The term “endocrine” was coined by Starling to contrast the actions of hormones secreted internally (hence endocrine) from those substances that are secreted onto external surfaces (exocrine, e.g., sweat or saliva).1 The term “hormone” is derived from the Greek hormân, “to set in motion, stimulate,” a derivative of hormḗ meaning “impetus” or “impulse.” This describes well the dynamic actions of hormones and their ability to induce cellular responses and their regulation of the major physiologic processes of growth, reproduction, metabolism, and the maintenance of homeostasis (e.g., glucose and calcium). The release and actions of hormones are controlled by means of predominantly negative “feedback loops,” as exemplified by the hypothalamus-pituitary-adrenal (HPA) axis (see Figure 22-1).
- Diabetes mellitus.
- Thyroid disorders: hypothyroidism, hyperthyroidism, goiter.
- Menstrual disorders and/or hirsutism, usually due to polycystic ovarian syndrome (PCOS).
- Hypogonadism (in association with erectile dysfunction).
- Osteoporosis and metabolic bone disease.
- Subfertility (delay or difficulty in conceiving).
- Disorders of growth or puberty.
Endocrine disorders (the “endocrinopathies”) are common, and are increasing in frequency. They encompass some of most prevalent of the chronic diseases, including diabetes mellitus3 and increasingly obesity.4,5 Endocrine diseases affect the entire system of endocrine glands, the hormones, synthesized and secreted by these glands, and the target organs that are susceptible to the effects of these hormones. Endocrine disorders are complex and their diagnosis is complicated by four interacting components:6,7
- The hypothalamus (Figure 22-3) contains most of the “sensing” organs and tissues, and is the part of the brain that monitors crucial determinants of homeostasis; that is, water, electrolyte and osmotic balance, metabolism, the fed and fasted state, and the stress response. Additionally, over the course of a lifetime, conception, pregnancy, growth, development, sexual maturation, and senescence are also regulated by the hypothalamus. Various “biologic clocks” exist that are linked into and exert control over the 24-hour circadian rhythm, the 28-day menstrual cycle, and the longer temporal cycles associated with growth, development, and sexual maturation, including as an example the timing of the onset of puberty. The hypothalamus most significantly is the link between the endocrine and nervous systems. The hypothalamus produces releasing and inhibiting factors that control the hormones of the pituitary, as well as other hormones throughout the body, via the pituitary—the second major component of the endocrine system.
- The pituitary is a small pea-sized endocrine gland that regulates all of the major endocrine glands located throughout the body. It does this by the release of trophic hormones that stimulate the growth of the other endocrine glands, or by the release of hormones that stimulate the endocrine glands to release the hormones synthesized within that gland itself. Except for oxytocin, all the hormones released by the major endocrine glands are under negative feedback control (meaning that the presence of circulating hormone downregulates further production of that hormone).
- Major endocrine glands includes the bilobed thyroid, the four parathyroid glands, the paired adrenal glands (sited atop the kidneys), the endocrine pancreas, and the gonads, testes, and ovaries). These glands synthesize and release the hormones that have the major effects on metabolism, water and electrolyte balance, glucose and calcium homeostasis, the stress response, as well as conception, growth, and development.
- Hormones are a class of signaling molecules, produced by endocrine glands that are generally transported by the circulatory system to target organs to regulate physiology and behavior (Box 22-1). Hormone production and function is complex, and includes biosynthesis and storage of a particular hormone in a particular gland, secretion (on receipt of the correct signal—often another hormone—by the gland), transport to the target cells/tissues, and recognition of the hormone by the target cell, via hormonal binding to a cell surface or intracellular receptor, resulting in transmission and amplification of the hormonal signal. The last stage is breakdown of the hormone.
In essence, it is either deficiencies or excess of these hormones of the major endocrine glands that result in significant disease states.8 Malignancies of the endocrine glands are rare. There are a number of key aspects of endocrine disease about which dentists need to know:
- Pathophysiology and management of the various endocrine diseases. This ensures the safe delivery of dental care, the ability to possibly prevent disease progression or worsening morbidity, and to avoid serious potentially life-threatening complications of the patient’s disease.
- Complications that can arise from undiagnosed or poorly managed endocrine disease. This includes knowledge of potentially life-threatening medical emergencies and the subsequent need to alter treatment planning (including awareness of potential drug interactions) or implement additional measures and resources so as to prevent the likelihood of such emergencies from occurring.
- Manifestations of the disease in/on the stomatognathic system. Recognition of the stomatognathic manifestations of endocrine disease is needed for the diagnosis of such conditions and also to identify those patients with poorly controlled or undiagnosed disease.
There are five major classes of hormones (classified by their molecular weight and size and their precursor substrates; see Table 22-1),9 and their function can be broadly classified into three areas of physiologic activity: growth and differentiation; maintenance of homeostasis; and reproduction.
Hormone release is the end-product of a long cascade of intracellular events. Polypeptide hormones, for example, require neural or endocrine stimulation of the cell to initiate transcription from DNA to a specific messenger RNA (mRNA) and subsequent translation into a polypeptide product. This product is often a precursor molecule or “prohormone” that is biologically inactive, and is then further processed and packaged into granules, in the Golgi apparatus. These granules are transported to the plasma membrane before release, which is itself regulated by a complex combination of intracellular regulators.
Hormone secretion can be (1) continuous, as seen with the thyroid hormones, with a half-life of 7–10 days for T4 and 6–10 hours for T3, and with little variation in levels over the day, month, and year; or (2) pulsatile, which is the normal pattern for the gonadotrophins—that is, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—with a large amount of hormone released in a pulse every 1–2 hours, depending on the phase of the menstrual cycle. Growth hormone (GH) is also secreted in a pulsatile fashion, but with undetectable levels between pulses.
There are major factors that control the release of various hormones over days, for example the circadian rhythm, weeks, and months, and in the case of the growth and sex hormones over years.10 The menstrual cycle is an example of a longer and more complex (28-day) biologic rhythm.11 Other regulatory factors include physiologic “stress” and acute illness, which produce rapid increases in adrenocorticotropic hormone (ACTH) and cortisol, GH, prolactin, epinephrine, and norepinephrine. Over the course of the sleep–wake cycle the secretion of GH and prolactin is increased, especially during the rapid eye movement (REM) phase of sleep. Food intake results in many hormones being released to regulate the body’s control of energy intake and expenditure, and these are therefore profoundly influenced by feeding and fasting. Secretion of insulin is increased, while testosterone and GH are decreased after ingestion of food, and secretion of a number of hormones is altered during prolonged food deprivation.
Most hormones are secreted directly into the circulation from the endocrine glands. In contrast to this, the hormones released from the hypothalamus are excreted at much higher concentrations and are confined to the pituitary portal system. Many hormones are bound to proteins within the circulation—it is important to note that only the free (unbound) hormone is available to the tissues and is biologically active. This binding to the plasma proteins serves to buffer against very rapid changes in plasma levels of the hormone and additionally plays a role in regulation of hormonal activity. Many of the tests of endocrine function measure the total rather than the free hormone, giving rise to difficulties in interpretation when the binding proteins are altered in disease states or by drugs. Binding proteins comprise both specific, high-affinity proteins of limited capacity, such as thyroxine-binding globulin (TBG), cortisol-binding globulin (CBG), sex-hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-binding proteins (e.g., IGF-BP3); and other, less specific,, low-affinity protein carriers, such as prealbumin and albumin.
Table 22‐1 Major classes of hormones.
|2||Amino acid derivatives||Catecholamines:
* Released by the “classic” endocrine glands: pituitary, thyroid, parathyroid, pancreatic islet cells, adrenals, and gonads.
† Synthesized from cholesterol-based precursors.
# An exception is thyroid hormones, which act via cytoplasmic receptors.
These are broadly divided as follows:
- Cell surface or membrane receptors: typically, transmembrane receptors that contain hydrophobic sections spanning the lipid-rich plasma membrane and trigger internal cellular messengers.
- Nuclear receptors: these typically bind hormones and translocate them to the nucleus, where they bind hormone-response elements of nuclear DNA via characteristic amino acid sequences (so-called zinc fingers). Abnormalities of hormone receptors can be a rare cause of endocrine disease. The activation of intracellular kinases, phosphorylation, release of intracellular calcium and other “second messenger” pathways, and the direct stimulation of DNA transcription result in some or all of the following:
- Stimulation or release of preformed hormone from storage granules.
- Stimulation or synthesis of hormone and other cellular components.
- Opening or closing of ion (e.g., calcium channels) or water channels (e.g., aquaporin water channels).
- Activation or deactivation of other DNA-binding proteins, leading to stimulation or inhibition of DNA transcription.
The sensitivity and/or number of receptors for a hormone can be decreased after prolonged exposure to a high hormone concentration (downregulation). Equally, the reverse is true when stimulation is absent or minimal: the receptors are increased in number and/or sensitivity (upregulation).
Primary and Secondary Endocrine Gland Failure
Primary endocrine gland failure occurs when there is dysfunction or removal of the specific end-organ endocrine gland—the thyroid, parathyroid, endocrine pancreas, adrenal glands, or gonads (ovaries and testes). Causes of primary endocrine gland dysfunction or destruction include autoimmune disease, atrophic change, inflammatory or neoplastic infiltration, or complications related to treatment, such as radiotherapy or surgical removal of the gland.
Secondary disorders of the same endocrine axes are caused by diseases of the pituitary gland. The key to diagnosing the site of the disease, either primary or secondary, requires understanding of the negative feedback control system so as to correctly interpret blood tests used in the investigation of endocrine diseases. Primary hormone deficiency due to a disease process of the endocrine end-organ (e.g., thyroid, adrenal, or gonad) will lead to a loss of negative feedback and subsequent elevation in the corresponding anterior pituitary trophic (stimulating) hormone. In secondary gland failure, there will be low or “inappropriately normal” levels of the pituitary trophic hormone in the presence of low end-organ hormone levels; for example, if a patient has low circulating free T3 (fT3) and T4 levels in the context of low thyroid-stimulating hormone (TSH) levels, then the site of the disease is likely to be in or of the pituitary gland.
Investigations of Endocrine Function 12
See Table 22-2.
Basal Blood Level
Basal hormone levels are especially useful for systems with long half-lives (e.g., T4 and T3, insulin-like growth factor-1 [IGF-1], androstenedione, SHBG) that vary little over the short term and so samples taken at any specific time are satisfactory.
For those hormones that fluctuate in accordance with the circadian rhythm (e.g., testosterone and cortisol), measurements must be taken at an appropriate time of day, which is 11:00 am for testosterone, while the patient is fasted, and between 8:00 and 11:00 am for cortisol, also with the patient fasted. LH/FSH, estrogen, and progesterone vary with time of menstrual cycle, and renin/aldosterone may vary with sodium intake, posture, and age.
Measurement of stress-related hormones (e.g., catecholamines, prolactin, GH, and cortisol) can be problematic, as the patient may be stressed by their attendance at the hospital or by the venipuncture itself, leading to falsely high levels. Sampling via an indwelling cannula at some time after the initial venipuncture overcomes this problem.
This is done over the course of 24 hours and has the advantage of providing an “integrated mean” of a day’s secretion of select hormones, namely the catecholamines and cortisol. However, in practice these results are often complicated by poor patient compliance and incomplete/wrongly timed collection. Age, sex, and weight of the patient are also confounding factors.
Stimulation and Suppression Tests
In general, stimulation tests are used to confirm suspected deficiency, and suppression tests to confirm suspected excessive levels of hormone secretion. These tests are valuable in instances when the secretory capacity of a gland is damaged, such that despite maximal stimulation by the trophic hormone, there is diminished output of primary hormone. For example, with the short ACTH stimulation test for adrenal reserve, the healthy subject shows a normal response, while the subject with primary hypoadrenalism (Addison’s disease) demonstrates an impaired cortisol response to the injection of cosyntropin (Synacthen®, Mallinckrodt, Dublin, Ireland), a potent ACTH analogue.15
Table 22‐2 Diagnosis of endocrine disorders.
|Gland/Disease||Hormonal Problem||Diagnostic Assays/Investigations|
|Acromegaly||Growth hormone (GH) excess||
|Cushing’s syndrome||Excess cortisol||
|Addison’s disease||Low cortisol
|Pheochromocytoma||Excess epinephrine and/or norepinephrine||
|Hyperthyroidism||Excess T4 and/or T3||
|Hypothyroidism||Low T4 and/or T3||
|Male—hypogonadism||Low serum testosterone||
|Female—ovarian failure||Loss of ovarian estradiol||
(follicle-stimulating hormone and luteinizing hormone)
Causes of Endocrine Disease
Endocrine diseases can be divided into two major disease states: hormone excess and hormone deficiency (Table 22-3).16 Hormone resistance can be considered as a separate and distinct third condition,17 but in practice the effect is one of hormone deficiency.
Hormone excess can be caused by autoimmune disorders, the excess therapeutic administration of hormones, or autonomous release with tumors, as can be seen with benign adenomas of the parathyroid, pituitary, and adrenal glands.
The commonest cause of hormone deficiency is from glandular destruction by autoimmune diseases (Table 22-4) and iatrogenic causes, namely surgery and radiotherapy. Rare cases include infection, inflammation, infarction, hemorrhage, or tumor infiltration. Autoimmune-mediated damage is highly prevalent, as seen with Hashimoto’s thyroiditis and that of the pancreatic islet β cells in type 1 diabetes mellitus (T1DM).
Hormone resistance results in a disease state that is similar to that seen with hormone deficiency, but diagnosis is more difficult and complicated as there are usually normal levels of the hormone on testing. The more severe hormone resistance disorders are due to inherited defects in membrane receptors, nuclear receptors, or the pathways that transduce receptor signals. These disorders are characterized by defective hormone action despite the presence of increased hormone levels. The most prevalent acquired forms of functional hormone resistance include insulin resistance in type 2 diabetes mellitus (T2DM) and leptin resistance in obesity.8,18
Table 22‐3 Endocrine disorders.
|Multiple endocrine neoplasia (MEN)||
(excess corticosteroid administration)
|Hypofunction (Hormone Deficiency)|
(congenital adrenal hyperplasia)
|Nutritional (vitamin) deficiency||
|Signaling pathway mutations||
* Of neuroendocrine origin, derived from primitive stem cells of the gut wall, but can occur throughout the body.
Table 22‐4 Endocrine glands and autoimmune disease(s).
|Clinical Syndrome||Organ||Prevalence (if known*)||Antibody||Antigen|
|Thyroid||1 in 100||Thyroid-stimulating immune-globulin
|Thyroid-stimulating hormone receptor|
(e.g., growth hormone deficiency, diabetes insipidus)
|Thyroid||1 in 100||Thyroid microsomal||Thyroid peroxidase enzyme (TPO)|
|Primary hypoparathyroidism||Parathyroid||Parathyroid chief cell|
(adrenal cortex but sparing medulla)
|Type 1 diabetes mellitus||Pancreas
|1 in 500||Autoantibodies to GAD67 and GAD65||Glutamic acid decarboxylase (GAD)|
|Pernicious anemia§ (stomach)||Gastric parietal cell
|Primary ovarian failure||Ovary||1 in 500|
|Primary testicular failure||Testis|
|Vitiligo (skin)†||Skin melanocytes||Anti-melanocyte|
* Prevalence for Northern European/Caucasian populations.
Stomatognathic system manifestations:
† Associated with lichen planus, including oral lichen planus.
‡ Hyperpigmentation (“bronzing”) and increased number of melanotic macules of the oral mucosa.
Associated diseases include myasthenia gravis and autoimmune liver diseases.
HYPOTHALAMUS AND PITUITARY
The hypothalamus (Figure 22-3) contains vital sensors to monitor and control key functions such as appetite, thirst, thermal regulation, the sleeping/waking cycle (circadian rhythm), the menstrual cycle, and the response to stress, exercise, and mood. It serves to integrate the many neural and endocrine inputs to control the release of pituitary hormone-releasing factors. The hypothalamic neurons secrete both pituitary hormone-releasing and pituitary-inhibitory factors (and hormones) via the portal (vein) system, which passes down the stalk into the pituitary.19
The pituitary gland is a pea-sized structure situated at the base of the brain within the sella turcica, and is in intimate association with the hypothalamus. It plays a key role in the control of the endocrine system via feedback mechanisms, and hence has been termed the “conductor of the endocrine orchestra.”20
The pituitary gland is divided into two anatomically, functionally, and developmentally distinct structures: the anterior and posterior lobes.
Anterior Pituitary (Adenohypophysis)
The anterior pituitary hormones (Figures 22-3 and 22-4) are under predominantly positive control by the hypothalamic-releasing hormones, apart from the release of prolactin, which is under tonic inhibition by dopamine. Therefore, pathologic conditions that interrupt the flow of hormones between the hypothalamus and the pituitary gland result in deficiencies of most hormones, but the oversecretion of prolactin. The anterior pituitary is a mixture of cells that produce GH, ACTH, TSH, LH, FSH, and prolactin. ACTH, TSH, FSH, and LH are all intermediaries in their respective endocrine axes; each responds to a specific hypothalamic hormone (Figure 22-5) and, in turn, acts upon an end-organ gland to bring about the endocrine response.
There are five major anterior pituitary axes:
- Gonadotrophin axis.
- Growth axis.
- Prolactin (lactation) axis.
- Thyroid axis.
- Adrenal axis.21
The role of the anterior pituitary hormone prolactin is for the initiation and maintenance of lactation. Prolactin levels are increased during pregnancy, breast-feeding, nipple stimulation, stress, and chest wall injury, and by medications with antidopaminergic properties (e.g., antipsychotics).
Posterior Pituitary (Neurohypophysis)
The posterior pituitary (Figures 22-3 and 22-4) is a group of neural cells that are an extension of the hypothalamus and have secretory capacity. The posterior pituitary only secretes two hormones, arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), and oxytocin, both of which are nonapeptides (oligopeptides formed from nine amino acids; Figure 22-5). The primary physiologic functions of oxytocin include contraction of the myoepithelial cells of the alveoli of the mammary gland, which is important during lactation as part of the “let-down response,” and contraction of the uterus during childbirth and immediately postpartum.
Hormone excess is seen with pituitary adenomas that are usually benign and slow growing. The symptoms related to the physical enlargement of the adenoma include visual impairment or headache. Occasionally these are detected incidentally as a finding on a magnetic resonance imaging (MRI) or computer tomography (CT) scan. They can result in increased secretion of the hormone(s) produced by the cells represented in these lesions and/or decreased secretion of other hormones due to compression by the tumor. In contrast, pituitary apoplexy (pituitary infarction) has a dramatic presentation with a sudden and severe headache, often with diplopia. Evaluation of masses within the sella turcica is best done with MRI (see Figure 22-6) and evaluation of the hormonal profile.
Defects of the hypothalamic-releasing hormones or of the pituitary trophic hormones can be selective or multiple. Selective deficiencies of GH, LH/FSH, ACTH, TSH, and vasopressin (ADH) are all seen from a variety of causes. Multiple deficiencies usually result from a tumor. There is generally a progressive loss of anterior pituitary function, with GH and the gonadotrophins usually being the first trophic hormones affected. Hyperprolactinemia, rather than prolactin deficiency, occurs relatively early, because of loss of tonic inhibitory control by dopamine. TSH and ACTH secretion is usually the last to be affected. Panhypopituitarism refers to deficiency of all anterior pituitary hormones and it is most commonly caused by pituitary tumors, or as a consequence of the surgery or radiotherapy used in the treatment of such tumors. ADH and oxytocin secretion will only be significantly affected if the hypothalamus is involved, either by a hypothalamic tumor or by suprasellar extension of a pituitary lesion. ADH and oxytocin deficiency is rarely seen with an uncomplicated pituitary adenoma. In general, the symptoms of deficiency of a pituitary-stimulating hormone are the same as primary deficiency of the peripheral endocrine end-organ; for example, TSH deficiency results in primary hypothyroidism and so causes similar symptoms due to lack of thyroid hormone secretion.22
The symptoms and signs will reflect the extent of the hypothalamic and/or pituitary deficiencies, with mild deficiencies being generally clinically silent.
- Secondary hypothyroidism and adrenal failure both lead to tiredness and general malaise.
- Hypothyroidism results in weight gain, slowed mentation, slowness of action, dry skin, and cold intolerance.
- Hypoadrenalism causes mild hypotension, hyponatremia, and, ultimately, cardiovascular collapse during severe intercurrent stressful illness.
- Gonadotrophin/gonadal deficiency leads to loss of libido, loss of secondary sexual hair, amenorrhea, and erectile dysfunction.
- Hyperprolactinemia can cause galactorrhea and hypogonadism, including amenorrhea.
- GH deficiency causes growth failure in children and impaired wellbeing in some adults.
- Weight increase can be due to hypothyroidism.
- Weight loss can occur with severe combined deficiency (pituitary cachexia).
- Panhypopituitarism when long-standing gives the classic picture of pallor with hairlessness (“alabaster skin”).
Treatment entails hormone replacement by synthetic equivalents. Steroid and thyroid hormones are essential for life. Both are given as oral replacement drugs, as in primary thyroid and adrenal deficiency, aiming to restore biochemical normality (see Table 22-5).
Table 22‐5 Hypopituitarism: hormone replacement regimens.
Source: Fleseriu M, Hashim IA, Karavitaki N, et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(11):3888–3921.
(starting dose 10 mg on rising/5 mg lunchtime/5 mg evening)
ABNORMALITIES OF GROWTH AND STATURE
GH is the pituitary factor responsible for growth in humans. GH secretion is stimulated by growth hormone-releasing hormone (GHRH), released into the portal system from the hypothalamus (Figure 22-7). There is a separate GH-stimulating system that interacts with ghrelin, a hormone that is synthesized by the stomach. It is unknown how the two systems interact. GH binds to receptors mainly found on liver cells, which results in turn in the release of IGF-1, for which there are multiple binding proteins (IGF-BP) in the plasma. Of these, IGF-BP3 can be measured to assess GH status. The metabolic actions of this system are increased collagen and protein synthesis; retention of calcium, phosphorus, and nitrogen (necessary for anabolism; i.e., the building of molecules); and opposing the actions of insulin. GH release is intermittent, mainly nocturnal during REM sleep, and is significantly increased during adolescence, but afterward declines.
Apart from GH, the following factors play a role in the normal linear growth of humans:
- Genetics: children of short parents will probably be short and vice versa.
- Nutrition: inadequate nutrients result in impaired growth, either from inadequate dietary intake or small bowel disease, for example coeliac disease.
- General health: serious systemic disease, such as chronic infection, will impair growth.
- Intrauterine growth retardation: this will result in poor long-term growth, whereas premature infants tend to catch up.
- Emotional deprivation and psychologic factors: these play a role in growth and development, although the mechanisms are complex and not fully understood.
Growth Assessment and Treatment
Growth charts and associated computer programs are now available for national and specific ethnic groups to monitor and predict a child’s final height. The Centers for Disease Control and Prevention (CDC) have readily available (downloadable) growth charts consisting of a series of percentile curves that illustrate the distribution of selected body measurements in US children (Figures 22-8 and 22-9).23,24 These growth charts are also essential for predicting the treatment and prognosis of orthodontic and/or orthognathic treatment.25
Growth Failure (Short Stature)
This is usually noted by the child’s parents. Height velocity is more helpful than current height. This requires at least two measurements some months apart and, ideally, multiple serial measurements. Height velocity is the rate of current growth (centimeters per year), while the current attained height is largely dependent upon previous growth. Computer programs are available to calculate the key indices, which include standard deviation scores based on the degree of deviation from age/sex norms.26
Further investigations include dynamic assessment of GH levels, IGF and IGF-BP3 blood levels, thyroid function tests, and assessment of bone age, by radiographs of the nondominant wrist and karyotyping in females for Turner’s syndrome.27
Risk Factors for Short Stature
Risk factors for short stature include:28
- Intrauterine growth retardation, and weight and gestation at birth.
- Systemic disorders, especially small bowel disease.
- Congenital abnormalities (i.e., skeletal, chromosomal, or other).
- Endocrine status, particularly thyroid.
- Dietary intake.
- Drugs, especially steroids for asthma.
- Emotional, psychological, family, and school problems.
A child with normal growth velocity is unlikely to have significant endocrine disease and the most common cause of short stature in this situation is pubertal or “constitutional” delay. However, low growth velocity without an apparent systemic cause requires investigation (Table 22-6), as does sudden cessation of growth, since this suggests major physical disease, and in the absence of findings of systemic disease then a cerebral tumor or hypothyroidism is most likely.
Tall stature (as opposed to gigantism/acromegaly) is most commonly hereditary, because of having tall parents. However, if the child’s stature is usually tall and not consistent with the stature of the parents, chromosomal abnormalities such as Klinefelter syndrome or Marfan syndrome, or metabolic abnormalities, need to be considered. GH excess is a very rare cause and is usually clinically evident.
Acromegaly and Gigantism (Growth Hormone Excess)
GH is released from the somatotropic cells within the lateral wings of the anterior pituitary gland and is the primary trophic hormone responsible for postnatal growth and development. GH excess causes what is more formally termed pituitary gigantism in children if this occurs before fusion of the epiphyseal plate (growth). Gigantism is a nonspecific term that denotes excessive growth in a pediatric patient.29 GH excess results in acromegaly if it occurs after the bony growth plates have fused. In almost all cases this is due to GH-secreting pituitary adenoma.
GH’s major trophic effect is the release of IGFs from the liver. IGFs, as their name suggest, are proteins with significant homology to insulin, with a wide range of functions, but principally act to increase bone growth (specifically bone length). Although many cells have GH receptors and may respond to GH, the vast majority of the growth-stimulating effects of GH are mediated by IGF-1. GH release is under positive regulation by the hypothalamic peptide GH-releasing hormone. The amount and pattern of GH production and IGF release change markedly across the life cycle, with maximal release during the intense growth periods of late childhood and adolescence and low levels with advanced age. GH is released from the pituitary in a pulsatile fashion, with peak secretion at night. Thus, serum GH values vary considerable over the course of a 24-hour period, so a random sample may not reliably indicate true GH levels. In contrast, IGF-1 serum levels are relatively constant over the course of the day, so an IGF-1 sample can be taken at any time of the day and is indicative of GH levels.
Gigantism is very rare, with 0.6% reported in a large pediatric cohort.30 Acromegaly is rare, with an overall prevalence of estimated prevalence in Europe of 30–70 individuals per million, affecting men and women equally.31 The rapid growth seen with gigantism can be distinguished from that of precocious puberty. In gigantism, growth occurs in the absence of early secondary sexual characteristics, as the pituitary tumors (somatotroph adenomas) that lead to GH excess result in the loss of production of other pituitary hormones, particularly the gonadal trophic hormones, FSH, and LH, which are responsible for sexual development. Mild to moderate obesity is also commonly seen in these patients.
The mean age at diagnosis of acromegaly is usually 40–45 years, but as the progression of disease is so slow, the interval from the onset of symptoms until diagnosis can be as much as 12 years. Manifestations include the classic facial appearance of coarse facies, macrognathia, macroglossia, large diastemas, and enlargement of the nose and frontal bones (frontal bossing) (Figure 22-10). Soft tissue edema, due to a direct effect of GH on sodium retention, leads to a “doughy” feel to the hands and feet, as well as an increase in shoe, hat, glove, and ring sizes. Patients can also have increased sweating, deepening of the voice due to enlargement of the thyroid cartilage and vocal cords, enlargement of the synovium and cartilages with hypertrophic arthropathy (knees, ankles, hips, spine, and other joints), skin tags, nerve compression (causing paresthesia of the hands, as in carpal tunnel syndrome), enlargement of the soft tissues of the pharynx and larynx (which can lead to obstructive sleep apnea), increased risk of uterine leiomyomata, colonic polyps, and organomegaly (including the thyroid, heart, liver, kidneys, and prostate). Some 50% of patients with GH excess develop hypertension, 10% develop cardiomegaly with heart failure, which accounts for much of the increased mortality associated with acromegaly and 30% develop insulin resistance or T2DM. Surprisingly, patients seldom independently seek care as the changes are so insidious, and treatment is often initiated when a relative or friend, who has not seen the patient for some time, notes the typical changes as described here.17
Table 22‐6 Clinical features of common causes of short stature.
|Cause||Family History||Growth Pattern||Bone Age||Comments|
|Familial short stature||Positive||
|Growth hormone (GH) deficiency||Rare||
Worsens over time
|Small bowel disease
Diagnosis is often made on the clinical presentation, with a third diagnosed by the changes in appearance, a quarter because of the visual field defects and/or headache, and the reminder by an astute clinician, including the patient’s family physician (investigating potential causes for hypertension), dermatologist, and in particular the dentist.32 Key investigations are serum GH levels, IGF-1 levels, MRI, which will reveal a pituitary adenoma, visual field examination, and glucose challenge test.
Untreated acromegaly results in significant morbidity and increased rate of premature death. The aims of treatment are to establish a “safe” GH level and a normal IGF-1 level. If present, hypopituitarism also needs to be addressed. Concurrent hypertension and/or diabetes should be treated with conventional agents, but usually resolve with treatment of the acromegaly.
Treatment is usually surgical, most commonly by a transsphenoidal approach, or transfrontal for large adenomas, with radiotherapy reserved for situations in which GH levels fail to normalize. There are three potential targets for medical therapy: (1) somatostatin receptor agonists, either octreotide or lanreotide, which are given as monthly depot injections—these are generally effective, but do increase the risk for the development of gallstones; (2) dopamine agonists, either bromocriptine or cabergoline, which are best for patients with mild residual disease; and (3) growth hormone receptor antagonist, that is pegvisomant, a genetically modified analogue of GH that is reserved for patients who otherwise fail all other interventions.33
Stomatognathic Manifestations and Complications of Acromegaly
The predominant clinical findings in acromegaly—prognathism with evolving or established class III malocclusion; the development of significant diastemas, especially of the mandibular dentition; and radiographic findings of enlarged sella and frontal bossing (on lateral cephalogram)—mean that hygienists, dentists, and dental-related specialists are key in making the initial diagnosis of acromegaly. Following diagnosis and appropriate treatment, oral health professionals can facilitate oral rehabilitation. However, even patients with treated acromegaly can still have ongoing disease-related morbidities, which need to be identified on taking a comprehensive medical history. The key concerns in particular are treatment-refractory hypertension, valvopathy, and obstructive sleep apnea (OSA). The sleep apnea seen in association with acromegaly is predominantly obstructive and is related to thickening of walls of the upper airway, including the soft palate. However, the patient with acromegaly and sleep apnea presents special problems, as retropositioning the mandible to treat the prognathism is inconsistent with the principles involved in the management of OSA, necessitating alteration in conventional treatment planning.34,35
Hyperprolactinemia can be caused by hyperplasia of the so-called lactotroph cells (prolactinomas) or decreased tonic dopaminergic inhibition of prolactin secretion (e.g., compression by a central nervous system tumor).36 Prolactinomas can cause hypogonadism by suppressing gonadotropin secretion. In women, hypogonadism results in low serum estrogen levels that can present as oligomenorrhea, amenorrhea, infertility, and osteoporosis. In men, hypogonadism causes low serum testosterone concentrations that result in decreased libido and energy, decreased facial hair growth, loss of muscle mass, and osteoporosis. Hyperprolactinemia in men may also be associated with impotence even when the serum testosterone concentration is normal. It can cause galactorrhea (leakage of milk from the breast other than during lactation) in women, but this only occurs very rarely in men.
Prolactinomas are relatively common, accounting for 30–40% of all clinically recognized pituitary adenomas. The diagnosis is made more frequently in women than in men, especially between the ages of 20 and 40 years, presumably because the hyperprolactinemia disrupts their menstrual cycle.37 Such tumors can be identified by the enlargement of sella turcica incidentally observed on lateral cephalograms.38
Prolactinomas can be treated with dopamine agonists, such as cabergoline or bromocriptine. These drugs have the dual effect of decreasing hormone secretion and tumor size. If the adenoma does not respond to increasing doses of these medications or there is imminent visual loss, transsphenoidal surgery is required for removal of the tumor.39
DISORDERS OF ANTIDIURETIC HORMONE
Thirst and the symptoms of thirst, xerostomia and the signs of dehydration, namely hyposalivation and dry mucous membranes of the mouth, are of course of great relevance to the clinical practice of oral healthcare providers. Thirst and water regulation are largely controlled by vasopressin, also known as antidiuretic hormone (ADH). ADH is synthesized in the hypothalamus and then migrates in neurosecretory granules via axonal pathways to the posterior pituitary. Pituitary diseases that spare the hypothalamus do not lead to ADH deficiency, as the hormone still can “leak,” even from the end of a damaged axon.
The kidney is the predominant site of action of ADH at normal concentrations. ADH stimulation of the vasopressin-2 (V2) receptors allows the collecting ducts to become permeable to water, via the migration of aquaporin-2 water channels, resulting in the reabsorption of hypotonic luminal fluid. ADH acts to reduce diuresis (i.e., less urine) and results in retention of water. At high concentrations, ADH can also cause vasoconstriction, via the V1 receptors present in the vascular tissues, thus limiting blood supply to the kidneys, resulting in further water retention and less urine output.
ADH is regulated by osmoreceptors in the anterior hypothalamus that can sense plasma osmolality. ADH secretion is suppressed at levels below 280 mOsm/kg, thus allowing maximal urine formation (diuresis). Above this level, plasma vasopressin increases in direct proportion to plasma osmolality. At the upper limit of normal (295 mOsm/kg), maximum antidiuresis is achieved (little if any urine production), with thirst being experienced at about 298 mOsm/kg.
Disorders of ADH are in essence disorders of water balance. ADH deficiency is termed diabetes insipidus (DI) and is a syndrome characterized by the inability for the kidneys to retain water.40 It can be caused by inadequate pituitary production of ADH (termed central DI), or resistance to the actions of ADH on the kidneys (termed nephrogenic DI). DI can also be gestational, or present as an iatrogenic artefact of alcohol or some types of drug abuse. The primary presenting symptom is polyuria (>3 L/d), and resultant hypernatremia, nocturia, and compensatory polydipsia (excessive thirst/water intake). Daily urine output may reach as much as 10–15 L, leading to dehydration that may be very severe if the thirst mechanism or consciousness is impaired or if the patient is denied fluid. Diagnosis of DI is made by a water deprivation test, requiring medical supervision.41
Treatment is with the synthetic vasopressin (ADH) analogue desmopressin (also known as DDAVP, 1-desamino-8-d-arginine vasopressin, desamino cys-1-d-arginine-8 vasopressin), which has the advantages of a longer duration of action than vasopressin and no vasoconstrictive effects. It is reliably given by an intranasal spray 10–40 μg once or twice daily, but can also be given orally (100–200 μg three times daily or intramuscularly 2–4 μg daily). For patients with DI, a reversible underlying cause (e.g., a hypothalamic tumor) should be investigated for and treated, if found. Other causes of polyuria and polydipsia include diabetes mellitus (DM), hypokalemia, and hypercalcemia, which should be excluded. In the case of DM, the cause is an osmotic diuresis secondary to glycosuria, which leads to dehydration and increased thirst, owing to the hypertonicity of the extracellular fluid.42
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE
Excessive ADH (syndrome of inappropriate antidiuretic hormone, SIADH) is a syndrome of too much total body water and consequent hyponatremia, of which the electrolyte disturbance is the main concern and the cause of the presenting clinical features.43 Major causes of SIADH include central nervous system (CNS) disturbances such as stroke, infection, trauma, and hemorrhage. Other causes are medications, serious illness (especially in the elderly), and some types of cancer. The clinical presentation tends to be slow, with the patient exhibiting confusion, nausea, irritability, and, later, fits and coma, but with no edema. Mild symptoms usually occur with plasma sodium levels below 125 mmol/L and serious manifestations occurring below 115 mmol/L.44 The elderly may show symptoms with milder abnormalities. SIADH needs to be differentiated from dilutional hyponatremia due to excess infusion of glucose/water solutions or diuretic administration (thiazides or amiloride). ACTH deficiency can give a very similar biochemical picture to SIADH; therefore, it is necessary to ensure that the HPA axis is intact, particularly in neurosurgical patients, in whom consequently ACTH deficiency is relatively common.
Table 22‐7 Physiologic effects of the thyroid hormones.
|Cardiovascular system|| Heart rate
|Respiratory center||Maintains normal
|Neuromuscular function|| Muscle contraction and relaxation
Muscle protein turnover
|Sympathetic nervous system|| Catecholamine sensitivity
β-adrenergic receptor numbers on:
heart, skeletal muscle, adipose cells, and lymphocytes
Cardiac α-adrenergic receptors
|Gastrointestinal system||Gut motility|
| Hepatic gluconeogenesis/glycolysis
Intestinal glucose absorption
Cholesterol synthesis and degradation
Management entails identifying the underlying cause and correcting this, when possible. Symptomatic relief includes fluid restriction, with an intake of only 500–1000 mL water daily; if complied with, this will usually correct the biochemical abnormalities. Such fluid restriction can result in salivary hypofunction and so directly contribute to higher rates of dental decay, and candidiasis.45,46 Newly available, ADH (V2) antagonists (e.g., tolvaptan, sold as Samsca® in the United States; Otsuka America Pharmaceutical, Rockville, MD, USA) are being used with good effect.47
Thyroid disease occurs frequently and is the most common endocrine disease. The thyroid gland synthesizes three hormones: (1) thyroxine (T4), which is a prohormone; (2) triiodothyronine (T3), the active hormone that is critical in regulating the body’s metabolic rate; and (3) calcitonin, which regulates bone metabolism. Adequate levels of thyroid hormone are essential in infants for normal CNS development, in children for normal skeletal growth and maturation, and in adults for the normal function of multiple organ systems (Table 22-7). In general, there are five main types of thyroid disease, and disease can be intercurrent in the same patient:
- Hypothyroidism (termed “myxedema” when it occurs in adults and “cretinism” when it occurs in infants and children), caused by a deficiency of thyroid hormones.
- Hyperthyroidism (thyrotoxicosis), due to an excess of thyroid hormones with consequent significant clinical issues, especially of the cardiovascular system.
- Abnormal thyroid function tests (TFTs), in an otherwise euthyroid (the state of having normal thyroid gland function) patient.
- Structural abnormalities, mainly goiter, which may be seen as diffuse enlargement of the thyroid gland, or single or multiple nodules, due to focal enlargement of only a portion of the gland,
Thyroid disease has prevalence of 6% as of 2019 and it is estimated that over 12% of Americans will develop some form of thyroid disease over the course of their lifetime.48 Of these, some 60% are unaware of their condition. Thyroid diseases are far more common in women. The management for most thyroid disorders is life-long and well tolerated. In the United States, autoimmune inflammation is the most common cause of thyroid disease whilst worldwide hypothyroidism and goiter due to iodine deficiency is much more common.49 Although thyroid nodules are common, thyroid cancer is rare. Thyroid cancer accounts for less than 1% of all cancer in the US,50 although it is the most common endocrine tumor and makes up greater than 90% of all cancers of the endocrine glands.51
Thyroid Gland: Anatomy and Physiology
The thyroid gland consists of two lateral lobes connected by an isthmus, closely attached to the thyroid cartilage and to the upper end of the trachea, and thus moves on swallowing. Embryologically, it originates from the base of the tongue and descends to the middle of the neck. Remnants of thyroid tissue can sometimes be found at the base of the tongue (lingual thyroid) and along the line of its descent.
Internally, the thyroid gland consists of follicles lined by cuboidal epithelioid cells within which is colloid (iodinated glycoprotein thyroglobulin), synthesized by the follicular cells. Each follicle is surrounded by basement membrane, and between them are parafollicular cells containing the C cells that secrete calcitonin. The thyroid also synthesizes triiodothyronine (T3), which acts at the cellular level, and L-thyroxine (T4), which is the prohormone. Inorganic iodine is essential for the synthesis of the two thyroid hormones and the precursor molecule, thyroglobulin (Figure 22-11). Globally, dietary iodine deficiency is a major cause of thyroid disease. Dietary supplementation of salt and bread has reduced the number of areas where “endemic goiter” still occurs. Surprisingly, in Western countries iodine deficiency is now a concern, given the decline in adventitious iodine in dairy products with use of noniodoform disinfectants in milk production and “food fads,” with the use of noniodized rock salt in place of iodized salt in cooking. In the United States iodine intakes have fallen, and it is uncertain whether the iodine status for most pregnant woman is satisfactory, leading to calls for systematic iodine supplementation.52
In plasma, more than 99% of all T4 and T3 is bound to hormone-binding proteins: TBG, thyroid-binding prealbumin, and albumin. Only unbound—that is, free—hormone is biologically active. Circulating T4 is peripherally deiodinated to T3, which has a far greater affinity for its receptors than T4. T3 binds to the two thyroid hormone nuclear receptors (TR-α and TR-β) of the target cells to cause gene transcription.
Control of the hypothalamic-pituitary-thyroid axis is, as is universal throughout the endocrine system, by negative feedback control. Thyrotropin-releasing hormone (TRH) is a peptide produced in the hypothalamus, which stimulates the pituitary to secrete TSH (Table 22-8). TSH, in turn, stimulates growth and activity of the thyroid follicular cells, which consequently secrete T3 and T4 into the circulation. T3 and T4 both exert negative feedback on the hypothalamus, leading to a decrease in the secretion of TRH and so a decrease in TSH and in turn a decrease in T3 and T4. The decrease in circulating T3 and T4 prompts increased release of TRH and, again, in turn an increase in TSH and then T3 and T4.
Hypothyroidism, defined as the inadequate release of the two thyroid hormones T3 and T4, is usually primary; that is, due to disease of the thyroid gland, However, it may be secondary, due to disease of hypothalamic or pituitary, with consequent reduction in TSH, and so a decline in T3 and T4 release by an otherwise intact thyroid gland.
Hypothyroidism is one of the most common endocrine conditions, with a prevalence rate of 4.6% for the US population. Approximately 0.3% present with clinically overt disease and the remaining 4.3% with subclinical disease (decreased T3 and T4 levels but no clinical evidence of disease).53 Of those with subclinical hypothyroidism, 2% per annum develop clinically evident hypothyroidism, hence the lifetime prevalence for an individual is higher—perhaps as high as 9% for women and 1% for men, with mean age at diagnosis around 60 years.54
- Atrophic (autoimmune) thyroiditis. This is associated with the development of antithyroid autoantibodies with consequent lymphoid infiltration of the thyroid glands, and eventual atrophy and fibrosis. It is associated with other autoimmune conditions including pernicious anemia, vitiligo, and other endocrinopathies.55,56
Table 22‐8 Thyroid function tests and role in clinical practice.
Normal Hypothalamic-Pituitary Function Indication Serum TSH* Serum T4 Serum T3 Euthyroid Normal Normal Normal Primary hypothyroidism High Low Normal or low Subclinical hypothyroidism High Normal Normal Hyperthyroidism Low High or normal High Subclinical hyperthyroidism Low Normal Normal
- If serum TSH is normal—no further testing indicated or required.
- If serum TSH is HIGH—the lab will add free T4 to determine degree of hypothyroidism.
- If serum TSH is LOW—both free T4 and T3 are added to the patient’s sample to determine degree of hyperthyroidism.
Clinical indications for additional testing:
- Pituitary/hypothalamic disease suspected, e.g., a young woman with amenorrhea and fatigue: test TSH.
- Patient has symptoms of hyper- or hypothyroidism and normal TSH result: test T4.
* With central hypothyroidism, serum TSH may be low, normal, or slightly high.
T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.
- Hashimoto’s thyroiditis. This is most common in middle-aged women. High levels of autoantibodies are developed and directed against thyroid peroxidase (the enzyme that coverts T4 to T3).Atrophic changes are followed by regeneration, with this cycle leading to clinically evident generalized goiter, which is firm and hard on palpation.
- Postpartum thyroiditis. A destructive form of thyroiditis associated with the immune changes of pregnancy, this can occur up to year post parturition. It confers, as seen with most pregnancy-associated endocrine disease, a lifetime risk for the development of permanent hypothyroidism, necessitating ongoing screening for affected women.57
Defective Hormone Synthesis
- Iodine deficiency. This can result in endemic goiter, which can be massive, due to borderline iodine deficiency with consequent TSH stimulation, and therefore hyperplasia and hypertrophy of the thyroid gland. At a global scale, approximately 2 billion people suffer from iodine deficiency, of which approximately 50 million people present clinical features of hypothyroidism. The effect of chronic iodine deficiency and related hypothyroidism leads to cretinism in children, which causes growth delay, short stature, and severe cognitive impairment.58
Hypothyroidism produces many symptoms and signs, but these can be subtle and difficult to distinguish from other causes of tiredness and fatigue. The alternate term “myxedema” refers to the typical appearance of patients with long-standing significant hypothyroidism, due to the accumulation of mucopolysaccharides in the subcutaneous tissues, presenting with mucinous, nonpitting edema, particularly of the hands, feet, and eyelids. The clinical presentation includes dry hair, thick skin, deepening of the voice, weight gain, complaints of cold intolerance, and bradycardia. Diagnosis is difficult in children, young women, and the elderly and TSH and serum T3 and T4 should be undertaken to exclude hypothyroidism in these subjects, even if only suspected. If hypothyroidism is proven (low T3 and T4), investigations are required to differentiate primary disease from diseases affecting the hypothalamus-pituitary-thyroid axis.59
The commonest treatment for hypothyroidism is synthetic T4 (thyroxine), levothyroxine (sold in the United States as Synthroid®, AbbVie, North Chicago, IL, USA; Levoxyl®, Pfizer Medical, New York, USA; Tirosint®, IBSA Pharma, Parsippany, NJ, USA; and Euthyrox®, Provell Pharmaceuticals, Honey Brook, PA, USA).60 The goals of treatment are amelioration of the patient’s symptoms, normalization of the serum TSH levels, reduction in the size of goiter (if present), and, of most concern, avoidance of overtreatment (iatrogenic thyrotoxicosis). Both the initial and maintenance doses of levothyroxine are titrated to effect, based on the serum T4 and TSH and serial electrocardiograms, to exclude the development of atrial fibrillation, a known complication of hyperthyroidism.61 The starting dose is 100 μg/daily for the young and fit with no cardiovascular disease; 50 μg/daily for the small, frail, and elderly; and even lower (i.e., 25 μg/daily) in patients with severe, long-standing hypothyroidism or with a history of ischemic heart disease. The usual maintenance dose is 100–150 μg daily.
Myxedema Coma and “Madness”
This can occur as the culmination of severe, long-standing hypothyroidism or can be precipitated by an acute event in a poorly controlled hypothyroid patient, such as infection, myocardial infarction, cold exposure, surgery, or the administration of sedative drugs, especially opioids. The presenting features frequently do not result in a coma, but rather with variable degrees of altered consciousness, such as confusion and lethargy. However, in rare instances, the initial presentation is with prominent psychotic features, termed “myxedema madness.” If this is unrecognized, patients will progress to coma. The other major clinical findings will be of hypothermia, which needs to be assessed by manually examining the patient, in particular the hands (peripheries), as many automatic thermometers do not record subnormal temperatures.62 The patient’s vital signs will demonstrate marked hypotension and bradycardia (slow pulse) and blood tests will reveal marked hypoglycemia and hyponatremia (decreased serum sodium levels). Myxedema coma is a medical emergency, with a poor prognosis, requiring prompt hospitalization. The key aspects of treatment are replacement T4 and T3. In addition, prophylactic hydrocortisone 100 mg is administered intravenously (every eight hours) until adrenal insufficiency is excluded, as well as intensive supportive measures, including mechanical ventilation, fluids, and vasopressor drugs to correct hypotension, passive rewarming), and intravenous dextrose. Empirical antibiotic treatment is usually also given. Ongoing cardiorespiratory monitoring for arrhythmias is also mandated. The mortality rate, even with the best inpatient care, is 30–50%.63
Hyperthyroidism (also termed thyrotoxicosis) is defined as thyroid overactivity with consequent increased release and greater circulating levels of T3 and T4. Hyperthyroidism is common. The reported overall prevalence is about 3%, with men and women over 65 years having the highest prevalence, of which 50% are taking levothyroxine. In the National Health and Nutrition Examination Survey, there was a bimodal distribution based on age, with prevalence highest in those subjects aged 20–39 years and those aged older than 79 years.53
- The use of supraphysiologic doses of levothyroxine that may be intentional, e.g., in patients’ post treatment for thyroid malignancy in order to maintain suppression of serum TSH.
- Amiodarone-induced thyrotoxicosis.64 Amiodarone is a class III antiarrhythmic agent (Vaughan Williams’ classification) that blocks the potassium channels of the atrial, nodal cardiac muscle cells and the ventricular tissues (which coordinate the heartbeat). Its main effect is to prolong repolarization of the cardiac muscle and is indicated for the treatment and prevention of ventricular fibrillation and ventricular tachycardia.65,66 It causes both hypothyroidism and hyperthyroidism due to its high iodine content and its direct toxic effect on the thyroid.67
- Graves’ disease, a “classic” autoimmune condition, is the most common cause in young patients. It features the development of autoantigenic serum immunoglobulin (Ig) G antibodies that bind to the TSH receptors in the thyroid, thus stimulating thyroid hormone overproduction and secretion. Other autoimmune antibodies develop concurrently, similar to those seen in autoimmune hypothyroidism, including antibodies to thyroid peroxidase (TPO) and thyroglobulin antibodies. These can occur in up to 80% of cases and result perversely in hypothyroidism.
- Toxic nodular goiter (solitary or multinodular) with autonomous production and release of T3 and T4. Common in the elderly population.68
- Subacute thyroiditis (also known as subacute granulomatous thyroiditis, or de Quervain’s thyroiditis) of likely viral etiology. Its main feature is painful goiter.
- Postpartum thyroiditis (see earlier).
- Eye signs. Lid lag and “stare,” which can occur with hyperthyroidism of any cause. However, there are other features that are distinct with Graves’ orbitopathy (described later).
- Skin. Graves’ dermopathy is rare and can occur on any extensor surface. Pretibial myxedema is the most commonly described and is an infiltration of the skin on the shin. Thyroid acropachy is very rare and consists of clubbing and new periosteal bone formation of the fingers, causing marked swelling.
- Excessive growth rate/velocity. Common in children together with weight gain or behavioral problems, such as hyperactivity.
- Cardiovascular. In the elderly, a frequent presentation is with atrial fibrillation, other types of tachycardias, and/or heart failure. TFTs are mandatory in patients with atrial fibrillation.
- Apathetic thyrotoxicosis in elderly patients presents with a clinical picture more like that of hypothyroidism.
- Serum TSH, which will be reduced in hyperthyroidism (<0.05 mU/L).
- Raised free T4 or T3 confirms the diagnosis; T4 is almost always raised, but T3 is a more sensitive indicator of hyperthyroidism.
- TSH receptor–stimulating antibodies (TSHR-Ab), which are 99% specific for Graves’ disease.
- Thyroid peroxidase (TPO) and thyroglobulin antibodies are present in 80% of cases of Graves’ disease.
- Scintiscan 99Tm is useful if there is doubt as to the nature of the goiter.
The hyperthyroidism of Graves’ disease is treated by reducing thyroid hormone synthesis with an antithyroid drug, or by reducing the amount of thyroid tissue with radioiodine (131iodine) treatment or thyroidectomy. Radioiodine is more often the first line of treatment in North America. Treatment approaches vary around the world, indicative that no single approach is ideal.
- Radioactive 131I is given orally and, since iodine preferentially concentrates in the thyroid, the gland is then slowly destroyed over the course of months by the local radiotherapy effect. It is contradicted in pregnant and breast-feeding women.69
- Antithyroid drugs. The main drugs are the thionamides: propylthiouracil, carbimazole (not available in the United States), and the active metabolite of the latter, methimazole, which inhibits the function of TPO, reducing oxidation and organification of iodide. Remission rates are in the range of 30–60%. The major toxicity with these agents is a selective agranulocytosis, but this only occurs in less than 1% of patients.
- Surgery. Generally, this will be a total thyroidectomy. That is typically an option for patients who relapse after antithyroid drugs and who prefer this treatment to radioiodine.
- Beta blockers, in particular propranolol (20–40 mg every 6 h), or longer-acting selective β1 receptor blockers, such as atenolol, may be helpful to control the adrenergic symptoms, especially in the early stages before the antithyroid treatment is fully effective.
- Surveillance. 40–70% of patients may relapse following antithyroid drug therapy. Hypothyroidism occurs in most patients treated by drugs or radioiodine, and is inevitable after total thyroidectomy, hence these patients will need to be maintained on appropriately titrated, life-long replacement levothyroxine.
< ?sup Start?>There is a small risk of increased overall mortality seen in patients with hyperthyroidism. The major long-term consequence of treatment for hyperthyroidism is an increased risk of osteoporosis. Marked TSH suppression leads to the development of atrial fibrillation, requiring cardiac rate-limiting drugs such as digoxin, with an attendant risk for thromboembolic stroke. Hence anticoagulant prophylaxis is required, either with either warfarin or increasingly with direct oral anticoagulants (DOACs; previously known as new oral anticoagulant agents or NOACs), which include apixaban (Eliquis®, Pfizer Medical), dabigatran (Pradaxa®, Boehringer Ingelheim, Ridgefield, CT, USA), rivaroxaban (Xarelto®, Janssen Pharmaceuticals, Titusville, NJ, USA), and edoxaban (Savaysa®, Daiichi Sankyo, Basking Ridge, NJ, USA).70< ?sup End?>
Graves’ orbitopathy, also known as thyroid eye disease (TED), is an autoimmune inflammatory disorder of the orbit and periorbital tissues. It has distinctive clinical features, including the “stare,” due to retraction of the upper eyelid with lid lag, and swelling of the orbit, causing an exophthalmos of variable severity. It occurs most commonly in association with Graves’ disease, but can also be seen, albeit more rarely, with Hashimoto’s thyroiditis, and even in patients who are otherwise euthyroid. The condition mostly affects the middle-aged (30–50 years of age) and predominantly women. Cigarette smoking raises the incidence eightfold. Annual incidence is 16 per 100,000 in women and 3 per 100,000 in men.71 About 3–5% have severe disease with intense pain, and sight-threatening corneal ulceration or compression of the optic nerve. Unilateral orbitopathy can occur, but this is rare.
Initial treatment entails regulation of thyroid hormone levels and limitation of further damage to the eye, with the use of topical lubricants to prevent corneal damage. High-dose corticosteroids are effective in the initial reduction of the orbital inflammation. Radiotherapy has been trialed, but there is controversy as to its efficacy, as is the case with selenium, which is limited to the treatment of mild disease. As of January 2020, the US Food and Drug Administration (FDA) approved the use of the medication Tepezza® (teprotumumab-trbw; Horizon Therapeutics, Lake Forest, IL, USA) for the treatment of adults with TED.72 Teprotumumab-trbw is a monoclonal antibody that binds IGF-1R. In TED pathogenic orbital disease, autoantibodies stimulate the orbital fibroblasts, resulting in the production of hyaluronan (a high molecular mass polysaccharide), causing the marked infiltration and so swelling of the eyelids and orbital tissues and resulting in the clinical features of TED. Teprotumumab blocks the stimulatory effects of pathogenic autoantibodies on the orbital fibroblasts.73 Orbital decompression surgery is indicated in severe eye disease to prevent blindness from optic nerve compression. Surgery is also indicated, after the incipient thyroid disease has been stable for six months, to improve function and to increase lubrication of the corneal surface to prevent corneal keratitis and for cosmesis.74
A thyroid crisis (or “thyroid storm”) is a rare, life-threatening exacerbation of hyperthyroidism, which presents with fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment. Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially involving the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism. In-hospital management is required, which includes intensive monitoring, supportive care, identification and treatment of the precipitating cause, and measures that reduce thyroid hormone synthesis; that is, large doses of antithyroid drugs, such as propylthiouracil. Propranolol is also given to reduce tachycardia and other adrenergic manifestations.
Thyroid Hormone Resistance
This occurs when the effectiveness of thyroid hormone is reduced and includes flaws in thyroid hormone action, transport, or metabolism. These are rare, in general have a genetic basis, and to date there is limited effective treatment. There are three main causes:
- Thyroid hormone cell membrane transport defect.
- Thyroid hormone metabolism defect.
- Thyroid hormone action defects.
Goiter (Thyroid Enlargement)
Goiter is a swelling of the anterior base of the neck resulting from an enlarged thyroid gland, which may be visible or only evident on palpation (see Table 22-9). In the United States where iodine deficiency is rare, up to 15% of the population have palpable goiter and as many as 50% microscopic nodules. In areas of the world where iodine deficiency is common and widespread, up to 90% of the population have significant goiter, termed “endemic goiter.”75,76
Table 22‐9 Goiter: types and causes.
viral (infective) thyroiditis
The initial screening for thyroid dysfunction starts by examining and then palpating the thyroid gland for diffuse changes or nodules, which may be single or multiple. It is performed as part of a head and neck examination, which could be argued to be within the remit of dentists and represents a comprehensive examination of the patient, with a focus on dental disease, but in the context of potential disease of the related regional anatomy. The thyroid gland is examined with the patient’s head extended to one side and with the examiner using the fingers of both hands to palpate the thyroid gland. Next, the patient is instructed to swallow, during which time the examiner can evaluate the anatomic extent of the lobules using the last three fingers of one hand. Note that the right lobule is usually larger than the left and that on relaxation, the thyroid outline cannot be observed in a healthy patient. Any anatomic abnormality of the thyroid gland is defined by its consistency, size, tenderness, and growth. If an abnormal finding is discovered, hormone and function and imaging studies, particularly ultrasound, needs to follow, with consideration for ultrasound-guided fine needle aspiration (FNA) biopsy.77
Thyroid carcinoma is the most common malignancy of the endocrine system. Thyroid neoplasms can arise in each of the cell types that populate the gland, including thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal and vascular elements, as well as metastases from other sites (Table 22-10). Over the last 30 years, the incidence of thyroid cancer has increased from 4.9 to 14.3 cases per 100,000 individuals in the United States, with over 65,000 cases diagnosed in 2015.78
The risk factors for thyroid malignancy are (1) exogenous, namely exposure to radiotherapy of the head and/or head and neck region, which can include cranial radiotherapy, or from nuclear fallout following explosions of nuclear power plants, at Chernobyl (1986)79 and more recently Fukushima (2011);80 and (2) endogenous, specifically genetic abnormalities, patients who have a family history of papillary thyroid cancer in two or more first-degree relatives, multiple endocrine neoplasia type 2 (MEN 2), or other genetic syndromes associated with thyroid malignancy, such as Cowden’s syndrome, familial polyposis, and Carney complex.51
Table 22‐10 Thyroid malignancies.
Source: Data from Clayman, G. Thyroid cancer: thyroid cancer symptoms, diagnosis, and treatments. www.endocrineweb.com/conditions/thyroid-cancer/thyroid-cancer.
(Arising from Thyroid Epithelium)
|Follicular epithelial cell|
|Poorly differentiated carcinomas||3–5%|
|Anaplastic (undifferentiated) carcinoma||1%|
(Arising from the C
|Medullary thyroid cancer||<10%|
|Multiple endocrine neoplasia 2|
Breast, melanoma, lung, kidney
Papillary and Follicular Cancer
As most tumors are still TSH responsive, levothyroxine suppression of TSH is a mainstay of initial thyroid cancer treatment, followed by partial or near-total thyroidectomy (depending on the size of the tumor). This is followed by radioablation of the remnant thyroid gland (and tumor). Serum thyroglobulin is a sensitive marker of residual/recurrent thyroid cancer after initial treatment.
Anaplastic Thyroid Cancer
This is a poorly differentiated and aggressive cancer with a dismal prognosis, with most patients dying within six months of their diagnosis.
Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) can be sporadic or familial, and accounts for about 5% of thyroid cancers. There are three familial forms of MTC: MEN 2A, MEN 2B, and familial MTC without other features of MEN.81 The management of MTC is primarily surgical, as these tumors, unlike papillary and follicular thyroid cancer, do not take up radioiodine. Targeted small molecule tyrosine kinase inhibitors (TKIs) have shown benefit in large or recurrent disease. Examples include cabozantinib (sold in the United States as Cabometyx® and Cometriq®, Exelixis, Alameda, CA, USA), which inhibits the tyrosine kinases c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2), and vandetanib (Caprelsa®, Sanofi Genzyme, Cambridge, MA, USA) acts as a kinase inhibitor of a number of cell receptors, mainly VEGFR, epidermal growth factor receptor (EGFR), and RET-tyrosine kinase.82 The TKIs that target vascular growth receptors that have a role in angiogenesis have been shown to increase the risk of medication-related osteonecrosis of the jaws (MRONJ), particularly if given concurrently (fivefold increased MRONJ risk) with either a bisphosphonate or denosumab.83 External radiation treatment has also been shown to provide benefit.
Treatment follows the guidelines used for other forms of lymphoma.
Stomatognathic Manifestations and Complications of Thyroid Disease
Both hypothyroidism and hyperthyroidism can occur in the same patient, because patients with clinically significant hypothyroidism are on replacement levothyroxine, and there is the risk of overtreatment and iatrogenic thyrotoxicosis. Similarly, patients on treatment for their hypothyroidism can develop marked hypothyroidism if they omit a number of doses, or if they are on an insufficient dose. Therefore, dentists need to be familiar with the symptoms and signs of both hypothyroidism and hyperthyroidism.
Patients with a history of thyroid cancer have probably undergone surgery or radioactive iodine therapy that can affect the adjacent regional tissues. Salivary gland dysfunction is one of the most common side effects of high-dose 131I therapy for thyroid cancer.84,85 131I targets the salivary glands, where it is concentrated and secreted into saliva. Dose-related damage to the salivary parenchyma results from 131I irradiation and causes salivary gland swelling, pain, and hypofunction.86–89
Dental Management of the Patient with Thyroid Gland Disorders
Patients with autoimmune thyroid diseases (Hashimoto’s thyroiditis) may also be susceptible to other autoimmune connective tissue disorders, including Sjögren syndrome. Antinuclear antibodies (ANAs) are found in one-third of patients with autoimmune thyroid disorders, and Sjögren syndrome is found in nearly one-tenth of ANA-positive patients with autoimmune thyroid disorders.90 The most common additional autoimmune disease identified in patients with primary Sjögren syndrome has been hypothyroidism;91 also, there is a 7–17% prevalence of detectable thyroid antibodies in patients with Sjögren syndrome and rheumatoid arthritis.92 Therefore, the thyroid patient who presents with signs and symptoms of hyposalivation and xerophthalmia should be evaluated for Sjögren syndrome.84,93–95
In hypothyroidism, the orofacial findings include myxedema of the skin, an enlarged tongue (macroglossia), compromised periodontal health, delayed tooth eruption, delayed wound healing, and a hoarse voice. Salivary gland enlargement, changes in taste, and burning mouth symptoms have also been reported.96,97
Patients with hypothyroidism are susceptible to cardiovascular diseases; therefore, consultation with the patient’s medical provider is indicated. Patients who have atrial fibrillation may be taking anticoagulants, depending on the severity of the arrhythmia. The use of epinephrine-containing local anesthetics is not contraindicated if the patient’s hypothyroidism is well controlled, but in patients who have cardiovascular disease (congestive heart failure, atrial fibrillation) or who have uncertain control of their thyroid disease, local anesthetic and retraction cord soaked with epinephrine can be used, but cautiously. Hypothyroidism, especially if uncontrolled, can also lead to respiratory depression, so that patient positioning should be carefully considered when treating such patients. Consideration should be given to treating patients in a semi-upright position, with oxygen supplementation via nasal prongs or by the mask used in providing nitrous oxide to patients.
Hypothyroid patients are sensitive to CNS depressants and so these medications should be used carefully, with input from the patient’s physician. For postoperative pain control, narcotic use should be limited, since there is greater susceptibility to these agents in patients with hypothyroidism. Patients with long-standing hypothyroidism may experience increased bleeding after trauma or surgery. The presence of excess subcutaneous mucopolysaccharides (due to decreased degradation) may impair the ability of small vessels to constrict if severed or traumatized, and this may result in increased postoperative hemorrhage from such infiltrated tissues, including mucosa and skin. Delayed wound healing may also occur due to decreased metabolic activity of the fibroblasts. However, a study of well-controlled primary hypothyroid patients who had been provided with dental implants demonstrated no significantly increased risk for implant failure when compared with matched normal controls.98
Hyperthyroidism can exacerbate the patient’s response to dental pain and anxiety. Routine examination of the head and neck may disclose signs of thyroid disease, including changes in oculomotor function, protrusion of the eyes, enlargement of the thyroid, and so difficulty in swallowing, or of the tongue. The patient may demonstrate excessive sweating. The greatest concern is the development of thyrotoxicosis or a “thyroid storm,” which includes symptoms of extreme irritability and delirium, hypotension, vomiting, and diarrhea.99 It can be triggered by surgery, sepsis, and trauma. Emergency medical treatment is required for this condition. Epinephrine is contraindicated, and elective dental care should be deferred for patients who have hyperthyroidism and exhibit signs or symptoms of thyrotoxicosis.
Increased susceptibility to infection may develop as an adverse side effect of antithyroid agents, which can cause agranulocytosis or leukopenia. Propylthiouracil can also cause sialolith formation and can increase the anticoagulant effects of warfarin. Certain analgesics must be used with caution in these patients. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may cause increased levels of circulating T4, leading to thyrotoxicosis. NSAIDs can also decrease the effect of beta blockers.50 The use of epinephrine requires special consideration when treating hyperthyroid patients and those taking nonselective beta blockers.
DISORDERS OF THE ADRENAL GLANDS (CORTEX)
The normal adrenal glands weigh 6–11 g each, are located above the kidneys, and have their own rich blood supply.100 Within the glands is the adrenal cortex, which produces three classes of corticosteroid hormones:
- Glucocorticoids (e.g., cortisol).
- Mineralocorticoids (e.g., aldosterone). Glucocorticoids and mineralocorticoids act through specific nuclear receptors, regulating aspects of the response to physiologic stress, and controlling blood pressure as well as electrolyte and glucose homeostasis.
- Adrenal androgen precursor (dehydroepiandrosterone [DHEA]) prohormones that are converted in peripheral target cells, principally the gonads, to become the sex steroids that, in turn, act via nuclear androgen and estrogen receptors. The sex steroids interact with androgen receptors that stimulate or control the development and maintenance of male characteristics, that is testosterone, or with the estrogen receptors, so regulating both the menstrual and the reproductive cycles.
Adrenal steroidogenesis occurs in a zone-specific fashion, with mineralocorticoid synthesis occurring in the outer zona glomerulosa, glucocorticoid synthesis in the zona fasciculata, and adrenal androgen synthesis in the inner zona reticularis (Figure 22-12).
All the steroid hormones are derivatives of cholesterol (Figure 22-13). The steroidogenic pathway requires the import of cholesterol into the mitochondrion, a process initiated by the action of the steroidogenic acute regulatory (StAR) protein, which shuttles cholesterol from the outer to the inner mitochondrial membrane. Regulation of the production of glucocorticoids and adrenal androgens is under the control of the HPA axis (Figure 22-13).
Mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system. Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary. Hypothalamic release of corticotrophin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress. CRH in turn stimulates the release of ACTH by the cells of the anterior pituitary. ACTH is the pivotal regulator of cortisol synthesis, with additional short-term effects on mineralocorticoid and adrenal androgen synthesis. The release of CRH, and subsequently ACTH, occurs in a pulsatile fashion that follows a circadian rhythm, under the control of the hypothalamus. Reflecting this pattern of ACTH secretion, adrenal cortisol secretion is also circadian, with peak levels in the morning and low levels in the evening
Diagnostic tests assessing the HPA axis makes use of the fact that it is regulated by negative feedback (Figure 22-1). Glucocorticoid excess is diagnosed by the dexamethasone suppression test. Dexamethasone, a potent glucocorticoid, suppresses CRH/ACTH and therefore lowers endogenous cortisol levels. If cortisol production is autonomous (e.g., from an adrenal adenoma), ACTH is already suppressed and the dexamethasone has little additional effect. If cortisol production is driven by an ACTH-producing pituitary adenoma, dexamethasone suppression is ineffective at low doses, but usually induces suppression at high doses. If cortisol production is driven by an ectopic source of ACTH, such as an ACTH-producing tumor, this is usually unaffected by dexamethasone suppression. Therefore, the dexamethasone suppression test is useful both in establishing the diagnosis of Cushing’s syndrome (corticoid excess) and in differentiating the cause.101 Conversely, to assess glucocorticoid deficiency, ACTH stimulation of cortisol production is used. The standard ACTH stimulation test involves administration of cosyntropin (Synacthen, a potent ACTH agonist) parenterally and the collection of blood samples at 0, 30, and 60 minutes to check the cortisol level.102 A normal response is defined as a cortisol level >20 μg/dL or an increment of >10 μg/dL over baseline. Alternatively, an insulin tolerance test (ITT) can be used to assess adrenal insufficiency.
Mineralocorticoid production is controlled by the RAA regulatory cycle, which is initiated by the release of renin from the juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to angiotensin I in the liver. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor), resulting in increased aldosterone production and vasoconstriction. Aldosterone enhances sodium retention and potassium excretion, and increases renal arterial perfusion pressure, which in turn regulates renin release. As mineralocorticoid synthesis is primarily under the control of the RAA system, disorders of the hypothalamic-pituitary axis generally do not adversely affect adrenal gland synthesis of aldosterone.
Cushing’s Syndrome (Glucocorticoid Excess)
Cushing’s syndrome reflects a constellation of clinical features that result from the chronic effects of glucocorticoid excess, of any etiology and any source. Cushing’s syndrome is rare, with an annual incidence of 1–2 per 100,000 population. The disorder can be ACTH dependent (e.g., pituitary corticotrope adenoma) or ACTH independent (e.g., adrenocortical tumor). Overwhelmingly, the medical use of glucocorticoids is the commonest cause of Cushing’s syndrome. Only 10% of patients with Cushing’s syndrome have a primary—that is, adrenal—cause of their disease.103 The term “Cushing’s disease” is specific to glucocorticoid excess caused by a pituitary adenoma secreting ACTH.
Ectopic ACTH production is predominantly caused by occult carcinoid tumors, most frequently in the lung, but also in the thymus or pancreas. Advanced small cell lung cancer can also cause ectopic ACTH production.104
Given that glucocorticoids (see Table 22-11) affect almost all cells of the body, the signs of cortisol excess impact multiple physiologic systems. In addition, excess glucocorticoid secretion overcomes the ability of a key kidney enzyme system (11 β-hydroxysteroid dehydrogenase type 2 or 11β-HSD2) to rapidly inactivate cortisol to cortisone. Cortisone has minimal mineralocorticoid activity, whereas cortisol has some degree of mineralocorticoid action, which manifest as diastolic hypertension, hypokalemia, and edema. Excess glucocorticoids also interfere with central regulatory systems, leading to suppression of gonadotropins with subsequent hypogonadism and amenorrhea, and suppression of the hypothalamic-pituitary-thyroid axis, resulting in decreased TSH secretion.
Table 22‐11 Major actions of glucocorticoids.
|Organ/ Physiologic System||Increased or Stimulated||Decreased or Inhibited|
|Renal (Kidneys) System||Sodium retention
Uric acid production
|Free water clearance|
|Hematologic System||Circulating neutrophils||Host response to infection, delayed hypersensitivity response
Lymphocyte transformation, circulating lymphocytes, circulating eosinophils
The diagnosis of Cushing’s syndrome should be considered when the following key clinical features are evident in the patient (see Figure 22-14): fragility of the skin, with easy bruising and broad (>1 cm), purplish striae, and signs of proximal myopathy, with the patient struggling to stand up from a chair (without the use of hands). Patients with Cushing’s syndrome may develop marked hypercoagulopathy, so are at acutely increased risk of deep vein thrombosis and subsequent pulmonary embolism. Psychiatric symptoms of marked anxiety and/or depression are also common, but acute paranoia or frank psychosis may also occur.101
Overt untreated Cushing’s syndrome is associated with a poor prognosis. In ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor. In Cushing’s syndrome, the treatment of choice is selective removal of the pituitary corticotrophic-producing tumor, usually via a transsphenoidal approach.
Conn’s Syndrome (Mineralocorticoid Excess)
Hyperaldosteronism, the excessive release of the principal mineralocorticoid, aldosterone, typically presents as hypertension, given the adverse effects on the renin-angiotensin system that so powerfully controls renal perfusion and homeostasis, and blood pressure. The commonest cause is primary hyperaldosteronism, excess production of aldosterone by the adrenal zona glomerulosa, typically occurring with bilateral micronodular adrenal hyperplasia. Infrequently, Conn’s syndrome occurs due to an adrenocortical carcinoma.
The clinical hallmark of mineralocorticoid excess is hypokalemic hypertension, but not hypernatremia, with the serum sodium tending to be normal due to the concurrent fluid retention, which in some cases can lead to marked peripheral edema. Severe hypokalemia can be associated with muscle weakness, overt proximal myopathy, or, in severe cases, hypokalemic paralysis, or tetany.105 Diagnostic screening for mineralocorticoid excess is not currently recommended for all patients with hypertension, but should be considered in hypertensive patients younger than 40 years, treatment-refractory hypertension, hypokalemia, or the finding of an adrenal mass. The accepted screening test is concurrent measurement of plasma renin and aldosterone with subsequent calculation of the aldosterone–renin ratio, but the serum potassium needs to be normalized prior to testing.
With the diagnosis of hyperaldosteronism, CT imaging of the adrenal glands is needed. The treatment provided is dependent on the patient’s age and fitness for surgery. Laparoscopic adrenalectomy is the preferred approach. Medical treatment, which can also be considered prior to surgery to avoid postsurgical hypoaldosteronism, is usually with the mineralocorticoid receptor antagonist spironolactone.106
Addison’s Disease (Adrenal Insufficiency)
The US prevalence of adrenal insufficiency (Table 22-12) is 5 in 10,000 in the general population. Disorders of the hypothalamic-pituitary axis are more frequent, with a prevalence of 3 in 10,000, whereas primary adrenal insufficiency has a prevalence of 2 in 10,000, with about half of cases due to genetic causes (e.g., congenital adrenal hyperplasia). Primary adrenal insufficiency is most commonly caused by autoimmune destruction of the adrenal gland, with some 60–70% developing adrenal insufficiency as part of an autoimmune polyglandular syndrome (APS). APS1, an autosomal recessive disorder also termed APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), is the underlying cause in 10% of patients affected by APS.107 These patients invariably develop chronic mucocutaneous candidiasis, which usually manifests in childhood and precedes adrenal insufficiency by years or decades. Coincident autoimmune-induced endocrinopathies most frequently include thyroid autoimmune disease, vitiligo, and premature ovarian failure. Less commonly, T1DM and pernicious anemia (with consequent vitamin B12 deficiency) may occur. Rare causes of adrenal insufficiency involve destruction of the adrenal glands as a consequence of infection, with tuberculous adrenalitis still a frequent cause of disease in developing countries. Hemorrhage, or more rarely bilateral bulky metastatic infiltration with replacement of the adrenal glands, can also result in hypoadrenalism.
The commonest cause of adrenal insufficiency is iatrogenic, arising from suppression of the HPA axis as a consequence of exogenous glucocorticoid treatment (see Tables 22-13 and 22-14).108 This has a reported prevalence of some 0.5–2% of the population in developed countries. Secondary adrenal insufficiency is the consequence of dysfunction of the hypothalamic-pituitary component of the HPA axis. Excluding iatrogenic impairment of the HPA axis (exogenous corticosteroid use), the majority of cases are caused by pituitary or hypothalamic tumors, or their treatment by surgery or radiotherapy.
In principle, the clinical features of primary adrenal insufficiency (Figure 22-15) are characterized by the loss of both glucocorticoid and mineralocorticoid secretion. In contrast, in secondary adrenal insufficiency only glucocorticoid deficiency is evident, as the adrenal itself is intact and can still be regulated by the RAA system. Adrenal androgen secretion is disrupted in both primary and secondary adrenal insufficiency. Hypothalamic-pituitary disease can lead to additional clinical manifestations due to the involvement of other endocrine axes, or visual impairment with bitemporal hemianopia caused by compression of the optic chiasma. Iatrogenic adrenal insufficiency caused by exogenous glucocorticoid suppression of the HPA axis and its abrupt cessation can cause all of the symptoms associated with glucocorticoid deficiency, but the patient will appear cushingoid from the preceding “overexposure” to glucocorticoids.
Table 22‐12 Adrenal insufficiency (hypoadrenalism): classification.
|1. Primary Adrenal Insufficiency
|2. Secondary Adrenal Insufficiency|
Table 22‐13 Therapeutic use of corticosteroids.
Acute adrenal insufficiency usually occurs after a prolonged period of nonspecific complaints and is more frequently observed in patients with primary adrenal insufficiency, due to the loss of both glucocorticoid and mineralocorticoid secretion. The associated postural hypotension is a “red flag,” as the patient may then progress to hypovolemic shock. Adrenal insufficiency may also mimic the features of an acute abdomen with abdominal tenderness, nausea, vomiting, and fever. An adrenal crisis can be triggered by an intercurrent illness, surgery, or other stress.109
Table 22‐14 Glucocorticoid equivalencies.
Source: Data from Nicolaides NC, Pavlaki AN, Maria Alexandra MA, et al. Glucocorticoid therapy and adrenal suppression. Updated 2018. In: Feingold KR, Anawalt B, Boyce A, et al. (Eds.), Endotext. South Dartmouth, MA: MDText.com. www.ncbi.nlm.nih.gov/books/NBK279156/.
|Glucocorticoid||Equivalent Dose (mg)||Potency||Biologic Half-life (h)|
The diagnosis of adrenal insufficiency is established by the short cosyntropin test (Synacthen), a safe and reliable tool with excellent diagnostic sensitivity. The ITT is an alternate, but can be hazardous to the patient, and requires supervision by a specialist physician.
Acute adrenal insufficiency requires immediate rehydration (1 L/hour of saline infusion) with cardiac monitoring and glucocorticoid replacement by bolus injection of 100 mg hydrocortisone, followed by further hydrocortisone supplementation (100–200 mg hydrocortisone over the course of 24 h). Mineralocorticoid replacement can wait until the daily hydrocortisone dose has been reduced to <50 mg, because at higher doses the hydrocortisone provides sufficient stimulation of the mineralocorticoid receptors.
Glucocorticoid replacement (Table 22-15) for the treatment of chronic adrenal insufficiency should be administered at a dose that replaces the physiologic daily cortisol production, typically orally administered hydrocortisone at a dose of 15–25 mg, in two divided doses: 10–20 mg in the mornings and 5 mg in the evenings, mimicking the natural circadian levels of cortisol.
Mineralocorticoid replacement in primary adrenal insufficiency is achieved by the use of 100–150 μg of fludrocortisone. Its efficacy is assessed by measuring the blood pressure, while both sitting and standing, to detect a postural drop indicative of hypovolemia, and assessing serum sodium, potassium, and plasma renin levels. Adrenal androgen replacement is an option for patients with a lack of energy, or with features of androgen deficiency, such as loss of libido.
Table 22‐15 Indications for corticosteroid use.
|Therapeutic Uses||Supplementation for Hypoadrenalism|
dose dependent on patient’s weight and age
(or dexamethasone 5 mg/day)
|Antineoplastic (hematologic malignancy)||3. Replacement (“Stress”) Corticosteroids|
|HPA axis impairment (exogenous corticosteroid use):
po; per oral
This is an adrenal tumor that produces epinephrine, norepinephrine, or both catecholamines. Patients are hypertensive, with headache, sweating, tachycardia, palpitations, and pallor. Occasionally, these can be syndromic, as part of Multiple Endocrine Neoplasia Syndrome Type 2B (MEN2B) presenting with a marfanoid habitus, high arched palate, neuromas (of the tongue, buccal mucosa, lips, conjunctivae, and eyelids), and corneal nerve thickening. The diagnosis of pheochromocytoma is confirmed by measuring urinary and plasma catecholamine levels.110
Stomatognathic Manifestations and Complications of Disorders of the Adrenal Gland
Hyperadrenocorticism (Glucocorticoid Excess or Cushing’s Syndrome)
The primary orofacial feature of Cushing’s syndrome is a round, moon face due to muscle wasting and accumulation of fat. Surface capillaries in the face and other skin regions become fragile, rendering them readily susceptible to hematomas after mild trauma. The facial skin has a ruddy color that simulates “glowing health”; acne and excessive facial hair (hirsutism) are also commonly seen. Long-standing Cushing’s syndrome in children produces delayed growth and development, including of the skeletal and dental structures. Many of the systemic findings of Cushing’s syndrome are similar to those seen in patients on moderate- to high-dose glucocorticoid therapy, and these patients are considered to be immunosuppressed. Therefore, oral signs and symptoms of immunosuppression can be seen, including oral candidiasis, recurrent herpes labialis and herpes zoster infections, gingival and periodontal diseases, and impaired wound healing.
Hypoadrenocorticism (Glucocorticoid Deficiency or Addison’s Disease)
The primary orofacial feature of Addison’s disease is unusual skin pigmentation, most intensely of the sun-exposed areas due to ACTH stimulation of the melanocytes. Facial freckles and moles appear darker, in addition to the development of a tan-like complexion (“bronzing” of the skin and sometimes of the oral mucosa), which does not fade on cessation of sunlight exposure. The mucocutaneous junctions undergo increased pigmentation, including the lips, but hyperpigmentation can also involve the intraoral mucosal surfaces, such as the gingival margins, buccal mucosa, palate, and lingual surface of the tongue. The oral pigmentations appear as irregular spots that range from pale brown to gray or black.111
Dental Management of Patients with Adrenal Gland Disorders
Hyperadrenocorticism (Glucocorticoid Excess or Cushing’s Syndrome)
Dental management of the patient with Cushing’s syndrome must take into consideration concomitant medical conditions that can include hypertension and heart failure, depression or psychosis, as well as DM and osteoporosis. Patients will present with easy bruising of the skin, impaired wound healing, and the infective consequences of immunosuppression. Prophylactic antibiotic coverage should be considered prior to surgery (extractions) for active dentoalveolar infections.
Assessment of the ability to withstand stress is an essential component of treatment planning for patients with Cushing’s syndrome and other patients who have been on long-term moderate- to high-dose glucocorticoid therapy (see Table 22-12). Stress may be induced by an invasive surgical procedure, the onset of infection, an exacerbation of an underlying disease, or a serious life event, such as the death of a family member.112 When normal individuals undergo stress, the plasma cortisol levels can double, due to the inherent ability of the adrenal glands to significantly increase cortisol production. But, in a patient with adrenal insufficiency, adrenal function is inadequate to produce sufficient cortisol in response to stress. Consequently, the patient may experience severe hypotension, with cardiovascular events such as stroke, coma, and death. Patients with established severe adrenal insufficiency usually require premedication with oral or intramuscular glucocorticoids before an invasive procedure. Dosages must be agreed upon with the patient’s physician; a frequent regimen is to double the daily dose of oral glucocorticoids the day before the surgery and on the day of surgery.113
Hypoadrenocorticism (Glucocorticoid Deficiency or Addison’s Disease)
Dental management is similar to that for the patient who has taken long-term moderate to high doses of glucocorticoids (see earlier), since Addison’s disease is frequently treated with exogenous glucocorticoids. The oral health practitioner must be able to recognize and provide initial management of an acute adrenal crisis (intramuscular or intravenous hydrocortisone) when treating these patients.114
Use of Replacement Corticosteroid Therapy (“Stress Steroids” or “Steroid Cover”)
Cortisol (hydrocortisone) is essential to maintain vasomotor tone, and so normal blood pressure, by sensitizing the alpha-adrenergic receptors (alpha 1A, 1B, and 1D receptors) of the vasculature to circulating epinephrine and norepinephrine and increasing catecholamine release from the adrenal cortex. If insufficient cortisol is produced at times of marked physiologic stress, this can result in vasodilation, reduced cardiac return, and potential hypotensive cardiac shock, leading to collapse and death. Significant physiologic stressors include severe infection and/or injury; that is, surgery and intubation associated with general anesthesia.115–117
Table 22‐16 Dental procedures and recommended replacement corticosteroids.
|Risk Category||Dental Procedure||Hydrocortisone||Prednisone||Dexamethasone|
|Moderate to severe||
day of surgery
and 24 hours
within 2 hours of procedure
Iatrogenic adrenal insufficiency is caused by suppression of the HPA axis due to exogenous glucocorticoid therapy. The mean cortisol production rate is 5.7 mg/m2/day, or about 10 mg/day (equal to 2.5 mg of prednisone or 0.5 mg of dexamethasone) (see Table 22-15).118 Body surface area (BSA) is used to calculate the dose of a drug relative to the patient’s “ideal” body weight, resulting in a dose per meter squared (m2). The BSA is a better indicator of the patient’s “ideal” body weight because it is less affected by abnormal adipose mass, and this is useful when giving drugs with a narrow therapeutic safety index, such as chemotherapy agents. Of the various formulations, the Mosteller equation is simpler and considered more accurate: