled, cool and dry skin, developmental delay, pallor, myxedema and goiter.79-82
Diagnosis is confirmed through lab tests indicated low levels of thyroid hormone and elevated levels of TSH (defined under the American Academy of Pediatrics as a TSH> 20mIU). Treatment is with levothyroxine with many infants achieving normal growth and development, particularly if diagnosis is made within the first 10 days and normal levels of T4 are achieved within the first 2-3 months of life. Congenital hypothyroidism should be considered an endocrine emergency according to a recent study presented at the 86th annual meeting of the American Thyroid Association. In the presentation, about 50% of children identified as having congenital hypothyroidism had a delayed diagnosis and about the same percentage were inadequately treated.79-82
Myxedema and Hypothyroidism
The term myxedema may be confusing because it is used to describe dermatologic changes seen in hypothyroidism and, in Graves’ disease, in hyperthyroidism. Myxedema coma, however, is a life-threatening condition resulting from severe hypothyroidism that is either untreated or poorly treated. It can be precipitated by trauma such as infection, heart failure, physical injury, cardiovascular disease, pregnancy or drug therapy.
Myxedema coma (in which the patient may not actually be comatose) has 25-65% mortality. There is currently no set of criteria by which to diagnose myxedema coma. Characteristics include:68
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 90 • An altered mental state • Hypothermia • A precipitating factor or traumatic event • Reduced T4/T3 levels • Increased TSH (which may be decreased or normal in secondary hypothyroidism—see below)
However, a recent study indicated that few patients diagnosed with myxedema coma presented with all the features. The authors recommended the following screening tool based on a review of the literature:68
Proposed Classification for Myxedema coma
Criterion Score Total Scores are added, resulting in 3 Glasgow Coma categories: Most likely, likely and unlikely for Scale Myxedema coma
0-10 4 Total Category Recommendation 11-13 3 Score
14 2 8-10 Most Treatment for 15 0 Likely myxedema coma: TSH airway management, cardiac monitoring, thyroid hormone replacement, glucocorticoids, supportive measures
> 30mU/L 2 5-7 Likely Treat if no other causes 15-30mU/L 1 can be found Low fT4 (< 1 0.6ng/dL) Hypothermia 1 <5 Unlikely Consider other possible o (<95 F) 1 causes. i.e., Bradycardia hypothermia, (<60bpm) 1 hypoventilation Precipitating syndromes, septic event/trauma shock
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 91 Thyroxine-binding Globulin Deficiency
Thyroxine-binding globulin deficiency can be recognized by low to normal total T4 levels along with a normal TSH and with no clinical signs or symptoms of any thyroid disorder. The condition is considered non-harmful.3,70-71
Thyroxine circulates by reversibly with high avidity but low capacity primarily to thyroxine-binding globulin (TBG). Minor amounts of thyroxine may also be bound by prealbumin (transthyretin) and albumin. TBG may be low due to gene defects — the gene for TBG is found on the X-chromosome (Xq22) and is a member of the serine protease inhibitor superfamily — TBG does not, however, have protease activity.
TBG deficiency can also be acquired due to hyperthyroidism, kidney disease such as nephrotic syndrome or chronic renal failure, chronic liver disease, Cushing Syndrome, severe systemic illness or it may be drug-induced.
Disorders Associated with Autoimmune Hypothyroidism
While it is not yet clear why, an autoimmune disease places patients at a higher risk for a second or more autoimmune disease including distinct genetic syndromes comprising multiple autoimmune endocrinopathies (MAE). There are three types of MAE known, also known as polyglandular autoimmune (PGA) syndromes and autoimmune polyendocrine syndromes (APS). These are multiple endocrine deficiencies (insufficiencies).3,70-71
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 92 Type I MAE is also known as autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) or as Whitaker syndrome and was first described in the 1940s. Type I MAE is characterized by the presence of inflammatory infiltrates and three main types of autoantibodies receptor molecules, hormones and cytokines, particularly IFN-Ω and IFN-α. There does not appear to be an association with HLA. Type I MAE is associated with hypoparathyroidism, Addison’s disease and mucocutaneous candidiasis.
Autoimmune thyroiditis is found in approximately 10-15% of cases of Type I MAE. In addition, Type I MAE is associated with increased risk of Type I diabetes, primary hypogonadism, autoimmune hepatitis, pernicious anemia and ovarian failure. The mucocandidiasis occurs first, usually in patients under the age of 5. This is followed within 5 years by hypoparathyroidism. The last to appear is Addison’s disease before the age of 15. Type I MAE is rare in the US but found more frequently in Europe in populations of Finns, Sardinians, and Iranian Jews.
Other cases have been described in populations of northern Italy and Britain, Norway and Germany. Most cases appear to be transmitted as an autosomal recessive trait with no gender preferences. Type II MAE (also known as Schmidt’s Syndrome) is the most common of the multiple autoimmune endocrinopathies. It occurs with Addison’s disease and autoimmune thyroid disease (usually Hashimoto’s thyroiditis) and/or Type I diabetes.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 93 Myasthenia gravis, celiac disease and hypogonadism are also commonly found in these patients. Type II MAE generally occurs in adulthood during the 3rd and 4th decades. Frequency is approximated 0.0014-0.0020%. Type II MAE appears to be triggered by an environmental factor. The disorder is 3-4 times more common in women than men. Symptoms depend on which endocrinopathy is the first to appear.
Secondary and Tertiary Hypothyroidism
Secondary (central) hypothyroidism is extremely rare — even rarer is a specific deficiency of TSH as it is more common to find multiple pituitary hormone deficiencies, as for example, a result of a sellar meningioma or primary empty sella syndrome.3,72,73 The TSH and TRH stimulation tests are used to distinguish primary, secondary and tertiary (hypothalamic) hypothyroidism.
In primary hypothyroidism, exogenous TSH will not increase the production of thyroid hormone. In secondary hypothyroidism, TSH will induce an increase in the production of thyroid hormone. In tertiary hypothyroidism where the hypothalamus is not releasing TRH, patients will show a delayed and an exaggerated response to TRH stimulation. Prolactin levels are used as a control for the thyroid hormone response.
Summary
The thyroid gland is critical to health and wellness and while the basic functions have been well understood for decades, there is still much to understand. One of the greatest achievements in preventive medicine
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 94 has been the significant decline in congenital hypothyroidism, yet more can be done. Understanding the functions, biosynthesis and metabolism of thyroid hormones has increased dramatically, yet there is still much that is not known.
Preventive measures are in their infancy, yet it is clear that maintaining overall health, eating a nutritious diet, rational supplementation and screening for thyroid diseases all play an important role in either prevention or early detection. Considering the use of combination T4/T3 may be the first step in personalized medicine as can adjusting the hormone replacement dose based on the personal response of the individual patient rather than basing the dosage solely on biochemical parameters. Clinicians informed about the varied diagnostic tests and learning about the varied types of thyroid diseases and treatments will be better able to identify the needed course of care earlier on when an issue of thyroid disease and metabolic disturbances become evident.
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nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 95 1. The thyroid gland has been called the “Master Gland” because it
a. produces parathormone. b. is a member of the hormone-responsive nuclear transcription factors superfamily. c. is active in virtually every cell of the body. d. plays a vital role in controlling calcium and phosphate levels.
2. True or False: Embryologically, the developing thyroid forms the floor of the pharynx, around the base of the tongue, descending the neck to its adult location.
a. True b. False
3. The thyroid is supplied by the superior and inferior thyroid arteries, and on rare occasions, there is an additional artery known as the
a. innominate artery. b. subclavian artery. c. deep artery. d. thyroidea ima.
4. Thyroid hormone is
a. required for normal human growth and development. b. required for the regulation of metabolism in infants and adolescents. c. mostly active during the neonatal and pre-adolescent periods. d. primarily used for the production of iodine.
5. Thyroid hormone ______begins with the organification of iodide to iodine and then condensed onto tyrosine residues found on thyroglobulin protein.
a. absorption b. secretion c. synthesis d. conversion
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 96 6. The main function of the thyroid gland is to produce the thyroid hormones, known as
a. thyroxine (T4) and triiodothyrodine (T3). b. prohormones. c. parathyrin and polypeptide. d. deiodinase D1 and D2.
7. An important control point for thyroid hormone biosynthesis is ______by three different deiodinases.
a. feedback control b. de-iodination c. metabolism d. dysgenesis
8. True or False: The parathyroid glands are part of the thyroid gland located in the colloid-filled center of the gland.
a. True b. False
9. The deiodinase D1 is
a. critical for the control by feedback inhibition of thyroid hormone synthesis. b. significant in the pituitary. c. stimulated by selenium deficiency. d. found at high levels in the liver, kidney and in the thyroid gland.
10. The ______detects T3 levels produced by the action of the D2 deiodinase.
a. hypothalamus b. pituitary c. thymus d. thyroid
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 97 11. Which of the following is an adipocyte hormone that regulates appetite by inhibiting both food intake and increasing energy expenditure?
a. D2 deiodinase b. Pituitary hormone c. Thyrotropin d. Leptin
12. Parafollicular cells (C cells) secrete calcitonin, which has the effect of
a. producing T3 thyroid hormones. b. increasing the serum calcium levels in the body. c. decreasing the serum calcium levels in the body. d. increase sodium levels in the body.
13. Triiodothyrodine (T3) is the active hormone in the thyroid
a. and it has a longer half-life than T4. b. while T4 has a longer half-life than T3. c. and it converts to T4 in most tissue. d. that serves as a prohormone.
14. The nuclear thyroid receptor (nTR) isoforms α and the β provide the primary action of triiodothyrodine (T3) and they undergo ______modification.
a. posttranslational b. transcendental c. transcriptional d. pre-elongation
15. True or False: Resting energy expenditure is highly sensitive to changes in thyroid hormone levels and the BMR correlates with both lean body mass and with the levels of thyroid hormone.
a. True b. False
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 98 16. A thyroid hormone defect more commonly seen is a reduced T3 binding and irreversible interactions with corepressors and it may be clinically manifested by goiter and
a. elevated cholesterol. b. abnormal TSH. c. chronic constipation. d. euthyroid, with possible tachycardia.
17. Significant reductions in basal metabolic rate (BMR) can result in
a. hypercalcemia and weight loss. b. weight loss and undernutrition. c. weight gain and obesity. d. hypoxia and diabetes.
18. ______can be defined as the regulated production of heat in response to environmental changes in temperature and diet.
a. Adaptive thermogenesis b. Adaptive dysgenesis c. Posttranslational modification d. Posttranslational synthesis
19. True or False: Brown adipose tissue (BAT) is important only in neonates—and hibernating animals.
a. True b. False
20. The primary sites of action regarding cholesterol and lipid metabolism are
a. thyroid and pituitary glands. b. hypothalamus and parathyroid glands. c. the liver and brown adipose tissue (BAT). d. the pituitary gland and white adipose tissue (WAT).
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 99 21. Patients with hypothyroidism may exhibit the following clinical condition:
a. hypolipidemia. b. weight loss. c. increased risk of non-alcoholic fatty liver disease (NAFLD). d. increased hepatic lipid oxidation.
22. Simple nontoxic goiter is a non-inflammatory or non- neoplastic hypertrophy of the thyroid that
a. is often cancerous with an enlarged thyroid. b. may appear diffusely or as nodules. c. always appears as diffuse goiter. d. is synonymous with Graves’ disease.
23. Goiter is about 4 times more common
a. in women than it is in men. b. in non-pregnant women. c. in individuals under age 40, compared to those over 40. d. in adults consuming dairy products, compared to those avoiding dairy products.
24. True or False: With simple nontoxic goiter, thyroid function often remains normal except in cases of severe iodine deficiency.
a. True b. False
25. Which of the following is NOT considered a cause of goiter?
a. Iodine deficiency b. Consuming large amounts of broccoli c. Consuming dairy products d. Iodine supplements
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 100 26. Patients with hyperthyroid disease may exhibit the following clinical condition:
a. increased total cholesterol b. weight gain with an increased risk of obesity. c. increased risk of non-alcoholic fatty liver disease (NAFLD). d. increased basal metabolic rate.
27. Table salt has been iodized since the 1920s to prevent endemic goiter and
a. cretinism. b. obesity. c. hyperthyroid disease. d. hepatic lipid oxidation.
28. Graves’ disease is
a. an autoimmune disorder. b. more common in women. c. more common with increasing age. d. All of the above
29. ______is a life-threatening condition resulting from severe hypothyroidism that is either untreated or poorly treated, can be precipitated by trauma such as infection, heart failure, physical injury, cardiovascular disease, pregnancy or drug therapy.
a. Plummer’s disease b. Thyroiditis c. Diffuse goiter d. Myxedema coma
30. True or False: Surgery is overall the most successful treatment for Graves’ disease, but patients must take replacement hormone for the rest of their lives.
a. True b. False
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 101 31. When should TSH levels be measured in patients being treated for hypothyroidism?
a. 4–8 weeks after initiating treatment b. At 12-month intervals c. Before initiating treatment d. At 6-month intervals
32. Thyroid storm is a severe and often sudden form of
a. hypothyroidism. b. a myxedema coma. c. hyperthyroidism. d. non-alcoholic fatty liver disease (NAFLD).
33. Thyroid storm may be life-threatening, commonly because of
a. significantly higher than normal TSH. b. cardiovascular effects such as tachycardia, arrhythmias or cardiovascular collapse. c. inflammation of the thyroid gland. d. apoptosis and parenchymal destruction.
34. True or False: Partial thyroidectomy is most commonly recommended as partial thyroidectomy has significantly better outcomes than total thyroidectomy.
a. True b. False
35. Thyroid orbitopathy is an autoimmune inflammatory disorder that occurs in 90% of patients with
a. Diffuse goiter. b. Graves’ disease. c. Plummer’s disease. d. Thyroiditis.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 102 36. The mitochondria in BAT have very high numbers of mitochondria containing UCP-1 that when activated stimulates
a. the respiratory chain. b. the shiver response. c. tremors. d. glycolysis.
37. ______is a significant factor in thyroid orbitopathy.
a. Apoptosis b. Parenchymal destruction c. Plummer’s disease d. Oxidative stress
38. True or False: There is currently no set of criteria by which to diagnose myxedema coma.
a. True b. False
39. Approximately ___ of patients with Graves’ disease will experience some ophthalmopathy.
a. 25% b. half c. 60% d. 10%
40. ______is often first-line treatment of Graves’ disease.
a. β-adrenergic blockade b. Corticosteroid therapy c. Radioactive ablation of the thyroid d. Acetaminophen for cooling
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 103 41. Radioactive ablation is also contraindicated in patients who are suspected of having
a. toxic adenomas. b. thyroid cancer. c. toxic multinodular goiter. d. Graves’ disease.
42. True or False: Surgery is an important part of the multimodal treatment plan for patients with thyroid storm.
a. True b. False
43. In the context of testing for thyroid disease, women who are planning a pregnancy should
a. be universally screened. b. use the ‘‘aggressive case finding” approach. c. be tested for medullary thyroid cancer (MTC). d. have a genetic test performed.
44. Thyroxine-binding globulin deficiency can be recognized by low to normal total T4 levels along
a. harmful symptoms of thyroid disorder. b. with clinical signs or symptoms of thyroid disorder. c. with a normal TSH. d. multinodular goiter.
45. Congenital hypothyroidism is the inadequate production of thyroid hormone in newborns, caused
a. by iodine deficiency. b. in most cases, by maternal anti-thyroid antibodies. c. by an umbilical hernia. d. by multinodular goiter.
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 104 CORRECT ANSWERS:
1. The thyroid gland has been called the “Master Gland” because it
c. is active in virtually every cell of the body.
“The thyroid gland has been called the Master Gland because it is active in virtually every cell of the body, regulating cellular respiration, energy expenditure, overall metabolism, growth and development of cells and tissues.”
2. True or False: Embryologically, the developing thyroid forms the floor of the pharynx, around the base of the tongue, descending the neck to its adult location.
a. True
“Embryologically, the developing thyroid forms the floor of the pharynx, around the base of the tongue, descending the neck in the adult.”
3. The thyroid is supplied by the superior and inferior thyroid arteries, and on rare occasions, there is an additional artery known as the
d. thyroidea ima.
“The superior and inferior thyroid arteries supply the thyroid. Relatively rarely, there is an additional artery, the thyroidea ima that originates from the aortic arch or the innominate artery, entering the gland at the inferior border of the isthmus.”
4. Thyroid hormone is
a. required for normal human growth and development.
“The main function of the thyroid gland is to produce the thyroid hormones, thyroxine (T4) and triiodothyrodine (T3). Thyroid hormone is required for both normal growth and development as well as for the regulation of metabolism in the adult.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 105 5. Thyroid hormone ______begins with the organification of iodide to iodine and then condensed onto tyrosine residues found on thyroglobulin protein.
c. synthesis
“Thyroid hormone synthesis begins with the conversion (organification) of iodide to iodine and condensed onto tyrosine residues found on thyroglobulin.”
6. The main function of the thyroid gland is to produce the thyroid hormones, known as
a. thyroxine (T4) and triiodothyrodine (T3).
““The main function of the thyroid gland is to produce the thyroid hormones, thyroxine (T4) and triiodothyrodine (T3).”
7. An important control point for thyroid hormone biosynthesis is ______by three different deiodinases.
b. de-iodination
“De-iodination by three different deiodinases, D1, D2 and D3, found in different levels in various tissues, including the liver, is an important control point for thyroid hormone biosynthesis.”
8. True or False: The parathyroid glands are part of the thyroid gland located in the colloid-filled center of the gland.
b. False
“The parathyroid glands are 4 small glands usually located at the posterior portions of the thyroid and which produce parathyroid hormone (PTH) and play a vital role in controlling calcium and phosphate levels. The parathyroid glands share blood supply, lymphatic drainage and venous supply with the thyroid.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 106 9. The deiodinase D1 is
d. found at high levels in the liver, kidney and in the thyroid gland.
“The deiodinases are peroxidases. D1 is not significant in the pituitary, so is not believed to be critical for the control by feedback inhibition of thyroid hormone synthesis. D1 is found at high levels in the liver, kidney and in the thyroid gland itself and is expressed on the cellular membrane in these tissues.”
10. The ______detects T3 levels produced by the action of the D2 deiodinase.
a. hypothalamus
”The hypothalamus detects T3 levels produced by the action of the D2 deiodinase.”
11. Which of the following is an adipocyte hormone that regulates appetite by inhibiting both food intake and increasing energy expenditure?
d. Leptin
“Leptin is an adipocyte hormone that acts as a signal from adipose tissue to the brain, regulating appetite by inhibiting both food intake and increasing energy expenditure.…”
12. Parafollicular cells (C cells) secrete calcitonin, which has the effect of
c. decreasing the serum calcium levels in the body. “Parafollicular cells (C cells) secrete calcitonin in response to hypercalcemia, causing a decrease in serum calcium levels.”
13. Triiodothyrodine (T3) is the active hormone in the thyroid
b. while T4 has a longer half-life than T3.
“Triiodothyrodine (T3) is the active form of hormone while T4 has a longer half-life than T3. Thyroxine (T4) is converted to T3 in most tissues, thus serving as a prohormone.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 107 14. The nuclear thyroid receptor (nTR) isoforms α and the β provide the primary action of triiodothyrodine (T3) and they undergo ______modification.
a. posttranslational
“Triiodothyrodine (T3) action is primarily exerted through its nuclear thyroid receptor (nTR) isoform. There are two primary isoforms of the nTR — the α and the β isoforms. Both isoforms undergo posttranslational modification.”
15. True or False: Resting energy expenditure is highly sensitive to changes in thyroid hormone levels and the BMR correlates with both lean body mass and with the levels of thyroid hormone.
a. True
“Resting energy expenditure is highly sensitive to changes in thyroid hormone levels and the BMR correlates with both lean body mass and with the levels of thyroid hormone.”
16. A thyroid hormone defect more commonly seen is a reduced T3 binding and irreversible interactions with corepressors and it may be clinically manifested by goiter and
d. euthyroid, with possible tachycardia.
“Defect: This is more commonly seen. Reduced T3 binding and irreversible interactions with corepressors… Clinical: Goiter, enhanced metabolic rates, hyperphagia. Generally euthyroid, with possible tachycardia. Possible, short stature, impaired hearing, bone defects, ADHD.”
17. Significant reductions in basal metabolic rate (BMR) can result in
c. weight gain and obesity.
“The basal metabolic rate or BMR is the main source of energy outlay — significant reductions in BMR can result in weight gain and obesity while increases in BMR can result in weight loss and undernutrition.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 108 18. ______can be defined as the regulated production of heat in response to environmental changes in temperature and diet.
a. Adaptive thermogenesis
“Facultative or adaptive thermogenesis can be defined as the regulated production of heat in response to environmental changes in temperature and diet.”
19. True or False: Brown adipose tissue (BAT) is important only in neonates and hibernating animals.
b. False
“In humans, there is both visceral and subcutaneous BAT and until recently, was considered important only in neonates — and hibernating animals. However, it is becoming clear that in the adult, BAT thermogenesis has important functions as well, mainly to generate classical non-shiver related heat.”
20. The primary sites of action regarding cholesterol and lipid metabolism are
c. the liver and brown adipose tissue (BAT).
“The primary sites of action regarding cholesterol and lipid metabolism are the liver and BAT.”
21. Patients with hypothyroidism may exhibit the following clinical condition:
c. increased risk of non-alcoholic fatty liver disease (NAFLD).
“Clinically, these effects can be seen in patients with hypothyroidism: … Increased risk of non-alcoholic fatty liver disease (NAFLD). In patients with hyperthyroid disease: Increased basal metabolic rate; Weight loss; Decreased total cholesterol; Decreased triglyceride levels; Increased hepatic lipid oxidation; Hyperglycemia and worsening glycemic control in Type 2 diabetes patients.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 109 22. Simple nontoxic goiter is a non-inflammatory or non- neoplastic hypertrophy of the thyroid that
b. may appear diffusely or as nodules.
“Simple nontoxic goiter is a non-inflammatory or non- neoplastic hypertrophy of the thyroid that may appear diffusely or as nodules.”
23. Goiter is about 4 times more common
a. in women than it is in men.
“Goiter is about 4 times more common in women than in men, increasing risk is associated with age. Nodules are also less frequent in men, but have a greater tendency to be malignant, when found.”
24. True or False: With simple nontoxic goiter, thyroid function often remains normal except in cases of severe iodine deficiency.
a. True
“Thyroid function often remains normal except in cases of severe iodine deficiency.”
25. Which of the following is NOT considered a cause of goiter?
c. Consuming dairy products
“Table salt has been iodized since the 1920s to prevent cretinism and endemic goiter…. The use of table salt has been discouraged in the U.S., and around the world to control hypertension. It is believed that other foods contain sufficient iodine. However, in some populations such as in children with food restrictions or adults avoiding dairy productsi intake of iodine may not be adequate.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 110 26. Patients with hyperthyroid disease may exhibit the following clinical condition:
d. increased basal metabolic rate.
“In patients with hyperthyroid disease: Increased basal metabolic rate; Weight loss; Decreased total cholesterol; Decreased triglyceride levels; Increased hepatic lipid oxidation; Hyperglycemia and worsening glycemic control in Type 2 diabetes patients.”
27. Table salt has been iodized since the 1920s to prevent endemic goiter and
a. cretinism.
“Table salt has been iodized since the 1920s to prevent cretinism and endemic goiter.”
28. Graves’ disease is
a. an autoimmune disorder. b. more common in women. c. more common with increasing age. d. All of the above [correct answer]
“Graves’ disease is an autoimmune disorder. As with many if not most autoimmune disorders, it is more common in women and more common with increasing age.”
29. ______is a life-threatening condition resulting from severe hypothyroidism that is either untreated or poorly treated, can be precipitated by trauma such as infection, heart failure, physical injury, cardiovascular disease, pregnancy or drug therapy.
d. Myxedema coma
“The term myxedema may be confusing because it is used to describe dermatologic changes seen in hypothyroidism and, in Graves’ disease, in hyperthyroidism. Myxedema coma, however, is a life-threatening condition resulting from severe hypothyroidism that is either untreated or poorly treated. It can be precipitated by trauma such as infection, heart failure,
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 111 physical injury, cardiovascular disease, pregnancy or drug therapy.”
30. True or False: Surgery is overall the most successful treatment for Graves’ disease, but patients must take replacement hormone for the rest of their lives.
a. True
“Surgery is overall the most successful treatment for Graves’ disease, but patients must take replacement hormone for the rest of their lives.”
31. When should TSH levels be measured in patients being treated for hypothyroidism?
a. 4–8 weeks after initiating treatment
“Patients being treated for established hypothyroidism should have serum TSH measurements done at 4–8 weeks after initiating treatment or after a change in dose. Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12- month intervals, or more frequently if the clinical situation dictates otherwise.”
32. Thyroid storm is a severe and often sudden form of
c. hyperthyroidism.
“Thyroid storm is a severe and often sudden form of hyperthyroidism – it may result from untreated or inadequately treated Graves’ disease, multinodular goiter, solitary nodules or ingestion of excess thyroid hormone, either as levothyroxine or as a glandular preparation.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 112 33. Thyroid storm may be life-threatening, commonly because of
b. cardiovascular effects such as tachycardia, arrhythmias or cardiovascular collapse.
“Thyroid storm may be life-threatening, commonly because of cardiovascular effects such as tachycardia, arrhythmias or cardiovascular collapse.”
34. True or False: Partial thyroidectomy is most commonly recommended as partial thyroidectomy has significantly better outcomes than total thyroidectomy.
b. False
“Total thyroidectomy is most commonly recommended as total thyroidectomy has significantly better outcomes than partial thyroidectomy.”
35. Thyroid orbitopathy is an autoimmune inflammatory disorder that occurs in 90% of patients with
b. Graves’ disease.
“Thyroid orbitopathy is an autoimmune inflammatory disorder that occurs (90%) in patients with Graves’ disease.”
36. The mitochondria in BAT have very high numbers of mitochondria containing UCP-1 that when activated stimulates
a. the respiratory chain.
“The mitochondria in BAT have very high numbers of mitochondria containing UCP-1 that when activated stimulates the respiratory chain.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 113 37. ______is a significant factor in thyroid orbitopathy.
d. Oxidative stress
“Oxidative stress is also a significant factor in thyroid orbitopathy.”
38. True or False: There is currently no set of criteria by which to diagnose myxedema coma.
a. True
“There is currently no set of criteria by which to diagnose myxedema coma.”
39. Approximately ___ of patients with Graves’ disease will experience some ophthalmopathy.
a. 25%
“Approximately 25% of patients with Graves’ disease will experience some ophthalmopathy.”
40. ______is often first-line treatment of Graves’ disease.
c. Radioactive ablation of the thyroid
“Radioactive ablation of the thyroid is a safe, effective and often first-line treatment of Graves’ disease, toxic adenomas and toxic multinodular goiter.”
41. Radioactive ablation is also contraindicated in patients who are suspected of having
b. thyroid cancer.
“Radioactive ablation of the thyroid is a safe, effective and often first-line treatment of Graves’ disease, toxic adenomas and toxic multinodular goiter. Contraindications include pregnancy, lactation, intention to get pregnant and the inability to comply with safety recommendations. Radioactive ablation is also contraindicated in patients who are suspected of having
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 114 thyroid cancer. The treatment may worsen or cause orbitopathy, but this is controversial.”
42. True or False: Surgery is an important part of the multimodal treatment plan for patients with thyroid storm.
b. False
“A multimodality treatment approach to patients with thyroid storm should be used. Multimodality treatment includes β- adrenergic blockade, ATD therapy, inorganic iodide, corticosteroid therapy, cooling with acetaminophen and cooling blankets, volume resuscitation, nutritional support, and respiratory care and monitoring in an intensive care unit, as appropriate for an individual patient.”
43. In the context of testing for thyroid disease, women who are planning a pregnancy should
b. use the ‘‘aggressive case finding” approach.
“Screening for thyroid Universal screening is not recommended for patients who are pregnant or are planning pregnancy, including assisted reproduction. ‘‘Aggressive case finding,’ rather than universal screening, should be considered for patients who are planning pregnancy. Screening for hypothyroidism should be considered in patients over age 60. ‘Aggressive case finding’ should be considered in those at increased risk for hypothyroidism.”
44. Thyroxine-binding globulin deficiency can be recognized by low to normal total T4 levels along
c. with a normal TSH.
“Thyroxine-binding globulin deficiency can be recognized by low to normal total T4 levels along with a normal TSH and with no clinical signs or symptoms of any thyroid disorder. The condition is considered non-harmful.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 115 45. Congenital hypothyroidism is the inadequate production of thyroid hormone in newborns, caused
a. by iodine deficiency.
“Congenital hypothyroidism (formerly termed cretinism) is the inadequate production of thyroid hormone in newborns. It can occur because of iodine deficiency, anatomic defects, rarely by maternal anti-thyroid antibodies or an inborn error in thyroid metabolism. Signs and symptoms are not always evident at birth but can include: decreased activity, poor feeding and weight gain, small stature or poor growth, jaundice, decreased stooling or constipation, hypotonia, large anterior fontanelle, hoarse cry, coarse facial features, macroglossia, large fontanelles, umbilical hernia, mottled, cool and dry skin, developmental delay, pallor, myxedema and goiter.”
nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 116 References Section
The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.
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nursece4less.com nursece4lesscom nursece4less.com nursece4less.com 117 crossover study. J Clin Endocrinol Metab. 2013 May;98(5):1982- 90. 12. Wartofsky L. (2013). Combination L-T3 and L-T4 therapy for hypothyroidism. Curr Opin Endocrinol Diabetes Obes. 2013 Oct;20(5):460-6. 13. Visser WE, Friesema EC, Visser TJ. (2011). Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol. 2011 Jan; 25(1):1-14. 14. Verge CF, et al. (2012). Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab. 2012 Dec; 97(12):4515-23. 15. Drigo, Rafael Arrojo, et al. (2013). Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochimica et Biophysica Acta (BBA)-General Subjects 1830.7 (2013): 3956-3964. 16. Jansen, Peter LM, and Frank G. Schaap. (2015). Pituitary TSH controls bile salt synthesis. Journal of hepatology 62.5 (2015): 1005-1007. 17. Song, Yongfeng, et al. (2015). Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF- 4α/CYP7A1 axis. Journal of hepatology 62.5 (2015): 1171-1179. 18. Pierre, Joseph F., et al. (2016). Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice. American Journal of Physiology-Gastrointestinal and Liver Physiology 311.2 (2016): G286-G304. 19. Dentice, Monica, et al. (2013). The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation. Biochimica et Biophysica Acta (BBA)-General Subjects 1830.7 (2013): 3937-3945. 20. Annerbo, Sylvia, and Johan Lökk. (2013). A clinical review of the association of thyroid stimulating hormone and cognitive impairment. ISRN endocrinology. 21. Le, Trang N., Francesco S. Celi, and Edmond P. Wickham. (2014). SAT-0153: Thyroid Stimulating Hormone Levels Are Associated with Cardiometabolic Risk Factors in Euthyroid Adolescents. 22. Kluge, Michael, et al. (2013). Ghrelin suppresses nocturnal secretion of luteinizing hormone (LH) and thyroid stimulating hormone (TSH) in patients with major depression. Journal of psychiatric research 47.9 (2013): 1236-1239. 23. Roelfsema, Ferdinand, and Johannes D. Veldhuis (2013). Thyrotropin secretion patterns in health and disease. Endocrine reviews 34.5 (2013): 619-657.
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